詳細

中川　和彦 （ナカガワ　カズヒコ）

  • 医学科　特任教授
Last Updated :2024/04/23

コミュニケーション情報 byコメンテータガイド

  • コメント

    肺がんを中心に抗がん剤の化学療法、早期臨床試験等を専門分野としており、がん患者の緩和医療、患者・家族とのコミュニケーションの促進を図ることによる全人的癌診療の実現に努めています。

  • 報道関連出演・掲載一覧

    ＜報道関連出演・掲載一覧＞ ●2024/1/27 　NHK Eテレ「ETV特集：肺がんサバイバー第二弾」 　肺がんについて ●2023/11/30 　毎日新聞 　分子標的薬について ●2023/12/5 　静岡新聞 　分子標的薬について ●2023/12/16 　夕刊フジ 　分子標的薬について ●2023/11/27 　愛媛新聞 　分子標的薬について ●2023/11/21 　宮崎日日新聞　 　分子標的薬について ●2023/11/20 　長崎新聞 　分子標的薬について ●2023/11/16 　信濃毎日新聞　 　分子標的薬について ●2021/10/4 　読売テレビ「情報ライブミヤネ屋」 　小倉智昭さんの肺にがんが転移したことについて ●2020/2/22・25　釧路新聞他 　小細胞肺がんについて ●2019/10/10 　日刊工業新聞 　EGFR遺伝子異変を有する肺がん患者に新たな治療法を確立し、 従来の治療法から再増悪リスクを40%以上減少することを証明したことについて ●2018/10/27 　TBS系JNNニュース 　医療セミナー内の講演の様子について ●2018/10/５ 　関西テレビ報道ランナー 　がん免疫療法について ●2018/10/2 　読売テレビ「かんさい情報ネット ten.」 　本庶佑氏がノーベル賞を受賞したことについて ●2018/9/7 　読売新聞 　がん治療について ●2018/4/20 　関西医事新報 　「化学療法ｗｐ横断的に実施する専門家を育成」 ●2017/2/2 読売テレビ「かんさい情報ネット ten.」 2月からのオプジーボ薬価改定について ●2017/1/17 　オプシーボ＋高脂血症薬の併用で 　がん治療「効果アップ」について ●2016/10/30 　毎日放送「映像'16」 　がん治療における最新の化学療法や主治医として ●2016/10/3 　読売テレビ「かんさい情報ネット ten.」 　PD1抗体、オプジーボについて ●2016/8/2 　毎日新聞 　がん医療における緩和医療等について ●2015/05/12 　毎日放送「VOICE」 　進行がん患者に対する新薬の治験について。 ●2019/9/7 　読売新聞 　遺伝子」の異常に着目した肺がん治療について

研究者情報

学位

  • 博士(医学)（2001年03月 熊本大学）

ホームページURL

J-Global ID

研究キーワード

  • 臨床腫瘍学   Medical Oncology   

現在の研究分野（キーワード）

    肺がんを中心に抗がん剤の化学療法、早期臨床試験等を専門分野としており、がん患者の緩和医療、患者・家族とのコミュニケーションの促進を図ることによる全人的癌診療の実現に努めています。

研究分野

  • ライフサイエンス / 呼吸器内科学

学歴

  •         - 1983年   熊本大学   医学部
  •         - 1983年   熊本大学   Faculty of Medicine

所属学協会

  • 西日本胸部臨床腫瘍臨床研究機構(WJTOG)   がん分子標的治療研究会   欧州癌治療学会(ESMO)   日本呼吸器内視鏡学会   日本臨床腫瘍学会   日本呼吸器学会   日本癌治療学会   世界肺癌学会(IASLC/WCLC)   米国臨床腫瘍学会(ASCO)   日本内科学会   日本癌学会   日本肺癌学会   

研究活動情報

論文

  • Hidetoshi Hayashi; Kenji Chamoto; Ryusuke Hatae; Takashi Kurosaki; Yosuke Togashi; Kazuya Fukuoka; Megumi Goto; Yasutaka Chiba; Shuta Tomida; Takayo Ota; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Takeshi Yoshida; Tsutomu Iwasa; Kaoru Tanaka; Masayuki Takeda; Tomoko Hirano; Hironori Yoshida; Hiroaki Ozasa; Yuichi Sakamori; Kazuko Sakai; Keiko Higuchi; Hitoshi Uga; Chihiro Suminaka; Toyohiro Hirai; Kazuto Nishio; Kazuhiko Nakagawa; Tasuku Honjo
    Journal of Clinical Investigation 134 7 2024年04月
  • Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Kenji Sawa; Yoshimasa Shiraishi; Ryota Saito; Junko Tanizaki; Yosuke Tamura; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Takaaki Tokito; Kenji Nagata; Takeshi Masuda; Yasushi Nakamura; Kazuko Sakai; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    British journal of cancer 2024年03月 
    BACKGROUND: Immune-related adverse events (irAEs) have been found to predict PD-L1 inhibitor efficacy in metastatic NSCLC. However, the relation of irAEs to clinical outcome for nonmetastatic NSCLC has remained unknown. METHODS: In this multicenter prospective study of Stage III NSCLC treated with PACIFIC regimen, the relation of irAEs to PFS was evaluated by 8-week landmark analysis to minimise lead-time bias as well as by multivariable analysis adjusted for baseline factors. irAEs were categorised as mild or nonmild according to whether they were treated with systemic steroid. RESULTS: Median PFS was 16.0 months, not reached, and 9.7 months for patients without (85 cases) or with mild (21 cases) or nonmild (21 cases) irAEs, respectively. Multivariable analysis indicated that nonmild irAEs were associated with poor PFS, with HRs of 3.86 (95% CI, 1.31-11.38) compared with no irAEs and 11.58 (95% CI, 2.11-63.63) compared with mild irAEs. This pattern was consistent after irAE grade, the number of durvalumab doses and immune profiles (PD-L1 score, CD8+ tumour-infiltrating lymphocyte density, and tumour mutation burden) were taken into consideration. CONCLUSIONS: The development of mild irAEs might predict a better survival outcome, whereas immunosuppressive steroid-treated irAEs were associated with a worse outcome, regardless of baseline clinical and immune profiles.
  • Yoshimasa Shiraishi; Junji Kishimoto; Shunichi Sugawara; Hideaki Mizutani; Haruko Daga; Koichi Azuma; Hirotaka Matsumoto; Osamu Hataji; Kazumi Nishino; Masahide Mori; Takehito Shukuya; Haruhiro Saito; Motoko Tachihara; Hidetoshi Hayashi; Asuka Tsuya; Kazushige Wakuda; Noriko Yanagitani; Tomohiro Sakamoto; Satoru Miura; Akito Hata; Morihito Okada; Toshiyuki Kozuki; Yuki Sato; Taishi Harada; Koichi Takayama; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Isamu Okamoto
    JAMA oncology 2023年12月 
    IMPORTANCE: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. OBJECTIVE: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. DESIGN, SETTING, AND PARTICIPANTS: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. INTERVENTIONS: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. RESULTS: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. CONCLUSIONS AND RELEVANCE: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. TRIAL REGISTRATION: Japan Registry of Clinical Trials Identifier: jRCT2080224500.
  • Kazushige Wakuda; Hiroyuki Yamaguchi; Hirotsugu Kenmotsu; Minoru Fukuda; Kentaro Ito; Yuko Tsuchiya-Kawano; Kentaro Tanaka; Taishi Harada; Yuki Nakatani; Satoru Miura; Toshihide Yokoyama; Tomomi Nakamura; Miiru Izumi; Atsushi Nakamura; Satoshi Ikeda; Koichi Takayama; Kenichi Yoshimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Kenji Sugio
    JTO clinical and research reports 4 12 100587 - 100587 2023年12月 
    INTRODUCTION: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. METHODS: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. RESULTS: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%-90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%-99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo-not reached). The overall response rate was 64.0% (95% CI: 45.2%-82.8%), median PFS was 11.5 months (95% CI: 6.9 mo-not reached), and median survival time was 23.7 months (95% CI: 16.5 mo-not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). CONCLUSIONS: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. TRIAL REGISTRATION: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.
  • Tomohiro Sakamoto; Taichi Matsubara; Takayuki Takahama; Toshihide Yokoyama; Atsushi Nakamura; Takaaki Tokito; Tatsuro Okamoto; Hiroaki Akamatsu; Masahide Oki; Yuki Sato; Kazunori Tobino; Satoshi Ikeda; Masahide Mori; Chihiro Mimura; Ken Maeno; Satoru Miura; Toshiyuki Harada; Kunihiro Nishimura; Manabu Hiraoka; Hirotsugu Kenmotsu; Junya Fujimoto; Mototsugu Shimokawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    JAMA network open 6 12 e2347700  2023年12月 
    IMPORTANCE: Biomarker testing for driver mutations is essential for selecting appropriate non-small cell lung cancer (NSCLC) treatment but is insufficient. OBJECTIVE: To investigate the status of biomarker testing and drug therapy for NSCLC in Japan for identifying problems in treatment. DESIGN, SETTING, AND PARTICIPANTS: The REVEAL cohort study included retrospective data collection and prospective follow-up from 29 institutions across Japan. Of 1500 patients diagnosed with advanced or recurrent NSCLC between January 1 and March 18, 2021, 1479 were eligible. Cases recognized at the wrong clinical stage (n = 12), diagnosed outside the study period (n = 6), not treated according to eligibility criteria before recurrence (n = 2), and with deficient consent acquisition procedure (n = 1) were excluded. MAIN OUTCOMES AND MEASURES: The primary end point was the biomarker testing status. Treatment-related factors were examined. RESULTS: Among the 1479 patients included in the analysis, the median age was 72 (range, 30-95) years; 1013 (68.5%) were men; 1161 (78.5%) had an Eastern Cooperative Oncology Group performance status 0 or 1; 1097 (74.2%) were current or past smokers; and 947 (64.0%) had adenocarcinoma. Biomarker status was confirmed in 1273 patients (86.1%). Multigene testing was performed in 705 cases (47.7%); single-gene testing, in 847 (57.3%); and both, in 279 (18.9%). Biomarker testing was performed for EGFR in 1245 cases (84.2%); ALK, in 1165 (78.8%); ROS1, in 1077 (72.8%); BRAF, in 803 (54.3%); and MET, in 805 (54.4%). Positivity rates among 898 adenocarcinoma cases included 305 (34.0%) for EGFR, 29 (3.2%) for ALK, 19 (2.1%) for ROS1, 11 (1.2%) for BRAF, and 14 (1.6%) for MET. Positivity rates among 375 nonadenocarcinoma cases were 14 (3.7%) for EGFR, 6 (1.6%) for ALK, 1 (0.3%) for ROS1, 3 (0.8%) for BRAF, and 8 (2.1%) for MET. Poor physical status, squamous cell carcinoma, and other comorbidities were associated with hampered multigene testing. Targeted therapy was received as first-line treatment by 263 of 278 cases (94.6%) positive for EGFR, 25 of 32 (78.1%) positive for ALK, 15 of 24 (62.5%) positive for ROS1, 9 of 12 (75.0%) positive for BRAF, and 12 of 19 (63.2%) positive for MET. Median overall survival of patients with positive findings for driver gene alteration and who received targeted therapy was 24.3 (95% CI, not reported) months; with positive findings for driver gene alteration and who did not receive targeted therapy, 15.2 (95% CI, 7.7 to not reported) months; and with negative findings for driver gene alteration, 11.0 (95% CI, 10.0-12.5) months. Multigene testing for nonadenocarcinomas and adenocarcinomas accounted for 705 (47.7%) of all NSCLC cases. CONCLUSIONS AND RELEVANCE: These findings suggest that multigene testing has not been sufficiently implemented in Japan and should be considered prospectively, even in nonadenocarcinomas, to avoid missing rare driver gene alterations.
  • Tomohiro Maniwa; Jiro Okami; Tomohiro Miyoshi; Masashi Wakabayashi; Hiroshige Yoshioka; Takahiro Mimae; Makoto Endo; Aritoshi Hattori; Kazuo Nakagawa; Tetsuya Isaka; Mitsuhiro Isaka; Ryosuke Kita; Yuta Sekino; Noriko Mitome; Keiju Aokage; Hisashi Saji; Ryu Nakajima; Morihito Okada; Masahiro Tsuboi; Hisao Asamura; Haruhiko Fukuda; Shun-Ichi Watanabe
    The Journal of thoracic and cardiovascular surgery 2023年11月 
    OBJECTIVE: The optimal region of lymph node dissection (LND) during segmentectomy in patients with small peripheral non-small cell lung cancer requires clarification. Through a supplemental analysis of the Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L, we investigated the associated factors, distribution, and recurrence pattern of lymph node metastases (LNMs) and proposed the optimal LND region. METHODS: Of the 1106 patients included in the JCOG0802/WJOG4607L, 1056 patients with LNDs were included in this supplemental analysis. We investigated the distribution and recurrence pattern of LNMs along with the radiologic findings (with ground-glass opacity, part-solid tumor; without ground-grass opacity component, pure-solid tumor). RESULTS: The radiologic findings were the only significant factor for LNMs. Of 533 patients with part-solid tumors, 8 (1.5%) had LNMs. Further, only 3 (0.5%) patients had pN2 disease, and no patients had interlobar LNMs from nonadjacent segments. Of the 523 patients with pure-solid tumors, 55 (10.5%) had LNMs, and 28 (5.4%) had pN2 disease. Five patients had metastases to nonadjacent interlobar lymph nodes (LNs). Two (2.0%) patients with S6 tumors had upper mediastinal LNMs. In addition, the incidence of mediastinal LN recurrence in patients with S6 lung cancer was greater in those who underwent selective LND than those who underwent systematic LND (P = .0455). CONCLUSIONS: Nonadjacent interlobar and mediastinal LND have little impact on pathologic nodal staging in patients with part-solid tumors. In contrast, selective LND is recommended at least for patients with pure-solid tumors.
  • Takeshi Masuda; Satoru Miura; Yuki Sato; Motoko Tachihara; Akihiro Bessho; Atsushi Nakamura; Taichi Miyawaki; Kohei Yoshimine; Masahide Mori; Hideaki Shiraishi; Kosuke Hamai; Koji Haratani; Sumiko Maeda; Eriko Tabata; Chiyoe Kitagawa; Junko Tanizaki; Takumi Imai; Shohei Nogami; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Noboru Hattori
    Scientific Reports 13 1 2023年11月 
    Abstract Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.
  • Takehiro Uemura; Hirotsugu Kenmotsu; Daisuke Hazama; Shunsuke Teraoka; Hiroshi Kobe; Koichi Azuma; Teppei Yamaguchi; Takeshi Masuda; Toshihide Yokoyama; Kohei Otsubo; Koji Haratani; Daisuke Hayakawa; Masahide Oki; Shinnosuke Takemoto; Tomohiro Ozaki; Yusaku Akashi; Akito Hata; Hiroya Hashimoto; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer medicine 2023年11月 
    BACKGROUND: Actionable tumor genomic alterations, primarily EGFR mutations, occur in nearly 70% of Japanese advanced nonsquamous non-small cell lung cancer (NSCLC) patients. Standard assessment of tumor tissue includes rapid testing for EGFR mutations, ALK fusions and ROS1 fusions. We conducted a prospective observational study (WJOG13620L) of follow-on next-generation sequencing of circulating tumor DNA (ctDNA) in patients without driver alterations after EGFR testing. METHODS: Patients with untreated advanced (Stage IIIB-IV or relapsed) nonsquamous NSCLC without EGFR mutations according to single-plex testing of tumor tissue, were enrolled into this study. Patients with other known driver mutations or who underwent comprehensive genomic profiling were excluded. Plasma was analyzed by Guardant360, and the primary endpoint was the proportion of patients with pathogenic gene alterations in at least one of nine genes. RESULTS: Among the 72 patients enrolled, ALK and ROS1 fusions were tested in 86.1% and 65.2%, respectively. Alterations in pre-defined genes were detected in 21 patients (29.2%; 95% confidence interval: 19.0-41.1, p < 0.001 [one-sided null hypothesis proportion of 10%]), including RET fusion (n = 1) and mutations in KRAS (n = 11), EGFR (n = 5), ERBB2 (n = 3), and BRAF (n = 1). Median time from sample submission to results was 8 days (range, 5-17 days). CONCLUSION: Rapid follow-on comprehensive testing of ctDNA should be considered prior to first-line treatment for patients with advanced nonsquamous NSCLC when no alterations are detected after single-plex tissue testing.
  • Satoshi Ikeda; Masahiro Tsuboi; Kazuko Sakai; Toshihiro Misumi; Hiroaki Akamatsu; Hiroyasu Shoda; Noriaki Sakakura; Atsushi Nakamura; Yasuhisa Ohde; Hidetoshi Hayashi; Kyoichi Okishio; Morihito Okada; Ichiro Yoshino; Jiro Okami; Kazuhisa Takahashi; Norihiko Ikeda; Masayuki Tanahashi; Yuichi Tambo; Haruhiro Saito; Shinichi Toyooka; Hidetoshi Inokawa; Toyofumi Chen-Yoshikawa; Toshihide Yokoyama; Tatsuro Okamoto; Noriko Yanagitani; Masahide Oki; Makoto Takahama; Kenji Sawa; Hirohito Tada; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Kazuto Nishio
    Molecular oncology 2023年10月 
    The phase III IMPACT study (UMIN000044738) compared adjuvant gefitinib with cisplatin plus vinorelbine (cis/vin) in completely resected epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Although the primary endpoint of disease-free survival (DFS) was not met, we searched for molecular predictors of adjuvant gefitinib efficacy. Of 234 patients enrolled in the IMPACT study, 202 patients were analyzed for 409 cancer-related gene mutations and tumor mutation burden using resected lung cancer specimens. Frequent somatic mutations included tumor protein p53 (TP53; 58.4%), CUB and Sushi multiple domains 3 (CSMD3; 11.8%), and NOTCH1 (9.9%). Multivariate analysis showed that NOTCH1 co-mutation was a significant poor prognostic factor for overall survival (OS) in the gefitinib group and cAMP response element binding protein (CREBBP) co-mutation for DFS and OS in the cis/vin group. In patients with NOTCH1 co-mutations, gefitinib group had a shorter OS than cis/vin group (Hazard ratio 5.49, 95% CI 1.07-28.00), with a significant interaction (P for interaction = 0.039). In patients with CREBBP co-mutations, the gefitinib group had a longer DFS than the cis/vin group, with a significant interaction (P for interaction = 0.058). In completely resected EGFR-mutated NSCLC, NOTCH1 and CREBBP mutations might predict poor outcome in patients treated with gefitinib and cis/vin, respectively.
  • Junko Tanizaki; Hiroaki Kuroda; Toshihide Yokoyama; Makoto Takahama; Hiroyasu Shoda; Atsushi Nakamura; Yoshitaka Kitamura; Nobuaki Mamesaya; Yoshihisa Kadota; Kenji Sawa; Kyoichi Okishio; Morihito Okada; Chihiro Suminaka; Kenta Noda; Kazuko Sakai; Yasutaka Chiba; Kazuto Nishio; Kenji Chamoto; Tasuku Honjo; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    JTO Clinical and Research Reports 100590 - 100590 2023年10月
  • Kazushige Wakuda; Hirotsugu Kenmotsu; Yuki Sato; Atsushi Nakamura; Hiroaki Akamatsu; Motoko Tachihara; Satoru Miura; Toshihide Yokoyama; Keita Mori; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    BMC cancer 23 1 902 - 902 2023年09月 
    BACKGROUND: The ALTA-1L study compared brigatinib with crizotinib in untreated ALK-rearranged non-small cell lung cancer (NSCLC) patients, demonstrating the efficacy of brigatinib. Although the median progression-free survival (PFS) of brigatinib group was 24.0 months, the one-year PFS rate was 70%. In the NEJ009 study, patients with EGFR mutations showed improved outcomes with gefitinib plus chemotherapy compared with gefitinib monotherapy. To evaluate the efficacy of the combination of brigatinib with chemotherapy for patients with ALK-rearranged NSCLC, we designed B-DASH study (WJOG 14720L). METHODS: B-DASH study is a multicenter, two-arm, phase II study. Eligible patients have untreated stage IIIB, stage IIIC, stage IV, or postoperative relapse ALK-rearranged nonsquamous NSCLC. Patients will be randomized in a 1:1 ratio to receive brigatinib (180 mg once daily with a 7-day lead-in period at 90 mg) monotherapy or carboplatin (area under the curve = 5 on day 1) plus pemetrexed (500 mg/m2 on day 1) and brigatinib in a 3-week cycle for up to four cycles, followed by pemetrexed and brigatinib as maintenance therapy. The target hazard ratio of 0.62 is set based on the NEJ009 study. With one-sided alpha = 0.20 and power = 0.8, the sample size for the B-DASH study was calculated to be 110, considering the possibility of patients dropping out. The primary endpoint is PFS. The key secondary endpoints are the overall response rate and overall survival. We will evaluate tumor-derived DNA from plasma specimens before treatment, 42 days after administering the study drug, and on the day of progressive disease. Recruitment began in November 2021 and is ongoing. DISCUSSION: The efficacy of combination therapy with tyrosine kinase inhibitors and cytotoxic chemotherapy was demonstrated in patients with EGFR mutations but remains unclear in patients with ALK-rearranged NSCLC. The B-DASH study is the only trial of brigatinib combined with chemotherapy in patients with untreated ALK-rearranged NSCLC. TRIAL REGISTRATION: jRCT identifier: jRCTs041210103.
  • Hirotsugu Kenmotsu; Nobuyuki Yamamoto; Toshihiro Misumi; Kiyotaka Yoh; Haruhiro Saito; Shunichi Sugawara; Koji Yamazaki; Kazuhiko Nakagawa; Kenji Sugio; Takashi Seto; Shinichi Toyooka; Hiroshi Date; Tetsuya Mitsudomi; Isamu Okamoto; Kohei Yokoi; Hideo Saka; Hiroaki Okamoto; Yuichi Takiguchi; Toshiaki Takahashi; Masahiro Tsuboi
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology JCO2300179  2023年09月 
    Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The JIPANG study is an open-label phase III trial evaluating the efficacy of pemetrexed plus cisplatin (PemP) versus vinorelbine plus cisplatin (NP) as adjuvant chemotherapy in patients with stage II-IIIA nonsquamous non-small-cell lung cancer (NSCLC). Here, we report the long follow-up overall survival (OS) data. Eligible patients were randomly assigned to receive either PemP or NP. The primary end point was recurrence-free survival (RFS), and the secondary end point included OS. This analysis was performed using data collected 5 years after the last patient enrollment. Among 804 patients enrolled, 783 patients were eligible (384 for NP and 389 for PemP). The updated median RFS was 37.5 months in the NP arm and 43.4 months in the PemP arm with a hazard ratio of 0.95 (95% CI, 0.79 to 1.14). At a median follow-up of 77.3 months, the OS rates at 3 and 5 years were 84.1% and 75.6% versus 87.0% and 75.0% with a hazard ratio of 1.04 (95% CI, 0.81 to 1.34). This long-term follow-up analysis showed that PemP had similar efficacy to NP in both RFS and OS for this population, with one of the longest OS data compared with the historical data.
  • Tatsuya Yoshida; Toru Kumagai; Ryo Toyozawa; Ryohei Katayama; Makoto Nishio; Takashi Seto; Koichi Goto; Nobuyuki Yamamoto; Yuichiro Ohe; Kentarou Kudou; Takayuki Asato; Pingkuan Zhang; Kazuhiko Nakagawa
    Cancer science 114 9 3698 - 3707 2023年09月 
    The phase 2, single-arm, multicenter, open-label J-ALTA study evaluated the efficacy and safety of brigatinib in Japanese patients with advanced ALK+ non-small-cell lung cancer (NSCLC). One expansion cohort of J-ALTA enrolled patients previously treated with ALK tyrosine kinase inhibitors (TKIs); the main cohort included patients with prior alectinib ± crizotinib. The second expansion cohort enrolled patients with TKI-naive ALK+ NSCLC. All patients received brigatinib 180 mg once daily (7-day lead-in at 90 mg daily). Among 47 patients in the main cohort, 5 (11%) remained on brigatinib at the study end (median follow-up: 23 months). In this cohort, the independent review committee (IRC)-assessed objective response rate (ORR) was 34% (95% CI, 21%-49%); median duration of response was 14.8 months (95% CI, 5.5-19.4); median IRC-assessed progression-free survival (PFS) was 7.3 months (95% CI, 3.7-12.9). Among 32 patients in the TKI-naive cohort, 25 (78%) remained on brigatinib (median follow-up: 22 months); 2-year IRC-assessed PFS was 73% (90% CI, 55%-85%); IRC-assessed ORR was 97% (95% CI, 84%-100%); the median duration of response was not reached (95% CI, 19.4-not reached); 2-year duration of response was 70%. Grade ≥3 adverse events occurred in 68% and 91% of TKI-pretreated and TKI-naive patients, respectively. Exploratory analyses of baseline circulating tumor DNA in ALK TKI-pretreated NSCLC showed associations between poor PFS and EML4-ALK fusion variant 3 and TP53. Brigatinib is an important treatment option for Japanese patients with ALK+ NSCLC, including patients previously treated with alectinib.
  • Kazuto Nishio; Kazuko Sakai; Makoto Nishio; Takashi Seto; Carla Visseren-Grul; Michelle Carlsen; Tomoko Matsui; Sotaro Enatsu; Kazuhiko Nakagawa
    Translational lung cancer research 12 8 1702 - 1716 2023年08月 
    BACKGROUND: An exploratory, proof-of-concept, liquid biopsy addendum to examine biomarkers within cell-free DNA (cfDNA) in the RELAY phase 3, randomized, double-blind, placebo-controlled study was conducted. RELAY showed improved progression-free survival (PFS) with ramucirumab (RAM), a human immunoglobulin G1 vascular endothelial growth factor receptor 2 antagonist, plus erlotinib (ERL), a tyrosine kinase inhibitor, compared with placebo (PL) plus ERL. METHODS: Treatment-naïve patients with endothelial growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer were randomized (1:1) to RAM + ERL or PL + ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations and EGFR-activating mutation allele counts were investigated by next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR), respectively. cfDNA concentration and fragment size were evaluated by real-time polymerase chain reaction and the BioAnalyzer. Patients with a valid baseline plasma sample were included (70 RAM + ERL, 61 PL + ERL). RESULTS: TP53 mutation was the most frequently co-occurring baseline gene alteration (43%). Post-study treatment discontinuation EGFR T790M mutation rates were 54.5% (6/11) and 41.2% (7/17) by ddPCR, and 22.2% (2/9) and 29.4% (5/17) by NGS, in the RAM + ERL and PL + ERL arms, respectively. EGFR-activating mutation allele count decreased at Cycle 4 in both treatment arms and was sustained at follow-up with RAM + ERL. PFS improved for patients with no detectable EGFR-activating mutation at Cycle 4 vs. those with detectable EGFR-activating mutation. Total cfDNA concentration increased from baseline at Cycle 4 and through to follow-up with RAM + ERL. cfDNA fragment size was similar between treatment arms at baseline [mean (standard deviation) base pairs: RAM + ERL, 173.4 (2.6); PL + ERL, 172.9 (3.2)] and was shorter at Cycle 4 with RAM + ERL vs. PL + ERL [169.5 (2.8) vs. 174.1 (3.3), respectively; P<0.0001]. Baseline vs. Cycle 4 paired analysis showed a decrease in cfDNA fragment size for 84% (48/57) and 23% (11/47) of patient samples in the RAM + ERL and PL + ERL arms, respectively. CONCLUSIONS: EGFR-activating mutation allele count was suppressed, total cfDNA concentration increased, and short fragment-sized cfDNA increased with RAM + ERL, suggesting the additional anti-tumor effect of RAM may contribute to the PFS benefit observed in RELAY with RAM + ERL vs. PL + ERL. TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT02411448.
  • Hye Ryun Kim; Shunichi Sugawara; Jong-Seok Lee; Jin-Hyoung Kang; Naoki Inui; Toyoaki Hida; Ki Hyeong Lee; Tatsuya Yoshida; Hiroshi Tanaka; Cheng-Ta Yang; Makoto Nishio; Yuichiro Ohe; Tomohide Tamura; Nobuyuki Yamamoto; Chong-Jen Yu; Hiroaki Akamatsu; Shigeru Takahashi; Kazuhiko Nakagawa
    Cancer medicine 12 16 17061 - 17067 2023年08月 
    BACKGROUND: ONO-4538-52/TASUKI-52 was performed in Japan, Korea, and Taiwan to determine the oncological effectiveness and safety of combining nivolumab or placebo with bevacizumab plus platinum chemotherapy for the initial (first-line) treatment of patients with advanced non-squamous non-small cell lung cancer (nsNSCLC). At the interim analysis (minimum follow-up, 7.4 months), the independent radiology review committee-assessed progression-free survival was significantly longer in the nivolumab arm, but overall survival (OS) data were immature. METHODS: Here, we present the updated OS data. Patients with treatment-naïve stage IIIB/IV or recurrent nsNSCLC without driver mutations in ALK, EGFR, or ROS1, were randomized 1:1 to receive either nivolumab or placebo. Patients in both arms received paclitaxel, carboplatin, and bevacizumab, administered 3-weekly for a maximum of 6 cycles. Nivolumab/placebo and bevacizumab were subsequently continued until disease progression or unacceptable toxicity. RESULTS: Overall, 550 patients were randomized. At the time of the analysis (minimum follow-up: 19.4 months), the median OS was longer in the nivolumab arm than in the placebo arm (30.8 vs. 24.7 months; hazard ratio 0.74, 95% confidence interval 0.58-0.94). The 12-month OS rates were 81.3% vs. 76.3% in the nivolumab vs. placebo arms, respectively. The respective 18-month OS rates were 69.0% vs. 61.9%. CONCLUSION: Nivolumab plus platinum chemotherapy and bevacizumab demonstrated longer OS vs. the placebo combination. We believe this regimen is viable as a standard, first-line treatment for patients with advanced nsNSCLC without driver mutations in ALK, EGFR, or ROS1.
  • Yoshihiko Fujita; Hiromichi Matsuoka; Yasutaka Chiba; Junji Tsurutani; Takeshi Yoshida; Kiyohiro Sakai; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    Oncology letters 26 2 355 - 355 2023年08月 
    There have been few studies on predictive biomarkers that may be useful to select the most suitable opioids to optimize therapeutic efficacy in individual patients with cancer pain. We recently investigated the efficacy of morphine and oxycodone using single nucleotide polymorphisms (SNPs) of the catechol-O-methyltransferase (COMT) rs4680 gene as a biomarker (RELIEF study). To explore additional biomarkers that may enable the selection of an appropriate opioid for individual patients with cancer pain, three SNPs were examined: C-C motif chemokine ligand 11 (CCL11; rs17809012), histamine N-methyltransferase (HNMT; rs1050891) and transient receptor potential V1 (TRPV1; rs222749), which were screened from 74 pain-related SNPs. These SNPs, which were identified as being significantly associated with the analgesic effect of morphine, were then used to genotype the 135 patients in the RELIEF study who had been randomized into a morphine group (n=69) or an oxycodone group (n=66). The present study then assessed whether the SNPs could also be used as selective biomarkers to predict which opioid(s) might be the most suitable to provide pain relief for patients with cancer. Oxycodone tended to provide superior analgesic effects over morphine in patients carrying the genotype AA for the CCL11 rs17809012 SNP (P=0.012 for interaction), suggesting that it could serve as a potential biomarker for personalized analgesic therapy for patients suffering with cancer pain.
  • Chihiro Sato; Hisato Kawakami; Ryo Tanaka; Hironaga Satake; Kentaro Inoue; Yutaka Kimura; Junya Fujita; Ryohei Kawabata; Yasutaka Chiba; Taroh Satoh; Kazuhiko Nakagawa
    Scientific reports 13 1 10826 - 10826 2023年07月 
    Adjuvant S-1 monotherapy is the standard of care for stage II gastric cancer (GC) after curative resection in Japan, but its efficacy for microsatellite instability-high (MSI-H) tumors has remained unknown. Among a multi-institutional cohort of patients with stage II GC who underwent R0 resection followed by S-1 adjuvant chemotherapy between February 2008 and December 2018, we assessed MSI status with an MSI-IVD Kit (Falco). MSI status was assessable for 184 (88.5%) of the 208 enrolled patients, with MSI-H being identified in 24 (13.0%) individuals. Although neither relapse-free survival (RFS) (hazard ratio [HR] = 1.00, p = 0.997) nor overall survival (OS) (HR = 0.66, p = 0.488) differed between MSI-H versus microsatellite-stable (MSS) patients, MSI-H patients showed a nonsignificant but better RFS (HR = 0.34, p = 0.064) and OS (HR = 0.22, p = 0.057) than did MSS patients after adjustment for background characteristics by propensity score (PS) analysis. Gene expression analysis in the PS-matched cohort suggested that recurrence was associated with the immunosuppressive microenvironment in MSI-H tumors but with expression of cancer/testis antigen genes in MSS tumors. Our data reveal a better adjusted survival for MSI-H versus MSS stage II GC treated with S-1 adjuvant therapy, and they suggest that mechanisms of recurrence differ between MSI-H and MSS tumors.
  • Tsuneo Shimokawa; Hiroaki Okamoto; Ryunosuke Machida; Yuki Misumi; Yukio Hosomi; Yasuto Yoneshima; Hiroshi Tanaka; Kyoichi Okishio; Junichi Simizu; Koichi Goto; Hiroaki Akamatsu; Kaoru Kubota; Kazuhiko Nakagawa; Hidehito Horinouchi; Masahiko Ando; Tomoko Kataoka; Yuichiro Ohe
    Lung cancer (Amsterdam, Netherlands) 181 107195 - 107195 2023年07月 
    OBJECTIVES: Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that carboplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC. MATERIALS AND METHODS: This was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intravenously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on days 1-3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on days 1 and 8) intravenously every 3 weeks for 4 cycles. RESULTS: In total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.85 (95% CI, 0.65-1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 (95% CI, 4.5-5.2) months (HR, 0.85 (95% CI, 0.66-1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm). CONCLUSIONS: The CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.
  • Makoto Nishio; Shinji Atagi; Koichi Goto; Yukio Hosomi; Takashi Seto; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshige Yoshioka; Naoyuki Nogami; Makoto Maemondo; Seisuke Nagase; Isamu Okamoto; Noboru Yamamoto; Yuriko Igawa; Kosei Tajima; Masahiro Fukuoka; Nobuyuki Yamamoto; Kazuto Nishio
    Translational lung cancer research 12 6 1167 - 1184 2023年06月 
    BACKGROUND: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR-positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses. METHODS: Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP). RESULTS: Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes. CONCLUSIONS: EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin.
  • Koji Haratani; Atsushi Nakamura; Nobuaki Mamesaya; Shigeki Mitsuoka; Yasuto Yoneshima; Ryota Saito; Junko Tanizaki; Yasuhito Fujisaka; Akito Hata; Kosuke Tsuruno; Tomohiro Sakamoto; Shunsuke Teraoka; Masahide Oki; Hiroshi Watanabe; Yuki Sato; Yusuke Nakano; Tomoyuki Otani; Kazuko Sakai; Shuta Tomida; Yasutaka Chiba; Akihiko Ito; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hidetoshi Hayashi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 18 10 1334 - 1350 2023年06月 
    INTRODUCTION: The PACIFIC regimen of consolidation therapy with the programmed cell death-ligand 1 (PD-L1) inhibitor durvalumab after definitive concurrent chemoradiation therapy has become a standard of care for individuals with unresectable stage III non-small cell lung cancer (NSCLC). However, about half of treated patients experience disease progression within 1 year, with the mechanisms of treatment resistance being poorly understood. We here performed a nationwide prospective biomarker study to explore the resistance mechanisms (WJOG11518L/SUBMARINE). METHODS: A total of 135 patients with unresectable stage III NSCLC who received the PACIFIC regimen were included for comprehensive profiling of the tumor microenvironment by immunohistochemistry, transcriptome analysis, and genomic sequencing of pretreatment tumor tissue as well as flow cytometric analysis of circulating immune cells. Progression-free survival (PFS) was compared based on these biomarkers. RESULTS: The importance of preexisting effective adaptive immunity in tumors were revealed for treatment benefit regardless of genomic features. We also identified CD73-expression by cancer cells as a mechanism of resistance to the PACIFIC regimen. Multivariable analysis of immunohistochemistry data with key clinical factors as covariables indicated that low CD8+ tumor-infiltrating lymphocytes (TILs) density and the high CD73+ cancer cells were independently associated with poor durvalumab outcome (HRs, 4.05 [95% CI, 1.17-14.04] for CD8+ TILs; 4.79 [95% CI, 1.12-20.58] for CD73). In addition, whole-exome sequencing of paired tumor samples suggested that cancer cells eventually escaped immune pressure as a result of neoantigen plasticity. CONCLUSIONS: Our study emphasizes the importance of functional adaptive immunity in stage III NSCLC, and implicates CD73 as a promising treatment target, thus providing insight forming a basis for development of a new treatment approach in NSCLC.
  • Kimio Yonesaka; Hidetoshi Hayashi; Atsushi Nakamura; Yuki Sato; Koichi Azuma; Shinya Sakata; Motoko Tachihara; Satoshi Ikeda; Toshihide Yokoyama; Kentaro Ito; Yukihiro Yano; Hirotaka Matsumoto; Haruko Daga; Akito Hata; Kazuko Sakai; Yasutaka Chiba; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 2023年06月 
    BACKGROUND: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has limited treatment options for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Although osimertinib or afatinib alone induced drug-resistant clones with EGFR secondary mutation in a preclinical model, its combination prevented the appearance of these mutations. We investigated alternating-dose therapy of osimertinib and afatinib in patients with EGFR-mutant NSCLC in a single-arm Phase II trial. METHODS: Treatment-naïve patients with stage IV NSCLC harboring an activating EGFR mutation were enrolled. Alternating cycles of osimertinib (80 mg/day) followed by afatinib (20 mg/day) were administered every 8 weeks. Genomic analysis was performed using circulating tumor DNA obtained before and after the treatment. RESULTS: Among the 46 enrolled patients, the median progression-free survival was 20.2 months. The overall response rate was 69.6%. The median overall survival was not reached. Among the 26 plasma samples obtained after the acquisition of resistance, 3 showed an increased MET gene copy number, and 1 showed BRAF mutation. Meanwhile, no EGFR secondary mutation was detected. CONCLUSION: The efficacy of our treatment was not significantly different from osimertinib alone, as reported previously in untreated advanced NSCLC patients with EGFR mutations. Although the sample size was limited, this treatment may prevent the emergence of EGFR secondary mutations that trigger drug resistance. Further studies are warranted to establish the significance of this treatment. CLINICAL TRIAL REGISTRATION: jRCTs051180009.
  • Toshiaki Takakura; Hiroaki Kanemura; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa; Hidetoshi Hayashi
    JTO clinical and research reports 4 6 100523 - 100523 2023年06月 
    Resistance to ROS1 tyrosine kinase inhibitors is inevitable, but it has been unclear whether crizotinib might be effective after the development of entrectinib resistance. We here present a case of ROS1-rearranged NSCLC that responded to crizotinib after tumor progression due to MET polysomy during entrectinib treatment. This case suggests that crizotinib is an effective option for patients with MET polysomy, even after disease progression on entrectinib.
  • Satoshi Ikeda; Masahiro Tsuboi; Kazuko Sakai; Toshihiro Misumi; Hiroaki Akamatsu; Yasuo Iwamoto; Noriaki Sakakura; Atsushi Nakamura; Yasuhisa Ohde; Hidetoshi Hayashi; Kyoichi Okishio; Morihito Okada; Ichiro Yoshino; Jiro Okami; Kazuhisa Takahashi; Norihiko Ikeda; Tetsuya Mitsudomi; Hirohito Tada; Kazuhiko Nakagawa; Kazuto Nishio
    Journal of Clinical Oncology 41 16{\_}suppl 8524 - 8524 2023年06月 
    8524 Background: Although osimertinib has recently become an option for adjuvant therapy in many countries, biomarkers predicting the efficacy of adjuvant EGFR-TKI and the risk of postoperative recurrence in completely resected NSCLC harboring EGFR mutations have not been fully investigated. Methods: This IMPACT-TR study is an exploratory biomarker study for completely resected, EGFR-mutated NSCLC patients who received gefitinib or cisplatin plus vinorelbine (cis/vin) in a phase III IMPACT study (Trial registration number: UMIN000044738. Funding: AstraZeneca K.K.). Surgically resected lung cancer tissue specimens were analyzed for co-existing somatic mutations and tumor mutation burden (TMB) determined by Oncomine Tumor Mutation Load, and these data were matched with disease free survival (DFS) and overall survival (OS) data. Results: Of the 234 patients in the IMPACT study, 211 patients were enrolled, and 202 patients in the Per Protocol Set were analyzed. The most frequent co-existing somatic mutation was TP53 (58.4%), followed by CSMD3 (11.8%), NOTCH1 (9.9%) and SYNE1 (9.9%). The median TMB was 6.67 mutations/Mb, and only 15.2% had ≥10 mutations/Mb. EGFR mutation subtypes, TP53 co-mutation and TMB were not associated with DFS or OS in either the gefitinib or cis/vin groups. In the gefitinib group, patients with NOTCH1 mutation had significantly shorter OS (hazard ratio [HR] 4.18, 95%CI 1.65-10.61, p=0.003) and tended to have shorter DFS (HR 1.44, 95%CI 0.62-3.37, p=0.399) than those without NOTCH1 mutation. In the cis/vin group, patients with CREBBP mutation had significantly shorter DFS (HR 2.70, 95%CI 1.05-6.97, p=0.040) and tended to have shorter OS (HR 3.05, 95%CI 0.90-10.37, p=0.074) than those without CREBBP mutation. Conclusions: This study suggested that NOTCH1 mutation may be a biomarker to predict poor response to adjuvant gefitinib and CREBBP mutation to predict poor response to cis/vin in patients with completely resected, EGFR-mutated NSCLC. Clinical trial information: UMIN000044738 .
  • Hisato Kawakami; Yu Sunakawa; Eisuke Inoue; Ryo Matoba; Kenta Noda; Toshiyuki Sato; Chihiro Suminaka; Mami Yamaki; Yasuhiro Sakamoto; Ryohei Kawabata; Atsushi Ishiguro; Yusuke Akamaru; Yosuke Kito; Hiroshi Yabusaki; Jin Matsuyama; Masazumi Takahashi; Akitaka Makiyama; Hidetoshi Hayashi; Kenji Chamoto; Tasuku Honjo; Kazuhiko Nakagawa; Wataru Ichikawa; Masashi Fujii
    European Journal of Cancer 2023年05月
  • Keiju Aokage; Kenji Suzuki; Hisashi Saji; Masashi Wakabayashi; Tomoko Kataoka; Yuta Sekino; Haruhiko Fukuda; Makoto Endo; Aritoshi Hattori; Takahiro Mimae; Tomohiro Miyoshi; Mitsuhiro Isaka; Hiroshige Yoshioka; Ryu Nakajima; Kazuo Nakagawa; Jiro Okami; Hiroyuki Ito; Hiroaki Kuroda; Masahiro Tsuboi; Norihito Okumura; Makoto Takahama; Yasuhisa Ohde; Tadashi Aoki; Yasuhiro Tsutani; Morihito Okada; Shun-Ichi Watanabe
    The Lancet. Respiratory medicine 2023年03月 
    BACKGROUND: Although segmentectomy is a widely used surgical procedure, lobectomy is the standard procedure for resectable non-small-cell lung cancer (NSCLC). This study aimed to evaluate the efficacy and safety of segmentectomy for NSCLC up to 3 cm in size, including ground-glass opacity (GGO) and predominant GGO. METHODS: A multicentre, single-arm, confirmatory phase 3 trial was conducted across 42 institutions (hospitals, university hospitals, and cancer centres) in Japan. Segmentectomy with hilar, interlobar, and intrapulmonary lymph node dissection was performed as protocol surgery for patients with a tumour diameter of up to 3 cm, including GGO and dominant GGO. Eligible patients were those aged 20-79 years with an Eastern Cooperative Oncology Group performance score of 0 or 1 and clinical stage IA tumour confirmed by thin-sliced CT. The primary endpoint was 5-year relapse-free survival (RFS). This study is registered with the University Hospital Medical Information Network Clinical Trials (UMIN000011819), and is ongoing. FINDINGS: A total of 396 patients were registered from Sept 20, 2013, to Nov 13, 2015, of whom 357 underwent segmentectomy. At a median follow-up of 5·4 years (IQR 5·0-6·0), the 5-year RFS was 98·0% (95% CI 95·9-99·1). This finding exceeded the 87% of the pre-set threshold 5-year RFS and the primary endpoint was met. Grade 3 or 4 early postoperative complications occurred in seven patients (2%), but no grade 5 treatment-related deaths occurred. INTERPRETATION: Segmentectomy should be considered as part of standard treatment for patients with predominantly GGO NSCLC with a tumour size of 3 cm or less in diameter, including GGO even if it exceeds 2 cm. FUNDING: National Cancer Centre Research and Development Fund and Japan Agency for Medical Research and Development.
  • 寺岡 俊輔; 赤松 弘朗; 高森 信吉; 三浦 理; 洪 泰浩; 三角 俊裕; 山本 信之; 中川 和彦
    和歌山医学 74 1 25 - 25 和歌山医学会 2023年03月
  • Takaki Akamine; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Yasushi Yatabe; Shun-Ichi Watanabe
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 63 3 2023年03月 
    OBJECTIVES: With recent improvements in surgical techniques for segmentectomy, we hypothesized that segmentectomy is feasible and more effective than wedge resection for non-small-cell lung cancer (NSCLC). We compared perioperative and oncological outcomes for segmentectomy and wedge resection. METHODS: We performed a retrospective analysis of 720 patients who underwent sublobar resection (segmentectomy, 479; wedge resection, 241) for clinical stage 0 or I NSCLC from January 2017 to June 2020. An adequate surgical margin was defined as a surgical margin distance of ≥2 cm or ≥ the total tumour size. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method for clinical stage IA. RESULTS: There was no significant difference in the rate of major (grade ≥III) complications between segmentectomy (1.7%) and wedge resection (1.2%) (P = 0.76). The probability of obtaining adequate surgical margins was significantly higher with segmentectomy (71.4%) versus wedge resection (59.5%) (P = 0.002), and the difference was especially prominent for clinical stage IA2 (75.3% vs 56.9%; P = 0.012). Among patients with clinical stage IA, segmentectomy significantly improved the RFS compared with wedge resection (hazard ratio 2.7; 95% confidence interval 1.60-4.61; log-rank P < 0.001). Subgroup analysis based on the tumour status revealed that segmentectomy had a better RFS in clinical stage IA2 (P < 0.001) and in pure-solid tumours (P = 0.022) than wedge resection. CONCLUSIONS: We demonstrate that segmentectomy is a feasible procedure with comparable safety outcomes and better surgical margins and cancer control than wedge resection, particularly for clinical stage IA2 NSCLC.
  • Masaya Yotsukura; Yuji Muraoka; Yukihiro Yoshida; Kazuo Nakagawa; Kouya Shiraishi; Takashi Kohno; Yasushi Yatabe; Shun-Ichi Watanabe
    Annals of surgical oncology 30 2 851 - 858 2023年02月 
    BACKGROUND: The 8th edition of the TNM stage classification of lung cancer was developed based on an evaluation of the 5-year prognosis using an international database. Since recurrence after 5 years postoperatively is known to develop, the applicability of the stage classification beyond 5 years after treatment needs to be evaluated. PATIENTS AND METHODS: Postoperative prognosis and prognostic indicators were analyzed using data for 648 patients of pathological stage IA adenocarcinoma, who underwent complete resection between 2007 and 2012. RESULTS: The median age was 66 years (interquartile range 60-73 years), and the median follow-up duration was 100 months (interquartile range 70-116 months). Overall survival probabilities for pathological stage IA1, IA2, and IA3 patients were 100%, 96.3%, and 91.5% at 5 postoperative years, and 94.2%, 89.8%, and 83.5% at 10 postoperative years, respectively (IA1 vs IA2: p = 0.05; IA2 vs IA3: p = 0.05). Multivariate analysis for overall survival of patients who survived without recurrence for 5 postoperative years revealed that age (hazard ratio 3.21, p = 0.02) was the only factor that was significantly associated with long-term survival. Stage classification (IA1, IA2, or IA3) was not an associated factor. The incidence of secondary primary lung cancer continued to increase, resulting in an estimated probability of 8.6% at 10 postoperative years. CONCLUSIONS: For patients who survived without recurrence for 5 postoperative years, age, not stage classification, was associated with survival thereafter. The long-term follow-up strategy does not need to be modified according to the stage classification, and screening for secondary primary lung cancer should be considered.
  • Masaya Yotsukura; Yuji Muraoka; Yukihiro Yoshida; Kazuo Nakagawa; Kouya Shiraishi; Takashi Kohno; Yasushi Yatabe; Shun-Ichi Watanabe
    Annals of surgical oncology 30 2 859 - 860 2023年02月
  • Masayuki Takeda; Mototsugu Shimokawa; Atsushi Nakamura; Kaname Nosaki; Yasutaka Watanabe; Terufumi Kato; Daisuke Hayakawa; Hiroshi Tanaka; Toshiaki Takahashi; Masahide Oki; Motoko Tachihara; Daichi Fujimoto; Hidetoshi Hayashi; Kakuhiro Yamaguchi; Shoichiro Yamamoto; Eiji Iwama; Koichi Azuma; Kazuo Hasegawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 177 44 - 50 2023年01月 
    BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is an established standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). However, of such patients who have received prior treatment with a first- or second-generation EGFR TKI, only approximately half are eligible for osimertinib therapy because its indication as second-line treatment and beyond is limited to metastatic NSCLC that is positive for the T790M resistance mutation of the EGFR gene. This study was initiated at the request of a dedicated network for patients with lung cancer in Japan. METHODS: We conducted a phase II study to assess the efficacy of osimertinib in patients with EGFR mutation-positive NSCLC in whom systemic disease (T790M-negative) progressed after treatment with first- or second-generation EGFR TKIs and platinum-based chemotherapy. The primary end point was response rate (assessed by a central imaging reviewer). RESULTS: From August 2020 to February 2021, 55 patients from 15 institutions were enrolled in the study. The overall response for primary analysis was achieved in 16 patients (29.1 %; 95 % CI, 17.6-42.9), which exceeded the threshold response rate necessary for analysis. Stable disease was found in 16 patients (29.1 %), and progressive disease, in 18 (32.7 %). The median length of progression-free survival (PFS) was 4.07 months (95 % CI 2.10-4.30), and the rate of 12-month PFS was 17.3 %. CONCLUSIONS: Osimertinib demonstrated modest antitumor activity against progressive EGFR T790M-negative disease.
  • Seiichiro Mitani; Hisato Kawakami; Osamu Shiraishi; Hiroaki Kanemura; Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Kimio Yonesaka; Yasutaka Chiba; Takushi Yasuda; Kazuhiko Nakagawa
    Esophagus : official journal of the Japan Esophageal Society 20 2 290 - 290 2023年01月
  • Takashi Kurosaki; Kenji Chamoto; Shinichiro Suzuki; Hiroaki Kanemura; Seiichiro Mitani; Kaoru Tanaka; Hisato Kawakami; Yo Kishimoto; Yasuharu Haku; Katsuhiro Ito; Toshiyuki Sato; Chihiro Suminaka; Mami Yamaki; Yasutaka Chiba; Tomonori Yaguchi; Koichi Omori; Takashi Kobayashi; Kazuhiko Nakagawa; Tasuku Honjo; Hidetoshi Hayashi
    Frontiers in immunology 14 1325462 - 1325462 2023年 
    INTRODUCTION: The clinical relevance of soluble forms of programmed cell death-1 (sPD-1) and programmed cell death-ligand 1 (sPD-L1) remains unclear. We here investigated the relation between the efficacy of PD-1 blockade and pretreatment plasma levels of sPD-1 and sPD-L1 across a broad range of cancer types. METHODS: We retrospectively analyzed clinical data from 171 patients with advanced solid tumors who received nivolumab or pembrolizumab monotherapy regardless of treatment line. The concentrations of sPD-1 and sPD-L1 were measured with a fully automated immunoassay (HISCL system). RESULTS: The study subjects comprised patients with head and neck cancer (n = 50), urothelial cancer (n = 42), renal cell cancer (n = 37), gastric cancer (n = 20), esophageal cancer (n = 10), malignant pleural mesothelioma (n = 6), or microsatellite instability-high tumors (n = 6). High or low levels of sPD-1 or sPD-L1 were not significantly associated with progression-free survival (PFS) or overall survival (OS) for PD-1 blockade in the entire study population. Comparison of treatment outcomes according to combinations of high or low sPD-1 and sPD-L1 levels, however, revealed that patients with low sPD-1 and high sPD-L1 concentrations had a significantly poorer PFS (HR of 1.79 [95% CI, 1.13-2.83], p = 0.01) and a tendency toward poorer OS (HR of 1.70 [95% CI, 0.99-2.91], p = 0.05) compared with all other patients. CONCLUSION: Our findings suggest that the combination of low sPD-1 and high sPD-L1 levels is a potential negative biomarker for PD-1 blockade therapy.
  • Yuichi Ozawa; Nobuyuki Yamamoto; Kouji Yamamoto; Kentaro Ito; Hirotsugu Kenmotsu; Hidetoshi Hayashi; Takehito Shukuya; Daichi Fujimoto; Shunichi Sugawara; Seiji Niho; Yuichiro Ohe; Hiroaki Okamoto; Kazuhiko Nakagawa; Katsuyuki Kiura; Ichiro Yoshino; Akihiko Gemma
    Japanese Journal of Lung Cancer 63 3 161 - 181 2023年 
    Objective. Although data accumulated in clinical trials have higher accuracy compared to real-world data and are irreplaceably valuable, most previous clinical trial data have been left unutilized. Methods. The Japan Lung Cancer Society (JLCS) asked six clinical trial groups that conducted randomized clinical trials on curative chemoradiation for locally advanced non-small cell lung cancer (NSCLC) to provide data. After obtaining consent from all six groups, data were collected from August 2019 to June 2021. Results. Eight trials, JCOG9812, JCOG 0301, NJLCG0601, OLCSG0007, WJTOG0105, WJOG5008L, SPECTRA, and TORG1018, were included. More than 3000 data items were integrated into 408 items by adjusting their definitions and units. The total number of collected cases was 1288: median age (range), 66 (30-93) years; sex (male/female) 1064/224; histological type (squamous cell carcinoma/adenocarcinoma/other NSCLC/unknown) 517/629/138/4; and stage IIIA/B, 536/752. The median overall survival was 24.6 months, with 2-, 5-, and 10-year survival rates of 51.1%, 22.5%, and 13.8%, respectively, in all enrollments. The median progression-free survival (PFS) was 9.5 months, with 2-, 5-, and 10-year PFS rates of 22.4%, 13.0%, and 9.1%, respectively. Part of the information in the database has been made available on the JLCS web page, and the JLCS members were provided the right to propose research using the database. Conclusion. The integration and sharing of clinical trial data for research purposes was made real by the nonprofit, academic organization, the JLCS. This database will lead to innovative researches and contribute to the improvement of lung cancer treatment and future research.
  • Kana Fujimoto; Satomi Watanabe; Yuto Yasuda; Emi Date; Yasuhiro Kawabata; Hiroaki Kanemura; Takayuki Takahama; Kimio Yonesaka; Norishige Iizuka; Ken-Ichi Takahashi; Osamu Kawakami; Tomohiro Ozaki; Kazuhiko Nakagawa
    Thoracic cancer 14 2 214 - 217 2023年01月 
    High-grade fetal lung adenocarcinoma (H-FLAC) is a rare tumor, with little known of its response to chemotherapy with or without an immune checkpoint inhibitor or of its molecular profile. We report the first case of a 56-year-old man with stage IV H-FLAC who was successfully treated with carboplatin plus nab-paclitaxel in combination with atezolizumab. In addition, the tumor was found to be positive for amplification of the human epidermal growth factor receptor 2 gene.
  • Seiichiro Mitani; Hisato Kawakami; Osamu Shiraishi; Hiroaki Kanemura; Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Kimio Yonesaka; Yasutaka Chiba; Takushi Yasuda; Kazuhiko Nakagawa
    Esophagus : official journal of the Japan Esophageal Society 20 2 281 - 289 2022年12月 
    BACKGROUND: Neoadjuvant docetaxel plus cisplatin and 5-FU (NAC-DCF) and adjuvant nivolumab monotherapy are the standard care for locally advanced resectable esophageal squamous cell carcinoma (ESCC). However, no effective biomarkers have been found in perioperative setting. We investigated how programmed death-ligand 1 (PD-L1) changes before and after NAC-DCF and how it relates to the therapeutic effect of NAC-DCF in resectable ESCC. METHODS: PD-L1 expression in paired diagnostic biopsy and surgically resected tissues from ESCC patients who underwent surgical resection after receiving two or three NAC-DCF cycles was evaluated. PD-L1 positivity was defined as a combined positive score (CPS) of 10% ≤ . Gene expression analysis was conducted using samples before NAC-DCF. RESULTS: Sixty-six paired samples from 33 patients were included in PD-L1 expression analysis, and 33 Pre-NAC samples acquired by diagnostic biopsy were included in gene expression analysis. Pretreatment, 3 (9%), 13 (39%), and 17 (52%) patients harbored tumors with CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. After NAC-DCF, 5 (15%), 15 (45%), and 13 (39%) tumors presented CPS ranges of < 1%, 1%-10%, and 10% ≤ , respectively. The concordance rate between Pre-and Post-NAC-DCF samples was 45%. Patients with PD-L1-negative tumors both before and after NAC-DCF (n = 9) had shorter survival and different gene expression profile characterized by upregulation in WNT signaling or neutrophils. CONCLUSIONS: A substantial PD-L1 expression alteration was observed, resulting in low concordance rate before and after NAC-DCF. Tumors persistently lacking PD-L1 had distinct gene expression profile with worse clinical outcomes, raising the need for further investigation.
  • Atsushi Miyamoto; Hirofumi Michimae; Yasuharu Nakahara; Shinobu Akagawa; Kazuhiko Nakagawa; Yuji Minegishi; Takashi Ogura; Shigeto Hontsu; Hiroshi Date; Kazuhisa Takahashi; Sakae Homma; Kazuma Kishi
    Respiratory investigation 61 2 284 - 295 2022年12月 
    BACKGROUND: The clinical questions of whether chemotherapy as initial treatment, compared with best supportive care (BSC), improves overall survival (OS) and whether it increases the occurrence risk of acute exacerbation of idiopathic interstitial pneumonia (IIP) in patients with advanced-stage lung cancer and IIP remain inconclusive. This study addresses these issues, given that chemotherapy-related acute exacerbation of IIP may be a direct cause of mortality in these patients. METHODS: We enrolled 1003 patients from 110 Japanese institutions and collected clinical profiles from 707 and 296 patients in the chemotherapy (men: women, 645:62; mean age, 70.4 ± 6.9 years) and BSC (men: women, 261:35; mean age, 75.2 ± 7.8) groups, respectively. We used propensity score matching to create 222 matched pairs from both groups using patient demographic data (age, sex, smoking status, performance status, history of acute exacerbation of IIP, desaturation on exertion, clinical diagnosis of IIP, high-resolution computed tomography findings, serum fibrotic markers, pulmonary function status, and lung cancer histopathology). Logistic or Cox regression analyses were performed using matched data to assess the effects of chemotherapy on the risk of acute exacerbation of IIP or OS, respectively. RESULTS: In the well-matched cohort, chemotherapy improved OS (hazard ratio: 0.629, 95% confidence interval [CI]: 0.506-0.783, p < 0.0001); however, it involved significant acute exacerbation of IIP (odds ratio: 1.787, 95% CI: 1.026-3.113) compared to BSC. CONCLUSIONS: Compared with BSC, chemotherapy can improve OS in patients with advanced-stage lung cancer and IIP; however, it increases the risk of acute exacerbation of IIP.
  • Yukihiro Yoshida; Nozomu Saeki; Masaya Yotsukura; Kazuo Nakagawa; Hirokazu Watanabe; Yasushi Yatabe; Shun-Ichi Watanabe
    JTCVS open 12 410 - 425 2022年12月 
    OBJECTIVE: We aimed to visualize complicated patterns of lymph node metastases in surgically resected non-small cell lung cancer by applying a data mining technique. METHODS: In this retrospective study, 783 patients underwent lobectomy or pneumonectomy with systematic mediastinal lymph node dissection for non-small cell lung cancer between January 2010 and December 2018. Surgically resected lymph nodes were classified according to the International Association for the Study of Lung Cancer lymph node map. Network analysis generated patterns of lymph node metastases from stations 1 to 14, and the degree of connection between 2 lymph node stations was assessed. RESULTS: The median number of lymph nodes examined per patient was 20, and the pathological N category was pN0 in 428 cases, pN1 in 132, pN2 in 221, and pN3 in 2. N1 lymph node stations had strong associations with superior mediastinal lymph node stations for patients with primary tumors in the upper lobes and with station 7 for the lower lobes. There was also a connection from the N1 lymph node stations to superior mediastinal lymph node stations in the lower lobes. In the right middle lobe, an even distribution from station 12m toward stations 2R, 4R, and 7 was noted. We released an interactive web application to visualize these data: http://www.canexapp.com. CONCLUSIONS: Lymph node metastasis patterns differed according to the lobe bearing the tumor. Our results support the need for clinical trials to further investigate selective mediastinal lymph node dissection.
  • Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Kiyohiro Sakai; Takeshi Yoshida; Miki Nakura; Ryo Sakamoto; Chihiro Makimura; Yoichi Ohtake; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Tatsuya Okuno; Naoki Takegawa; Koji Haratani; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    The Oncologist 2022年11月 
    Abstract Background We hypothesized that the high-dose opioid requirement in patients carrying the rs4680-GG variant in the COMT gene encoding catechol-O-methyltransferase would be greater for patients taking morphine than for those taking oxycodone, thus providing a much-needed biomarker to inform opioid selection for cancer pain. Methods A randomized, multicenter, open-label trial was conducted at a Japanese hospital’s palliative care service. Patients with cancer pain treated with regular doses of nonsteroidal anti-inflammatory drugs or acetaminophen were enrolled and randomized (1:1) into morphine (group M) and oxycodone (group O) groups. The minimum standard dose of immediate-release (IR) oral opioids was repeatedly administered by palliative care physicians to achieve pain-reduction goals (Pain reduction ≥ 33% from baseline and up to ≤ 3 on a numerical rating scale). The primary endpoint was the proportion of subjects requiring high-dose opioids on day 0 with the GG genotype. Results Of 140 participants who developed cancer-related pain among 378 subjects registered and pre-screened for the genotype, 139 were evaluated in the current study. Among patients carrying a COMT rs4680-GG genotype, 48.3% required high-dose opioids in group M, compared with the 20.0% in group O (95% CI, 3.7%-50.8%; P = .029). Of those with the non-GG genotype, 41.5% treated with morphine and 23.1% with oxycodone required high-dose opioids (95% CI, 3.3%-38.3%; P = 0.098). Conclusion Using the COMT rs4680 genotype alone is not recommended for selecting between morphine and oxycodone for pain relief.
  • Nobuyuki Katakami; Toshihide Yokoyama; Satoshi Morita; Tatsuro Okamoto; Yoshiko Urata; Yoshihiro Hattori; Yasuo Iwamoto; Yuki Sato; Norihiko Ikeda; Toshiaki Takahashi; Haruko Daga; Tetsuya Oguri; Yasuhito Fujisaka; Kazumi Nishino; Shunichi Sugawara; Toshiyuki Kozuki; Masahide Oki; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    International journal of clinical oncology 28 1 79 - 88 2022年11月 
    BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.
  • Toshio Shimizu; Kazuhiko Nakagawa; Hidetoshi Hayashi; Tsutomu Iwasa; Hisato Kawakami; Satomi Watanabe; Noboru Yamamoto; Kan Yonemori; Takafumi Koyama; Jun Sato; Kenji Tamura; Keiichi Kikuchi; Kenichiro Akaike; Shiho Takeda; Masayuki Takeda
    Investigational new drugs 41 1 1 - 12 2022年11月 
    To determine the maximum tolerated dose (MTD) and recommended dose (RD) of orally-administered bendamustine in Japanese patients with advanced solid tumors. The optimal dosing schedule, safety, pharmacokinetics, and preliminary antitumor effects were also evaluated. A multicenter, open-label trial with a standard 3 + 3 design and dose escalation by dose-limiting toxicity (DLT) was conducted. The treatment schedules were once daily for 7, 14, and 21 days every 3 weeks as one cycle. The total dose per cycle was increased from 175 to 840 mg/m2. Eighteen patients were enrolled in this study. DLT occurred in one of six patients at 75 mg/m2/day × 7 days, and one of three patients at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days. However, the delayed recovery from a decrease in neutrophil or platelet count hampered the start of subsequent treatment cycles, and the trend was more prominent at 37.5 mg/m2/day × 14 days and 25 mg/m2/day × 21 days than in 75 mg/m2/day × 7 days. MTD was determined as 75 mg/m2/day × 7 days to allow acceptable hematologic recovery. The pharmacokinetics of orally-administered bendamustine were generally dose-dependent; however, the inter-individual variability is relatively large. The major adverse events were hematologic toxicities; gastrointestinal disorders were generally mild. Adverse drug reactions did not lead to the discontinuation of the drug. A partial response was observed in two of six patients (prostatic small cell carcinoma and thymic carcinoma) at 75 mg/m2/day × 7 days. The RD and optimal dosing schedule of orally-administered bendamustine was 75 mg/m2 once daily for 7 days every 3 weeks for the treatment of advanced solid tumors. (Trial registration number ClinicalTrials.gov NCT03604679. Registration date July 27, 2018).
  • Masaya Yotsukura; Kazuo Nakagawa; Chihiro Takemura; Yukihiro Yoshida; Kimiteru Ito; Hirokazu Watanabe; Masahiko Kusumoto; Yasushi Yatabe; Shun-Ichi Watanabe
    Japanese journal of clinical oncology 52 11 1321 - 1326 2022年11月 [査読有り]
     
    INTRODUCTION: This study explored the predictors of a histological aggressive component in ground glass opacity-containing lung adenocarcinoma. METHODS: Of the 2388 patients who underwent resection for lung cancer at our institute between 2017 and 2020, we collected data on the 501 patients with ground glass opacity-containing adenocarcinoma with a total diameter of ≤2 cm. Using a historical cohort, we identified histological aggressive components that were related to a poor prognosis in early-stage adenocarcinoma. A multivariable analysis was conducted to identify predictors for the presence of a histological aggressive component. RESULTS: Lymphovascular invasion and predominant micropapillary or solid patterns were identified as histological aggressive components by a prognostic analysis using a historical cohort. Of the 501 patients included, 36 (7.2%) had at least one histological aggressive component. A multivariate analysis showed that a consolidation/tumour ratio > 0.5 (P < 0.01), maximum standardized uptake value on positron emission tomography ≥1.5 (P = 0.01) and smoking index >20 pack-years (P = 0.01) were predictors of the presence of a histological aggressive component. A total of 98% of cases without any of the above factors did not have a histological aggressive component. CONCLUSIONS: Approximately 7% of ground glass opacity-containing small adenocarcinomas contained histological aggressive component. A consolidation/tumour ratio > 0.5, maximum standardized uptake value ≥ 1.5 and smoking index >20 pack-years were predictors for such cases. These predictors may be useful for screening patients with a potentially high risk of a poor prognosis and for prioritizing resection without delay.
  • 武田 真幸; 下川 元継; 中村 敦; 野崎 要; 渡辺 恭孝; 加藤 晃史; 早川 乃介; 田中 洋史; 高橋 利明; 立原 素子; 林 秀敏; 藤本 大智; 山口 覚博; 山本 将一朗; 岩間 映二; 東 公一; 沖 昌英; 長谷川 一男; 山本 信之; 中川 和彦
    肺癌 62 6 660 - 660 (NPO)日本肺癌学会 2022年11月
  • 中村 敦; 善家 義貴; 仁保 誠治; 岡本 龍郎; 原 聡志; 赤澤 結貴; 細見 幸生; 林 秀敏; 寺岡 俊輔; 横山 俊秀; 尾崎 智博; 上野 清伸; 行徳 宏; 三角 俊裕; 中川 和彦; 山本 信之; 坪井 正博
    肺癌 62 6 648 - 648 (NPO)日本肺癌学会 2022年11月
  • 阪本 智宏; 松原 太一; 高濱 隆幸; 横山 俊秀; 中村 敦; 時任 高章; 岡本 龍郎; 赤松 弘朗; 沖 昌英; 佐藤 悠城; 飛野 和則; 西村 邦裕; 平岡 学; 釼持 広知; 藤本 淳也; 下川 元継; 山本 信之; 中川 和彦
    肺癌 62 6 491 - 491 (NPO)日本肺癌学会 2022年11月
  • 未治療EGFR陽性NSCLCに対するOsimertinib+BevacizumabとOsimertinibのランダム化第2相試験 WJOG9717L
    桐田 圭輔; 釼持 広知; 坂井 和子; 盛 啓太; 加藤 晃史; 菅原 俊一; 米嶋 康臣; 東 公一; 中川 和彦; 山本 信之; 西尾 和人; 高橋 利明
    肺癌 62 6 566 - 566 (NPO)日本肺癌学会 2022年11月
  • 切除可能非小細胞肺癌II-IIIA期における可溶性免疫因子の検討(WJOG12319LTR)
    谷崎 潤子; 黒田 浩章; 横山 俊秀; 高濱 誠; 庄田 浩康; 中村 敦; 北村 嘉隆; 豆鞘 伸昭; 門田 嘉久; 光岡 茂樹; 沖塩 協一; 岡田 守人; 坂井 和子; 千葉 康敬; 西尾 和人; 茶本 健司; 本庶 佑; 山本 信之; 中川 和彦; 林 秀敏
    肺癌 62 6 594 - 594 (NPO)日本肺癌学会 2022年11月
  • Kohsuke Isomoto; Koji Haratani; Takahiro Tsujikawa; Yusuke Makutani; Hisato Kawakami; Masayuki Takeda; Kimio Yonesaka; Kaoru Tanaka; Tsutomu Iwasa; Hidetoshi Hayashi; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 174 71 - 82 2022年10月 
    OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a key therapeutic modality for advanced non-small cell lung cancer (NSCLC), but most patients experience primary or acquired resistance to these drugs. We here explored the mechanisms underlying both types of ICI resistance by analysis of the tumor immune microenvironment (TME). MATERIALS AND METHODS: Four patients who experienced a long-term response to ICI treatment (progression-free survival [PFS] of ≥12 months) followed by disease progression, after which a rebiopsy was immediately performed (cohort-A), as well as four patients who experienced early tumor progression during ICI treatment (PFS of <9 weeks, cohort-B) were enrolled in this retrospective study. The pretreatment TME was evaluated by 16- or 17-color multiplex immunohistochemistry (mIHC)-based spatial profiling at the single-cell level for both cohorts. In cohort-A, changes in the TME after disease progression during ICI treatment were also investigated by mIHC analysis and transcriptomic analysis. RESULTS: Pretreatment tumor tissue from cohort-B manifested poor infiltration of tumor-reactive CD8+ T cells characterized by CD39 and CD103 expression or by programmed cell death-1 expression, implicating insufficient recognition of tumor cells by CD8+ T cells as a mechanism of primary ICI resistance. Analysis of the paired tumor specimens from cohort-A revealed various changes in the TME associated with acquired ICI resistance, including substantial infiltration of myeloid-derived suppressor cells and M2-type tumor-associated macrophages without a marked decline in the number of tumor-reactive CD8+ T cells; a decrease in the number of tumor-reactive CD8+ T cells; and an apparent decrease in neoantigen presentation by tumor cells. CONCLUSION: The presence of intratumoral tumor-reactive CD8+ T cells may be a prerequisite for a long-term response to ICI treatment in advanced NSCLC, but it is not sufficient for cancer cell eradication. Various TME profiles are associated with acquired ICI resistance, suggesting that patient-specific strategies to overcome such resistance may be necessary.
  • がん遺伝子パネル検査FoundationOneによる肺癌の遺伝子変異の測定
    米阪 仁雄; 高濱 隆幸; 黒崎 隆; 川中 雄介; 金村 宙昌; 磯本 晃佑; 鈴木 慎一郎; 三谷 誠一郎; 中川 和彦; 白石 直樹; 小田 いつき; 西郷 和真; 池川 敦子; 福岡 和也; 武田 真幸; 西尾 和人
    肺癌 62 5 439 - 439 (NPO)日本肺癌学会 2022年10月
  • がん遺伝子パネル検査FoundationOneによる肺癌の遺伝子変異の測定
    米阪 仁雄; 高濱 隆幸; 黒崎 隆; 川中 雄介; 金村 宙昌; 磯本 晃佑; 鈴木 慎一郎; 三谷 誠一郎; 中川 和彦; 白石 直樹; 小田 いつき; 西郷 和真; 池川 敦子; 福岡 和也; 武田 真幸; 西尾 和人
    肺癌 62 5 439 - 439 (NPO)日本肺癌学会 2022年10月
  • 進展型小細胞肺癌における免疫チェックポイント阻害薬の効果と腫瘍微小免疫環境の関連
    金村 宙昌; 林 秀敏; 原谷 浩司; 中川 和彦; 冨田 秀太; 谷崎 潤子; 鈴木 慎一郎; 川中 雄介; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 大谷 知之; 伊藤 彰彦; 坂井 和子; 西尾 和人
    肺癌 62 5 442 - 442 (NPO)日本肺癌学会 2022年10月
  • Hirotsugu Kenmotsu; Kazushige Wakuda; Keita Mori; Terufumi Kato; Shunichi Sugawara; Keisuke Kirita; Yasuto Yoneshima; Koichi Azuma; Kazumi Nishino; Shunsuke Teraoka; Takehito Shukuya; Ken Masuda; Hidetoshi Hayashi; Ryo Toyozawa; Satoru Miura; Daichi Fujimoto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Toshiaki Takahashi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 17 9 1098 - 1108 2022年09月 
    INTRODUCTION: To evaluate the efficacy and safety of osimertinib plus bevacizumab for previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations. METHODS: We conducted a randomized, open-label, phase 2 study at 21 institutions in Japan. Previously untreated patients with advanced nonsquamous NSCLC harboring EGFR-sensitizing mutations received either osimertinib (80 mg, daily) plus bevacizumab (15 mg/kg, every 3 wk) or osimertinib monotherapy, and were stratified according to sex, stage, and EGFR mutation status. The primary end point was progression-free survival (PFS) in the intention-to-treat population, assessed by means of blinded, independent central radiologic review. RESULTS: Between January 2018 and September 2018, a total of 122 patients were enrolled (osimertinib + bevacizumab arm, 61 patients; osimertinib monotherapy arm, 61 patients). At a median follow-up duration of 19.8 months, the median PFS was 22.1 months for osimertinib plus bevacizumab and 20.2 months for osimertinib monotherapy, with a hazard ratio of 0.862 (60% confidence interval: 0.700-1.060, 95% confidence interval: 0.531-1.397, one-sided stratified log-rank p = 0.213). Adverse events of grade 3 or worse were observed in 34 patients (56%) in the osimertinib plus bevacizumab arm and 29 (48%) in the osimertinib monotherapy arm. In addition, two (3%) and 11 patients (18%) experienced any grade pneumonitis, respectively, and grade 3 pneumonitis was observed in one patient (2%) in each arm. CONCLUSIONS: This study failed to exhibit the efficacy of osimertinib plus bevacizumab for improving the PFS among patients with nonsquamous NSCLC harboring EGFR mutations as first-line treatment.
  • Naoki Haratake; Mototsugu Shimokawa; Takashi Seto; Hiroshige Yoshioka; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Tetsuya Mitsudomi
    International journal of clinical oncology 27 9 1404 - 1412 2022年09月 
    BACKGROUND: Pemetrexed is common cytotoxic chemotherapy among non-squamous non-small cell lung cancer (non-Sq-NSCLC) patients; however, among epidermal growth factor receptor (EGFR)-positive lung cancer, there is no clear evidence to support the efficacy of sequential treatment with pemetrexed. MATERIAL AND METHODS: We performed a post-hoc analysis of subsequent chemotherapies among 144 patients who received the post-protocol treatment in the phase III trial WJTOG 3405 comparing gefitinib to cisplatin plus docetaxel, and analyzed the effect of pemetrexed on overall survival (OS). RESULTS: Patients with treatment including pemetrexed exhibited significantly longer OS in comparison to those without pemetrexed; the median OS in the pemetrexed + and pemetrexed- patients were 40.7 months and 28.0 months, respectively (0.55 of HR [95% CI: 0.38-0.80, p = 0.0020]). On the other hand, other treatments, including docetaxel, TS-1 and paclitaxel showed no significant impact on OS. The multivariate analysis with a time-dependent Cox proportional hazards model showed that treatment including pemetrexed, as well as PS 0 and post-operative recurrence, were independent predictors of a good prognosis. Moreover, among patients who received at least four lines of prior treatment, pemetrexed + treatment also significantly prolonged OS in comparison to pemetrexed- treatment (median OS pemetrexed + vs. pemetrexed-: 44.4 months vs. 32.6 months; HR: 0.55 [95% CI: 0.31-0.94, p = 0.0290]). CONCLUSIONS: Sequential treatment including pemetrexed against EGFR-mutated NSCLC might be associated with a better outcome. It was considered that pemetrexed should be administered without fail as a sequential treatment to improve the prognosis of EGFR-mutated NSCLC as well as like EGFR-tyrosine kinase inhibitors.
  • Satoru Hagiwara; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Chishina; Yoriaki Komeda; Akihiro Yoshida; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo
    Hepatology research : the official journal of the Japan Society of Hepatology 52 9 754 - 761 2022年09月 
    AIM: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. METHODS: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. RESULTS: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty-eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. CONCLUSION: In rare cases, HBsAg-positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected.
  • Hiroaki Kanemura; Hidetoshi Hayashi; Shuta Tomida; Junko Tanizaki; Shinichiro Suzuki; Yusuke Kawanaka; Asuka Tsuya; Yasushi Fukuda; Hiroyasu Kaneda; Keita Kudo; Takayuki Takahama; Ryosuke Imai; Koji Haratani; Yasutaka Chiba; Tomoyuki Otani; Akihiko Ito; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    JTO clinical and research reports 3 8 100373 - 100373 2022年08月 
    Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.
  • Satoru Hagiwara; Takeshi Yoshida; Naoshi Nishida; Hiroshi Ida; Kazuomi Ueshima; Yasunori Minami; Masahiro Takita; Tomoko Aoki; Masahiro Morita; Hirokazu Cishina; Yoriaki Komeda; Akihiro Yoshida; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo
    Hepatology research : the official journal of the Japan Society of Hepatology 52 10 888 - 892 2022年07月 
    AIM: We report a rare case of immune-related cholangitis in which the natural course could be demonstrated. CASE PRESENTATION: Eight courses of pembrolizumab maintenance therapy were given as first-line treatment for squamous cell lung cancer; however, the patient was subsequently hospitalized due to a rapid increase in hepatobiliary enzymes. On endoscopic ultrasound, the common bile duct was dilated to 11 mm, and the wall, throughout its length from the papilla, was thickened. Endoscopic retrograde cholangiopancreatography showed no obvious stenosis in the lower bile duct; however, a parapapillary diverticulum was found, and papillary incision and bile duct plastic stent insertion were carried out. However, the liver disorder did not improve and overt jaundice appeared subsequently; therefore, an immune-related cholangitis was suspected, and prednisolone (PSL) 35 mg/day was introduced from day 59 of admission. Following PSL initiation, a decrease in serum bilirubin level was observed; however, significant decrease was not observed in alkaline phosphatase. Given the history of recurrent infectious cholangitis, magnetic resonance cholangiopancreatography was carried out on day 70 of admission. The intrahepatic bile duct showed stenosis and dilated findings, which was considered to be a factor for repeated infectious cholangitis. CONCLUSION: No previous case reports have described the changes and progression in bile duct images in immune-related adverse events. Therefore, this case is noteworthy for considering the progression of immune-related cholangitis.
  • がん疼痛に対するオピオイド選択のための多型バイオマーカーの探索
    藤田 至彦; 松岡 弘道; 鶴谷 純司; 千葉 康敬; 酒井 清裕; 吉田 健史; 大武 陽一; 小山 敦子; 西尾 和人; 中川 和彦
    Palliative Care Research 17 Suppl. S.179 - S.179 (NPO)日本緩和医療学会 2022年07月
  • Hiroaki Akamatsu; Shunsuke Teraoka; Shinkichi Takamori; Satoru Miura; Hidetoshi Hayashi; Akito Hata; Yukihiro Toi; Yoshimasa Shiraishi; Nobuaki Mamesaya; Yuki Sato; Naoki Furuya; Jun Oyanagi; Yasuhiro Koh; Toshihiro Misumi; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research OF1-OF7  2022年06月 
    PURPOSE: To explore the efficacy of retreatment with immune checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer (NSCLC) who responded to prior ICI and had adequate ICI-free interval. PATIENTS AND METHODS: Patients with advanced NSCLC who had achieved complete response (CR), partial response (PR), or stable disease for ≥6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval ≥60 days before registration. Patients were treated with nivolumab (240 mg) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561). RESULTS: Sixty-one patients were enrolled during October 2017 to February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAE) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% [95% confidence interval (CI), 2.8-18.7%] and median PFS of 2.6 months (95% CI, 1.6-2.8 months) while 5 responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (HR, 2.02; P = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%). CONCLUSIONS: Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
  • 高濱 隆幸; 米阪 仁雄; 白石 直樹; 小田 いつき; 池川 敦子; 西郷 和真; 福岡 和也; 中川 和彦
    近畿大学医学雑誌 47 1-2 19 - 25 近畿大学医学会 2022年06月 
    近年、次世代シークエンサー(NGS)の臨床応用が進み、がんに生じた遺伝子変化を網羅的に解析することが可能となった。包括的がんゲノムプロファイリング(CGP)検査を実施することで、がん化に関わる原因遺伝子が明らかになると同時に、治療の選択肢が増え、恩恵を受ける症例が出てきている。近畿大学病院ゲノム医療センターでは、2019年に日本においてCGP検査が保険適応を受けて以降、がん関連遺伝子検査がスムーズに進むよう業務を行っている。エキスパートパネルの運営を通して、患者や主治医への適切な遺伝子解析結果を届けることを目標とし、また二次的所見への対応などを行ってきた。本稿では、CGP検査の現状について概説し、特に課題の多い出口戦略について、治療への到達率を高めるために必要なことは何か考察をしたい。(著者抄録)
  • Tomohiro Nakayama; Koji Haratani; Takashi Kurosaki; Kaoru Tanaka; Kazuhiko Nakagawa
    Translational Cancer Research 11 6 1824 - 1828 2022年06月
  • Hiroaki Akamatsu; Shunsuke Teraoka; Shinkichi Takamori; Satoru Miura; Hidetoshi Hayashi; Akito Hata; Yukihiro Toi; Yoshimasa Shiraishi; Nobuaki Mamesaya; Yuki Sato; Naoki Furuya; Jun Oyanagi; Yasuhiro Koh; Toshihiro Misumi; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 2022年05月 
    PURPOSE: To explore the efficacy of retreatment with immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) patients who responded to prior ICI and had adequate ICI-free interval. PATIENTS AND METHODS: Advanced NSCLC patients who had achieved complete response (CR), partial response (PR), or stable disease for {greater than or equal to}6 months with prior ICI therapy preceding progression were prospectively enrolled. All patients should have had ICI-free interval {greater than or equal to} 60 days before registration. Patients were treated with nivolumab (240 mg/body) every 2 weeks until progression. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival, and safety (Trial Identifier, UMIN000028561). RESULTS: Sixty-one patients were enrolled during October 2017-February 2020, with 59 analyzed for efficacy. Regarding prior ICI, 41 patients had CR or PR. Median treatment on ICI and median ICI-free intervals were 8.1 months and 9.2 months, respectively. Twenty patients experienced immune-related adverse events (irAEs) that required discontinuation of prior ICI. Nivolumab retreatment demonstrated ORR of 8.5% (95% confidence interval [CI]: 2.8-18.7%) and median PFS of 2.6 months (95% CI: 1.6-2.8 months) while five responders had 11.1 months of median PFS. In the multivariate analysis, ICI-free interval was the only predictive factor of PFS (hazard ratio: 2.02, p = 0.02), while prior efficacy or history of irAE was not. Common adverse events were skin disorders (23%), malaise (20%), and hypoalbuminemia (15%). CONCLUSION: Even in patients who initially responded to prior ICI and had ICI-free interval, once resistance occurred, retreatment with nivolumab had limited efficacy.
  • Hidetoshi Hayashi; Kimio Yonesaka; Atsushi Nakamura; Daichi Fujimoto; Koichi Azuma; Shinya Sakata; Motoko Tachihara; Satoshi Ikeda; Toshihide Yokoyama; Osamu Hataji; Yukihiro Yano; Katsuya Hirano; Haruko Daga; Hideaki Okada; Yasutaka Chiba; Kazuko Sakai; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 168 38 - 45 2022年04月 
    INTRODUCTION: Alternation of osimertinib and afatinib is a potential approach to overcome osimertinib resistance and to allow complementation of drug efficacy without compromising safety in patients with epidermal growth factor receptor gene (EGFR)-mutated non-small cell lung cancer (NSCLC). METHODS: Treatment-naive patients with stage IV NSCLC harboring an activating EGFR mutation (L858R or exon-19 deletion) were enrolled. Alternating cycles of osimertinib at 80 mg/day for 8 weeks followed by afatinib at 20 mg/day for 8 weeks were administered. The primary end point was 12-month progression-free survival (PFS) probability. RESULTS: Forty-six patients were enrolled and treated with study therapy. The 12-month PFS probability was 70.2% (60% confidence interval [CI], 63.9-75.6%; 95% CI, 54.2-81.5%), which did not meet the primary end point. After a median follow-up time of 25.7 months, the median PFS was 21.3 months (95% CI, 16.3 months-not reached). The overall response rate was 69.6% (95% CI, 54.2-82.3%). The most common treatment-related adverse events (any grade or grade ≥ 3, respectively) were diarrhea (73.9%, 4.3%), rash acneiform (63.0%, 2.2%), and paronychia (52.2%, 0%). Five cases of pneumonitis, two of grade 2 and thres of grade 3, were apparent, all of which developed during osimertinib treatment. Exploratory evaluation of circulating tumor DNA suggested that coexisting TP53 mutations did not influence PFS for the alternating therapy. CONCLUSIONS: Alternating therapy with osimertinib and afatinib for treatment-naive patients with EGFR- mutated advanced NSCLC did not meet its primary end point, despite the encouraging efficacy and safety profile of this treatment strategy.
  • Makoto Nishio; Kazuto Nishio; Martin Reck; Edward B Garon; Fumio Imamura; Tomoya Kawaguchi; Hiroyuki Yamaguchi; Satoshi Ikeda; Katsuya Hirano; Carla Visseren-Grul; Matteo Ceccarelli; Sameera R Wijayawardana; Annamaria Zimmermann; Tomoko Matsui; Sotaro Enatsu; Kazuhiko Nakagawa
    JTO clinical and research reports 3 4 100303 - 100303 2022年04月 
    Introduction: Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). Methods: Period 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. Results: From December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3-73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). Conclusions: RELAY+ was found to have a favorable benefit-risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.
  • Hidetoshi Hayashi; Shunichi Sugawara; Yasushi Fukuda; Daichi Fujimoto; Satoru Miura; Keiichi Ota; Yuichi Ozawa; Satoshi Hara; Junko Tanizaki; Koichi Azuma; Shota Omori; Motoko Tachihara; Kazumi Nishino; Akihiro Bessho; Yasutaka Chiba; Koji Haratani; Kazuko Sakai; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 5 893 - 902 2022年03月 
    PURPOSE: Although the efficacy of programmed cell death-1 (PD-1) blockade is generally poor for non-small cell lung cancer (NSCLC) with activating mutations of the epidermal growth factor receptor (EGFR) gene, EGFR tyrosine kinase inhibitors (TKIs) may improve the tumor immune microenvironment. We performed a randomized study to assess whether nivolumab improves outcome compared with chemotherapy in such patients previously treated with EGFR-TKIs. PATIENTS AND METHODS: Patients with EGFR-mutated NSCLC who acquired EGFR-TKI resistance not due to a secondary T790M mutation of EGFR were randomized 1:1 to nivolumab (n = 52) or carboplatin-pemetrexed (n = 50). The primary endpoint was progression-free survival (PFS). RESULTS: Median PFS and 1-year PFS probability were 1.7 months and 9.6% for nivolumab versus 5.6 months and 14.0% for carboplatin-pemetrexed [log-rank P < 001; hazard ratio (HR) of 1.92, with a 60% confidence interval (CI) of 1.61-2.29]. Overall survival was 20.7 and 19.9 months [HR, 0.88 (95% CI, 0.53-1.47)], and response rate was 9.6% and 36.0% for nivolumab and carboplatin-pemetrexed, respectively. No subgroup including patients with a high tumor mutation burden showed a substantially longer PFS with nivolumab than with carboplatin-pemetrexed. The T-cell-inflamed gene expression profile score (0.11 vs. -0.17, P = 0.036) and expression of genes related to cytotoxic T lymphocytes or their recruitment were higher in tumors that showed a benefit from nivolumab. CONCLUSIONS: Nivolumab did not confer a longer PFS compared with carboplatin-pemetrexed in the study patients. Gene expression profiling identified some cases with a favorable tumor immune microenvironment that was associated with nivolumab efficacy.
  • J Tanizaki; K Yonemori; K Akiyoshi; H Minami; H Ueda; Y Takiguchi; Y Miura; Y Segawa; S Takahashi; Y Iwamoto; Y Kidera; K Fukuoka; A Ito; Y Chiba; K Sakai; K Nishio; K Nakagawa; H Hayashi
    Annals of oncology : official journal of the European Society for Medical Oncology 33 2 216 - 226 2022年02月 
    BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
  • Kohsuke Isomoto; Koji Haratani; Satomi Watanabe; Masayuki Takeda; Tsutomu Iwasa; Kazuhiko Nakagawa
    Investigational new drugs 40 1 194 - 197 2022年02月 
    Extramammary Paget disease (EMPD) is a rare cutaneous adenocarcinoma that usually is of epidermal origin and shows glandular differentiation and that is treated by wide local excision depending on the disease extent. For widely metastatic disease, however, a standard treatment remains to be established. Similar to breast cancer, EMPD has been found to overexpress human epidermal growth factor receptor 2 (HER2) or hormone receptors (HRs). Whereas HER2-directed therapy was recently shown to be effective for HER2-positive EMPD, the potential role of endocrine therapy for HR-positive EMPD has remained unknown. We here report a case of metastatic EMPD with HR positivity that was successfully treated with the selective estrogen receptor modulator tamoxifen. This first-line treatment of systemic metastasis resulted in durable tumor regression for > 20 months without any treatment-related toxicities. This is the first report to reveal the promise of tamoxifen as a safe and effective treatment for HR-positive metastatic EMPD.
  • Takashi Seto; Kaname Nosaki; Mototsugu Shimokawa; Ryo Toyozawa; Shunichi Sugawara; Hidetoshi Hayashi; Haruyasu Murakami; Terufumi Kato; Seiji Niho; Hideo Saka; Masahide Oki; Hiroshige Yoshioka; Isamu Okamoto; Haruko Daga; Koichi Azuma; Hiroshi Tanaka; Kazumi Nishino; Rie Tohnai; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Journal for immunotherapy of cancer 10 2 2022年02月 
    BACKGROUND: PD-L1 expression on tumor cells is a marker of PD-1/PD-L1 antibody treatment efficacy for advanced non-small cell lung cancer (NSCLC). PD-L1 antibody (atezolizumab) prolongs overall survival (OS) compared with platinum doublet as first-line treatment for NSCLC with high PD-L1 expression. Bevacizumab enhanced cytotoxic agent and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor efficacy in non-squamous (NS)-NSCLC, and PD-1/PD-L1 antibodies in preclinical models. METHODS: This single-arm phase II study investigated clinical benefits of adding bevacizumab 15 mg/kg to atezolizumab 1200 mg fixed dose in a first-line setting for advanced NS-NSCLC patients with PD-L1 expression ≥50% without EGFR/ALK/ROS1 alterations. Primary endpoint was objective response rate (ORR) assessed by central review committee. Secondary endpoints were progression-free survival (PFS), duration of response (DOR), OS, and safety. RESULTS: Of 39 enrolled patients, 33 (84.6%) had stage IV NSCLC and 36 (92.3%) had smoking history. As of March 31, 2020, no patient had a complete response and 25 patients had a partial response (ORR=64.1%, 95% CI 47.18 to 78.80). Twelve-month PFS and OS rates were 54.9% (35.65 to 70.60) and 70.6% (50.53 to 83.74), respectively. The median DOR in 25 responders was 10.4 months (4.63-not reached). The median treatment cycle was 12 (1 to 27). Nineteen patients discontinued study treatment because of disease progression (N=17) or immune-related adverse events (AEs) (N=2) (sclerosing cholangitis or encephalopathy). There were 23 serious AEs in 12 patients, but no grade 4/5 toxicity. CONCLUSIONS: Atezolizumab with bevacizumab is a potential treatment for NS-NSCLC with high PD-L1 expression. TRIAL REGISTRATION NUMBER: JapicCTI-184038.
  • Bob T Li; Egbert F Smit; Yasushi Goto; Kazuhiko Nakagawa; Hibiki Udagawa; Julien Mazières; Misako Nagasaka; Lyudmila Bazhenova; Andreas N Saltos; Enriqueta Felip; Jose M Pacheco; Maurice Pérol; Luis Paz-Ares; Kapil Saxena; Ryota Shiga; Yingkai Cheng; Suddhasatta Acharyya; Patrik Vitazka; Javad Shahidi; David Planchard; Pasi A Jänne
    The New England journal of medicine 386 3 241 - 251 2022年01月 
    BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies have not been approved for patients with non-small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody-drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively. METHODS: We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed. RESULTS: A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification. CONCLUSIONS: Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Lung01 ClinicalTrials.gov number, NCT03505710.).
  • Hirohito Tada; Tetsuya Mitsudomi; Toshihiro Misumi; Kenji Sugio; Masahiro Tsuboi; Isamu Okamoto; Yasuo Iwamoto; Noriaki Sakakura; Shunichi Sugawara; Shinji Atagi; Toshiaki Takahashi; Hidetoshi Hayashi; Morihito Okada; Hidetoshi Inokawa; Hiroshige Yoshioka; Kazuhisa Takahashi; Masahiko Higashiyama; Ichiro Yoshino; Kazuhiko Nakagawa
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 40 3 231 - 241 2022年01月 
    PURPOSE: To investigate the efficacy of gefitinib as an adjuvant therapy for non-small-cell lung cancer patients with EGFR mutation. PATIENTS AND METHODS: IMPACT (WJOG6410L; University Hospital Medical Information Network Clinical Trials Registry: UMIN000006252), a randomized, open-label, phase III study, included patients with completely resected pathologic stage II-III non-small-cell lung cancer harboring EGFR mutations (exon 19 deletion or L858R) during September 2011 to December 2015. Patients were randomly assigned to receive gefitinib (250 mg once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8; cis/vin) once every 3 weeks for four cycles. The primary end point was disease-free survival (DFS). RESULTS: Overall, 234 patients were randomly assigned. Among 232 eligible patients (116 each; excluding two who withdrew consent), the median DFS was 35.9 and 25.1 months in the gefitinib and cis/vin groups, respectively. However, Kaplan-Meier curves crossed around 4 years after surgery with no statistically significant difference (stratified log-rank P = .63; hazard ratio by stratified Cox proportional hazards model = 0.92; 95% CI, 0.67 to 1.28). Overall survival (OS) was also not different (stratified log-rank P = .89; hazard ratio = 1.03; 95% CI, 0.65 to 1.65), with the 5-year OS rates being 78.0% and 74.6% in the gefitinib and cis/vin groups, respectively. Treatment-related deaths occurred in 0 and three patients in the gefitinib and cis/vin groups, respectively. CONCLUSION: Although adjuvant gefitinib appeared to prevent early relapse, it did not prolong DFS or OS. However, similar DFS and OS may justify adjuvant gefitinib in the selected patient subsets, especially those deemed ineligible for platinum-doublet adjuvant therapy; however, this was not a noninferiority trial.
  • Kimio Yonesaka; Junko Tanizaki; Osamu Maenishi; Koji Haratani; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Kazuko Sakai; Yasutaka Chiba; Asuka Tsuya; Hiroki Goto; Eri Otsuka; Hiroaki Okida; Maki Kobayashi; Ryoto Yoshimoto; Masanori Funabashi; Yuuri Hashimoto; Kenji Hirotani; Takashi Kagari; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 2 390 - 403 2022年01月 
    PURPOSE: EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated EGFR-mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in EGFR-mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in EGFR-mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in EGFR-mutated NSCLC. EXPERIMENTAL DESIGN: Paired tumor samples were obtained from 48 patients with EGFR-mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in EGFR-mutated NSCLC cells. RESULTS: We showed augmented HER3 expression in EGFR-mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An in vitro study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple EGFR-mutated cancers, and enhanced the anticancer activity of HER3-DXd. CONCLUSIONS: Our findings help clarify the mechanisms of HER3 regulation in EGFR-mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in EGFR-mutated NSCLC.
  • Shinichiro Suzuki; Kimio Yonesaka; Takeshi Teramura; Toshiyuki Takehara; Ryoji Kato; Hitomi Sakai; Koji Haratani; Junko Tanizaki; Hisato Kawakami; Hidetoshi Hayashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 28 2 428 - 428 2022年01月
  • Tomoyuki Otani; Hiroaki Kanemura; Masatomo Kimura; Seiichiro Mitani; Masayuki Takeda; Mitsuru Matsuki; Noriomi Matsumura; Takao Satou; Kazuhiko Nakagawa; Akihiko Ito
    International journal of surgical pathology 30 6 10668969211069963 - 10668969211069963 2022年01月 
    Only four cases of colorectal adenocarcinoma with a yolk sac tumor (YST) component have been reported in the English literature. No genetic investigation has been performed in these cases. We report a case of colorectal adenocarcinoma in which the recurrent tumor had a YST component. A 49-year-old woman presented with a pelvic tumor three years after endoscopic mucosal resection of sigmoid colon adenocarcinoma. The pelvic tumor consisted of an undifferentiated carcinoma component and a YST component. The serum alpha-fetoprotein level was elevated to 42 ng/mL. Treatment as conventional colorectal carcinoma produced some anticancer effects, but the patient died 14 months after the recurrence and 49 months after the EMR. With the help of the next-generation sequencing results of the recurrent tumor, APC c.835 - 8A > G and TP53 c.524G > A (p.R175H) mutations were identified by direct sequencing in both the primary and the recurrent tumors, confirming the relationship between the two metachronous tumors.
  • Yusuke Makutani; Hisato Kawakami; Takahiro Tsujikawa; Kanako Yoshimura; Yasutaka Chiba; Akihiko Ito; Junichiro Kawamura; Koji Haratani; Kazuhiko Nakagawa
    Frontiers in oncology 12 956270 - 956270 2022年 
    Matrix metalloproteinase 14 (MMP14) expression is implicated in progression of colorectal cancer, but its role in the tumor microenvironment (TME) has been unclear. The relevance of MMP14 to colorectal cancer progression was explored by analysis of transcriptomic data for colorectal adenocarcinoma patients (n = 592) in The Cancer Genome Atlas. The role of MMP14 in the TME was investigated in a retrospective analysis of tumor samples from 86 individuals with stage III colorectal cancer by single cell-based spatial profiling of MMP14 expression as performed by 12-color multiplex immunohistochemistry (mIHC). Analysis of gene expression data revealed that high MMP14 expression was associated with tumor progression and implicated both cancer-associated fibroblasts (CAFs) and tumor-associated macrophages in such progression. Spatial profiling by mIHC revealed that a higher percentage of MMP14+ cells among intratumoral CAFs (MMP14+ CAF/CAF ratio) was associated with poorer relapse-free survival. Multivariable analysis including key clinical factors identified the MMP14+ CAF/CAF ratio as an independent poor prognostic factor. Moreover, the patient subset with both a high MMP14+ CAF/CAF ratio and a low tumor-infiltrating lymphocyte density showed the worst prognosis. Our results suggest that MMP14+ CAFs play an important role in progression of stage III colorectal cancer and may therefore be a promising therapeutic target.
  • Yu Okubo; Jumpei Kashima; Takashi Teishikata; Yuji Muraoka; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Hirokazu Watanabe; Masahiko Kusumoto; Shun-Ichi Watanabe; Yasushi Yatabe
    Journal of thoracic oncology 17 1 67 - 75 2022年01月 [査読有り]
     
    INTRODUCTION: Because several articles have reported a prognostic association with the radiologic features of ground-glass opacity, we explored whether the histologic presence of a lepidic component had similar significance. METHODS: We retrospectively evaluated 380 consecutive surgically resected lung adenocarcinomas (ADCs) of pathologic (p)stage IA. The tumors were classified into lepidic-positive and lepidic-negative ADCs. Clinicopathologic characteristics, radiographic ground-glass opacity status, and disease-free survival were compared between lepidic-positive and lepidic-negative ADCs and between part-solid and solid nodules on computed tomography images. RESULTS: Of the 380 cases, 176 (46.3%) were lepidic-positive ADCs. Of the overall patients with pT1, lepidic-positive ADCs were found to have significantly better recurrence-free survival (5 y, 95.4% versus 87.0%, p = 0.005), but this significance was not reproduced in pT1 subcategories (pT1a, pT1b, and pT1c). Furthermore, the presence of the lepidic component was not an independent prognostic factor in the multivariate analysis (hazard ratio = 0.46 [95% confidence interval: 0.19-1.14], p = 0.09). We also analyzed the extent of the lepidic component with 10% incremental valuables. Although we found that a 10% or greater extent of lepidic component made the recurrence-free survival difference the largest, a clear prognostic impact was not obtained with this cutoff point. CONCLUSIONS: Although lepidic-positive ADCs tended to have a favorable outcome, the lepidic component was not a clear independent prognostic factor in pstage I ADC.
  • Shinya Sakata; Kohei Otsubo; Hisako Yoshida; Kentaro Ito; Atsushi Nakamura; Shunsuke Teraoka; Naohisa Matsumoto; Yoshimasa Shiraishi; Koji Haratani; Motohiro Tamiya; Satoshi Ikeda; Satoru Miura; Junko Tanizaki; Shota Omori; Hiroshige Yoshioka; Akito Hata; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer science 113 1 221 - 228 2022年01月 
    Considering the increasing number of identified driver oncogene alterations, additional genetic tests are required to determine the treatment for advanced non-small-cell lung cancer (NSCLC). Next-generation sequencing can detect multiple driver oncogenes simultaneously, enabling the analysis of limited amounts of biopsied tissue samples. In this retrospective, multicenter study (UMIN ID000039523), we evaluated real-world clinical data using the Oncomine Dx Target Test Multi-CDx System (Oncomine DxTT) as a companion diagnostic system. Patients with NSCLC who were tested for a panel of 46 genes using the Oncomine DxTT between June 2019 and January 2020 were eligible for enrollment. Patients from 19 institutions affiliated to the West Japan Oncology Group were recruited. The primary endpoint of the study was the success rate of genetic alteration testing in four driver genes (EGFR, ALK, ROS1, and BRAF) using the Oncomine DxTT. In total, 533 patients were enrolled in the study. The success rate of genetic alteration testing for all four genes was 80.1% (95% CI 76.5%-83.4%). Surgical resection was associated with the highest success rate (88.0%), which was significantly higher than that for bronchoscopic biopsy (76.8%, P = .005). Multivariate analysis revealed a significant difference for surgical resection alone (P = .006, 95% CI 1.36-6.18, odds ratio 2.90). Although the success rate of genetic alteration testing immediately after Oncomine DxTT induction was not sufficient in this study, optimizing specimen quantity and quality may improve the use of driver gene testing in clinical settings.
  • Shinichiro Suzuki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Junko Tanizaki; Ryoji Kato; Seiichiro Mitani; Yusuke Kawanaka; Takashi Kurosaki; Yoshikazu Hasegawa; Takafumi Okabe; Kaoru Tanaka; Yusaku Akashi; Tomohiro Ozaki; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    European journal of cancer (Oxford, England : 1990) 161 44 - 54 2022年01月 
    BACKGROUND: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown. METHODS: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included. TB was estimated on the basis of the sum of the diameters of measurable target lesions as per Response Evaluation Criteria in Solid Tumours. Progression-free survival (PFS) in the ICI cohort was evaluated as per TB as a preplanned primary objective, with the analysis based on propensity score-weighted survival curves and estimation of restricted mean survival time (RMST). The Chemo cohort served as a control to determine whether TB is predictive of ICI treatment outcomes. The ICI+Chemo cohort was exploratory. The relation of TB to tumour immune status was assessed by immune-related gene expression profiling (irGEP) of pretreatment tumour tissue. RESULTS: In the ICI cohort, patients with a low TB showed a significantly longer PFS than did those with a high TB (median, 17.9 vs 4.3 months; weighted hazard ratio, 0.32 [95% confidence interval, 0.19-0.53]). No such difference was apparent in the other cohorts. A significant difference in overall survival was also observed only in the ICI cohort. RMST-based analysis confirmed these results. The irGEP analysis implicated M2-type macrophages, angiogenesis and transforming growth factor-β as well as protumourigenic signalling pathways in ICI resistance conferred by a high TB. CONCLUSION: A high TB was associated with a poor outcome of ICI therapy for advanced NSCLC as a result of immunosuppressive phenotypes. Development of combination or novel treatment strategies for such disease is thus warranted.
  • Ernest Nadal; Hidehito Horinouchi; Jin-Yuan Shih; Kazuhiko Nakagawa; Martin Reck; Edward B Garon; Yu-Feng Wei; Jens Kollmeier; Bente Frimodt-Moller; Emily Barrett; Olga Lipkovich; Carla Visseren-Grul; Silvia Novello
    Drug safety 45 1 45 - 64 2022年01月 
    INTRODUCTION: RELAY was a global, double-blind, placebo-controlled phase III study that demonstrated superior progression-free survival (PFS) for ramucirumab plus erlotinib (RAM + ERL) versus placebo plus erlotinib (PBO + ERL) in the first-line treatment of patients with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) mutation-positive, metastatic non-small-cell lung cancer (NSCLC). OBJECTIVE: This article provides an in-depth analysis of the safety profile of RAM + ERL versus PBO + ERL observed in RELAY. METHODS: Eligible patients met these criteria: stage IV NSCLC; EGFR exon 19 deletion or exon 21 substitution (L858R) mutation; Eastern Cooperative Oncology Group performance status 0 or 1; and no central nervous system metastases. Patients were randomized (1:1) to receive erlotinib 150 mg/day orally plus either ramucirumab 10 mg/kg intravenously or matching placebo once every 2 weeks, until disease progression or unacceptable toxicity. The primary endpoint was PFS. Safety was evaluated based on reported treatment-emergent adverse events (AEs) and clinical laboratory assessments. RESULTS: The safety population comprised 446 patients (221 in RAM+ERL arm; 225 in PBO + ERL arm) who received at least one dose of study drug between January 2016 and February 2018. The overall incidence of grade ≥ 3 AEs was higher with RAM + ERL than with PBO + ERL, primarily driven by grade 3 hypertension. Grade ≥ 3 dermatitis acneiform and diarrhea were also reported more frequently in the RAM + ERL arm. The increased incidence of AEs with RAM + ERL was easily detected through routine monitoring and managed through dose adjustments and appropriate supportive care. CONCLUSION: This in-depth safety analysis from RELAY supports that RAM + ERL, irrespective of the increased incidence of AEs, does not affect a patient's ability to benefit from treatment. CLINICAL TRIAL REGISTRATION NUMBER: NCT02411448.
  • Naonori Kawakubo; Yu Okubo; Masaya Yotsukura; Yukihiro Yoshida; Kazuo Nakagawa; Kan Yonemori; Hirokazu Watanabe; Yasushi Yatabe; Shun-Ichi Watanabe
    The Journal of surgical research 272 61 - 68 2021年12月 
    BACKGROUND AND OBJECTIVES: Mediastinal germ cell tumor (MGCT) is a relatively rare tumor. Complete resection after chemotherapy is a standard treatment against this disease. However, the risk factors of incomplete resection are unclear. Therefore, we analyzed survival rates and risk factors for incomplete resection based on preoperative imaging. METHODS: We retrospectively reviewed the medical records of patients (n = 56) with MGCT operated at National Cancer Center Hospital, and analyzed preoperative computed tomography (CT) data in terms of relationship of the tumor and vessels, and investigated survival rate and risk factors for incomplete resection. RESULTS: A total of 56 patients underwent resection of MGCT. The 5-y progression-free survival (PFS) and overall survival (OS) were 79% and 83%. In multivariate analysis, complete resection was the only significant prognostic factor for better PFS (hazard ratio (HR) = 9.083, P= 0.00021) and OS (HR = 5.519, P= 0.0445). The preoperative CT finding of arteries (including the aorta, right brachiocephalic artery, left common carotid artery, and left subclavian artery) surrounded by the tumor was a predictor of incomplete resection (odds ratio = 10.089, P= 0.049). CONCLUSIONS: Complete resection is essential for improving the survival of MGCT, and the risk stratification using preoperative CT imaging brings important information to achieve the complete resection.
  • 谷崎 潤子; 鈴木 慎一郎; 金村 宙昌; 岩朝 勤; 川上 尚人; 田中 薫; 吉田 健史; 米阪 仁雄; 伊藤 彰彦; 坂井 和子; 木寺 康裕; 福岡 和也; 千葉 康敬; 西尾 和人; 中川 和彦; 林 秀敏
    近畿大学医学雑誌 46 3-4 20A - 20A 近畿大学医学会 2021年12月
  • Miyako Satouchi; Kaname Nosaki; Toshiaki Takahashi; Kazuhiko Nakagawa; Keisuke Aoe; Takayasu Kurata; Akimasa Sekine; Atsushi Horiike; Tatsuro Fukuhara; Shunichi Sugawara; Shigeki Umemura; Hideo Saka; Isamu Okamoto; Nobuyuki Yamamoto; Hiroshi Sakai; Kazuma Kishi; Nobuyuki Katakami; Hidehito Horinouchi; Toyoaki Hida; Hiroaki Okamoto; Shinji Atagi; Tatsuo Ohira; Shi Rong Han; Kazuo Noguchi; Victoria Ebiana; Katsuyuki Hotta
    Cancer science 112 12 5000 - 5010 2021年12月 
    This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.
  • Satoru Hagiwara; Tomohiro Watanabe; Masatoshi Kudo; Kosuke Minaga; Yoriaki Komeda; Ken Kamata; Masatomo Kimura; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuomi Ueshima; Yasunori Minami; Tomoko Aoki; Masahiro Takita; Masahiro Morita; Hirokazu Cishina; Hiroshi Ida; Ah-Mee Park; Naoshi Nishida
    Scientific Reports 11 1 9242 - 9242 2021年12月 
    AbstractImmune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are widely used to treat advanced metastatic cancers. Neutralisation of PD-1 or CTLA-4 by ICIs results in immune-related adverse events (irAEs). The clinicopathological features of twelve patients with hepatic irAEs were evaluated and compared to those of ten patients with autoimmune hepatitis (AIH) or graft-versus-host disease (GVHD). No significant difference was seen in serum levels of transaminases, whereas serum levels of IgG and anti-nuclear antibody were higher in patients with AIH than in those with GVHD or hepatic irAEs. Inflammation was limited to the liver lobes in patients with GVHD or hepatic irAEs, whereas patients with AIH exhibited both portal and lobular inflammation. Immunohistochemical analyses revealed a predominant infiltration of CD8+ T cells and defective accumulation of regulatory T cells (Tregs) expressing forkhead box p3 (FOXP3) in the lobular areas of patients with hepatic irAEs and GVHD. In contrast, periportal lesions of patients with AIH were characterised by an infiltration of CD4+ T cells, CD8+ T cells, CD20+ B cells, and FOXP3+ Tregs. Overall, the activation of CD8+ T cells in the absence of activation of Tregs potentially underlies the immunopathogenesis of hepatic irAEs.
  • Nobuyuki Yamamoto; Yoichi Nakanishi; Akihiko Gemma; Kazuhiko Nakagawa; Takahiko Sakamoto; Ayumi Akamatsu; Yuichiro Ohe
    Cancer science 112 11 4692 - 4701 2021年11月 
    Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).
  • Naoki Haratake; Hidetoshi Hayashi; Mototsugu Shimokawa; Yusuke Nakano; Koichi Azuma; Masahide Oki; Keiichi Ota; Hiroshige Yoshioka; Tomohiro Sakamoto; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Takashi Seto
    Clinical lung cancer 23 3 e257-e263  2021年10月 
    INTRODUCTION: Osimertinib is a standard first-line treatment for non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor gene (EGFR). However, tumors with the L858R mutation appear to be less sensitive to EGFR-tyrosine kinase inhibitors (TKIs) than those with exon-19 deletions, and subgroup analysis of the FLAURA study revealed that osimertinib did not significantly prolong overall survival (OS) compared with gefitinib or erlotinib in patients with the L858R. The RELAY study revealed a similar high efficacy of combination therapy with erlotinib plus ramucirumab (E+RAM) in patients with L858R and in those with exon-19 deletions. Patients who acquire the TKI resistance-associated T790M mutation during E+RAM treatment can also expect to receive benefit from second-line osimertinib. We have therefore planned a phase III study to evaluate the clinical efficacy of E+RAM compared with osimertinib monotherapy for untreated patients with advanced NSCLC harboring L858R. PATIENTS AND METHODS: A total of 230 patients will be enrolled. The primary end point is time to failure of strategy (TFS), which is defined for this study as the time from randomization of treatment until disease progression or death on osimertinib, or the time from randomization until first disease progression or death of the primary treatment when osimertinib is not administered in the E+RAM group. Secondary end points include OS and progression-free survival. CONCLUSION: This is the first phase III clinical trial to target only NSCLC patients with the L858R mutation. Its results may establish an optimal treatment for such individuals.
  • Taichi Miyawaki; Hirotsugu Kenmotsu; Hideyuki Harada; Yasuhisa Ohde; Yasutaka Chiba; Koji Haratani; Tamio Okimoto; Tomohiro Sakamoto; Kazushige Wakuda; Kentaro Ito; Takehiro Uemura; Shinya Sakata; Yoshihito Kogure; Yasumasa Nishimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    BMC cancer 21 1 1121 - 1121 2021年10月 
    BACKGROUND: Synchronous oligometastatic non-small cell lung cancer (NSCLC) is generally characterised by the limited number of metastases at the time of diagnosis. Several clinical trials have shown that local ablative therapy (LAT) at all sites of the disease might be beneficial for patients with oligometastatic NSCLC. In recent years, the combination of programmed cell death 1 (PD-1) inhibitors or programmed cell death ligand 1 with cytotoxic chemotherapy has become a new standard treatment for patients with metastatic NSCLC. Furthermore, multisite LAT would inherently reduce the overall tumour burden, and this could promote T cell reinvigoration to enhance the efficacy of PD-1 inhibitors. Few studies have evaluated the efficacy of the combination of PD-1 inhibitors with LAT at all sites of disease. The aim of the present multicentre single-arm phase II study is to evaluate the efficacy of LAT at all sites of disease following standard platinum doublet chemotherapy with pembrolizumab in patients with oligometastatic NSCLC. METHODS: Thirty patients with synchronous oligometastatic NSCLC will be enrolled in the trial. All patients will receive 2-4 cycles of a systemic treatment including pembrolizumab and chemotherapy as induction therapy. Patients who will receive LAT will be determined by a multidisciplinary tumour board, including medical oncologists, radiation oncologists, and thoracic surgeons. LAT will be administered at all sites of disease within 21-56 days of the last dose of induction therapy and will be followed by maintenance therapy within 42 days of the last day of LAT. The primary endpoint is the progression-free survival (PFS) rate of 24 months from the date of initiation of LAT. The secondary endpoints are toxicity, response to induction therapy, PFS, overall survival, and the frequency of LAT. DISCUSSION: This study will provide novel data on the efficacy and safety profile of the combination of LAT and chemotherapy plus immune-checkpoint inhibitors in patients with synchronous oligometastatic NSCLC. If the primary endpoint of this study is met, extensive phase III studies further assessing this strategy will be recommended. TRIAL REGISTRATION: jRCT identifier: jRCTs041200046 (date of initial registration: 28 October 2020).
  • 宿谷 威仁; 藤本 大智; 林 秀敏; 伊藤 健太郎; 小澤 雄一; 釼持 広知; 中川 和彦; 光冨 徹哉; 弦間 昭彦; 山本 信之
    肺癌 61 6 517 - 517 (NPO)日本肺癌学会 2021年10月
  • 白石 直樹; 田中 薫; 高濱 隆幸; 鈴木 慎一郎; 金村 宙昌; 磯本 晃佑; 林 秀敏; 米阪 仁雄; 中川 和彦
    肺癌 61 6 649 - 649 (NPO)日本肺癌学会 2021年10月
  • 岩本 康男; 多田 弘人; 光冨 徹哉; 杉尾 賢二; 坪井 正博; 岡本 勇; 坂倉 範昭; 菅原 俊一; 安宅 信二; 高橋 利明; 林 秀敏; 岡田 守人; 井野川 英利; 吉岡 弘鎮; 高橋 和久; 東山 聖彦; 吉野 一郎; 中川 和彦
    肺癌 61 6 594 - 594 (NPO)日本肺癌学会 2021年10月
  • 寺岡 俊輔; 赤松 弘朗; 林 秀敏; 藤本 大智; 早田 敦志; 原谷 浩司; 小澤 雄一; 吉田 健司; 岩朝 勤; 下川 敏雄; 富井 啓介; 中川 和彦; 山本 信之
    肺癌 61 6 498 - 498 (NPO)日本肺癌学会 2021年10月
  • 高森 信吉; 赤松 弘朗; 寺岡 俊輔; 林 秀敏; 三浦 理; 秦 明登; 戸井 之裕; 白石 祥理; 豆鞘 伸昭; 佐藤 悠城; 古屋 直樹; 洪 泰浩; 山本 信之; 中川 和彦
    肺癌 61 6 627 - 627 (NPO)日本肺癌学会 2021年10月
  • 米阪 仁雄; 谷崎 潤子; 前西 修; 川上 尚人; 田中 薫; 林 秀敏; 坂井 和子; 後藤 大輝; 小林 真季; 吉本 龍人; 大塚 絵里; 沖田 弘明; 舟橋 賢記; 橋本 悠里; 廣谷 賢志; 明松 隆志; 西尾 和人; 中川 和彦
    肺癌 61 6 623 - 623 2021年10月
  • 鈴木 慎一郎; 米阪 仁雄; 寺村 岳士; 竹原 俊幸; 加藤 了資; 酒井 瞳; 原谷 浩司; 谷崎 潤子; 川上 尚人; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 61 6 629 - 629 (NPO)日本肺癌学会 2021年10月
  • 福田 泰; 林 秀敏; 菅原 俊一; 佐藤 悠城; 三浦 理; 大田 恵一; 小澤 雄一; 原 聡志; 谷崎 潤子; 東 公一; 大森 翔太; 立原 素子; 西野 和美; 別所 昭宏; 原谷 浩司; 坂井 和子; 西尾 和人; 山本 信之; 中川 和彦
    肺癌 61 6 677 - 677 (NPO)日本肺癌学会 2021年10月
  • 上村 剛大; 釼持 広知; 福田 悟史; 宮脇 太一; 羽間 大祐; 神戸 寛史; 寺岡 俊輔; 松尾 規和; 山口 哲平; 益田 武; 横山 俊秀; 大坪 孝平; 橋本 大哉; 山本 信之; 中川 和彦
    肺癌 61 6 654 - 654 (NPO)日本肺癌学会 2021年10月
  • 金村 宙昌; 林 秀敏; 大谷 知之; 冨田 秀太; 鈴木 慎一郎; 原谷 浩司; 谷崎 潤子; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 西尾 和人; 伊藤 彰彦; 中川 和彦
    肺癌 61 6 499 - 499 (NPO)日本肺癌学会 2021年10月
  • ベンダムスチン塩酸塩経口剤(SyB C-0501)の進行性固形がん患者に対する第1相臨床試験
    武田 真幸; 中川 和彦; 林 秀敏; 岩朝 勤; 川上 尚人; 渡邉 諭美; 山本 昇; 米盛 勧; 小山 隆文; 佐藤 潤; 田村 研治; 菊池 圭一; 赤池 健一郎; 竹田 志保; 清水 俊雄
    日本癌治療学会学術集会抄録集 59回 O13 - 5 2021年10月
  • 小細胞癌のICI(Treatment of SCLC) 再発小細胞肺がんに対するペムブロリズマブ+アムルビシンの多施設共同第II相試験
    寺岡 俊輔; 赤松 弘朗; 林 秀敏; 藤本 大智; 早田 敦志; 原谷 浩司; 小澤 雄一; 吉田 健司; 岩朝 勤; 下川 敏雄; 富井 啓介; 中川 和彦; 山本 信之
    肺癌 61 6 498 - 498 (NPO)日本肺癌学会 2021年10月
  • ICIが有効であった進行・再発非小細胞肺がんに対するニボルマブの第II相試験(WJOG9616L)
    高森 信吉; 赤松 弘朗; 寺岡 俊輔; 林 秀敏; 三浦 理; 秦 明登; 戸井 之裕; 白石 祥理; 豆鞘 伸昭; 佐藤 悠城; 古屋 直樹; 洪 泰浩; 山本 信之; 中川 和彦
    肺癌 61 6 627 - 627 (NPO)日本肺癌学会 2021年10月
  • 小細胞癌のICI(Treatment of SCLC) 進展型小細胞肺癌における腫瘍微小免疫環境の網羅的解析
    金村 宙昌; 林 秀敏; 大谷 知之; 冨田 秀太; 鈴木 慎一郎; 原谷 浩司; 谷崎 潤子; 津谷 あす香; 福田 泰; 金田 裕靖; 工藤 慶太; 高濱 隆幸; 今井 亮介; 千葉 康敬; 西尾 和人; 伊藤 彰彦; 中川 和彦
    肺癌 61 6 499 - 499 (NPO)日本肺癌学会 2021年10月
  • オンコマイン検査成功率改善に向けた検査内製化と検査工程の見直し
    白石 直樹; 田中 薫; 高濱 隆幸; 鈴木 慎一郎; 金村 宙昌; 磯本 晃佑; 林 秀敏; 米阪 仁雄; 中川 和彦
    肺癌 61 6 649 - 649 (NPO)日本肺癌学会 2021年10月
  • 遺伝子異常未検出の非小細胞肺癌を対象とするGuardant360による遺伝子解析の前向き観察研究 WJOG13620L
    上村 剛大; 釼持 広知; 福田 悟史; 宮脇 太一; 羽間 大祐; 神戸 寛史; 寺岡 俊輔; 松尾 規和; 山口 哲平; 益田 武; 横山 俊秀; 大坪 孝平; 橋本 大哉; 山本 信之; 中川 和彦
    肺癌 61 6 654 - 654 (NPO)日本肺癌学会 2021年10月
  • EGFR変異陽性術後NSCLCに対するシスプラチン+ビノレルビンとゲフィチニブの第3相比較試験(WJOG6410L)
    岩本 康男; 多田 弘人; 光冨 徹哉; 杉尾 賢二; 坪井 正博; 岡本 勇; 坂倉 範昭; 菅原 俊一; 安宅 信二; 高橋 利明; 林 秀敏; 岡田 守人; 井野川 英利; 吉岡 弘鎮; 高橋 和久; 東山 聖彦; 吉野 一郎; 中川 和彦
    肺癌 61 6 594 - 594 (NPO)日本肺癌学会 2021年10月
  • 日本肺癌学会による既存肺がん臨床試験データの統合とデータベース化,及びその共有と再利用体制の構築
    小澤 雄一; 伊藤 健太郎; 釼持 広知; 宿谷 威仁; 林 秀敏; 藤本 大智; 大江 裕一郎; 岡本 浩明; 木浦 勝行; 菅原 俊一; 中川 和彦; 仁保 誠治; 吉野 一郎; 弦間 昭彦; 山本 信之
    肺癌 61 6 662 - 662 (NPO)日本肺癌学会 2021年10月
  • Hiroaki Akamatsu; Haruyasu Murakami; Hideyuki Harada; Junichi Shimizu; Hidetoshi Hayashi; Haruko Daga; Yoshikazu Hasegawa; Young Hak Kim; Terufumi Kato; Shoji Tokunaga; Yasumasa Nishimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 10 1745 - 1752 2021年10月 
    INTRODUCTION: About 10% of patients with locally advanced NSCLC (LA-NSCLC) harbor EGFR mutation and recent reports suggested the declined benefit with an immune checkpoint inhibitor in this population. The attempt that introduces EGFR tyrosine kinase inhibitor into the treatment of LA-NSCLC with EGFR mutation has been warranted. METHODS: Chemotherapy-naive patients with unresectable LA-NSCLC with sensitive EGFR mutation (exon 19 deletion or exon 21 L858R point mutation) were enrolled. Patients were treated with gefitinib (250 mg/d for 2 y) plus concurrent thoracic radiotherapy (64 Gy/32 fractions). The primary end point was progression-free survival (PFS) at 2 years (trial identifier, UMIN000008366). RESULTS: Between August 2012 and November 2017, a total of 28 patients were enrolled and 27 were eligible. The median age was 67 years (range: 45-74); never/current or former smoker in 15/12 patients, respectively; Eastern Cooperative Oncology Group performance status of 0/1 in 19/8; EGFR exon 19 deletion/exon 21 L858R in 13/14; and c-stage IIIA/IIIB in 14/13. The PFS rate at 2 years by independent review was 29.6% (one-sided 95% confidence interval [CI]: 17.6%-). The overall response rate was 81.5% (95% CI: 63.3%-91.3%), median PFS was 18.6 months (95% CI: 12.0-24.5 mo), and median overall survival was 61.1 months (95% CI: 38.1 mo-not reached). Approximately half of the patients exhibited solitary brain metastasis as their first site of relapse. Adverse events greater than or equal to grade 3 were fatigue, skin reaction, and appetite loss (3.7% each). CONCLUSIONS: This prospective study revealed the tolerability and the possible efficacy of gefitinib plus concurrent thoracic radiotherapy in patients with LA-NSCLC having EGFR mutation.
  • Kazuhiko Nakagawa; Ernest Nadal; Edward B Garon; Makoto Nishio; Takashi Seto; Nobuyuki Yamamoto; Keunchil Park; Jin-Yuan Shih; Luis Paz-Ares; Bente Frimodt-Moller; Annamaria H Zimmermann; Sameera Wijayawardana; Carla Visseren-Grul; Martin Reck
    Clinical cancer research : an official journal of the American Association for Cancer Research 27 19 5258 - 5271 2021年10月 
    PURPOSE: In EGFR-mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. PATIENTS AND METHODS: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. RESULTS: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. CONCLUSIONS: RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types.
  • EGFR阻害剤によるHER3の発現亢進及び抗HER3パトリツマブデルクステカンの抗腫瘍効果の増強
    米阪 仁雄; 谷崎 潤子; 前西 修; 坂井 和子; 後藤 大輝; 小林 真季; 吉本 龍人; 大塚 絵里; 沖田 弘明; 船橋 賢記; 橋本 悠里; 廣谷 賢志; 明松 隆志; 西尾 和人; 中川 和彦
    日本癌学会総会記事 80回 [E14 - 4] 2021年09月
  • Masafumi Yamaguchi; Hirohito Tada; Tetsuya Mitsudomi; Takashi Seto; Kohei Yokoi; Nobuyuki Katakami; Kazuhiko Nakagawa; Makoto Oda; Mitsunori Ohta; Toshiyuki Sawa; Motohiro Yamashita; Norihiko Iked; Hideo Saka; Masahiko Higashiyama; Hiroaki Nomori; Hiroshi Semba; Shunichi Negoro; Yasutaka Chiba; Mototsugu Shimokawa; Masahiro Fukuoka; Yoichi Nakanishi
    International journal of clinical oncology 26 12 2216 - 2223 2021年08月 
    BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.
  • Hiroyuki Yamaguchi; Kazushige Wakuda; Minoru Fukuda; Hirotsugu Kenmotsu; Hiroshi Mukae; Kentaro Ito; Kenji Chibana; Kohji Inoue; Satoru Miura; Kentaro Tanaka; Noriyuki Ebi; Takayuki Suetsugu; Taishi Harada; Keisuke Kirita; Toshihide Yokoyama; Yuki Nakatani; Kenichi Yoshimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Kenji Sugio
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 12 2121 - 2132 2021年08月 
    OBJECTIVES: Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating EGFR mutation-positive NSCLC. Nevertheless, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later owing to the effects of radiotherapy (RT). This study aimed to evaluate the efficacy of osimertinib against RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. METHODS: The OCEAN study was a two-cohort trial, involving 66 patients (T790M cohort [n = 40] and first-line cohort [n = 26]) with RT-naive CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary end point was brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with analysis of drug concentrations and plasma circulating tumor DNA. RESULTS: The median age of the patients was 69 years, and 30% of them were males. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90% confidence interval: 54.3%-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the Response Evaluation Criteria in Solid Tumors criteria was 70.0% (n = 20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median = 31.8 versus 8.3 mo; log-rank p = 0.032). The treatment-related pneumonitis was observed in four patients (10%). On or after day 22, the median trough blood and cerebrospinal fluid concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to cerebrospinal fluid penetration rates of osimertinib and AZ5104 were 0.79% and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of the patients before treatment, 11% and 3% of the patients on day 22, and 39% and 22% of the patients at the detection of progressive disease, respectively. CONCLUSIONS: This study evaluated the efficacy of osimertinib against RT-naive CNS metastasis from T790M-positive NSCLC. The primary end point was met, and the results revealed the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
  • Shinichiro Suzuki; Kimio Yonesaka; Takeshi Teramura; Toshiyuki Takehara; Ryoji Kato; Hitomi Sakai; Koji Haratani; Junko Tanizaki; Hisato Kawakami; Hidetoshi Hayashi; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 27 20 5697 - 5707 2021年08月 
    PURPOSE: Treatment with KRAS G12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRAS G12C NSCLC cells. EXPERIMENTAL DESIGN: Clones of sotorasib-sensitive KRAS G12C NSCLC H23 cells exposed to different concentrations of sotorasib were examined using whole-genomic transcriptome analysis, multiple receptor kinase phosphorylation analysis, and gene copy number evaluation. The underlying mechanisms of resistance were investigated using immunological examination, and a treatment aimed at overcoming resistance was tested in vitro and in vivo Results: Unbiased screening detected subclonal evolution of MET amplification in KRAS G12C NSCLC cells that had developed resistance to sotorasib in vitro MET knockdown using siRNA restored susceptibility to sotorasib in these resistant cells. MET activation by its amplification reinforced RAS cycling from its inactive form to its active form. In addition to RAS-mediated MEK-ERK induction, MET induced AKT activation independently of RAS. Crizotinib, a MET inhibitor, restored sensitivity to sotorasib by eliminating RAS-MEK-ERK as well as AKT signaling. MET/KRAS G12C dual inhibition led to tumor shrinkage in sotorasib-resistant xenograft mice. CONCLUSIONS: MET amplification leads to the development of resistance to KRAS G12C inhibitors in NSCLC. Dual blockade of MET and KRAS G12C could be a treatment option for MET amplified, KRAS G12C-mutated NSCLC.
  • Oiso N; Yanagihara S; Nakagawa K; Kawada A
    The Journal of Dermatology 48 8 e390 - e392 2021年08月 [査読有り]
  • Toshiharu Sakurai; Marco A De Velasco; Kazuko Sakai; Tomoyuki Nagai; Hiroki Nishiyama; Kentaro Hashimoto; Hirotsugu Uemura; Hisato Kawakami; Kazuhiko Nakagawa; Hiroyuki Ogata; Kazuto Nishio; Masatoshi Kudo
    Molecular oncology 2021年07月 
    Immune checkpoint inhibitors (ICIs) are widely used to treat various malignancies. Although the gut microbiome is known to influence the efficacy of ICIs on epithelial tumors, the functional interactions between gut taxa and colonic mucosa remain poorly understood. Here we performed transcriptomic profiling and 16S rRNA sequencing to investigate the relationships between mucosal gene expression and microbial composition with ICI responses and gastrointestinal immune-related adverse events (GI irAEs). In responders, genes related to DNA repair and cell cycle signatures were enriched in responders whereas signatures related to innate immune response, NFAT and IFN-γ signaling pathways were enriched in nonresponders. Gut microbial composition revealed an association between moderate GI irAE and favorable response to ICI therapy. Favorable therapeutic responses to ICI and GI irAE treatments were associated with taxa classified as Enterobacteriaceae and were related to ribonucleoprotein complex biogenesis, cytokine-mediated signaling pathway, tRNA metabolic process, and ribonucleoprotein complex assembly in the colon. These findings open new perspectives for improving the efficacy and safety of cancer immunotherapy.
  • Masaya Yotsukura; Noriko Motoi; Akihiko Yoshida; Yukihiro Yoshida; Kazuo Nakagawa; Shun-Ichi Watanabe
    Pathology international 2021年07月 
    We describe a rare case of malignant pleural mesothelioma (MPM) that developed squamous differentiation. MPM can present various patterns of histology, but squamous differentiation has not been reported in any surgically resected cases to date. The patient was a 50-year-old female without smoking habit who had right MPM and underwent pleurectomy/decortication after chemotherapy. Pathological examination of the surgical specimen found that the MPM contained squamous cancer cells with apparent keratinization close to the tubulopapillary epithelioid tumor cells. Squamous differentiation was recognized close to the mesothelial proliferation, and the topographical origin of the tumor could not be recognized in the lung. The tubulopapillary tumor cells were positive for cytokeratin 5/6, Wilms tumor-1, and calretinin, and negative for thyroid transcription factor-1 (TTF-1), claudin-4, and p40. Squamous cells were positive for cytokeratin 5/6 and p40, and negative for Wilms tumor-1, calretinin, and TTF-1. Loss of BRCA1 associated protein-1 (BAP1) was observed in both the tubulopapillary and squamous tumor cells. Based on the loss of BAP1 and no history of smoking, we diagnosed this case as a rare differentiation of biphasic-type MPM into squamous cell carcinoma.
  • Esuteru Hirokawa; Satomi Watanabe; Kazuko Sakai; Masayuki Takeda; Chihiro Sato; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    Thoracic Cancer 12 16 2283 - 2287 2021年07月 
    Epidermal growth factor receptor (EGFR) kinase domain duplication (KDD) has been identified as an oncogenic driver in 0.05% to 0.14% of non-small cell lung cancer (NSCLC) patients. However, little is known of the efficacy of EGFR tyrosine kinase inhibitors (TKIs) for such patients. Here, we report the case of a 45-year-old Japanese woman with NSCLC positive for EGFR-KDD (duplication of exons 18-25) who developed carcinomatous meningitis and showed a marked response to the EGFR-TKIs erlotinib and osimertinib. As far as we are aware, this is the first report of EGFR-TKI efficacy for carcinomatous meningitis in a NSCLC patient harboring EGFR-KDD.
  • Yuji Muraoka; Yukihiro Yoshida; Kazuo Nakagawa; Kimiteru Ito; Hirokazu Watanabe; Tetsuo Narita; Shun-Ichi Watanabe; Masaya Yotsukura; Noriko Motoi; Yasushi Yatabe
    The Journal of thoracic and cardiovascular surgery 2021年07月 
    OBJECTIVE: This retrospective study examined whether adding the maximum standardized uptake value of a primary tumor to the consolidation-to-tumor ratio from a high-resolution computed tomography scan can improve the predictive accuracy for pathological noninvasive lung cancer and lead to better patient selection for sublobar resection. METHODS: We included 926 patients with clinical stage IA non-small cell lung cancer. Pathological noninvasive cancer (n = 515) was defined as any case without lymphatic invasion, vascular invasion, or lymph node metastasis. The prediction accuracies of maximum standardized uptake value and consolidation-to-tumor ratio were evaluated using receiver operating characteristic curves and area under the curve. RESULTS: For consolidation-to-tumor ratio or maximum standardized uptake value alone, the area under the curves were 0.733 (95% confidence interval, 0.708-0.758) and 0.842 (95% confidence interval, 0.816-0.866), respectively. When the consolidation-to-tumor ratio and maximum standardized uptake value were combined, the area under the curve was 0.854 (95% confidence interval, 0.829-0.876). However, to obtain a predictive specificity of 97%, sensitivity needed to be 42.5% for the consolidation-to-tumor ratio, 38.3% for the maximum standardized uptake value, and 45.0% for these 2 in combination. CONCLUSIONS: Our results suggest that despite the high area under the curve for maximum standardized uptake value, caution is needed when using maximum standardized uptake value to select candidates for sublobar resection. We found that a low maximum standardized uptake value did not mean the tumor was a pathological noninvasive lung cancer. Therefore, using consolidation-to-tumor ratios from high-resolution computed tomography to decide whether sublobar resection is appropriate for patients with clinical stage IA non-small cell lung cancer is better than using maximum standardized uptake value when setting specificity to a conservative 97% for predicting pathological noninvasive lung cancer.
  • Hiroaki Akamatsu; Shunsuke Teraoka; Hidetoshi Hayashi; Daichi Fujimoto; Atsushi Hayata; Koji Haratani; Yuichi Ozawa; Takeshi Yoshida; Tsutomu Iwasa; Toshio Shimokawa; Keisuke Tomii; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    JTO clinical and research reports 2 7 100184 - 100184 2021年07月 
    Introduction: In patients with relapsed SCLC, amrubicin (AMR) is the current standard treatment in Japan. Nevertheless, its efficacy is not satisfactory and prognosis is poor. Preclinical study suggested that anthracycline agent might induce immunogenic cell death and work synergistically with immune checkpoint inhibitors. Methods: Patients with relapsed SCLC who relapsed after completion of platinum-containing regimen were registered. Patients were treated with pembrolizumab (200 mg, flat dose on d 1, every 3 wk for 2 y) plus AMR (40 mg/m2 on d 1-3, every 3 wk until progression). Primary end point was overall response rate (ORR). Secondary end points consisted of progression-free survival (PFS), overall survival, and safety. On the basis of the hypothesis that this treatment will improve ORR from 20% to 40% (0.1 of one-sided α and power of 0.8), 25 patients are required (trial identifier: NCT03253068). Results: Between November 2017 and October 2019, a total of 25 patients were enrolled. Most participants (88%) relapsed within 90 days after platinum-containing therapy and all patients were immune checkpoint inhibitor-naive. ORR, the primary end point, was 52.0% (95% confidence interval [CI]: 31.3%-72.2%). Median PFS was 4.0 months (95% CI: 2.8-7.0 mo), and PFS rate at 1 year was 14.4%. Median overall survival was 10.6 months (95% CI: 7.3-21.3 mo). Common adverse events greater than or equal to grade 3 were neutropenia (64%), leukopenia (40%), and febrile neutropenia (16%). No treatment-related deaths occurred. Conclusions: Among patients with relapsed SCLC, pembrolizumab plus AMR was effective and tolerable.
  • Ryoji Kato; Hidetoshi Hayashi; Kazuko Sakai; Shinichiro Suzuki; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Yoshikane Nonagase; Kaoru Tanaka; Takeshi Yoshida; Masayuki Takeda; Kimio Yonesaka; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    International Journal of Clinical Oncology 26 9 1628 - 1639 2021年06月 
    BACKGROUND: We here applied cancer personalized profiling by deep sequencing (CAPP-seq) to analysis of circulating tumor DNA (ctDNA) to identify resistance mechanisms in osimertinib-treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC). METHODS: The study included patients with EGFR activating mutation-positive advanced NSCLC who were positive for T790M in tumor tissue or plasma after previous treatment with an EGFR tyrosine kinase inhibitor, who received osimertinib at Kindai University Hospital between August 2014 and September 2017, and for whom plasma collected after progression on osimertinib was available. Clinical data were extracted from medical records. Patients with innate resistance to osimertinib were defined as those whose best response was progressive disease or stable disease for < 6 months, whereas patients with a complete or partial response or stable disease for > 6 months were considered as having acquired resistance. RESULTS: We performed CAPP-seq for 20 patients at progression on osimertinib. Distinct patterns of genomic alterations were apparent in patients with innate versus acquired resistance. Mutations in PIK3CA, KRAS, or BRAF and copy number gain for EGFR, ERBB2, or MET were more common in patients with innate resistance than in those with acquired resistance. In addition, one patient who underwent a repeat biopsy was found to harbor the C797S mutation of EGFR after disease progression during osimertinib rechallenge, with this mutation not having been detected at the time of initial progression on osimertinib. CONCLUSIONS: CAPP-seq analysis of ctDNA was able to identify potentially targetable genetic alterations in patients with osimertinib resistance.
  • 胸腔原発巨大Ewing肉腫の1切除例
    岡内 義隆; 須田 健一; 宗 淳一; 西野 将矢; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉; 田中 薫; 中川 和彦
    肺癌 61 3 238 - 238 (NPO)日本肺癌学会 2021年06月
  • Timothy A Yap; Kazuhiko Nakagawa; Nobukazu Fujimoto; Kozo Kuribayashi; Tormod Kyrre Guren; Luana Calabrò; Ronnie Shapira-Frommer; Bo Gao; Steven Kao; Ignacio Matos; David Planchard; Arkendu Chatterjee; Fan Jin; Kevin Norwood; Hedy L Kindler
    The Lancet. Respiratory medicine 9 6 613 - 621 2021年06月 
    BACKGROUND: Malignant pleural mesothelioma (MPM) has few treatment options. Pembrolizumab showed preliminary clinical benefit in programmed death ligand 1 (PD-L1)-positive MPM. We evaluated the efficacy and safety of pembrolizumab monotherapy in patients with previously treated MPM irrespective of PD-L1 status in the KEYNOTE-158 study. METHODS: The ongoing open-label, multicohort, single-arm, phase 2 KEYNOTE-158 study enrolled eligible adults (≥18 years) with MPM who had progression on or intolerance to standard therapy, Eastern Cooperative Oncology Group performance status 0-1, and biomarker-evaluable tumour samples. Individuals were enrolled from 35 academic facilities and community-based institutions across 14 countries in Australia, North America, Europe, and Asia. Participants received pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. The primary efficacy endpoint was objective response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on radiological imaging every 9 weeks for the first year of the study and every 12 weeks thereafter and assessed by independent central review. Efficacy and safety were analysed in all patients who received at least one dose of pembrolizumab. This trial is registered with ClinicalTrials.gov, NCT02628067. FINDINGS: Patients were enrolled in the MPM cohort between Feb 9, 2016, and Aug 16, 2016. As of June 27, 2019, 118 patients had been enrolled and received at least one dose of pembrolizumab. Ten (8% [95% CI 4-15]) patients had an objective response. Median duration of objective response was 14·3 months (range 4·0 to 33·9+), and 60% of objective responses were ongoing at 12 months. Objective responses were observed in six (8%) of 77 patients with PD-L1-positive MPM (median response duration 17·7 months [range 5·8 to 33·9+]) and four (13%) of 31 patients with PD-L1-negative MPM (10·2 months [4·0-16·6]). Median overall survival was 10·0 months (95% CI 7·6-13·4) and median progression-free survival was 2·1 months (2·1-3·9). Treatment-related adverse events occurred in 82 (69%) of 118 patients and serious adverse events that were considered to be treatment-related occurred in 14 (12%) of 118 patients. 19 (16%) patients had grade 3-4 treatment-related events, and most common of these were colitis (three patients), hyponatraemia (three), and pneumonitis (two). One patient died from treatment-related apnoea. By the end of the trial, 113 (96%) patients had discontinued pembrolizumab and progressive disease was the most common reason for discontinuation. INTERPRETATION: Pembrolizumab showed durable antitumour activity and manageable toxicity in patients with advanced MPM, regardless of PD-L1 status. Our data support the programmed death 1 (PD-1) and PD-L1 pathway as a potential therapeutic target in some patients with previously treated mesothelioma but biomarkers that can effectively identify such patients are yet to be elucidated. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA.
  • Kazuhiko Nakagawa; Takashi Kijima; Morihito Okada; Masahiro Morise; Motoyasu Kato; Katsuya Hirano; Nobukazu Fujimoto; Mitsuhiro Takenoyama; Hiroshi Yokouchi; Yuichiro Ohe; Toyoaki Hida; Keisuke Aoe; Takumi Kishimoto; Masato Hirokawa; Hironori Matsuki; Yutaro Kaneko; Taketo Yamada; Chikao Morimoto; Masayuki Takeda
    JTO clinical and research reports 2 6 100178 - 100178 2021年06月 
    Introduction: YS110, a humanized monoclonal antibody with a high affinity to CD26, exhibited promising antitumor activity and was generally well-tolerated in the phase 1 part of a phase 1 and 2 Japanese trial in patients with malignant pleural mesothelioma (MPM). Here we report the results of the phase 2 part of the study. Methods: The patients included were aged 20 years and older, had histologically confirmed MPM, were refractory to or intolerant of existing antineoplastic agents, and were not candidates for standard therapy. YS110 6 mg/kg, determined in the phase 1 dose-determination part, was given in 6-weekly cycles (5 × once-weekly infusions, followed by a 1-wk rest). Results: The study included 31 patients (median age = 68 y, 90.3% men); 64.5% had stage IV MPM, 90.3% had greater than or equal to 20% CD26 expression in tumor tissue, and 38.7% (12 patients) had previously received nivolumab. The 6-month disease control rate was 3.2%. The best overall response was partial response in one patient and stable disease in 14 patients. The median progression-free survival was 2.8 months (both in patients who had and had not previously received nivolumab-groups A and B, respectively). Respective progression-free survival rates at 6 months were 9.1% and 31.6% in groups A and B. The median overall survival was 9.7 months. A total of 30 patients (96.8%) had at least one adverse event. Common treatment-related adverse events were infusion-related reaction (16.1%), hiccups (9.7%), and interstitial lung disease (9.7%). There were no treatment-related deaths. Conclusions: The 6-month disease control rate did not exceed the predefined threshold, but YS110 revealed modest efficacy in response rate as salvage therapy in difficult-to-treat patients with MPM. YS110 was generally well tolerated.
  • Kazuto Nishio; Takashi Seto; Makoto Nishio; Martin Reck; Edward B Garon; Kazuko Sakai; Koichi Goto; Terufumi Kato; Yoichi Nakanishi; Toshiaki Takahashi; Nobuyuki Yamamoto; Katsuyuki Kiura; Yuichiro Ohe; Tomohide Tamura; Carla Visseren-Grul; Bente Frimodt-Moller; Rebecca R Hozak; Sameera R Wijayawardana; Annamaria Zimmermann; Gosuke Homma; Sotaro Enatsu; Kazuhiko Nakagawa
    JTO clinical and research reports 2 6 100171 - 100171 2021年06月 
    Introduction: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46-0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. Methods: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. Results: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431-0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424-1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317-0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). Conclusions: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.
  • がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験(Relief Study)
    松岡 弘道; 鶴谷 純司; 千葉 康敬; 藤田 至彦; 酒井 清裕; 吉田 健史; 大武 陽一; 名倉 美樹; 小山 敦子; 西尾 和人; 中川 和彦
    Palliative Care Research 16 Suppl. S217 - S217 (NPO)日本緩和医療学会 2021年06月
  • Hitomi Sakai; Hisato Kawakami; Takeshi Teramura; Yuta Onodera; Elizabeth Somers; Keiji Furuuchi; Toshimitsu Uenaka; Ryoji Kato; Kazuhiko Nakagawa
    Clinical and translational medicine 11 6 e454  2021年06月 
    BACKGROUND: The main function of folate receptor α (FOLRα) has been considered to mediate intracellular folate uptake and induce tumor cell proliferation. Given the broad spectrum of expression among malignant tumors, including gastric cancer (GC) but not in normal tissue, FOLRα represents an attractive target for tumor-selective drug delivery. However, the efficacy of anti-FOLRα monoclonal antibodies (mAbs) has not been proved so far, with the reason for this failure remaining unclear, raising the need for a better understanding of FOLRα function. METHODS: The distribution of FOLRα in GC cells was evaluated by immunohistochemistry. The impacts of FOLRα expression on the survival of GC patients and GC cell lines were examined with the Gene Expression Omnibus database and by siRNA of FOLRα. RNA-sequencing and Microarray analysis was conducted to identify the function of FOLRα. Proteins that interact with FOLRα were identified with shotgun LC-MS/MS. The antitumor efficacy of the anti-FOLRα mAb farletuzumab as well as the antibody-drug conjugate (ADC) consists of the farletuzumab and the tublin-depolymerizing agent eribulin (MORAb-202) was evaluated both in vitro and in vivo. RESULTS: FOLRα was detected both at the cell membrane and in the cytoplasm. Shorter overall survival was associated with FOLRα expression in GC patients, whereas reduction of FOLRα attenuated cell proliferation without inducing cell death in GC cell lines. Transcriptomic and proteomic examinations revealed that the FOLRα-expressing cancer cells possess a mechanism of chemotherapy resistance supported by MDM2, and FOLRα indirectly regulates it through a chaperone protein prohibitin2 (PHB2). Although reduction of FOLRα brought about vulnerability for oxaliplatin by diminishing MDM2 expression, farletuzumab did not suppress the MDM2-mediated chemoresistance and cell proliferation in GC cells. On the other hand, MORAb-202 showed significant antitumor efficacy. CONCLUSIONS: The ADC could be a more reasonable choice than mAb as a targeting agent for the FOLRα-expressing tumor.
  • がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験(Relief Study)
    松岡 弘道; 鶴谷 純司; 千葉 康敬; 藤田 至彦; 酒井 清裕; 吉田 健史; 大武 陽一; 名倉 美樹; 小山 敦子; 西尾 和人; 中川 和彦
    Palliative Care Research 16 Suppl. S217 - S217 (NPO)日本緩和医療学会 2021年06月
  • Osamu Nishiyama; Shigeki Shimizu; Koji Haratani; Kosuke Isomoto; Junko Tanizaki; Hidetoshi Hayashi; Ryo Yamazaki; Takashi Oomori; Yusaku Nishikawa; Akiko Sano; Kazuhiko Nakagawa; Yuji Tohda
    BMC pulmonary medicine 21 1 155 - 155 2021年05月 
    BACKGROUND: The utility of bronchoscopy for patients with suspected immune checkpoint inhibitor (ICI)-related pneumonitis is currently debatable. The purpose of this study was to examine the findings of bronchoalveolar lavage (BAL) analysis and transbronchial lung biopsy (TBLB) in non-small cell lung cancer (NSCLC) patients with ICI-related pneumonitis, and to elucidate the clinical significance of bronchoscopy for this health condition. PATIENTS AND METHODS: Consecutive NSCLC patients treated with ICIs, diagnosed with ICI-related pneumonitis after undergoing bronchoscopy between October 2015 and March 2019 were retrospectively screened. Findings of BAL fluid analysis and/or TBLB specimen histology were reviewed. RESULTS: Twelve patients underwent bronchoscopy for the diagnosis of ICI-related pneumonitis, ten of whom underwent BAL. An increase in the proportion of lymphocytes higher than 20% was observed in all ten patients. An increase in the proportion of neutrophils (> 10%) and eosinophils (> 10%) was observed in two and one patient, respectively. TBLB specimens were analyzed for eight patients. Major histologic findings included alveolitis in seven (87.5%) and organizing pneumonia (OP) in five (62.5%) patients. Other findings included acute lung injury and fibrosis. All twelve patients demonstrated favorable outcomes. CONCLUSION: A major characteristic of BAL analysis in ICI-related pneumonitis with NSCLC was an increased proportion of lymphocytes. The histologic features of lung tissue included alveolitis and/or OP. Acute lung injury and fibrosis were observed. Although the necessity of bronchoscopy should be determined on a case-by-case basis, it is necessary to assess these parameters when proper differential diagnosis is needed.
  • Masaya Yotsukura; Hisao Asamura; Noriko Motoi; Jumpei Kashima; Yukihiro Yoshida; Kazuo Nakagawa; Kouya Shiraishi; Takashi Kohno; Yasushi Yatabe; Shun-Ichi Watanabe
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 8 1312 - 1320 2021年04月 
    INTRODUCTION: The WHO classification of lung tumors defines adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) as cancers with no or limited histologic invasive components. The probability of patients with AIS or MIA being recurrence free for 5 years postoperatively has been found to be 100%. This study aimed to analyze the prognosis of patients with AIS or MIA after more than 5 postoperative years. METHODS: We reviewed the pathologic findings of 4768 patients who underwent resection for lung cancer between 1998 and 2010. Of these, 524 patients with curative resection for AIS (207 cases, 39.5%) and MIA (317 cases, 60.5%) were included. Postoperative recurrence, survival, and development of secondary primary lung cancer (SPLC) were analyzed. RESULTS: Of the included patients, 342 (65.3%) were of female sex, 333 (63.5%) were nonsmokers, and 229 (43.7%) underwent sublobar resection. Average pathologic total tumor diameter was 15.2 plus or minus 5.5 mm. Median postoperative follow-up period was 100 months (range: 1-237). No recurrence of lung cancer was observed for either AIS or MIA cases. Estimated 10-year postoperative disease-specific survival rates were 100% and 100% (p = 0.72), and overall survival rates were 95.3% and 97.8% (p = 0.94) for AIS and MIA cases, respectively. Estimated incidence rates of metachronous SPLC at 10 years after surgery were 5.6% and 7.7% for AIS and MIA, respectively (p = 0.45), and these were not correlated with the EGFR mutation status. CONCLUSIONS: Although the development of metachronous SPLC should be noted, the risk of recurrence is quite low at more than 5 years after resection of AIS and MIA. This finding strengthens the clinical value of distinguishing AIS and MIA from other adenocarcinomas of the lung.
  • Akira Hamada; Junichi Soh; Akito Hata; Kiyoshi Nakamatsu; Mototsugu Shimokawa; Yasushi Yatabe; Hiroyuki Oizumi; Masahiro Tsuboi; Hidehito Horinouchi; Ichiro Yoshino; Masayuki Tanahashi; Shinichi Toyooka; Morihito Okada; Hiroyasu Yokomise; Motohiro Yamashita; Yasumasa Nishimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Tetsuya Mitsudomi
    Clinical lung cancer S1525-7304 21 596 - 600 2021年04月 [査読有り]
     
    INTRODUCTION: We describe our ongoing multicenter, prospective, single-arm, phase II trial of neoadjuvant concurrent chemo-immuno-radiation therapy followed by surgical resection and adjuvant immunotherapy for resectable stage IIIA-B (discrete N2) non-small-cell lung cancer (NSCLC) (registered at the Japan Pharmaceutical Information Center, Clinical Trials Information-195069). PATIENTS AND METHODS: Key inclusion criteria include (1) clinical T1-3/T4 (tumor size) N2 stage IIIA-B NSCLC, and (2) pathologically confirmed N2 without extranodal invasion (based on diagnostic imaging). Patients will receive concurrent chemoradiotherapy (carboplatin [area under the curve = 2] and paclitaxel [40 mg/m2] on days 1, 8, 15, 22, and 29, with involved-field radiation therapy [RT] [dose 50 Gy] on days 1-25) and neoadjuvant immunotherapy (durvalumab [1500 mg] on days 1 and 29). Surgical resection with mediastinal lymph node dissection is performed within 2 to 6 weeks after RT. Consolidation therapy with durvalumab is administered for up to 1 year after surgery. The primary endpoint is major pathologic response (MPR) (≤10% residual viable tumor) according to the central pathological assessment. Secondary endpoints are progression-free survival, overall survival, and safety. The sample size is planned to be 31 patients based on the exact binomial distribution with a 1-sided significance level of 5% and a power of 80%, and assuming a threshold MPR rate of 40% and an expected MPR rate of 65%. CONCLUSION: This trial will help establish a novel treatment strategy for resectable N2-positive NSCLC.
  • 中村 敦; 坂田 晋也; 大坪 孝平; 伊藤 健太郎; 寺岡 俊輔; 松本 直久; 白石 祥理; 原谷 浩司; 田宮 基裕; 池田 慧; 益田 武; 時任 高章; 立原 素子; 高濱 隆幸; 吉田 寿子; 山本 信之; 中川 和彦
    日本呼吸器学会誌 10 増刊 144 - 144 (一社)日本呼吸器学会 2021年04月
  • 中村 敦; 坂田 晋也; 大坪 孝平; 伊藤 健太郎; 寺岡 俊輔; 松本 直久; 白石 祥理; 原谷 浩司; 田宮 基裕; 池田 慧; 益田 武; 時任 高章; 立原 素子; 高濱 隆幸; 吉田 寿子; 山本 信之; 中川 和彦
    日本呼吸器学会誌 10 増刊 144 - 144 (一社)日本呼吸器学会 2021年04月
  • Masayuki Takeda; Takayuki Takahama; Kazuko Sakai; Shigeki Shimizu; Satomi Watanabe; Hisato Kawakami; Kaoru Tanaka; Chihiro Sato; Hidetoshi Hayashi; Yoshikane Nonagase; Kimio Yonesaka; Naoki Takegawa; Tatsuya Okuno; Takeshi Yoshida; Soichi Fumita; Shinichiro Suzuki; Koji Haratani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Hisashi Handa; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    The oncologist 26 4 e588-e596  2021年04月 
    BACKGROUND: Implementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors. MATERIALS AND METHODS: We performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel-which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)-to patients with advanced or recurrent solid tumors before its approval in Japan. RESULTS: A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21-126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher's exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death-ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy. CONCLUSION: The FoundationOne CDx assay was performed with formalin-fixed, paraffin-embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs. IMPLICATIONS FOR PRACTICE: This prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.
  • Yoshitaka Zenke; Masahiro Tsuboi; Yasutaka Chiba; Kayoko Tsujino; Miyako Satouchi; Kenji Sawa; Junichi Shimizu; Haruko Daga; Daichi Fujimoto; Masahide Mori; Takuya Aoki; Toshiyuki Sawa; Shota Omori; Hideo Saka; Yasuo Iwamoto; Motoyasu Okuno; Tomonori Hirashima; Kosuke Kashiwabara; Motoko Tachihara; Nobuyuki Ymamoto; Kazuhiko Nakagawa
    JAMA oncology 7 6 904 - 909 2021年03月 
    Importance: Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients with stage III non-small-cell lung cancer. Objective: To evaluate survival and late toxic effects 10 years after patients were treated with curative CRT. Design, Setting, and Participants: This multicenter, phase 3 West Japan Thoracic Oncology Group (WJTOG) 0105 randomized clinical trial was conducted between September 2001 and September 2005 in Japan. Patients with histologically or cytologically confirmed non-small-cell lung cancer with unresectable stage III disease were assessed for eligibility. Additional data were analyzed from January 2018 to December 2019. Interventions: A total of 440 eligible patients were randomly assigned to groups as follows: A (control), 4 cycles of mitomycin/vindesine/cisplatin plus thoracic radiotherapy (TRT) of 60 Gy; B, weekly irinotecan/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of irinotecan/carboplatin consolidation; or C, weekly paclitaxel/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of paclitaxel/carboplatin consolidation. Main Outcomes and Measures: The primary outcome was 10-year survival probability after CRT. The secondary outcome was late toxic effects that occurred more than 90 days after initiating CRT. Results: From September 2001 to September 2005, 440 patients (group A, n = 146 [33.2%; median (range) age, 63 (31-74) years; 18 women (12.3%)]; group B, n = 147 [33.4%; median (range) age, 63 (30-75) years; 22 women (15.0%)]; group C, n = 147 [33.4%; median (range) age, 63 (38-74) years; 19 women (12.9%)]) were enrolled. The median (range) follow-up was 11.9 (7.6-13.3) years. In groups A, B, and C, median (range) overall survival times were 20.5 (17.5-26.0), 19.8 (16.7-23.5), and 22.0 (18.7-26.2) months, respectively, and 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. There were no significant differences in overall survival among treatment groups. The 10-year progression-free survival probabilities were 8.5%, 6.5%, and 11.1% in groups A, B, and C, respectively. Grade 3 or 4 late toxic effect rates were 3.4% (heart, 0.7%; lung, 2.7%) in group A, and those only affecting the lung represented 3.4% and 4.1% in groups B and C, respectively. No other cases of late toxic effects (grades 3/4) were observed since the initial report. Conclusion and Relevance: In this 10-year follow-up of a phase 3 randomized clinical trial, group C achieved similar efficacy and toxic effect profiles as group A 10 years after initiating treatment. These results serve as a historical control for the long-term comparisons of outcomes of future clinical trials of CRT. Trial Registration: UMIN Clinical Trial Registry: UMIN000030811.
  • 赤松 弘朗; 戸井 之裕; 林 秀敏; 藤本 大智; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之
    和歌山医学 72 1 41 - 41 和歌山医学会 2021年03月
  • 【病気とくすり2021 基礎と実践Expert's Guide】病原微生物・悪性新生物とくすり 悪性腫瘍 肺癌
    磯本 晃佑; 武田 真幸; 中川 和彦
    薬局 72 4 2124 - 2128 (株)南山堂 2021年03月
  • Nobukazu Fujimoto; Morihito Okada; Takashi Kijima; Keisuke Aoe; Terufumi Kato; Kazuhiko Nakagawa; Yuichiro Takeda; Toyoaki Hida; Kuninobu Kanai; Jun Hirano; Yuichiro Ohe
    JTO clinical and research reports 2 3 100135 - 100135 2021年03月 
    Introduction: We examined the long-term efficacy and safety of nivolumab, a human monoclonal antibody that inhibits interactions between the programmed cell death protein-1 receptor and its ligands (programmed death-ligand 1 and programmed death-ligand 2), in Japanese patients with malignant pleural mesothelioma (MPM). Methods: Japanese patients with previously treated MPM (one or two regimens) were enrolled in a single-arm, phase 2 study and received nivolumab intravenously 240 mg every 2 weeks until progressive disease or unacceptable toxicity. The primary end point was the centrally assessed objective response rate. Other end points included overall survival (OS), progression-free survival (PFS), treatment-related adverse events, and patient-reported outcomes (Lung Cancer Symptom Scale for mesothelioma and EuroQOL visual analog scale). Patient enrollment started on June 16, 2016. Here, we report 3-year follow-up data (cutoff date: November 12, 2019). Results: Thirty-four patients were enrolled. The centrally assessed objective response rate was previously reported (29.4%). The 2- and 3-year OS rates were 35.3% and 23.5%, respectively, and the corresponding PFS rates were 17.0% and 12.7%. Median OS and PFS were 17.3 and 5.9 months, respectively. Eight patients were alive at 3 years of follow-up. Nivolumab was well tolerated and no new safety signals were found. The patient-reported outcomes were maintained without marked deteriorations during the study. Conclusions: Our results reveal clinically relevant long-term efficacy and safety of nivolumab for the treatment of MPM.
  • James Chih-Hsin Yang; Tony S K Mok; Shun Lu; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Yuan-Kai Shi; Li Zhang; Ross A Soo; Satoshi Morita; Tomohide Tamura
    JTO clinical and research reports 2 3 100142 - 100142 2021年03月 
    Introduction: Despite recent advances in NSCLC treatment, specific data on the elderly population remain limited. In this post hoc subgroup analysis of the East Asia S-1 Trial in Lung Cancer (EAST-LC) trial, we compared S-1 and docetaxel (DTX) in patients aged 70 years old and above with pretreated advanced NSCLC. Methods: Patients were randomly assigned (1:1) to receive S-1 (orally, twice daily on d 1-28 of a 6-wk cycle) or DTX (intravenously, on d 1 of a 3-wk cycle). The initial S-1 dose was 80, 100, or 120 mg/day on the basis of body surface area, and the DTX doses were 60 mg/m2 (Japan) or 75 mg/m2 (outside Japan). The primary end point was overall survival, and secondary end points included progression-free survival, response rate, quality of life (QOL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30, and safety. Results: Among 189 patients aged 70 years and above assessed as the full analysis set, baseline characteristics were generally similar between treatment arms. The median overall survival was 14.7 (S-1) versus 12.1 months (DTX); the hazard ratio was equal to 0.76, with a 95% confidence interval (CI) of 0.54-1.07. The median progression-free survival was similar in both arms (both 4.1 mo, hazard ratio = 0.84, 95% CI: 0.60-1.18); and the response rate was 12.9% (S-1) and 14.0% (DTX). The adjusted mean QOL score difference (S-1-DTX until wk 48) was 7.41 (95% CI: 0.37-14.46). Safety profiles were generally consistent with those of the overall EAST-LC population. Conclusions: S-1 revealed comparable efficacy, safety, and QOL versus DTX in pretreated elderly patients with advanced NSCLC. Results were consistent with the overall EAST-LC data.
  • Jean Paty; Rickard Sandin; Arlene Reisman; Yi-Long Wu; Maria Rita Migliorino; Xiangdong Zhou; Ying Cheng; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Jesús Corral; Adam Płużański; Rolf Linke; Oren Meyers; Tony S Mok
    Future oncology (London, England) 17 7 783 - 794 2021年03月 
    Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.
  • Makoto Nishio; Tatsuya Yoshida; Toru Kumagai; Toyoaki Hida; Ryo Toyozawa; Tadasuke Shimokawaji; Koichi Goto; Kazuhiko Nakagawa; Yuichiro Ohe; Takashi Seto; Kentarou Kudou; Takayuki Asato; Pingkuan Zhang; Nobuyuki Yamamoto
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 3 452 - 463 2021年03月 
    INTRODUCTION: This phase 2 trial evaluated the efficacy and safety of brigatinib in patients with advanced ALK-positive NSCLC refractory to alectinib or other ALK tyrosine kinase inhibitors (TKIs). METHODS: This single-arm, multicenter, open-label study in Japanese patients consisted of a safety lead-in followed by an expansion stage in patients refractory to ALK TKI or those naive for ALK TKI. Patients received brigatinib 180 mg once daily with 7-day lead-in at 90 mg once daily. Primary end point was independent review committee (IRC)-assessed confirmed objective response rate per the Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: We report the results of the lead-in and expansion in the patients refractory to ALK TKI. Of 72 patients enrolled, 47 had alectinib as most recent ALK TKI (with or without previous crizotinib). At analysis cutoff, 14 of the 47 remained on brigatinib (median follow-up: 12.4 mo). In the alectinib-refractory population, IRC-assessed confirmed objective response rate was 34% (95% confidence interval [CI]: 21%-49%) with median duration of response of 11.8 months (95% CI: 5.5-16.4). Disease control rate was 79% (95% CI: 64%-89%). Median IRC-assessed progression-free survival was 7.3 months (95% CI: 3.7-9.3). Two of eight patients with measurable brain lesions at baseline had confirmed intracranial partial response. Brigatinib has been found to have antitumor activity in patients with G1202R, I1171N, V1180L, and L1196M secondary mutations. The safety profile in Japanese patients was consistent with that in previous reports in broader populations. CONCLUSIONS: Brigatinib has been found to have clinically meaningful efficacy in Japanese patients with ALK+ NSCLC refractory to alectinib (with or without previous crizotinib).
  • Ryoji Kato; Koji Haratani; Hidetoshi Hayashi; Kazuko Sakai; Hitomi Sakai; Hisato Kawakami; Kaoru Tanaka; Masayuki Takeda; Kimio Yonesaka; Kazuto Nishio; Kazuhiko Nakagawa
    British journal of cancer 124 5 914 - 924 2021年03月 
    BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB). RESULTS: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8+ T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8+ T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice. CONCLUSIONS: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8+ T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
  • Akira Ono; Haruyasu Murakami; Takashi Seto; Toshio Shimizu; Sawori Watanabe; Shigeru Takeshita; Kentaro Takeda; Junko Toyoshima; Itsuro Nagase; Erkut Bahceci; Maiko Morishita; Satoshi Morita; Masahiro Fukuoka; Kazuhiko Nakagawa
    Drugs in R&D 21 1 65 - 78 2021年03月 
    BACKGROUND AND OBJECTIVE: Anaplastic lymphoma kinase gene rearrangements (ALKr) resulting in EML4-ALK proteins occur in a subset of solid tumors and are targeted by ALK inhibitors. Given the development of drug resistance to ALK inhibitors, ALK inhibitors with different kinase selectivity are required. METHODS: This phase I, non-randomized, open-label study evaluated the dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity of ASP3026, a second-generation ALK inhibitor, in Japanese patients with solid tumors. Between 1 June 2011 and 20 January 2014, 29 patients received different daily doses of ASP3026 in the escalation (25 mg, n = 3; 50 mg, n = 3; 75 mg, n = 3; 125 mg, n = 4; 200 mg, n = 3; or 325 mg, n = 7) and expansion (200 mg, n = 6) cohorts. RESULTS: Three patients had DLTs at the 325-mg dose: cataract exacerbation, increased aspartate transaminase and alanine transaminase, and impaired hepatic function (all Grade 3 severity). Thus, the maximum tolerated dose was 200 mg. The treatment-emergent adverse event incidence was 100%; the most common events were nausea (n = 8, 27.6%), decreased appetite (n = 10, 34.5%), and fatigue (n = 9, 31.0%) of mild or moderate severity. Six patients were positive for ALK protein and three had ALKr. Two patients achieved partial responses: one with Ewing sarcoma (75-mg dose group) and one with an ALKr-positive inflammatory myofibroblastic tumor (125-mg dose group). CONCLUSION: ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile. CLINICAL TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov under the identifier NCT01401504 on July 25, 2011.
  • Hiroaki Akamatsu; Yukihiro Toi; Hidetoshi Hayashi; Daichi Fujimoto; Motoko Tachihara; Naoki Furuya; Sakiko Otani; Junichi Shimizu; Nobuyuki Katakami; Koichi Azuma; Naoko Miura; Kazumi Nishino; Satoshi Hara; Shunsuke Teraoka; Satoshi Morita; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    JAMA oncology 7 3 386 - 394 2021年03月 
    Importance: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. Objective: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. Design, Setting, and Participants: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. Interventions: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. Results: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). Conclusions and Relevance: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. Trial Registration: UMIN Clinical Trials Registry Identifier: UMIN000023761.
  • Kentaro Ito; Takeharu Yamanaka; Hidetoshi Hayashi; Yoshihiro Hattori; Kazumi Nishino; Haruki Kobayashi; Yuko Oya; Toshihide Yokoyama; Takashi Seto; Koichi Azuma; Tomoya Fukui; Toshiyuki Kozuki; Atsushi Nakamura; Kentaro Tanaka; Katsuya Hirano; Takashi Yokoi; Haruko Daga; Shinya Sakata; Daichi Fujimoto; Masahide Mori; Ken Maeno; Takuya Aoki; Atsuhisa Tamura; Satoru Miura; Satoshi Watanabe; Hiroaki Akamatsu; Osamu Hataji; Kensuke Suzuki; Shigeto Hontsu; Koji Azuma; Akihiro Bessho; Akihito Kubo; Motoyasu Okuno; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    European journal of cancer (Oxford, England : 1990) 145 183 - 193 2021年03月 
    BACKGROUND: The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. METHODS: We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. RESULTS: Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). CONCLUSION: The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.
  • Nobuyuki Yamamoto; Hideyuki Harada; Isamu Okamoto; Noriyuki Masuda; Kazushige Hayakawa; Miyako Satouchi; Toshinori Soejima; Makoto Nishio; Takuyo Kozuka; Koji Takeda; Masahiro Tanaka; Takashi Seto; Tomonari Sasaki; Hiroshi Tsubouchi; Yasuyuki Kakurai; Yasumasa Nishimura; Kazuhiko Nakagawa
    Clinical lung cancer 22 2 134 - 141 2021年03月 
    BACKGROUND: We evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti-epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non-small-cell lung cancer. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m2; days 1 and 8, vinorelbine 20 mg/m2). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period. RESULTS: Of 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non-squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%. CONCLUSION: Addition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non-small-cell lung cancer, particularly squamous cell carcinoma.
  • Ying Cheng; Tony S Mok; Xiangdong Zhou; Shun Lu; Qing Zhou; Jianying Zhou; Yingying Du; Ping Yu; Xiaoqing Liu; Chengping Hu; You Lu; Yiping Zhang; Ki Hyeong Lee; Kazuhiko Nakagawa; Rolf Linke; Chew Hooi Wong; Yiyun Tang; Fanfan Zhu; Keith D Wilner; Yi-Long Wu
    Lung cancer (Amsterdam, Netherlands) 154 176 - 185 2021年02月 
    OBJECTIVES: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial. MATERIALS AND METHODS: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review. RESULTS: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively. CONCLUSION: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.
  • Xiuning Le; Monique Nilsson; Jonathan Goldman; Martin Reck; Kazuhiko Nakagawa; Terafumi Kato; Luis Paz Ares; Bente Frimodt-Moller; Katharina Wolff; Carla Visseren-Grul; John V Heymach; Edward B Garon
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 2 205 - 215 2021年02月 
    The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
  • Tony S Mok; Ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Alka Chawla; Rafael Rosell; Jesus Corral; Maria Rita Migliorino; Adam Pluzanski; Kay Noonan; Yiyun Tang; Malaika Pastel; Keith D Wilner; Yi-Long Wu
    Drugs 81 2 257 - 266 2021年02月 
    BACKGROUND: ARCHER 1050, an ongoing, randomized, open-label, phase III trial of dacomitinib versus gefitinib in newly diagnosed patients with advanced non-small-cell lung cancer (NSCLC) and an EGFR-activating mutation, reported significant improvement in overall survival (OS) with dacomitinib. OBJECTIVE: This paper reports an updated OS analysis of ARCHER 1050 after an extended follow-up. PATIENTS AND METHODS: In this multinational, multicenter trial, adults (aged ≥ 18 years or ≥ 20 years in Japan and Korea) with newly diagnosed NSCLC and EGFR mutation (exon 19 deletion or exon 21 L858R substitution), and no history of central nervous system metastases, were randomized 1:1 to receive dacomitinib 45 mg/day (n = 227) or gefitinib 250 mg/day (n = 225). Randomization was stratified by race and EGFR mutation type. An ad hoc updated analysis of OS was conducted at the protocol-defined cut-off of 48 months from first dosing of the last enrolled patient (13 May 2019). RESULTS: After a median follow-up of 47.9 months, 133 (58.6%) patients had died in the dacomitinib arm and 152 (67.6%) in the gefitinib arm. The hazard ratio (HR) for OS was 0.748 (95% CI 0.591-0.947; two-sided P = 0.0155); median OS was 34.1 months with dacomitinib versus 27.0 months with gefitinib. The HR for OS in patients with dose reduction(s) in the dacomitinib arm (n = 154) compared with all patients in the gefitinib arm was 0.554 (95% CI 0.420-0.730); median OS was 42.5 months for patients with dose reduction(s) in the dacomitinib arm. The most common adverse events were diarrhea (87.7%), paronychia (61.7%), dermatitis acneiform (49.3%), and stomatitis (43.6%) with dacomitinib, and diarrhea (55.8%) and alanine aminotransferase increased (40.2%) with gefitinib. CONCLUSIONS: The OS benefit from first-line treatment with dacomitinib versus gefitinib was maintained after extended follow-up in patients with advanced NSCLC with EGFR-activating mutations. CLINICALTRIALS.GOV: NCT01774721 (registered 24 January 2013).
  • Hiroaki Kanemura; Masayuki Takeda; Shigeki Shimizu; Kazuhiko Nakagawa
    Thoracic cancer 12 4 549 - 552 2021年02月 
    Capmatinib is a MET tyrosine kinase inhibitor (TKI) that has recently been approved for the treatment of advanced non-small cell lung cancer (NSCLC) positive for skipping mutations of MET exon 14 (METex14). Drug-induced interstitial lung disease (ILD) is a relatively rare, but potentially serious, side effect of TKIs administered for lung cancer treatment. Here we report a case of capmatinib-induced ILD in a patient with NSCLC harboring a METex14 skipping mutation. Capmatinib should be immediately discontinued if ILD is suspected, and treatment with corticosteroid should be considered.
  • Masayuki Takeda; Mototsugu Shimokawa; Atsushi Nakamura; Kaname Nosaki; Yasutaka Watanabe; Terufumi Kato; Daisuke Hayakawa; Hiroshi Tanaka; Toshiaki Takahashi; Yoshihito Kogure; Motoko Tachihara; Daichi Fujimoto; Kakuhiro Yamaguchi; Naohiko Hamaguchi; Isamu Okamoto; Koichi Azuma; Kazuo Hasegawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 22 4 376 - 380 2021年01月 
    Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has recently been established as a standard treatment option for chemotherapy-naive patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, only about one-half of patients who have received prior treatment with a first- or second-generation EGFR-TKI are eligible for osimertinib therapy because its indication in the second-line setting is limited to metastatic NSCLC positive for the T790M resistance mutation of EGFR. The dose-escalation part of a study in which patients received osimertinib at doses of 20 to 240 mg once daily after the development of resistance to first- or second-generation EGFR-TKIs revealed a response rate of 21% and a median progression-free survival of 2.8 months for individuals whose tumors were negative for EGFR T790M. We have now designed a phase II study of osimertinib for patients with EGFR mutation-positive NSCLC who develop isolated central nervous system progression (T790M-negative or unknown) after first- or second-generation EGFR-TKI therapy (cohort 1) or who develop systemic disease progression (T790M-negative) after first- or second-generation EGFR-TKI therapy and platinum-based chemotherapy (cohort 2). A total of 70 patients (cohort 1, n = 17; cohort 2, n = 53) will be enrolled in this study, which originated from a suggestion of a dedicated network for patients with lung cancer in Japan.
  • Hiroshi Katayama; Junki Mizusawa; Haruhiko Fukuda; Shinichiro Nakamura; Kenich Nakamura; Nagahiro Saijo; Akira Yokoyama; Yuichro Ohe; Tetsu Shinkai; Kazuhiko Nakagawa; Tetsuya Abe; Shigeki Mitsuoka; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Masahiko Ando; Tomohide Tamura; Koji Takeda
    Japanese journal of clinical oncology 51 5 685 - 692 2021年01月 
    OBJECTIVE: Patients' actual age and performance status do not always accurately identify the 'fit elderly' for chemotherapy. This study aimed to determine whether four geriatric assessment tools could predict prognosis. METHODS: This study were analyzed using the data of two randomized phase III trials (JCOG0207 and JCOG0803/WJOG4307L) for elderly patients with advanced non-small cell lung cancer and included all eligible patients who were assessed before treatment with four geriatric assessment tools: the Barthel activities of daily living index, Lawton instrumental activities of daily living scale, Mini-Mental State Examination, and Geriatric Depression Scale-15. Univariable and multivariable analyses for overall survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as strata. RESULTS: This analysis included 330 patients aged 70-74, 75-79 or 80 or more (n = 95/181/54), with a performance status of 0 or 1 (n = 119/211). Patients were divided into three groups based on Mini-Mental State Examination and two groups based on Geriatric Depression Scale, but over 80% of patients had perfect scores for both activities of daily living and instrumental activities of daily living. In overall survival subgroup analyses by GA tool, only Mini-Mental State Examination scores were associated with substantial outcome differences (median survival times: 21.2, 13.5 and 12.2 months for scores 30, 29-24 and ≤23). After adjusting for baseline factors, the Mini-Mental State Examination, sex and performance status were tended to be worse overall survival. CONCLUSION: MMSE scores, performance status and sex, but not chronological age, effectively predicted the prognosis of elderly patients. Further studies should confirm that the Mini-Mental State Examination is useful for determining the indication of chemotherapy in elderly patients with advanced non-small cell lung cancer.
  • Sai-Hong Ignatius Ou; Yutaka Fujiwara; Alice T Shaw; Noboru Yamamoto; Kazuhiko Nakagawa; Frank Fan; Yuki Hao; Yanfei Gao; Pasi A Jänne; Takashi Seto
    JTO clinical and research reports 2 1 100108 - 100108 2021年01月 
    Introduction: Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation. Methods: Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety. Results: A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1-33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4-87.9) with a disease control rate of 100% (70.1-100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7-70.0) with a disease control rate of 88.3% (95% CI: 443.6-97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6-not reached) and 14.2 months (95% CI: 1.5-not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%). Conclusions: Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.
  • Takayasu Kurata; Kazuhiko Nakagawa; Miyako Satouchi; Takashi Seto; Takeshi Sawada; Shirong Han; Masae Homma; Kazuo Noguchi; Naoyuki Nogami
    Cancer treatment and research communications 29 100458 - 100458 2021年 
    INTRODUCTION: Pembrolizumab plus chemotherapy significantly improved outcomes over chemotherapy alone as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC) in phase 3 international trials. In the phase 1 KEYNOTE-011 study (parts B and C), we evaluated the safety/activity of pembrolizumab plus chemotherapy as first-line treatment in Japanese patients with advanced NSCLC. METHODS: Eligible patients received 4 cycles (every 3 weeks) of pembrolizumab 200 mg plus chemotherapy (cisplatin 75 mg/m2/carboplatin area under the curve [AUC] 5 mg/mL/min and pemetrexed 500 mg/m2 in part B [nonsquamous]; carboplatin AUC 6 mg/mL/min and paclitaxel 200 mg/m2/nab-paclitaxel 100 mg/m2 (weekly) in part C [squamous]), followed by maintenance pembrolizumab (and pemetrexed, part B). The primary endpoint was incidence of dose-limiting toxicities (DLTs) during the first 3 weeks of treatment. Overall response rate (ORR; RECIST v1.1 by central review) was exploratory. RESULTS: In part B (median follow-up, 16.0 months; n = 12) 1 DLT occurred (grade 4 hyponatremia). Grade ≥3 treatment-related adverse events (AEs) occurred in 9 patients (75%). Two patients had grade 5 treatment-related AEs (pneumonitis and interstitial lung disease). In part C (median follow-up, 9.9 months; n = 14), 2 DLTs occurred (both grade 3 febrile neutropenia). Grade ≥3 treatment-related AEs occurred in 11 patients (79%); none were fatal. ORR was 73% in part B and 50% in part C, irrespective of PD-L1 status. CONCLUSION: Safety results show first-line pembrolizumab plus chemotherapy is feasible in Japanese patients with advanced NSCLC. Antitumor activity was observed irrespective of PD-L1 status and was comparable to that in international studies. TRIAL REGISTER: ClinicalTrials.gov, NCT01840579.
  • Kazuko Sakai; Toshiharu Sakurai; Marco A De Velasco; Tomoyuki Nagai; Takaaki Chikugo; Kazuomi Ueshima; Yurie Kura; Takayuki Takahama; Hidetoshi Hayashi; Kazuhiko Nakagawa; Masatoshi Kudo; Kazuto Nishio
    Frontiers in oncology 11 763468 - 763468 2021年 
    Immune checkpoint inhibitors (ICIs) have become the standard of care for several cancers. However, ICI therapy has also been associated with various immune-related adverse events (irAEs). Clinical manifestations of immune-related colitis resemble those of inflammatory bowel diseases such as ulcerative colitis (UC). The composition of the bowel microflora is thought to influence the development of inflammatory bowel disease and irAE colitis. We profiled the gene expressions and microbe compositions of colonic mucosa from patients with solid cancers receiving anti-PD-L1 antibody treatment; we then compared the expression profiles associated with irAE colitis with those associated with UC. The pathway enrichment analysis revealed functional similarities between inflamed regions of irAE colitis and UC. The common enriched pathways included leukocyte extravasation and immune responses, whereas non-inflamed mucosa from patients with irAE colitis was distinct from patients with UC and was characterized by the recruitment of immune cells. A similarity between the microbiota profiles was also identified. A decreased abundance of Bacteroides species was observed in inflamed regions from both irAE colitis and UC based on a microbiota composition analysis of 16S rDNA sequencing. Pathways associated with molecule transport systems, including fatty acids, were enriched in inflamed and non-inflamed irAE colitis and inflamed UC, similar to Piphillin-inferred KEGG pathways. While UC is characterized by local regions of inflammation, ICI treatment extends to non-inflammatory regions of the colonial mucosa where immune cells are reconstituted. This analysis of the similarity and heterogeneity of irAE colitis and UC provides important information for the management of irAE colitis.
  • Motoko Tachihara; Kayoko Tsujino; Takeaki Ishihara; Hidetoshi Hayashi; Yuki Sato; Takayasu Kurata; Shunichi Sugawara; Isamu Okamoto; Shunsuke Teraoka; Koichi Azuma; Haruko Daga; Masafumi Yamaguchi; Takeshi Kodaira; Miyako Satouchi; Mototsugu Shimokawa; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Cancer management and research 13 9167 - 9173 2021年 
    Durvalumab (anti-programmed cell death ligand-1) administration after concurrent chemoradiotherapy (cCRT) has improved the survival of patients with unresectable, locally advanced (LA) stage III non-small cell lung cancer (NSCLC). Some patients are unable to complete cCRT and cannot receive immunotherapy due to poor performance status based on adverse events after cCRT. Immunotherapy plays an important role in anti-programmed cell death ligand-1 (PD-L1)-positive advanced NSCLC and is replacing chemotherapy. In addition, radiotherapy and immunotherapy have been reported to have a synergistic effect. This Phase II, multicenter study (DOLPHIN, WJOG11619L, JapicCTI-194840) is designed to assess the efficacy and safety of durvalumab plus concurrent curative radiation therapy for PD-L1-positive unresectable LA-NSCLC without chemotherapy. Unresectable LA stage III NSCLC patients aged 20 years or older with a World Health Organization/Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and PD-L1 positivity are enrolled. The patients will receive curative radiation therapy (60 Gy) plus durvalumab 10 mg/kg every 2 weeks (q2w) for up to 12 months until there is evidence of disease progression (PD) or unacceptable toxicity. The primary endpoint is the 12-month progression-free survival rate as assessed by an independent central review. The secondary endpoints are progression-free survival, overall survival, objective response rate, treatment completion rate, and safety. Recruitment began in September 2019.
  • A Phase II Study to Assess the Efficacy of Osimertinib in Patients With EGFR Mutation-positive NSCLC Who Developed Isolated CNS Progression (T790M-negative or Unknown) During First- or Second-generation EGFR-TKI or Systemic Disease Progression (T790M-negative) After Treatment With First- or Second-generation EGFR-TKI and Platinum-based Chemotherapy (WJOG12819L)
    Takeda M; Shimokawa M; Nakamura A; Nosaki K; Watanabe Y; Kato T; Hayakawa D; Tanaka H; Takahashi T; Kogure Y; Tachihara M; Fujimoto D; Yamaguchi K; Hamaguchi N; Okamoto I; Azuma K; Hasegawa K; Yamamoto N; Nakagawa; K
    Clin Lung Cancer. 22 4 376 - 380 2021年
  • Tomoya Fukui; Kazuko Sakai; Jiichiro Sasaki; Mikiko Ishihara Kakegawa; Satoshi Igawa; Hisashi Mitsufuji; Masayuki Takeda; Takayuki Takahama; Kazuhiko Nakagawa; Kazuto Nishio; Katsuhiko Naoki
    Cancer biomarkers : section A of Disease markers 31 2 119 - 126 2021年 
    BACKGROUND: The advancement of cancer genomics has allowed for multiplex gene assays using next-generation sequencing (NGS) to be practically implemented, however, a clinical practice system remains to be established. OBJECTIVE: We evaluated the feasibility of clinical sequencing using NGS-based multiplex gene assays between cooperating medical institutions in patients with advanced cancers. METHODS: In this observational study, DNA and RNA samples prepared from existing tumor tissues were subjected to comprehensive genomic profiling using targeted sequencing. RESULTS: From January 2017 to March 2019, 36 samples from 33 patients were assessed. Of all patients, 27 (82%) had lung cancer, with the median age of 50 years (range 38-83). Multiplex gene panel tests were successfully carried out on 35/36 (97%) samples. Potentially actionable gene alterations were identified in 10/30 (33%) samples (3 HER2, 2 KRAS, 2 ALK, 1 PIK3CA, 1 RET, and 1 CDKN2A). In the 6 samples examined for resistant mechanisms, ALK I1171N mutation and MET copy number gain were detected in 2 patients with ALK rearrangement-positive lung cancer. CONCLUSIONS: Clinical sequencing using NGS-based multiplex gene assays between collaborating domestic medical institutions was feasible, with a success rate of > 97%. Overall, clinical sequencing benefits therapeutic decision-making in patients with advanced cancer.
  • Satomi Watanabe; Masayuki Takeda; Tomoyuki Otani; Takeshi Yoshida; Kazuko Sakai; Elizabeth Olek; S Michael Rothenberg; Jennifer Kherani; Pearl P French; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    JCO precision oncology 5 2021年
  • Kenjiro Aogi; Hideki Takeuchi; Toshiaki Saeki; Keisuke Aiba; Kazuo Tamura; Keiko Iino; Chiyo K Imamura; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Makoto Wada; Tatsuo Akechi; Hirotoshi Iihara; Shoichiro Ohtani; Ayako Okuyama; Keiko Ozawa; Yong-Il Kim; Hidenori Sasaki; Yasuo Shima; Masayuki Takeda; Eijiro Nagasaki; Toshihiko Nishidate; Takahiro Higashi; Kouichi Hirata
    International journal of clinical oncology 26 1 1 - 17 2021年01月 
    Patients with cancer should appropriately receive antiemetic therapies against chemotherapy-induced nausea and vomiting (CINV). Antiemetic guidelines play an important role in managing CINV. Accordingly, the first Japanese antiemetic guideline published in 2010 by the Japan Society of Clinical Oncology (JSCO) has considerably aided Japanese medical staff in providing antiemetic therapies across chemotherapy clinics. With the yearly advancements in antiemetic therapies, the Japanese antiemetic guidelines require revisions according to published evidence regarding antiemetic management worldwide. A revised version of the first antiemetic guideline that considered several upcoming evidences had been published online in 2014 (version 1.2), in which several updated descriptions were included. The 2015 JSCO clinical practice guideline for antiemesis (version 2.0) (in Japanese) has addressed clinical antiemetic concerns and includes four major revisions regarding (1) changes in emetogenic risk categorization for anti-cancer agents, (2) olanzapine usage as an antiemetic drug, (3) the steroid-sparing method, and (4) adverse drug reactions of antiemetic agents. We herein present an English update summary for the 2015 JSCO clinical practice guideline for antiemesis (version 2.0).
  • Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Toshihide Yokoyama; Junko Tanizaki; Tomohiro Ozaki; Hiroshige Yoshioka; Takayasu Kurata; Yosuke Tamura; Yasuhito Fujisaka; Kaoru Tanaka; Yoshikazu Hasegawa; Keita Kudo; Yasutaka Chiba; Kazuhiko Nakagawa
    The oncologist 26 1 19-e52  2021年01月 
    LESSONS LEARNED: The combination of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer is a promising therapeutic strategy. Further investigation is warranted. BACKGROUND: We conducted a phase I/II trial of cisplatin plus nab-paclitaxel with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (NSCLC) to determine the recommended dose (RD) of nab-paclitaxel and to evaluate the safety and efficacy of this regimen. METHODS: In the phase I study, escalating doses of weekly nab-paclitaxel were administered together with cisplatin at 75 mg/m2 every 3 weeks and concurrent radiotherapy. In the phase II study, nab-paclitaxel was administered at the RD. RESULTS: In the phase I study, whereas no dose-limiting toxicity (DLT) was observed with nab-paclitaxel at 50 or 60 mg/m2 , one of six patients experienced DLT (esophagitis of grade 3) at 70 mg/m2 , determined as the RD. Twenty-four patients at RD were evaluable for safety and efficacy in phase II. Common toxicities included esophagitis (87.5%) and leukopenia (79.2%). Pneumonitis and treatment-related deaths were not observed, but 20 patients (83.3%) experienced radiation pneumonitis, with one case of grade 3 and four of grade 2, after completion of concurrent chemoradiotherapy. The 2-year overall survival and progression-free survival rates were 73.9% and 56.5% (95% confidence interval [CI], 34.3%-74.7%), respectively. CONCLUSION: Concurrent chemoradiation with nab-paclitaxel at 70 mg/m2 and cisplatin at 75 mg/m2 every 3 weeks showed encouraging feasibility and activity for locally advanced NSCLC.
  • Kazuhiko Nakagawa; Koichi Matsumura; Tayler Scory; Megan S Farris; Kelly A Larkin-Kaiser; Hironori Kikkawa; Jasmina I Ivanova; Keith D Wilner
    Future oncology (London, England) 17 1 103 - 115 2021年01月 
    Background: Five EGFR-tyrosine kinase inhibitors (EGFR TKIs) are currently available in the first-line setting for non-small-cell lung cancer (NSCLC) in Japan. The aim here was to compare the relative efficacy of EGFR TKIs in the Japanese population. Materials & methods: A systematic review identified randomized controlled trials examining the efficacy of first-line EGFR TKIs. A Bayesian network meta-analysis was used to assess these EGFR TKI comparisons for progression-free survival (PFS). Results: A total of seven randomized controlled trials were identified and considered for network meta-analysis. Dacomitinib showed a trend toward improved PFS versus all comparators. Conclusion: Dacomitinib demonstrated a trend toward improved PFS and therefore, should be considered one of the standard first-line therapies for Japanese patients diagnosed with EGFR+ non-small-cell lung cancer.
  • Takashi Kurosaki; Seiichiro Mitani; Kaoru Tanaka; Shinichiro Suzuki; Hiroaki Kanemura; Koji Haratani; Soichi Fumita; Tsutomu Iwasa; Hidetoshi Hayashi; Takeshi Yoshida; Kazuki Ishikawa; Mutsukazu Kitano; Naoki Otsuki; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Anti-cancer drugs 32 1 95 - 101 2021年01月 
    Immunotherapy has been shown to prolong survival in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) in front-line use; however, subsequent systemic therapy has not been optimized. This study aimed to evaluate the safety and efficacy of cetuximab-containing chemotherapy after immunotherapy. We retrospectively analyzed patients with recurrent or metastatic SCCHN who underwent cetuximab-containing regimens after progression on immunotherapy. Of the 22 patients who met the inclusion criteria, 21 received paclitaxel and cetuximab, and 1 carboplatin and fluorouracil and cetuximab after immunotherapy. Nine patients achieved a partial response, 10 patients had stable disease as their best response on cetuximab-containing chemotherapy, yielding an overall response rate and disease control rate of 40.9 and 86.4%, respectively. The median progression-free survival was 5.2 months, and the median overall survival was 14.5 months. Ten patients developed grade 3-4 adverse events, including neutropenia (31.8%), acneiform rash (9.1%), anemia (4.5%), hypertransaminasemia (4.5%) and stomatitis (4.5%). The most frequent cetuximab-related toxicities across all grades were skin reactions (77.3%), hypomagnesemia (40.9%), stomatitis (27.3%), paronychia (13.6%) and keratitis (4.5%). There was no treatment-related death. Taken together, cetuximab-containing chemotherapy was effective and feasible even after immunotherapy.
  • Hideo Saka; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Toshiaki Takahashi; Hidehito Horinouchi; Mitsuhiro Takenoyama; Nobuyuki Katakami; Hiroshi Tanaka; Koji Takeda; Miyako Satouchi; Hiroshi Isobe; Makoto Maemondo; Koichi Goto; Tomonori Hirashima; Koichi Minato; Nobumichi Yada; Tomohide Tamura
    Japanese journal of clinical oncology 51 1 106 - 113 2021年01月 
    BACKGROUND: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years. METHODS: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events. RESULTS: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%). CONCLUSIONS: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up.
  • Kazuko Sakai; Takayuki Takahama; Mototsugu Shimokawa; Koichi Azuma; Masayuki Takeda; Terufumi Kato; Haruko Daga; Isamu Okamoto; Hiroaki Akamatsu; Shunsuke Teraoka; Akira Ono; Tatsuo Ohira; Toshihide Yokoyama; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Kazuto Nishio
    Molecular oncology 15 1 126 - 137 2021年01月 
    The WJOG8815L phase II clinical study involves patients with non-small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third-generation EGFR-TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR-TKI-sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing-and T790M-EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation-positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression-free survival were observed between the sensitizing EGFR MF-high and sensitizing EGFR MF-low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).
  • Kazuko Sakai; Masahiro Tsuboi; Hirotsugu Kenmotsu; Takeharu Yamanaka; Toshiaki Takahashi; Koichi Goto; Haruko Daga; Tatsuo Ohira; Tsuyoshi Ueno; Tadashi Aoki; Kazuhiko Nakagawa; Koji Yamazaki; Yukio Hosomi; Koji Kawaguchi; Norihito Okumura; Yuichi Takiguchi; Akimasa Sekine; Tomohiro Haruki; Hiromasa Yamamoto; Yuki Sato; Hiroaki Akamatsu; Takashi Seto; Sho Saeki; Kenji Sugio; Makoto Nishio; Kazunori Okabe; Nobuyuki Yamamoto; Kazuto Nishio
    Cancer science 112 1 388 - 396 2021年01月 
    The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine/cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small cell lung cancer (Ns-NSCLC). This study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability. Tumor mutation burden (TMB) is thought to have a predictive value of immune checkpoint inhibitors. However, the relevance of TMB to cytotoxic chemotherapy remains unknown. This exploratory study investigates the relationship between tumor mutation profiles and clinical outcome of Pem/Cis. Formalin-fixed, paraffin-embedded tumor tissues (n = 389) were obtained from the patients. Mutation status of tissue DNA was analyzed by targeted deep sequencing. Epidermal growth factor receptor (EGFR) mutations were detected frequently in Ns-NSCLC (139/374). Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm versus Vnr/Cis arms. Pem/Cis in patients with high TMB (≥12-16 mut/Mb) tended to have improved survival. In patients with wild-type EGFR, TMB ≥ 12 mut/Mb was significantly associated with improved RFS with Pem/Cis versus Vnr/Cis (not reached vs 52.5 months; hazard ratio (HR) 0.477). It could be proposed that TMB was predictive of RFS benefit with Pem/Cis versus Vnr/Cis in Ns-NSCLC. Further investigation is required to determine whether TMB combined with EGFR mutation status could be used as a predictive biomarker.
  • Ryota Shibaki; Hiroaki Akamatsu; Terufumi Kato; Kazumi Nishino; Morihito Okada; Tetsuya Mitsudomi; Kazushige Wakuda; Kenichi Yoshimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Therapeutic advances in medical oncology 13 1758835920987647 - 1758835920987647 2021年 
    Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is a standard treatment in EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, previous data have suggested that EGFR-TKI has limited potential as adjuvant therapy. On the contrary, based on subset analysis with the immune checkpoint inhibitor (ICI) plus platinum-doublet chemotherapy in advanced NSCLC with EGFR mutation, we hypothesized that this combination was worth testing as adjuvant therapy in patients with EGFR-mutated NSCLC. Methods: Herein, we introduce our phase II study of cisplatin plus vinorelbine combined with atezolizumab as adjuvant therapy for completely resected NSCLC with EGFR mutation. Accrued patients will be pathological stage II-IIIA with completely resected NSCLC and whose tumors have EGFR mutation. Treatment comprises four cycles of cisplatin plus vinorelbine combined with atezolizumab followed by maintenance with atezolizumab. The primary endpoint is the disease-free survival (DFS) rate at 2 years. Secondary endpoints are DFS, overall survival, and safety. In total, 18 patients will be enrolled in this study. Discussion: Ongoing phase III trials of adjuvant ICI allow the inclusion of patients with EGFR mutation, but our current trial will provide the earliest clinical data on the efficacy of platinum-doublet chemotherapy with atezolizumab.
  • Hirotsugu Kenmotsu; Seiji Niho; Masahiro Tsuboi; Masashi Wakabayashi; Genichiro Ishii; Kazuo Nakagawa; Haruko Daga; Hiroshi Tanaka; Haruhiro Saito; Keiju Aokage; Toshiaki Takahashi; Toshi Menju; Takashi Kasai; Ichiro Yoshino; Koichi Minato; Morihito Okada; Junko Eba; Hisao Asamura; Yuichiro Ohe; Shun-Ichi Watanabe
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 36 4292 - 4301 2020年12月 
    PURPOSE: To verify the superiority of irinotecan plus cisplatin over etoposide plus cisplatin as postoperative adjuvant chemotherapy for patients with pathologic stage I-IIIA, completely resected, high-grade neuroendocrine carcinoma (HGNEC) of the lung. METHODS: This was a randomized, open-label, phase III study on patients with completely resected stage I-IIIA HGNEC of the lung. They were randomly assigned to receive either etoposide (100 mg/m2, days 1-3) plus cisplatin (80 mg/m2, day 1) or irinotecan (60 mg/m2, days 1, 8, 15) plus cisplatin (60 mg/m2, day 1) up to four cycles. The primary end point was relapse-free survival (RFS) in the intention-to-treat population. This trial was registered with the Japan Registry of Clinical Trials (jRCTs031180216). RESULTS: Between April 2013 and October 2018, 221 patients were enrolled (etoposide plus cisplatin arm, 111 patients; irinotecan plus cisplatin arm, 110 patients). In the second interim analysis, early termination of the trial was recommended because of futility. At a median follow-up of 24.1 months, the 3-year RFS was 65.4% for etoposide plus cisplatin and 69.0% for irinotecan plus cisplatin, with a hazard ratio of 1.076 (95% CI, 0.666 to 1.738; one-sided log-rank P = .619). Grade 3-4 adverse events were more frequent in the etoposide plus cisplatin arm, with febrile neutropenia (20% of 109 patients v 4% of 107 patients) and neutropenia (97% v 36%) being the most common. Meanwhile, grade 3-4 anorexia (6% v 11%) and diarrhea (1% v 8%) were more frequently observed in the irinotecan plus cisplatin arm. CONCLUSION: Irinotecan plus cisplatin is not superior to etoposide plus cisplatin for improving RFS in patients with completely resected HGNEC; thus, etoposide plus cisplatin remains the standard treatment.
  • Kenta Tsunekuni; Hisato Kawakami; Kazuaki Matsuoka; Hideki Nagase; Seiichiro Mitani; Kazuhiko Nakagawa
    Journal of clinical medicine 9 12 2020年12月 
    Trifluridine/tipiracil (FTD/TPI) (a.k.a. TAS-102) is a combination drug for metastatic colorectal cancer (CRC) and severely pretreated metastatic gastric/gastroesophageal junction (GEJ) cancers, comprising FTD, a thymidine-based antineoplastic nucleoside analog, and TPI, which enhances FTD bioavailability. Herein, in KRAS mutant murine colorectal cancer CT26 syngeneic models, we investigate whether combination therapy with DC101 (a surrogate ramucirumab antibody, rat antimouse vascular endothelial growth factor receptor (VEGFR)-2 monoclonal antibody (mAb)) improves FTD/TPI efficacy. Tumor growth inhibition (TGI) on day 15 was 38.0% and 30.6% upon DC101 monotherapy and FTD/TPI monotherapy respectively, and 60.3% upon combination therapy. Tumor volume was significantly lower (p < 0.001) upon combination treatment than upon FTD/TPI or DC101 monotherapy, indicating the additive effects of FTD/TPI and DC101. DNA-incorporated FTD levels on Day 8 were significantly higher in combination therapy with FTD/TPI (for 5 consecutive days) and DC101 (on alternate days for 7days) than in FTD/TPI monotherapy. Furthermore, vascular endothelial cell-specific marker CD31 was downregulated in DC101-treated tumors on day 8. These results indicate that combination therapy with FTD/TPI and DC101 is a promising treatment alternative regardless of KRAS mutations.
  • Miyako Satouchi; Kaname Nosaki; Toshiaki Takahashi; Kazuhiko Nakagawa; Keisuke Aoe; Takayasu Kurata; Akimasa Sekine; Atsushi Horiike; Tatsuro Fukuhara; Shunichi Sugawara; Shigeki Umemura; Hideo Saka; Isamu Okamoto; Nobuyuki Yamamoto; Hiroshi Sakai; Kazuma Kishi; Nobuyuki Katakami; Hidehito Horinouchi; Toyoaki Hida; Hiroaki Okamoto; Shinji Atagi; Tatsuo Ohira; Shi Rong Han; Kazuo Noguchi; Victoria Ebiana; Katsuyuki Hotta
    Cancer science 111 12 4480 - 4489 2020年12月 
    This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.
  • Makoto Nishio; Takashi Seto; Martin Reck; Edward B Garon; Chao-Hua Chiu; Kiyotaka Yoh; Fumio Imamura; Keunchil Park; Jin-Yuan Shih; Carla Visseren-Grul; Bente Frimodt-Moller; Annamaria Zimmermann; Gosuke Homma; Sotaro Enatsu; Kazuhiko Nakagawa
    Cancer science 111 12 4510 - 4525 2020年12月 
    In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia.
  • Sarina A Piha-Paul; Do-Youn Oh; Makoto Ueno; David Malka; Hyun Cheol Chung; Adnan Nagrial; Robin K Kelley; Willeke Ros; Antoine Italiano; Kazuhiko Nakagawa; Hope S Rugo; Filippo de Braud; Andrea Iolanda Varga; Aaron Hansen; Hui Wang; Suba Krishnan; Kevin G Norwood; Toshihiko Doi
    International journal of cancer 147 8 2190 - 2198 2020年10月 
    We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.
  • Hidetoshi Hayashi; Yuichi Takiguchi; Hironobu Minami; Kohei Akiyoshi; Yoshihiko Segawa; Hiroki Ueda; Yasuo Iwamoto; Chihiro Kondoh; Koji Matsumoto; Shin Takahashi; Hisateru Yasui; Toshiyuki Sawa; Yusuke Onozawa; Yasutaka Chiba; Yosuke Togashi; Yoshihiko Fujita; Kazuko Sakai; Shuta Tomida; Kazuto Nishio; Kazuhiko Nakagawa
    JAMA oncology 6 12 1931 - 1938 2020年10月 
    Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.
  • 当院におけるアベマシクリブの使用経験
    黒崎 隆; 岩朝 勤; 渡邉 諭美; 酒井 瞳; 橋本 幸彦; 菰池 佳史; 中川 和彦
    日本乳癌学会総会プログラム抄録集 28回 422 - 422 (一社)日本乳癌学会 2020年10月
  • EGFR陽性の切除不能・局所進行NSCLCに対するゲフィチニブ+胸部放射線同時併用の第II相試験(WJOG6911L)
    赤松 弘朗; 村上 晴泰; 原田 英幸; 林 秀敏; 駄賀 晴子; 長谷川 喜一; 金 永学; 加藤 晃史; 徳永 章二; 西村 恭昌; 山本 信之; 中川 和彦
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • EGFR-TKI増悪後のEGFR T790M陽性進行肺腺癌に対するオシメルチニブ+/-ベバシズマブの第2相試験(WJOG8715L)
    赤松 弘朗; 戸井 之裕; 林 秀敏; 藤本 大智; 立原 素子; 古屋 直樹; 大谷 咲子; 清水 淳市; 片上 信之; 東 公一; 三浦 奈保子; 西野 和美; 原 聡志; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • 分子標的治療・臨床試験 脳転移(放射線未治療)のあるNSCLCに対するOsimertinibの第II相試験 OCEAN study
    土屋 裕子; 山口 博之; 和久田 一茂; 福田 実; 釼持 広知; 知花 賢治; 三浦 理; 中川 和彦; 山本 信之; 杉尾 賢二
    日本癌治療学会学術集会抄録集 58回 WS22 - 4 (一社)日本癌治療学会 2020年10月
  • 伊藤 健太郎; 和久田 一茂; 山口 博之; 釼持 広知; 福田 実; 三浦 理; 知花 賢治; 中川 和彦; 山本 信之; 杉尾 賢二
    肺癌 60 6 563 - 563 (NPO)日本肺癌学会 2020年10月
  • 小澤 雄一; 山中 竹春; 伊藤 健太郎; 釼持 広知; 大江 裕一郎; 木浦 勝行; 菅原 俊一; 中川 和彦; 吉野 一郎; 弦間 昭彦; 山本 信之
    肺癌 60 6 641 - 641 (NPO)日本肺癌学会 2020年10月
  • 武田 真幸; 下川 元継; 中村 敦; 野崎 要; 渡辺 恭孝; 加藤 晃史; 早川 乃介; 田中 洋史; 高橋 利明; 沖 昌英; 立原 素子; 藤本 大智; 山口 覚博; 野上 尚之; 岡本 勇; 東 公一; 長谷川 一男; 山本 信之; 中川 和彦
    肺癌 60 6 579 - 579 (NPO)日本肺癌学会 2020年10月
  • 非扁平非小細胞肺癌に対するPem+CisとVnr+Cisの比較第III相試験における腫瘍変異負荷の意義(JIPANG-TR)
    坂井 和子; 坪井 正博; 釼持 広知; 後藤 功一; 大平 達夫; 中川 和彦; 細見 幸生; 滝口 裕一; 山本 寛斉; 赤松 弘朗; 佐伯 祥; 杉尾 賢二; 山本 信之; 西尾 和人
    日本癌学会総会記事 79回 OJ18 - 5 2020年10月
  • 鈴木 慎一郎; 原谷 浩司; 林 秀敏; 加藤 了資; 川中 雄介; 谷崎 潤子; 尾崎 智博; 黒崎 隆; 長谷川 喜一; 岡部 崇記; 明石 雄策; 千葉 康敬; 伊藤 彰彦; 中川 和彦
    肺癌 60 6 635 - 635 (NPO)日本肺癌学会 2020年10月
  • 豊澤 亮; 西尾 誠人; 吉田 達哉; 熊谷 融; 樋田 豊明; 下川路 伊亮; 後藤 功一; 大江 裕一郎; 瀬戸 貴司; 山本 信之; 工藤 健太郎; 朝戸 臣敬; Zhang Pingkuan; 中川 和彦
    肺癌 60 6 563 - 563 2020年10月
  • 金村 宙昌; 林 秀敏; 磯本 晃佑; 鈴木 慎一郎; 田中 薫; 吉田 健史; 武田 真幸; 中川 和彦
    肺癌 60 6 476 - 476 (NPO)日本肺癌学会 2020年10月
  • EGFR陽性の切除不能・局所進行NSCLCに対するゲフィチニブ+胸部放射線同時併用の第II相試験(WJOG6911L)
    赤松 弘朗; 村上 晴泰; 原田 英幸; 林 秀敏; 駄賀 晴子; 長谷川 喜一; 金 永学; 加藤 晃史; 徳永 章二; 西村 恭昌; 山本 信之; 中川 和彦
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • EGFR-TKI増悪後のEGFR T790M陽性進行肺腺癌に対するオシメルチニブ+/-ベバシズマブの第2相試験(WJOG8715L)
    赤松 弘朗; 戸井 之裕; 林 秀敏; 藤本 大智; 立原 素子; 古屋 直樹; 大谷 咲子; 清水 淳市; 片上 信之; 東 公一; 三浦 奈保子; 西野 和美; 原 聡志; 寺岡 俊輔; 森田 智視; 中川 和彦; 山本 信之
    肺癌 60 6 578 - 578 (NPO)日本肺癌学会 2020年10月
  • 鈴木 慎一郎; 原谷 浩司; 林 秀敏; 加藤 了資; 川中 雄介; 谷崎 潤子; 尾崎 智博; 黒崎 隆; 長谷川 喜一; 岡部 崇記; 明石 雄策; 千葉 康敬; 伊藤 彰彦; 中川 和彦
    肺癌 60 6 635 - 635 (NPO)日本肺癌学会 2020年10月
  • 岩間 映二; 坂井 和子; 高濱 隆幸; 下川 元継; 東 公一; 武田 真幸; 加藤 晃史; 駄賀 晴子; 寺岡 俊輔; 高橋 利明; 大平 達夫; 横山 俊秀; 山本 信之; 中川 和彦; 西尾 和人
    肺癌 60 6 630 - 630 (NPO)日本肺癌学会 2020年10月
  • 非扁平非小細胞肺癌に対するPem+CisとVnr+Cisの比較第III相試験における腫瘍変異負荷の意義(JIPANG-TR)
    坂井 和子; 坪井 正博; 釼持 広知; 後藤 功一; 大平 達夫; 中川 和彦; 細見 幸生; 滝口 裕一; 山本 寛斉; 赤松 弘朗; 佐伯 祥; 杉尾 賢二; 山本 信之; 西尾 和人
    日本癌学会総会記事 79回 OJ18 - 5 2020年10月
  • Hitomi Sakai; Atsuko Koyama; Kaoru Tanaka; Satomi Watanabe; Miki Nakura; Toshiko Yasuda; Makiko Hayashi; Miyuki Endo; Kazuhiko Nakagawa
    Asia-Pacific journal of clinical oncology 16 5 e185-e191  2020年10月 
    PURPOSE: Cancer treatment can alter patient appearance, leading to psychological, social, and behavioral issues. This study aimed to investigate distress and difficulties related to appearance concerns in Japanese cancer patients and to identify information and support needs among them. METHODS: We conducted a questionnaire survey using the Derriford Appearance Scale 59 (DAS59) among cancer patients with a prior history of chemotherapy, molecular targeted therapy, or immunotherapy, who were recruited from the Departments of Medical Oncology and Psychosomatic Medicine, Kindai University Hospital. RESULTS: Participants were 114 patients with a mean age of 62.9 years; 70.2% were female, 86.0% had metastatic or locally advanced unresectable cancer, and 78.1% had concerns about some aspect of their appearance. Mean DAS59 full-scale score was 77.7 ± 36.4. Younger and female participants were found to have higher full-scale scores in univariate analysis (P < .05 for both), and younger participants were found to have higher full-scale scores in multivariate analysis (P < .05). CONCLUSIONS: DAS59 scores had a wide distribution, suggesting that psychological distress due to appearance changes showed large individual differences. Young and female patients tended to have high DAS59 full-scale scores, but some older and male patients also had high scores. Basic information regarding appearance changes should be provided to all patients before initiating cancer treatment. Both information provision prior to treatment and care at the time of actual appearance changes are important, and should be handled through a multidisciplinary approach.
  • Kiyotaka Yoh; Shinji Atagi; Martin Reck; Edward B Garon; Santiago Ponce Aix; Denis Moro-Sibilot; Katherine B Winfree; Bente Frimodt-Moller; Annamaria Zimmermann; Carla Visseren-Grul; Kazuhiko Nakagawa
    Current medical research and opinion 36 10 1667 - 1675 2020年10月 
    OBJECTIVE: In the phase 3 RELAY trial, ramucirumab/erlotinib demonstrated superior progression-free survival (PFS) over placebo/erlotinib in patients with EGFR-mutated metastatic NSCLC (median PFS 19.4 versus 12.4 months; HR = 0.59, 95% CI = 0.46-0.76; p < .0001). Safety was consistent with established profiles for ramucirumab and erlotinib in NSCLC. Here, we present patient-reported outcomes. METHODS: Patients received oral erlotinib (150 mg daily) plus intravenous ramucirumab (10 mg/kg) or placebo Q2W until progressive disease or unacceptable toxicity. Patients completed the Lung Cancer Symptom Scale (LCSS) and EQ-5D questionnaires at baseline and every other cycle. Analyses included time to deterioration (TtD) for LCSS via Kaplan-Meier method and Cox models and changes from baseline using mixed-model repeated-measures regression analysis. RESULTS: Overall patient compliance for LCSS and EQ-5D was >95%. TtD did not differ between treatment arms for LCSS Total Score (HR = 0.962, 95% CI = 0.690-1.343) and Average Symptom Burden Index (HR = 1.012, 95% CI = 0.732-1.400). TtD of individual LCSS items (appetite loss, fatigue, cough, shortness of breath, pain, symptom distress, difficulties with daily activities, quality of life) indicated no difference between arms; however, patient-reported blood in sputum was worse for ramucirumab/erlotinib (HR = 1.987, 95% CI = 1.206-3.275). Results of LCSS mean changes from baseline were consistent with TtD, indicating no significant differences between treatment arms except for blood in sputum. Mean changes from baseline in EQ-5D index score (p = .94) and visual analogue scale (p = .95) revealed no overall differences in health status between treatment arms. CONCLUSIONS: Patients' overall quality of life and symptom burden did not differ with the addition of ramucirumab to erlotinib compared to placebo/erlotinib. These data support the clinical benefit of ramucirumab/erlotinib in untreated EGFR-mutated metastatic NSCLC.
  • Aurélien Marabelle; Marwan Fakih; Juanita Lopez; Manisha Shah; Ronnie Shapira-Frommer; Kazuhiko Nakagawa; Hyun Cheol Chung; Hedy L Kindler; Jose A Lopez-Martin; Wilson H Miller Jr; Antoine Italiano; Steven Kao; Sarina A Piha-Paul; Jean-Pierre Delord; Robert R McWilliams; David A Fabrizio; Deepti Aurora-Garg; Lei Xu; Fan Jin; Kevin Norwood; Yung-Jue Bang
    The Lancet. Oncology 21 10 1353 - 1365 2020年10月 
    BACKGROUND: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. METHODS: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. FINDINGS: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. INTERPRETATION: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
  • Yoshimasa Shiraishi; Junji Kishimoto; Kentaro Tanaka; Shunichi Sugawara; Haruko Daga; Katsuya Hirano; Koichi Azuma; Osamu Hataji; Hidetoshi Hayashi; Motoko Tachihara; Tetsuya Mitsudomi; Takashi Seto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Isamu Okamoto
    Clinical lung cancer 21 5 472 - 476 2020年09月 [査読有り]
     
    BACKGROUND: First-line treatment of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift to platinum combination therapy together with an immune checkpoint inhibitor (ICI). Bevacizumab is expected to enhance not only chemotherapy but also the efficacy of ICIs through blockade of vascular endothelial growth factor-mediated immunosuppression. We have now designed a randomized phase 3 study (APPLE, WJOG11218L, JapicCTI-194565) to evaluate the additional effect of bevacizumab administered together with platinum combination therapy and the ICI atezolizumab in patients with advanced nonsquamous NSCLC. PATIENTS AND METHODS: Cytotoxic chemotherapy-naive patients aged 20 years or older with a performance status of 0 or 1 are randomly assigned in a 1:1 ratio to receive either atezolizumab plus pemetrexed/carboplatin or atezolizumab, pemetrexed/carboplatin, and bevacizumab. Patients with genetic driver alterations such as those affecting EGFR or ALK are included if they have experienced disease progression or unacceptable adverse effects during treatment with at least one approved tyrosine kinase inhibitor. After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab is administered for up to 2 years until evidence of disease progression or development of unacceptable toxicity. The primary end point is progression-free survival. CONCLUSION: This is a phase 3 study to investigate the effect of adding bevacizumab to an ICI and platinum/pemetrexed combination therapy. If the primary objective is achieved, this study will provide a new standard treatment for cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC.
  • Kaoru Tanaka; Satoshi Morita; Masahiko Ando; Takuma Yokoyama; Atsushi Nakamura; Hiroshige Yoshioka; Takashi Ishiguro; Satoru Miura; Ryo Toyozawa; Tetsuya Oguri; Haruko Daga; Ryo Ko; Akihiro Bessho; Motoko Tachihara; Yasuo Iwamoto; Katsuya Hirano; Yoichi Nakanishi; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Isamu Okamoto
    Cancer 126 16 3648 - 3656 2020年08月 
    BACKGROUND: A randomized phase 3 study was performed to investigate the efficacy and safety of maintenance therapy with S-1 after induction therapy with carboplatin plus S-1 in patients with advanced squamous non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-naive patients with advanced or relapsed squamous NSCLC were treated with carboplatin (area under the curve of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1-14 every 3 weeks) as induction therapy. Patients who did not progress after 4 cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective of the study was to confirm the superiority of S-1 plus BSC in comparison with BSC alone with respect to progression-free survival. RESULTS: Of the 365 patients enrolled in the study, 347 participated in the induction phase, and 131 of these individuals were randomized to receive S-1 plus BSC (n = 67) or BSC alone (n = 64). The risk of disease progression was significantly lower for patients in the S-1 plus BSC arm than those in the BSC-alone arm (hazard ratio, 0.548; 95% confidence interval, 0.374-0.802; P = .0019). The most common toxicities during maintenance therapy with S-1 included anorexia, anemia, and fatigue, but most cases were not severe. CONCLUSIONS: Continued maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC previously treated with carboplatin plus S-1.
  • Masaya Yotsukura; Hisao Asamura; Shigeki Suzuki; Keisuke Asakura; Yukihiro Yoshida; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Noriko Motoi
    Data in brief 31 105785 - 105785 2020年08月 [査読有り]
     
    This article presents supplementary data for the research article by Yotsukura et al. entitled "Prognostic impact of cancer-associated active fibroblasts and invasive architectural patterns on early-stage lung adenocarcinoma" [1], which presented the postoperative prognosis for early-stage lung adenocarcinoma categorized according to histological findings. We included data of 1,032 resected cases of lung adenocarcinoma, which consisted of pathological stage IA invasive cancer and adenocarcinoma in situ resected at National Cancer Center Hospital, Tokyo, Japan, between 2007 and 2012. A pathological review was performed to assess total tumor size, size of invasion, histological subtype, lymphovascular invasion, and presence of cancer-associated active fibroblast (CAF). Tumor recurrence and overall survival were retrospectively recorded. Of the included cases, 166 (16.1%), and 866 (83.9%) were adenocarcinoma in situ and pathological stage IA, respectively. Pathological stage IA adenocarcinoma was further classified based on the histologial subtype and the presence of CAF. This data set may be useful for analyzing the postoperative prognosis of early-stage lung adenocarcinoma, in combination with detailed pathological findings including size of invasion, histological subtype, and presence of CAF.
  • 持続する上部消化管出血と高度直腸狭窄を伴うも経口摂取を継続した若年の原発不明癌症例
    酒井 瞳; 川中 雄介; 田中 薫; 武田 真幸; 前田 宗之; 中川 和彦
    Palliative Care Research 15 Suppl. S421 - S421 (NPO)日本緩和医療学会 2020年08月
  • Toshio Shimizu; Kazuto Nishio; Kazuko Sakai; Isamu Okamoto; Kunio Okamoto; Masayuki Takeda; Maiko Morishita; Kazuhiko Nakagawa
    Cancer chemotherapy and pharmacology 86 2 211 - 219 2020年08月 
    PURPOSE: This phase I study was conducted to evaluate the safety and pharmacokinetics of YM155, a potent, selective survivin inhibitor, in combination with erlotinib in patients with EGFR TKI refractory advanced non-small cell lung cancer (NSCLC). METHODS: The pimary objectives were to evaluate the safety and tolerability of YM155 at escalating doses (3.6, 4.8, 6.0, and 8.0 mg/m2/days) administered every 3 weeks as continuous intravenous infusion over 168 h in combination with erlotinib at a fixed dose (150 mg, once a day). Secondary objectives were to assess the pharmacokinetics of YM155, antitumor activity, and the relationship between biomarkers and efficacy. The changes in survivin expression in biopsied tumor pre- and post-YM155 administration and serum cytokine levels were also analyzed. RESULTS: Fifteen patients were treated. The most common YM155-related adverse event was the presence of urine microalbumin, whereas grades 3/4 toxicities were rare. One patient who received 4.8  mg/m2/days YM155 developed a dose-limiting grade 2 serum creatinine elevation. YM155 exposure in plasma showed dose proportionality across all dose ranges tested. No pharmacokinetic interaction occurred between YM155 and erlotinib. The serum cytokines IL-8, G-CSF, and MIP-1b showed decreasing trends in patients who achieved progression-free survival of ≥ 12 weeks. Durable stable disease for ≥ 24 weeks was observed in two patients. CONCLUSION: Up to 8.0 mg/m2/days YM155 administered every 3 weeks in combination with erlotinib exhibited a favorable safety profile and moderate clinical efficacy. These results suggest that inhibiting survivin is a potential therapeutic strategy for select patients with EGFR TKI refractory NSCLC. TRIAL REGISTRATION: UMIN000031912 at UMIN Clinical Trials Registry (UMIN-CTR).
  • Hitomi Sakai; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Molecular and clinical oncology 13 2 175 - 178 2020年08月 
    Anorectal melanoma is a rare disease with a poor prognosis and its response to immunotherapy remains poorly studied. The current study reports a case of recurrent anorectal melanoma in a 60-year-old woman that has exhibited a durable response to ipilimumab for >2 years. Given that the combination of nivolumab and ipilimumab was not approved for use in unresectable or metastatic melanoma at the time of presentation, the patient was initially treated with nivolumab monotherapy and switched to ipilimumab after nivolumab failure. The tumor was microsatellite stable, had an intermediate tumor mutation burden and was negative for programmed cell death-ligand-1 expression. However, the neutrophil-to-lymphocyte ratio in peripheral blood remained at <5 throughout the disease course. Although mucosal melanoma is not caused by ultraviolet radiation and has a lower mutation burden than cutaneous melanoma, the present case responded well to immunotherapy. Further evaluation of potential biomarkers for such patients is required.
  • Hiroaki Kanemura; Masayuki Takeda; Kazuhiko Nakagawa
    Translational lung cancer research 9 4 1617 - 1622 2020年08月
  • Kazuo Nakagawa; Yukihiro Yoshida; Masaya Yotsukura; Shun-Ichi Watanabe
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2020年07月 [査読有り]
     
    OBJECTIVES: The prognosis of patients with mediastinal lymph node (LN) metastasis (pN2 stage III disease) is still unsatisfactory. Both systemic and local recurrence should be prevented after curative surgery. The aim of this study was to explore the pattern of recurrence in patients with completely resected pN2 non-small-cell lung cancer (NSCLC) in the era of adjuvant chemotherapy. METHODS: We investigated 337 patients with completely resected cN0-1 and pN2 NSCLC from 2005 to 2016 at National Cancer Center Hospital, Japan. The patterns of recurrence were compared between patients who were managed by observation alone and those with adjuvant chemotherapy. In patients with regional LN recurrence, the pattern and site of recurrence were also explored. RESULTS: There were 195 (58.5%) men and 142 (41.5%) women with a mean age of 63.2 years. Fifty-five (16.3%) patients developed only regional LN recurrence, 116 (32.6%) patients developed only distant recurrence and 65 (19.3%) patients developed both regional LN recurrence and distant recurrence. The difference in the pattern of recurrence between patients with observation alone and those with adjuvant chemotherapy was not statistically significant (P = 0.145). As for the pattern of regional LN recurrence, 68 (20.2%) patients had LN recurrence inside the systematic nodal dissection area. CONCLUSIONS: Regional LN recurrence was observed in >30% of patients with completely resected pN2 NSCLC. About 20% of patients had recurrence inside the systematic nodal dissection area. Postoperative radiotherapy might be considered as an additional treatment strategy for these patients.
  • Yukihiro Yoshida; Masaya Yotsukura; Kazuo Nakagawa; Hirokazu Watanabe; Noriko Motoi; Shun-Ichi Watanabe
    The Thoracic and cardiovascular surgeon 2020年07月 [査読有り]
     
    BACKGROUND:  This retrospective study investigated the prognosis of patients with pathological N1 (pN1) nonsmall cell lung cancer (NSCLC). METHODS:  We included patients with pN1 NSCLC who underwent lobectomy or pneumonectomy with mediastinal lymph node dissection and achieved complete resection (R0) between January 2000 and December 2012. Patients who received neoadjuvant therapy were excluded. RESULTS:  A total of 249 patients were included. The mean age was 63.2 years, and 172 patients were males. Of the 249 patients, 200, 20, and 29 underwent lobectomy, bilobectomy, and pneumonectomy, respectively. The median observation period was 5.5 years. The 5-year overall survival (OS) rate was 64.6% (95% confidence interval: 58.3-70.4). Five-year OS rates were 79.8% for positive lymph nodes at station 13 or 14 (n = 57), 59.6% at station 12 (n = 72), 62.7% at station 11 (n = 69), and 56.9% at station 10 (n = 51) (log-rank test; p = 0.016); furthermore, the 5-year OS rate was 75.2% for patients with positive lymph nodes at a single station (n = 160) and 45.4% for patients with positive lymph nodes at multiple stations (n = 89) (log-rank test; p < 0.001). Five-year cumulative incidences of recurrence were equivalent between patients who received adjuvant chemotherapy and patients who did not (45.9 vs. 55.1%; Gray's test; p = 0.366). Distant recurrence was the most frequent mode of recurrence in both groups (70.8 and 67.3%). CONCLUSION:  The locations and the number of stations of the positive lymph nodes were identified as prognostic factors in patients with pN1 NSCLC. The primary mode of recurrence was distant recurrence irrespective of postoperative adjuvant chemotherapy.
  • Masaya Yotsukura; Hisao Asamura; Shigeki Suzuki; Keisuke Asakura; Yukihiro Yoshida; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Noriko Motoi
    Lung cancer (Amsterdam, Netherlands) 145 158 - 166 2020年07月 [査読有り]
     
    BACKGROUND: Invasion is a crucial indicator of the prognosis in lung adenocarcinoma. The 2015 WHO classification of lung tumors defined invasion of adenocarcinoma mainly by the presence of non-lepidic histological subtypes including papillary, acinar, micropapillary and solid patterns, and the presence of cancer-associated active fibroblasts (CAF). In this study, we focused specifically on early-stage lepidic adenocarcinoma with CAF to evaluate its prognostic significance. METHODS: We included 1032 resected cases of lung adenocarcinoma, which consisted of pathological stage IA invasive cancer and adenocarcinoma in situ (AIS). Invasive adenocarcinoma was classified into two subgroups according to the type of invasion, INV-1 and INV-2. We defined INV-1 as adenocarcinoma of a non-lepidic histological subtype with or without CAF, and INV-2 as lepidic adenocarcinoma with CAF. The clinicopathological characteristics and prognosis were retrospectively analyzed. RESULTS: Included cases were classified into 696 (67.4 %) INV-1, 170 (16.5 %) INV-2, and 166 (16.1 %) AIS. The estimated 5-year recurrence-free probabilities of INV-1, INV-2, and AIS were 92.9 %, 100 %, and 100 %, respectively (p <  0.001). Although there were significant differences between INV-1 and INV-2 in terms of gender (more males in INV-1, p =  0.039), smoking habit (more smokers in INV-1, p =  0.046), and lymphovascular invasion (more invasion in INV-1, p <  0.001), there was no difference between AIS and INV-2. CONCLUSION: The presence of CAF is not always associated with a worse prognosis, and therefore it does not seem appropriate to include the presence of CAF alone in diagnostic criteria for invasion in early-stage lung adenocarcinoma.
  • Aki K Kobayashi; Hidehito Horinouchi; Yuko Nakayama; Yuichiro Ohe; Masaya Yotsukura; Shinsuke Uchida; Keisuke Asakura; Yukihiro Yoshida; Kazuo Nakagawa; Shun-Ichi Watanabe
    Lung cancer (Amsterdam, Netherlands) 145 105 - 110 2020年07月 [査読有り]
     
    BACKGROUND: Local recurrence after definitive chemoradiation therapy, chemotherapy or radiotherapy with curative intent is often seen in patients with advanced non-small cell lung cancer. We evaluated the feasibility of salvage pulmonary resection after definitive non-surgical treatments and the postoperative morbidity and mortality rates. METHODS: We retrospectively analyzed the characteristics and medical courses of patients who had undergone salvage pulmonary resections after local relapse or progression between January 2000 and March 2018 at the National Cancer Centre Hospital, Tokyo, Japan. All the candidates were evaluated, and curability by surgical resection was assessed by a multidisciplinary tumor board. RESULTS: A total of 38 patient received salvage surgery: 26 of the patients were men, and the median age was 64.5 years (range, 20-78 years). Among these 38 patients, salvage lung resection was performed after chemoradiotherapy in 23 patients, after chemotherapy in 9 patients, and after radiotherapy with curative intent in 6 patients. The surgical resection methods were as follows: 26 lobectomies (2 bilobectomy, 15 right upper, 5 right lower, 1 right middle, 2 left lower and 1 left upper), 8 pneumonectomies (5 left and 3 right), and 4 segmentectomies. A complete resection (R0 resection) was achieved in 35 cases (92.1 %). Postoperative complications were observed in 3 patients (prolonged air leakage, bronchopleural fistula and surgical site infection in 1 patient each). No postoperative deaths occurred within 30 days after surgery. CONCLUSION: Along with better outcomes after definitive chemoradiotherapy, chemotherapy, and radiotherapy, the frequency of salvage surgery has been increasing in recent years. Salvage pulmonary resections after definitive non-surgical treatments with curative intent are feasible with an acceptable morbidity rate and oncological outcomes in thoroughly assessed patients.
  • 黒崎 隆; 川上 尚人; 中川 和彦
    日本消化器病学会雑誌 117 臨増総会 A26 - A26 (一財)日本消化器病学会 2020年07月
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木 慎一郎; 田中 薫; 佐藤 千尋; 金村 宙昌; 磯本 晃佑; 加藤 了資; 原谷 浩司; 三谷 誠一郎; 林 秀敏; 北野 睦三; 石川 一樹; 土井 勝美; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 151 - 151 (一社)日本頭頸部癌学会 2020年07月
  • 当院における分化型甲状腺癌および未分化癌に対するレンバチニブの使用経験
    吉田 健史; 田中 薫; 中川 和彦
    頭頸部癌 46 2 214 - 214 (一社)日本頭頸部癌学会 2020年07月
  • 頭頸部癌における免疫チェックポイント阻害薬後のセツキシマブ使用の有効性および安全性
    三谷 誠一郎; 田中 薫; 鈴木 慎一郎; 原谷 浩司; 文田 壮一; 川上 尚人; 吉田 健史; 林 秀敏; 北野 睦三; 土井 勝美; 石川 一樹; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 218 - 218 (一社)日本頭頸部癌学会 2020年07月
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木 慎一郎; 田中 薫; 佐藤 千尋; 金村 宙昌; 磯本 晃佑; 加藤 了資; 原谷 浩司; 三谷 誠一郎; 林 秀敏; 北野 睦三; 石川 一樹; 土井 勝美; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 151 - 151 (一社)日本頭頸部癌学会 2020年07月
  • 頭頸部癌における免疫チェックポイント阻害薬後のセツキシマブ使用の有効性および安全性
    三谷 誠一郎; 田中 薫; 鈴木 慎一郎; 原谷 浩司; 文田 壮一; 川上 尚人; 吉田 健史; 林 秀敏; 北野 睦三; 土井 勝美; 石川 一樹; 西村 恭昌; 中川 和彦
    頭頸部癌 46 2 218 - 218 (一社)日本頭頸部癌学会 2020年07月
  • Naohiro Makise; Taisuke Mori; Hiroshi Kobayashi; Kazuo Nakagawa; Eijitsu Ryo; Jun Nakajima; Shinji Kohsaka; Hiroyuki Mano; Hiroyuki Aburatani; Akihiko Yoshida; Tetsuo Ushiku
    Histopathology 76 7 1023 - 1031 2020年06月 [査読有り]
     
    AIMS: Ectomesenchymal chondromyxoid tumour (ECT) is a rare benign intraoral tumour which almost exclusively presents as a small mass of the anterior dorsal tongue. Recently, the RREB1-MRTFB (previously known as MKL2) fusion gene has been identified in 90% of ECTs, all located in the tongue, emphasising its genetic distinctiveness. Here, we report two mesenchymal tumours involving the superior mediastinum of adult women with RREB1-MRTFB fusions. METHODS AND RESULTS: Both tumours presented as well-circumscribed paravertebral masses that were clinically suspected to be schwannoma. After fragmented resection, recurrence was not observed at 27 and 18 months. Although tumours were originally unclassifiable, next-generation sequencing detected identical RREB1 (exon 8)-MRTFB (exon 11) fusion transcripts, which were validated by reverse transcriptase-polymerase chain reaction, Sanger sequencing, and fluorescence in-situ hybridisation. Both tumours shared hyalinised areas with round cells embedded in a cord or reticular manner. The tumour cells showed mild nuclear atypia of possible degenerative type with very low mitotic activity, and were at least focally positive for S100, glial fibrillary acidic protein, smooth muscle actin and epithelial membrane antigen. Overall, these findings suggest that they may represent previously undescribed extra-glossal ECT involving the mediastinum. However, the histology was not classic for ECT, because that in case 2 was predominated by storiform growth of spindle cells, whereas the tumour in case 1 lacked myxoid change. CONCLUSIONS: We have provided the first evidence that RREB1-MRTFB fusion is not limited to tumours in the head region, and whether such tumours represent extra-glossal ECTs requires further research.
  • 鈴木 慎一郎; 田中 薫; 金村 宙昌; 磯本 晃佑; 原谷 浩二; 林 秀敏; 武田 真幸; 中川 和彦
    気管支学 42 Suppl. S390 - S390 (NPO)日本呼吸器内視鏡学会 2020年06月
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    気管支学 42 Suppl. S391 - S391 (NPO)日本呼吸器内視鏡学会 2020年06月
  • Naiyer A Rizvi; Byoung Chul Cho; Niels Reinmuth; Ki Hyeong Lee; Alexander Luft; Myung-Ju Ahn; Michel M van den Heuvel; Manuel Cobo; David Vicente; Alexey Smolin; Vladimir Moiseyenko; Scott J Antonia; Sylvestre Le Moulec; Gilles Robinet; Ronald Natale; Jeffrey Schneider; Frances A Shepherd; Sarayut Lucien Geater; Edward B Garon; Edward S Kim; Sarah B Goldberg; Kazuhiko Nakagawa; Rajiv Raja; Brandon W Higgs; Anne-Marie Boothman; Luping Zhao; Urban Scheuring; Paul K Stockman; Vikram K Chand; Solange Peters
    JAMA oncology 6 5 661 - 674 2020年05月 
    Importance: Checkpoint inhibitors targeting programmed cell death 1 or its ligand (PD-L1) as monotherapies or in combination with anti-cytotoxic T-lymphocyte-associated antigen 4 have shown clinical activity in patients with metastatic non-small cell lung cancer. Objective: To compare durvalumab, with or without tremelimumab, with chemotherapy as a first-line treatment for patients with metastatic non-small cell lung cancer. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (MYSTIC) was conducted at 203 cancer treatment centers in 17 countries. Patients with treatment-naive, metastatic non-small cell lung cancer who had no sensitizing EGFR or ALK genetic alterations were randomized to receive treatment with durvalumab, durvalumab plus tremelimumab, or chemotherapy. Data were collected from July 21, 2015, to October 30, 2018. Interventions: Patients were randomized (1:1:1) to receive treatment with durvalumab (20 mg/kg every 4 weeks), durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy. Main Outcomes and Measures: The primary end points, assessed in patients with ≥25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory. Results: Between July 21, 2015, and June 8, 2016, 1118 patients were randomized. Baseline demographic and disease characteristics were balanced between treatment groups. Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab vs 12.9 months (95% CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P = .04 [nonsignificant]). Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17; P = .20). Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab vs 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53; P = .71). Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab vs chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74). Treatment-related adverse events of grade 3 or higher occurred in 55 (14.9%) of 369 patients who received treatment with durvalumab, 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy. These adverse events led to death in 2 (0.5%), 6 (1.6%), and 3 (0.9%) patients, respectively. Conclusions and Relevance: The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1. Exploratory analyses identified a bTMB threshold of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab. Trial Registration: ClinicalT rials.gov Identifier: NCT02453282.
  • Hidetoshi Hayashi; Kazuhiko Nakagawa
    International journal of clinical oncology 25 5 818 - 830 2020年05月 [査読有り]
     
    Immune checkpoint inhibitors (ICIs)-such as antibodies to programmed cell death-1 (PD-1), to its ligand PD-L1, or to cytotoxic T lymphocyte-associated protein-4 (CTLA-4)-are an evolving treatment option for several types of cancer, but only a limited number of patients benefit from such therapy. Preclinical studies have suggested that the combination of PD-1 or PD-L1 inhibitors with either cytotoxic chemotherapy or antibodies to CTLA-4 is a promising treatment strategy for advanced cancer. Indeed, combinations of cytotoxic chemotherapy and PD-1/PD-L1 inhibitors have been approved and are now used in clinical practice for the treatment of advanced non-small cell lung cancer and small cell lung cancer on the basis of positive results of large-scale clinical trials. In addition, the combination of antibodies to CTLA-4 (ipilimumab) and to PD-1 (nivolumab) has been found to confer a survival benefit in patients with melanoma or renal cell carcinoma. Several ongoing clinical trials are also investigating ICI combination therapy in comparison with standard therapy for other tumor types. The identification of patients likely to achieve a sufficient benefit from PD-1/PD-L1 inhibitor monotherapy remains a challenge; however, with the establishment of novel complementary biomarkers being needed. Preclinical and clinical investigations of immune-related adverse events of ICI combination therapy are also warranted to establish management strategies. In this review, we summarize the current landscape of combination therapy with PD-1/PD-L1 inhibitors plus either cytotoxic chemotherapy or CTLA-4 inhibitors to clarify the benefits of and outstanding clinical issues related to such treatment.
  • Makoto Nishio; Terufumi Kato; Seiji Niho; Noboru Yamamoto; Toshiaki Takahashi; Naoyuki Nogami; Hiroyasu Kaneda; Yuka Fujita; Keith Wilner; Mizuki Yoshida; Mitsuhiro Isozaki; Shinsuke Wada; Fumito Tsuji; Kazuhiko Nakagawa
    Cancer science 111 5 1724 - 1738 2020年05月 [査読有り]
     
    In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first-line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28-d cycles, in patients with EGFR-activating mutation-positive (EGFR-positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non-small cell lung cancer (NSCLC). The primary endpoint was progression-free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307-0.961]; 2-sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0-31.3] mo, 9.3 [95% CI, 7.4-14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first-line dacomitinib in Japanese patients with EGFR-positive advanced NSCLC.
  • Isamu Okamoto; Hiroshi Nokihara; Shogo Nomura; Seiji Niho; Shunichi Sugawara; Hidehito Horinouchi; Koichi Azuma; Yasuto Yoneshima; Haruyasu Murakami; Yukio Hosomi; Shinji Atagi; Tomohiro Ozaki; Atsushi Horiike; Yuka Fujita; Hiroaki Okamoto; Masahiko Ando; Nobuyuki Yamamoto; Yuichiro Ohe; Kazuhiko Nakagawa
    JAMA oncology 6 5 e196828  2020年05月 [査読有り]
     
    Importance: Few clinical trials have been specifically designed for elderly patients with advanced non-small cell lung cancer (NSCLC), and the anticipated increase in the number of such patients has prompted a search for new treatment options that provide a greater palliative benefit. Objective: To determine whether treatment with carboplatin plus pemetrexed followed by pemetrexed maintenance is noninferior compared with docetaxel monotherapy with regard to overall survival (OS) for elderly patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: This open-label, multicenter, noninferiority phase 3 randomized clinical trial was conducted at 79 institutions in Japan. Cytotoxic chemotherapy-naive patients with advanced nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and age of 75 years or older were enrolled between August 2013 and February 2017. Data were analyzed from November 2018 to February 2019. Interventions: Patients were randomized to receive either docetaxel monotherapy (60 mg/m2) every 3 weeks or 4 cycles of carboplatin (area under the curve of 5) plus pemetrexed (500 mg/m2) administered every 3 weeks followed by maintenance therapy with the same dose of pemetrexed for 3 weeks. Main Outcomes and Measures: The primary end point was OS analyzed on an intention-to-treat basis with a noninferiority margin of 1.154 for the upper limit of the 95% CI of the hazard ratio (HR) estimated with a stratified Cox regression model. Results: Of the 433 enrolled patients, 250 (57.7%) were male, and the median (range) age was 78 (75-88) years. The median OS was 15.5 months (95% CI, 13.6-18.4) in the docetaxel group (n = 217) and 18.7 months (95% CI, 16.0-21.9) in the carboplatin-pemetrexed group (n = 216), with a stratified HR for OS of 0.850 (95% CI, 0.684-1.056; P for noninferiority = .003). Progression-free survival was also longer in the carboplatin-pemetrexed group (unstratified HR, 0.739; 95% CI, 0.609-0.896). Compared with those in the docetaxel group, those in the carboplatin-pemetrexed had lower rates of leukopenia (60 of 214 [28.0%] vs 147 of 214 [68.7%]) and neutropenia (99 of 214 [46.3%] vs 184 of 214 [86.0%]) of grade 3 or 4 and of febrile neutropenia (9 of 214 [4.2%] vs 38 of 214 [17.8%]) and higher rates of thrombocytopenia (55 of 214 [25.7%] vs 3 of 214 [1.4%]) and anemia (63 of 214 [29.4%] vs 4 of 214 [1.9%]) of grade 3 or 4. Dose reductions were less frequent with carboplatin-pemetrexed. Conclusion and Relevance: Carboplatin-pemetrexed treatment followed by pemetrexed maintenance is a valid option for first-line treatment of elderly patients with advanced nonsquamous NSCLC. Trial Registration: University Hospital Medical Information Network Clinical Trials Registry Identifier: UMIN000011460.
  • Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa
    BMC medicine 18 1 111 - 111 2020年04月
  • Kohsuke Isomoto; Koji Haratani; Hidetoshi Hayashi; Shigeki Shimizu; Shuta Tomida; Takashi Niwa; Toshihide Yokoyama; Yasushi Fukuda; Yasutaka Chiba; Ryoji Kato; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Takashi Ogura; Tadashi Ishida; Akihiko Ito; Kazuhiko Nakagawa
    Clinical cancer research : an official journal of the American Association for Cancer Research 26 8 2037 - 2046 2020年04月 [査読有り]
     
    PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.
  • 金村 宙昌; 林 秀敏; 原谷 浩司; 米阪 仁雄; 中川 和彦; 萩原 智; 工藤 正俊; 大谷 知之; 伊藤 彰彦
    肺癌 60 2 149 - 150 (NPO)日本肺癌学会 2020年04月
  • 佐藤 千尋; 林 秀敏; 田中 薫; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 60 2 155 - 155 (NPO)日本肺癌学会 2020年04月
  • 鈴木 慎一郎; 原谷 浩司; 加藤 了資; 林 秀敏; 中川 和彦; 谷崎 潤子; 尾崎 智博; 岡部 崇記; 明石 雄策; 長谷川 喜一; 西尾 和人; 伊藤 彰彦
    肺癌 60 2 155 - 156 (NPO)日本肺癌学会 2020年04月
  • 米阪 仁雄; 林 秀敏; 鈴木 慎一郎; 加藤 了資; 武田 真幸; 中川 和彦; 岩間 映二; 岡本 勇; 安宅 信二; 西尾 和人
    肺癌 60 2 160 - 160 (NPO)日本肺癌学会 2020年04月
  • 加藤 了資; 林 秀敏; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 野長瀬 祥兼; 田中 薫; 吉田 健史; 武田 真幸; 米阪 仁雄; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖
    肺癌 60 2 148 - 148 (NPO)日本肺癌学会 2020年04月
  • 西尾 和人; 坂井 和子; 櫻井 俊治; 上嶋 一臣; 永井 知行; 林 秀敏; 川上 尚人; 高濱 隆幸; 武田 真幸; 中川 和彦
    肺癌 60 2 165 - 165 (NPO)日本肺癌学会 2020年04月
  • 原谷 浩司; 米阪 仁雄; 中川 和彦; 前西 修
    肺癌 60 2 160 - 160 (NPO)日本肺癌学会 2020年04月
  • 三谷 誠一郎; 川上 尚人; 中川 和彦
    臨床消化器内科 35 5 495 - 500 (株)日本メディカルセンター 2020年04月 
    ＜文献概要＞免疫チェックポイント阻害薬単剤の有効性は限定的であり,併用療法により,その有効性を高める試みが進んでいる.多くの併用療法が臨床試験において検討されている段階である.その代表的なものは,殺細胞性抗がん剤との併用,免疫チェックポイント阻害薬同士の併用であり,加えて,分子標的治療薬との併用も検討されている.治療開発が先行する他がん種の現況も紹介しつつ,消化器がんに対する免疫チェックポイント阻害薬と他剤との併用について解説する.
  • 磯本 晃佑; 原谷 浩司; 林 秀敏; 加藤 了資; 田中 薫; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦; 冨田 秀太; 丹羽 崇; 小倉 高志; 横山 俊秀; 福田 泰; 石田 直; 千葉 康敬; 谷崎 潤子
    肺癌 60 2 149 - 149 (NPO)日本肺癌学会 2020年04月
  • 田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 60 2 153 - 153 (NPO)日本肺癌学会 2020年04月
  • 岩朝 勤; 黒崎 隆; 鈴木 慎一郎; 田中 薫; 武田 真幸; 中川 和彦
    肺癌 60 2 164 - 164 (NPO)日本肺癌学会 2020年04月
  • CAPP-Seqを用いたLiquid biopsyによるT790M陽性非小細胞肺癌のオシメルチニブ耐性因子の検討
    加藤 了資; 林 秀敏; 原谷 浩司; 高濱 隆幸; 谷崎 潤子; 野長瀬 祥兼; 田中 薫; 吉田 健史; 武田 真幸; 米阪 仁雄; 中川 和彦; 坂井 和子; 西尾 和人; 金田 裕靖
    肺癌 60 2 148 - 148 (NPO)日本肺癌学会 2020年04月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響
    磯本 晃佑; 原谷 浩司; 林 秀敏; 加藤 了資; 田中 薫; 武田 真幸; 中川 和彦; 清水 重喜; 伊藤 彰彦; 冨田 秀太; 丹羽 崇; 小倉 高志; 横山 俊秀; 福田 泰; 石田 直; 千葉 康敬; 谷崎 潤子
    肺癌 60 2 149 - 149 (NPO)日本肺癌学会 2020年04月
  • 当院の非小細胞肺癌患者に対する遺伝子パネル検査の使用経験
    田中 薫; 鈴木 慎一郎; 金村 宙昌; 渡邉 諭美; 吉田 健史; 武田 真幸; 林 秀敏; 清水 重喜; 伊藤 彰彦; 中川 和彦
    肺癌 60 2 153 - 153 (NPO)日本肺癌学会 2020年04月
  • 免疫チェックポイント阻害薬奏効後に転移巣増大を来した肺癌症例の遺伝子的検討
    佐藤 千尋; 林 秀敏; 田中 薫; 武田 真幸; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 60 2 155 - 155 (NPO)日本肺癌学会 2020年04月
  • 肺線維症をもつ悪性胸膜中皮腫患者へのニボルマブ使用報告
    岩朝 勤; 黒崎 隆; 鈴木 慎一郎; 田中 薫; 武田 真幸; 中川 和彦
    肺癌 60 2 164 - 164 (NPO)日本肺癌学会 2020年04月
  • Takashi Seto; Koichi Azuma; Takeharu Yamanaka; Shunichi Sugawara; Hiroshige Yoshioka; Kazushige Wakuda; Shinji Atagi; Yasuo Iwamoto; Hidetoshi Hayashi; Isamu Okamoto; Hideo Saka; Shigeki Mitsuoka; Daichi Fujimoto; Kazumi Nishino; Atsushi Horiike; Haruko Daga; Takashi Sone; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yoichi Nakanishi
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 38 8 793 - 803 2020年03月 [査読有り]
     
    PURPOSE: Patients with non-small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy. PATIENTS AND METHODS: Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment. RESULTS: Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens. CONCLUSION: In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.
  • 渡邉 諭美; 中川 和彦
    薬局 71 4 2137 - 2140 (株)南山堂 2020年03月
  • 【病気とくすり2020 基礎と実践Expert's Guide】病原微生物・悪性新生物とくすり 悪性腫瘍 頭頸部癌
    田中 薫; 中川 和彦
    薬局 71 4 2125 - 2128 (株)南山堂 2020年03月
  • Hiroaki Kanemura; Hidetoshi Hayashi; Satoru Hagiwara; Tomoyuki Otani; Koji Haratani; Kimio Yonesaka; Akihiko Ito; Masatoshi Kudo; Kazuhiko Nakagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 3 e39-e42  2020年03月 [査読有り]
  • Nahomi Tokudome; Yasuhiro Koh; Hiroaki Akamatsu; Daichi Fujimoto; Isamu Okamoto; Kazuhiko Nakagawa; Toyoaki Hida; Fumio Imamura; Satoshi Morita; Nobuyuki Yamamoto
    BMC cancer 20 1 103 - 103 2020年02月 [査読有り]
     
    BACKGROUND: Epidermal growth factor receptor (EGFR)-sensitizing mutation, exon 19 deletion consists of several molecular variants. Influences of these variants on clinical response to EGFR tyrosine kinase inhibitors remain elusive. METHODS: West Japan Oncology Group 8114LTR is a prospective, multi-institutional biomarker study. Treatment naïve, advanced non-small-cell lung cancer patients with EGFR-sensitizing mutation received afatinib monotherapy. We conducted a preplanned subset analysis of patients harboring exon 19 deletion. Tumor tissue exon 19 deletion molecular variants were identified by blocking-oligo-dependent polymerase chain reaction (PCR) and by Luminex Technology. Plasma cfDNA was also obtained before and after the treatment and EGFR mutations were detected with multiplexed, pico-droplet digital PCR assay. RESULTS: Among 57 registered patients, twenty-nine patients were exon 19 deletion. Tissue DNA and cfDNA were available in 26 patients. Among the detected seven molecular variants, the most frequent was p.E746_A750delELREA (65.4%). According to the various classifications of molecular variants, twenty one (80.8%) were classified into 15-nucleotide deletion, one (3.8%) into 18-nucleotide deletion, and four patients (15.4%) into other insertion/substitution variant subgroups. The patient subgroup with 15-nucleotide deletion showed significantly longer progression-free survival than patients in other mixed insertion/substitution variant subgroup (p = 0.0244). CONCLUSIONS: The clinical significance of molecular variants of exon 19 deletion on the first line afatinib monotherapy is reported here for the first time. Further investigation is needed for development of better therapeutic strategies. TRIAL REGISTRATION: This trial was registered at UMIN Clinical Trials Registry at 2014/12/4 (UMIN000015847).
  • 消化器がん薬物療法up to date 切除不能進行再発胃癌に対するニボルマブ単独療法の臨床的予後予測因子の検討
    黒崎 隆; 川上 尚人; 三谷 誠一郎; 中川 和彦
    日本消化器病学会近畿支部例会プログラム・抄録集 112回 71 - 71 日本消化器病学会-近畿支部 2020年02月
  • Pulmonary tumor thrombotic microangiopathy(PTTM)により急激な転機をたどった下咽頭癌患者の一例
    川中 雄介; 川上 尚人; 中川 和彦; 吉田 健史; 清水 重喜
    日本内科学会雑誌 109 Suppl. 231 - 231 (一社)日本内科学会 2020年02月
  • irAE大腸炎を契機にICIの関与が疑われたStevens-Johnson症候群の1例
    黒崎 隆; 川上 尚人; 文田 壮一; 三谷 誠一郎; 中川 和彦
    日本内科学会雑誌 109 Suppl. 260 - 260 (一社)日本内科学会 2020年02月
  • Ryoji Kato; Hidetoshi Hayashi; Yasutaka Chiba; Eriko Miyawaki; Junichi Shimizu; Tomohiro Ozaki; Daichi Fujimoto; Ryo Toyozawa; Atsushi Nakamura; Toshiyuki Kozuki; Kentaro Tanaka; Shunsuke Teraoka; Kazuhiro Usui; Kazumi Nishino; Osamu Hataji; Keiichi Ota; Noriyuki Ebi; Sho Saeki; Yuki Akazawa; Motoyasu Okuno; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Journal for immunotherapy of cancer 8 1 2020年02月 [査読有り]
     
    BACKGROUND: Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response for non-small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of chemotherapy after PD-1 inhibitor treatment (CAP) compared with chemotherapy alone. METHODS: We conducted a retrospective observational cohort study for patients treated at 47 institutions across Japan between April 1, 2014 and July 31, 2017. Eligible patients had advanced or recurrent NSCLC who have undergone chemotherapy. Patients subsequently treated with chemotherapy (docetaxel with or without ramucirumab, S-1 or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort) were included. The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors. RESULTS: A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics-including age, histology, EGFR or ALK genetic alterations, and brain metastasis-differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 11.0% for the control cohort (ORR ratio 1.71; 95% CI 1.19 to 2.46; p=0.004). IPW-adjusted Kaplan-Meier curves showed that median progression-free survival (PFS) for the CAP and control cohorts was 2.8 and 2.7 months (IPW-adjusted HR 0.95; 95% CI 0.80 to 1.12; p=0.55), and median overall survival (OS) was 9.2 and 10.4 months (IPW-adjusted HR 1.05; 95% CI 0.86 to 1.28; p=0.63), respectively. CONCLUSIONS: After accounting for selection bias by propensity score analysis, CAP showed a significantly higher ORR compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into a PFS or OS advantage, suggesting that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.
  • Koji Haratani; Kimio Yonesaka; Shiki Takamura; Osamu Maenishi; Ryoji Kato; Naoki Takegawa; Hisato Kawakami; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Junji Tsurutani; Kazuto Nishio; Katsumi Doi; Masaaki Miyazawa; Kazuhiko Nakagawa
    The Journal of clinical investigation 130 1 374 - 388 2020年01月 [査読有り]
     
    Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3-targeting (HER3-targeting) antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti-PD-1 therapy, we found that treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd, the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins, including high-mobility group box-1 (HMGB-1), via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor-resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.
  • Hiroyuki Ito; Kenji Suzuki; Tomonori Mizutani; Keiju Aokage; Masashi Wakabayashi; Haruhiko Fukuda; Shun ichi Watanabe; Teruaki Koike; Yasuhiro Tsutani; Hisashi Saji; Kazuo Nakagawa; Yoshitaka Zenke; Kazuya Takamochi; Tadashi Aoki; Jiro Okami; Hiroshige Yoshioka; Satoshi Shiono; Morihito Okada
    Journal of Thoracic and Cardiovascular Surgery 2020年 [査読有り]
     
    © 2020 Objective: The aim of this study was to assess long-term outcomes after lobectomy in patients with clinical T1 N0 lung cancer based on thin-section computed tomography. Methods: We collected the data of patients with pathological adenocarcinoma who had undergone lobectomy. The patients were categorized into 4 groups according to a consolidation tumor ratio and tumor size. Groups A and B included tumors with consolidation tumor ratio ≤0.5 and size ≤3 cm. Group A consisted of tumors ≤2 cm. Group B consisted of the remaining tumors. Groups C and D consisted of tumors with consolidation tumor ratio >0.5. Group C consisted of those with tumors ≤2 cm and Group D consisted of tumors of size 2 to 3 cm. The 10-year overall survival and recurrence-free survival rates were examined. Results: Among the 543 patients, the 10-year overall survival was 80.4% and the 10-year recurrence-free survival rate was 77.1%. The 10-year overall survival for group A was 94.0%, 92.7% for group B, 84.1% for group C, and 68.8% for group D, and the 10-year recurrence-free survival rate for each group was 94.0%, 89.0%, 79.7%, and 66.1%, respectively. Group A + B showed better overall survival than group C + D (hazard ratio, 2.78; 95% confidence interval, 1.45-5.06) and better 10-year recurrence-free survival (hazard ratio, 2.74; 95% confidence interval, 1.55-4.88). No patient in group A had recurrence. Conclusions: Those patients with total tumor size ≤3 cm and consolidation tumor ratio ≤0.5 showed excellent prognosis and might be suitable candidates for sublobar resection. If noninferior survival of segmentectomy compared with lobectomy is confirmed in an ongoing Japan Clinical Oncology Group trial, segmentectomy will be included in the standard of care.
  • Yusuke Kawanaka; Hisato Kawakami; Shigeki Shimizu; Takeshi Yoshida; Hidetoshi Hayashi; Kazuto Nishio; Takao Satou; Kazuhiko Nakagawa
    Case Reports in Oncology 13 2 843 - 848 2020年 
    Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by tumor cell microemboli with occlusive fibrointimal remodeling in small pulmonary vessels. Platelet-derived growth factor (PDGF) has been implicated in the development of PTTM, and fibroblast growth factor (FGF) promotes PDGF signaling via PDGF receptor ß. We here describe a cancer patient who presented with dyspnea of uncertain etiology and whose condition worsened rapidly. A 68-year-old man with hypopharyngeal squamous cell carcinoma (cT4aN2bM0, stage IVA) was treated with surgery followed by radiation. Two years later, a lung metastatic lesion was surgically removed on the basis of suspected primary lung cancer. The patient was thereafter monitored without chemotherapy. Two months later, he had third-degree burns and received conservative therapy including debridement and application of trafermin (FGF2) spray. Two weeks later, he was hospitalized with complaints of fever and dyspnea. Pneumonia and pulmonary embolism were ruled out by chest computed tomography with pulmonary arterio-graphy, whereas intravascular lymphoma was excluded by laboratory testing. Malignant cells were detected in his peripheral blood on hospital day 8, and their number increased gradually thereafter. His respiratory symptoms worsened, and the patient died on hospital day 10. We concluded that the cause of death was PTTM, with the clinical course suggesting a possible relation to trafermin. This suggestion was supported by the detection of FGF receptor 2 overexpression in the primary tumor by immunostaining.
  • TAKASHI KUROSAKI; HISATO KAWAKAMI; SEIICHIRO MITANI; RYOHEI KAWABATA; TAKAYUKI TAKAHAMA; YOSHIKANE NONAGASE; SOICHI FUMITA; TOMOHIRO OZAKI; YASUTAKA CHIBA; TAKAO TAMURA; KAZUHIKO NAKAGAWA
    In Vivo 34 4 1921 - 1929 2020年
  • Helen Brown; Johan Vansteenkiste; Kazuhiko Nakagawa; Manuel Cobo; Thomas John; Craig Barker; Alexander Kohlmann; Alexander Todd; Matilde Saggese; Juliann Chmielecki; Aleksandra Markovets; Marietta Scott; Suresh S Ramalingam
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 1 138 - 143 2020年01月 [査読有り]
     
    INTRODUCTION: EGFR mutated (EGFRm) NSCLC tumors occasionally express programmed cell death ligand 1 (PD-L1), although frequency and clinical relevance are not fully characterized. We report PD-L1 expression in patients with EGFRm advanced NSCLC and association with clinical outcomes following treatment with osimertinib or comparator EGFR tyrosine kinase inhibitors in the FLAURA trial (phase III, NCT02296125). METHODS: Of 231 tissue blocks available from the screened population (including EGFRm-positive and -negative samples), 197 had sufficient tissue for PD-L1 testing using the SP263 (Ventana, Tucson, Arizona) immunohistochemical assay. Tumor cell (TC) staining thresholds of PD-L1 TC greater than or equal to 1%, TC greater than or equal to 25%, and TC greater than or equal to 50% were applied. Progression-free survival (PFS) was investigator-assessed, per Response Evaluation Criteria in Solid Tumor, version 1.1, according to PD-L1 expressors (TC ≥ 1%) or negatives (TC < 1%) in randomized patients. RESULTS: PD-L1 staining was successful in 193 of 197 patient formalin-fixed paraffin-embedded blocks; of these, 128 of 193 were EGFRm-positive and 106 of 128 patients were randomized to treatment (osimertinib: 54; comparator: 52). At the PD-L1 TC greater than or equal to 25% threshold, 8% (10 of 128) of EGFRm-positive tumors expressed PD-L1 versus 35% (23 of 65) of EGFRm-negative tumors. With the TC greater than or equal to 1% threshold, 51% (65 of 128) versus 68% (44 of 65) were mutation-positive and -negative, respectively, and with the TC greater than or equal to 50% threshold, 5% (7 of 128) versus 28% (18 of 65), were mutation-positive and -negative, respectively. For PD-L1 expressors (TC ≥ 1%), median PFS was 18.4 months with osimertinib and 6.9 months with comparator (hazard ratio = 0.30; 95% confidence interval: 0.15-0.60). For PD-L1-negative patients (TC < 1%), median PFS was 18.9 months with osimertinib and 10.9 months with comparator (hazard ratio = 0.37; 95% confidence interval: 0.17-0.74). CONCLUSIONS: Clinical benefit with osimertinib was unaffected by PD-L1 expression status.
  • James Chih-Hsin Yang; Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang; Jianxing He; Kazuhiko Nakagawa; Jin Hyoung Kang; Joo-Hang Kim; Rebecca R Hozak; Tuan Stevon Nguyen; Wan Li Zhang; Sotaro Enatsu; Tarun Puri; Mauro Orlando
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 15 1 91 - 100 2020年01月 [査読有り]
     
    INTRODUCTION: Clinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib. METHODS: This was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m2 intravenously 3-weekly + 250 mg/day orally) or gefitinib. RESULTS: In total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event. CONCLUSIONS: Addition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.
  • Kazuhiko Nakagawa; Toyoaki Hida; Hiroshi Nokihara; Masahiro Morise; Koichi Azuma; Young Hak Kim; Takashi Seto; Yuichi Takiguchi; Makoto Nishio; Hiroshige Yoshioka; Toru Kumagai; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Miyako Satouchi; Toshiyuki Kozuki; Ryo Koyama; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Takashi Asakawa; Morihiko Hayashi; Wakako Hasegawa; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 139 195 - 199 2020年01月 [査読有り]
     
    OBJECTIVES: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). METHODS: Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. RESULTS: Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). CONCLUSIONS: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.
  • Natasha B Leighl; Nina Karaseva; Kazuhiko Nakagawa; Byoung-Chul Cho; Jhanelle E Gray; Tina Hovey; Andrew Walding; Anna Rydén; Silvia Novello
    European journal of cancer (Oxford, England : 1990) 125 49 - 57 2020年01月 [査読有り]
     
    BACKGROUND: In the FLAURA trial, osimertinib demonstrated superior progression-free survival and a favorable toxicity profile to erlotinib or gefitinib as initial therapy in patients with EGFR-mutated advanced non-small-cell lung cancer. Patient-reported outcomes from FLAURA are discussed here. METHODS: Patients (N = 556) completed the EORTC QLQ-LC13 weekly for 6 weeks, then every 3 weeks, and the QLQ-C30 every 6 weeks. Prespecified key symptoms were cough, dyspnea, chest pain, appetite loss, and fatigue. Score changes from baseline to randomized treatment discontinuation were assessed using a mixed-effects model. A ≥10-point change was considered clinically relevant. Odds of improvement and time to deterioration were investigated. QLQ-C30 functioning scores were assessed post hoc. RESULTS: Questionnaire completion rates were >70% at most time points. Baseline mean scores were similar in the osimertinib and erlotinib/gefitinib arms. Scores improved in both arms, but none reached clinical relevance at 5% significance level. A statistically significant difference favoring osimertinib for chest pain was not clinically relevant (-6.84 vs -3.88; p = 0.021). Odds of improvement and time to deterioration were similar between treatments. In post hoc analyses, improvements favored osimertinib for emotional functioning (8.79 vs 4.91; p = 0.004) and social functioning (7.66 vs 1.74; p < 0.001). Cognitive functioning remained stable with osimertinib but deteriorated with erlotinib/gefitinib (0.03 vs -3.91; p = 0.005). CONCLUSIONS: Key symptoms improved from baseline in both treatment arms in FLAURA. Key symptom improvements that were both statistically significant and clinically relevant were not observed in favor of either treatment arm. CLINICAL TRIAL REGISTRATION: NCT02296125.
  • Takayuki Takahama; Koichi Azuma; Mototsugu Shimokawa; Masayuki Takeda; Hidenobu Ishii; Terufumi Kato; Haruhiro Saito; Haruko Daga; Yuko Tsuboguchi; Isamu Okamoto; Kohei Otsubo; Hiroaki Akamatsu; Shunsuke Teraoka; Toshiaki Takahashi; Akira Ono; Tatsuo Ohira; Toshihide Yokoyama; Kazuko Sakai; Nobuyuki Yamamoto; Kazuto Nishio; Kazuhiko Nakagawa
    Cancer 126 9 1940 - 1948 2020年01月 [査読有り]
     
    BACKGROUND: Liquid biopsy allows the identification of patients whose tumors harbor specific mutations in a minimally invasive manner. No prospective data have been available for the efficacy of osimertinib in patients with non-small cell lung cancer (NSCLC) who develop resistance to first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and who test positive for the TKI resistance-conferring T790M mutation of EGFR by liquid biopsy. Therefore, a phase 2 study was conducted to assess the efficacy and safety of osimertinib in such patients. METHODS: Eligible patients had advanced or recurrent NSCLC with known TKI-sensitizing mutations of EGFR, had documented disease progression after treatment with at least 1 first- or second-generation EGFR TKI, and were positive for the T790M mutation in plasma according to the Cobas EGFR Mutation Test v2 (Roche Diagnostics) or droplet digital polymerase chain reaction analysis. Patients were treated with osimertinib (80 mg/d) until disease progression. The primary endpoint was the overall response rate (ORR) in patients positive for T790M in plasma by the Cobas assay. RESULTS: Between June 2016 and November 2017, 276 patients were screened for their T790M status with a liquid biopsy. Seventy-four patients were positive for T790M in plasma, and 53 of these individuals were enrolled in the study. The ORR for evaluable patients positive for T790M in plasma by the Cobas assay (n = 49) was 55.1% (95% confidence interval [CI], 40.2%-69.3%). The median progression-free survival for all evaluable patients (n = 52) was 8.3 months (95% CI, 6.9-12.6 months). CONCLUSIONS: The results demonstrate the utility of liquid biopsy for the detection of T790M with the Cobas EGFR Mutation Test v2. Plasma genotyping with this assay is informative for treatment selection in clinical practice when tumor sampling is not feasible.
  • Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Koji Haratani; Takayuki Takahama; Ryoji Kato; Kimio Yonesaka; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 139 28 - 34 2020年01月 [査読有り]
     
    OBJECTIVES: The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. MATERIALS AND METHODS: A total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. RESULTS: Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P =  0.049). CONCLUSIONS: Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.
  • Kimio Yonesaka; Eiji Iwama; Hidetoshi Hayashi; Shinichiro Suzuki; Ryoji Kato; Satomi Watanabe; Takayuki Takahama; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Koichi Azuma; Yasutaka Chiba; Shinji Atagi; Kazuto Nishio; Isamu Okamoto; Kazuhiko Nakagawa
    Scientific reports 9 1 19501 - 19501 2019年12月 [査読有り]
     
    Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC). Preclinically, HER3 ligand heregulin induces resistance to EGFR-TKIs, whereas the pan-human EGFR family inhibitor afatinib remains effective. Here, we examined whether soluble heregulin levels have clinical implications for EGFR-mutant NSCLC treated with EGFR-TKIs. Soluble heregulin was immunologically measured in plasma from EGFR-mutant NSCLC patients. Cutoff values were determined by 1-year PFS ROC curve. The relationship between soluble heregulin and PFS following EGFR-TKI therapy was analyzed by Cox proportional hazards model. Seventy-three patients were enrolled: 44 were treated with 1st-generation and 29 with 2nd-generation EGFR-TKIs. Soluble heregulin levels varied (range: 274-7,138 pg/mL, median: 739 pg/mL). Among patients treated with 1st-generation EGFR-TKIs, those with high heregulin (n = 20, >800 pg/mL) had a tendency for shorter PFS than those with low heregulin (n = 24, <800 pg/mL), with median PFS of 322 and 671 days, respectively. Cox proportional hazards model also indicated a trend toward resistance against 1st-generation EGFR-TKIs (HR: 1.825, 95% CI: 0.865-4.318) but not against 2nd-generation EGFR-TKIs. Soluble heregulin potentially correlates with resistance to EGFR-TKIs but not 2nd-generation EGFR-TKIs in patients with EGFR-mutant NSCLC.
  • Naoki Takegawa; Junji Tsurutani; Hisato Kawakami; Kimio Yonesaka; Ryoji Kato; Koji Haratani; Hidetoshi Hayashi; Masayuki Takeda; Yoshikane Nonagase; Osamu Maenishi; Kazuhiko Nakagawa
    International journal of cancer 145 12 3414 - 3424 2019年12月 [査読有り]
     
    Therapies targeted to human epidermal growth factor receptor 2 (HER2) have proven effective against tumors positive for HER2 amplification, but there is an unmet clinical need for the treatment of tumors that express HER2 protein in the absence of HER2 amplification. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel antibody-drug conjugate composed of the anti-HER2 antibody and the topoisomerase I inhibitor, an exatecan derivative. It has shown efficacy against tumors that express HER2 and is currently under evaluation in clinical trials. We here show that the antitumor activity of [fam-] trastuzumab deruxtecan is dependent on the expression level of HER2 protein in colorectal cancer (CRC) cell lines negative for HER2 amplification. We established isogenic CRC cell lines that express various levels of HER2 protein in the absence of HER2 amplification, and we found that cells that express HER2 at a high level were sensitive to [fam-] trastuzumab deruxtecan but not to conventional HER2-targeted therapies. Furthermore, [fam-] trastuzumab deruxtecan manifested a bystander killing effect both in vitro and in vivo, with cells essentially negative for HER2 expression also being killed in the presence of HER2-expressing cells, an effect that has the potential to overcome heterogeneity of HER2 expression in CRC tumors. Our results thus suggest that [fam-] trastuzumab deruxtecan warrants further study as a potential treatment for CRC tumors that express HER2 protein in the absence of HER2 amplification.
  • Keisuke Asakura; Yukihiro Yoshida; Hiroyuki Sakurai; Kazuo Nakagawa; Noriko Motoi; Shun-Ichi Watanabe
    World journal of surgery 43 12 3259 - 3266 2019年12月 [査読有り]
     
    BACKGROUND: Good prognosis following surgery for metachronous lung cancer has been reported. However, prognostic factors have not been fully investigated. The purpose of this study was to identify the preoperative predictor of survival in metachronous lung cancer. METHODS: Patients who underwent a second pulmonary resection for metachronous lung cancer at our institution between 2000 and 2014 were analyzed. RESULTS: A retrospective chart review identified 86 eligible patients (of 6213; 1.4%). The 5-year overall survival was 77%. All 86 cancers met Martini and Melamed's criteria for second primary cancer. However, on pathological examination based on morphological concordance between the initial and metachronous cancer, 73 (85%) cases were diagnosed as second primary cancer and 13 (15%) as a possible recurrent tumor. The 5-year overall survivals were 82% for second primary cancers and 52% for possible recurrent tumors. Tumor doubling time > 180 days (p < 0.001), pathological diagnosis of second primary cancer (p = 0.013), pathological stage IA (p = 0.016), interval between resections > 2 years (p = 0.040), and consolidation/tumor diameter ratio ≤ 0.5 (p = 0.045) were associated with superior overall survival. Multivariate Cox regression analysis identified tumor doubling time > 180 days as the only independent predictor of overall survival (hazard ratio 3.600, 95% confidence interval 1.226-10.338; p = 0.0196). CONCLUSIONS: Surgical resection for metachronous lung cancer is effective and feasible. Particularly, a tumor doubling time > 180 days is associated with superior survival in patients with metachronous lung cancer.
  • 木村 豊; 白石 治; 岩間 密; 加藤 寛章; 川上 尚人; 奥野 達哉; 平木 洋子; 安田 篤; 新海 政幸; 今野 元博; 中川 和彦; 安田 卓司
    癌と化学療法 46 13 2173 - 2175 (株)癌と化学療法社 2019年12月 
    腎機能低下を伴う進行食道癌に対して術前化学療法(NAC)として5-FU+DTX+nedaplatin(NED)(UDON)療法を施行し、その有用性をretrospectiveに検討した。クレアチニン・クリアランス(Ccr)が50mL/min未満の進行食道癌5例を対象として、NACとしてUDON療法[5-FU640mg/m2(day1〜5)、NED72mg/m2(day1)、DTX28mg/m2(day1、15)、休薬2週間を1コース]を2コース施行した後に根治手術を施行した。化学療法の有害事象(AE)を評価し、臨床的な効果について検討した。患者背景は、男性4例、女性1例、年齢の中央値(範囲)79(58〜80)歳、performance status(PS)1:3、PS2:2例であった。腫瘍の主占居部位は、Ce 1、Ut 1、Mt 3例、進行度はcStage IIA1、IIIA2、IIIC2例であった。grade(Gr)3以上のAEは、好中球減少、低Na血症がそれぞれ2例、発熱性好中球減少、下痢がそれぞれ1例であった。抗腫瘍効果は部分奏効4例、安定1例、組織学的効果は、Gr 1a:Gr 1b=2:3であった。腎機能低下のため高用量CDDP投与が困難な進行食道癌患者に対するNACとして、UDON療法は有用である。(著者抄録)
  • H Yoshioka; M Shimokawa; T Seto; S Morita; Y Yatabe; I Okamoto; J Tsurutani; M Satouchi; T Hirashima; S Atagi; K Shibata; H Saito; S Toyooka; N Yamamoto; K Nakagawa; T Mitsudomi
    Annals of oncology : official journal of the European Society for Medical Oncology 30 12 1978 - 1984 2019年12月 
    BACKGROUND: Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data. PATIENTS AND METHODS: Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan-Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model. RESULTS: OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 [95% confidence interval (CI): 0.883-1.775, P = 0.2070]. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312-0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively. CONCLUSION: G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
  • Koji Haratani; Masayuki Takeda; Kazuhiko Nakagawa
    Journal of thoracic disease 11 12 5635 - 5642 2019年12月 [査読有り]
  • Yutaka Kimura; Osamu Shiraishi; Mitsuru Iwama; Hiroaki Kato; Hisato Kawakami; Tatsuya Okuno; Yoko Hiraki; Atsushi Yasuda; Masayuki Shinkai; Motohiro Imano; Kazuhiko Nakagawa; Takushi Yasuda
    Gan to kagaku ryoho. Cancer & chemotherapy 46 13 2173 - 2175 2019年12月 [査読有り]
     
    BACKGROUND: In Japan, pre-operative 5-FU and cisplatin(CDDP)(FP)combination therapy has been the standard neoadjuvant chemotherapy(NAC)for advanced resectable esophageal cancer(EC); furthermore, the efficacy of the docetaxel (DTX)-containing triplet regimen, FP plus DTX, has been reported. However, patients with impaired renal function should not receive high-dose CDDP. We have been developing a non-CDDP-containing triplet regimen, comprising 5-FU, DTX, and nedaplatin(NED)(UDON), on a phase Ⅰ/Ⅱtrial basis. This retrospective study aimed to investigate the safety and efficacy of NAC with UDON in advanced EC patients with impaired renal function. METHODS: Five patients with advanced resectable EC with impaired renal function were enrolled in this study. Patients received NAC(5-FU, 640mg/m / 2, days 1-5; DTX, 28 mg/m2, days 1 and 15; and NED, 72mg/m2, day 1, q28, 2 courses); following this, they underwent esophagectomy. The primary endpoint was response rate, and the secondary endpoint was adverse event(AE). RESULTS: The median age was 79 years (range: 58-80 years). The ECOG performance status was 1/2 : 3/2. The main tumor locations were Ce/Ut/Mt : 1/1/3 and the cStages were ⅡA/ⅢA/ⅢC : 1/2/2. The RR(CR/PR/SD/PD : 0/4/1/0)was 80%. The pathological response was grade 1a/1b : 2/3. Major grade 3 or 4 AEs included neutropenia(40%), febrile neutropenia(20%), diarrhea(20%), and hyponatremia( 40%). There was no treatment-related death or reoperation. CONCLUSIONS: NAC with UDON might be feasible and effective in patients with advanced resectable EC with impaired renal function, who are ineligible for high-dose CDDP administration. We are planning a phaseⅡclinical study based on the present results.
  • Kazuhiko Nakagawa; Edward B Garon; Takashi Seto; Makoto Nishio; Santiago Ponce Aix; Luis Paz-Ares; Chao-Hua Chiu; Keunchil Park; Silvia Novello; Ernest Nadal; Fumio Imamura; Kiyotaka Yoh; Jin-Yuan Shih; Kwok Hung Au; Denis Moro-Sibilot; Sotaro Enatsu; Annamaria Zimmermann; Bente Frimodt-Moller; Carla Visseren-Grul; Martin Reck
    The Lancet. Oncology 20 12 1655 - 1669 2019年12月 [査読有り]
     
    BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. FUNDING: Eli Lilly.
  • 川中 雄介; 鈴木 慎一郎; 加藤 了資; 原谷 浩司; 林 秀敏; 中川 和彦; 楠 進; 山岸 裕子; 寺山 敦之
    肺癌 59 6 785 - 785 (NPO)日本肺癌学会 2019年11月
  • Yoshioka Hiroshige; Shimokawa Mototsugu; Seto Takashi; Morita Satoshi; Yatabe Yasushi; Okamoto Isamu; Tsurutani Junji; Satouchi Miyako; Hirashima Tomonori; Atagi Shinji; Shibata Kazuhiko; Saito Hiroshi; Toyooka Shinichi; Yamamoto Nobuyuki; Nakagawa Kazuhiko; Mitsudomi Tetsuya
    肺癌 59 6 629 - 629 2019年11月
  • 西山 理; 佐野 安希子; 林 秀敏; 西川 裕作; 谷崎 潤子; 原谷 浩司; 中川 和彦; 東田 有智
    肺癌 59 6 547 - 547 (NPO)日本肺癌学会 2019年11月
  • 横山 俊秀; 丹羽 崇; 林 秀敏; 小倉 昌和; 谷崎 潤子; 尾崎 智博; 吉岡 弘鎮; 倉田 宝保; 田村 洋輔; 藤阪 保仁; 田中 薫; 長谷川 喜一; 千葉 康敬; 中川 和彦
    肺癌 59 6 672 - 672 (NPO)日本肺癌学会 2019年11月
  • 田中 薫; 谷崎 潤子; 野長瀬 祥兼; 原谷 浩司; 酒井 瞳; 加藤 了資; 渡邉 諭美; 吉田 健史; 佐藤 千尋; 林 秀敏; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 59 6 694 - 694 (NPO)日本肺癌学会 2019年11月
  • 鈴木 慎一郎; 加藤 了資; 原谷 浩司; 林 秀敏; 谷崎 潤子; 尾崎 智博; 長谷川 喜一; 大田 隆代; 千葉 康敬; 伊藤 彰彦; 坂井 和子; 西尾 和人; 中川 和彦
    肺癌 59 6 800 - 800 (NPO)日本肺癌学会 2019年11月
  • 加藤 了資; 林 秀敏; 米阪 仁雄; 原谷 浩司; 酒井 瞳; 高濱 隆幸; 岩朝 勤; 田中 薫; 吉田 健史; 武田 真幸; 金田 裕靖; 清水 重喜; 坂井 和子; 伊藤 彰彦; 西尾 和人; 中川 和彦
    肺癌 59 6 575 - 575 (NPO)日本肺癌学会 2019年11月
  • 米阪 仁雄; 岩間 映二; 林 秀敏; 高濱 隆幸; 谷崎 潤子; 武田 真幸; 東 公一; 安宅 信二; 岡本 勇; 中川 和彦
    肺癌 59 6 723 - 723 (NPO)日本肺癌学会 2019年11月
  • 武田 真幸; 坂井 和子; 林 秀敏; 田中 薫; 原谷 浩司; 高濱 隆幸; 加藤 了資; 米阪 仁雄; 西尾 和人; 中川 和彦
    肺癌 59 6 723 - 723 2019年11月
  • 杉本 藍; 福井 朋也; 佐々木 治一郎; 石原 未希子; 日吉 康弘; 井川 聡; 坂井 和子; 武田 真幸; 高濱 隆幸; 中川 和彦; 西尾 和人; 猶木 克彦
    肺癌 59 6 765 - 765 (NPO)日本肺癌学会 2019年11月
  • 原谷 浩司; 米阪 仁雄; 高村 史記; 前西 修; 宮澤 正顯; 中川 和彦
    肺癌 59 6 568 - 568 (NPO)日本肺癌学会 2019年11月
  • 木村 豊; 白石 治; 岩間 密; 加藤 寛章; 川上 尚人; 平木 洋子; 安田 篤; 新海 政幸; 今野 元博; 中川 和彦; 安田 卓司
    日本消化器病学会雑誌 116 臨増大会 A832 - A832 (一財)日本消化器病学会 2019年11月
  • 磯本 晃佑; 原谷 浩司; 林 秀敏; 清水 重喜; 富田 秀太; 丹羽 崇; 横山 俊秀; 福田 泰; 千葉 康敬; 加藤 了資; 谷崎 潤子; 田中 薫; 武田 真幸; 小倉 高志; 石田 直; 伊藤 彰彦; 中川 和彦
    肺癌 59 6 567 - 567 (NPO)日本肺癌学会 2019年11月
  • 野長瀬 祥兼; 武田 真幸; 東 公一; 林 秀敏; 原谷 浩司; 田中 薫; 米阪 仁雄; 石井 秀宜; 星野 友昭; 中川 和彦
    肺癌 59 6 765 - 765 (NPO)日本肺癌学会 2019年11月
  • Hayashi Hidetoshi; 茶本 健司; 冨樫 庸介; 中川 和彦; 本庶 佑
    肺癌 59 6 558 - 558 2019年11月
  • 服部 剛弘; 山中 竹春; 伊藤 健太郎; 宮本 信吾; 竹本 真之輔; 池田 慧; 牛尾 良太; 臼井 一裕; 三登 峰代; 阪本 智宏; 杉山 智英; 木村 智樹; 海老 規之; 石井 知也; 猪又 峰彦; 柏原 光介; 岡田 秀明; 木村 望; 中川 和彦; 山本 信之
    肺癌 59 6 667 - 667 (NPO)日本肺癌学会 2019年11月
  • Masayuki Takeda; Yuichiro Ohe; Hidehito Horinouchi; Toyoaki Hida; Junichi Shimizu; Takashi Seto; Kaname Nosaki; Takumi Kishimoto; Itaru Miyashita; Masayuki Yamada; Yutaro Kaneko; Chikao Morimoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 137 64 - 70 2019年11月 [査読有り]
     
    OBJECTIVES: CD26 is a transmembrane glycoprotein with dipeptidyl peptidase IV activity that is overexpressed in malignant pleural mesothelioma (MPM). We performed a phase I study to determine the maximum tolerated dose, pharmacokinetics, and antitumor activity of YS110, a monoclonal antibody to CD26, in Japanese patients with MPM intolerant of or refractory to prior standard therapies. MATERIAL AND METHODS: The study was designed as an open-label, 3 + 3 dose-escalation, phase I trial. Patients were sequentially assigned to three dosing cohorts (2, 4, or 6 mg/kg). Each 6-week treatment cycle consisted of YS110 administration weekly for 5 weeks followed by a 1-week rest period. Treatment was continued until disease progression, death, or intolerable toxicity. Corticosteroid, antihistamine, and acetaminophen administration before each infusion was adopted to limit infusion-related reactions (IRRs). RESULTS: Nine Japanese patients (seven men and two women, mean age of 62.2 years), three in each dosing cohort, were enrolled in the study. No patient developed a dose-limiting toxicity. Adverse events of grade 3 or 4 developed in seven patients, with the most common such event being a decreased lymphocyte count. Two patients had mild or moderate IRRs. The serum concentration of YS110 increased in a dose-dependent manner. Among seven patients evaluable for tumor response, four showed stable disease and one achieved a partial response. CONCLUSIONS: YS110 showed promising antitumor efficacy and was generally well tolerated in Japanese patients with advanced MPM at doses of up to 6 mg/kg. YS110 will be tested at 6 mg/kg in a subsequent phase II study.
  • Tsutomu Iwasa; Junji Tsurutani; Satomi Watanabe; Ryoji Kato; Yutaka Mizuno; Yasuyuki Kojima; Tsutomu Takashima; Nobuki Matsunami; Takashi Morimoto; Jun Yamamura; Shoichiro Ohtani; Yuko Tanabe; Tetsuhiro Yoshinami; Toshimi Takano; Yoshifumi Komoike; Kazuhiko Nakagawa
    BMC cancer 19 1 962 - 962 2019年10月 [査読有り]
     
    BACKGROUND: We previously reported the synergistic effect of S-1 and eribulin in preclinical models. In addition, our phase I study revealed the recommended dose for the phase II study of the combination therapy in advanced breast cancer (ABC) patients pre-treated with anthracycline and taxane. Our current study reports on the efficacy and safety of the combined use of eribulin and S-1 in patients with ABC and poor prognosis. METHODS: Patients with breast cancer who received prior anthracycline- and/or taxane-based therapy were assigned to receive a combination therapy of eribulin (1.4 mg/m2 on days 1 and 8, every 21 days) and S-1 (65 mg/m2, on days 1 to 14, every 21 days) for advanced/metastatic disease. All patients had at least one clinicopathological factor such as being oestrogen receptor negative, Human Epidermal Growth Factor Receptor 2 (HER2) receptor negative, presence of visceral involvement, presence of three or more metastatic sites, or having a disease-free interval shorter than 2 years. The primary endpoint was the independent-reviewer assessed objective response rate (ORR). Secondary endpoints were clinical benefit rate, disease control rate, progression-free survival (PFS), and overall survival (OS). RESULTS: This study enrolled 33 patients. Confirmed ORR was 33.3% (95% CI: 17.3 to 52.8). Median PFS was 7.5 months (95% CI: 4.0 to 14.3). Median OS time was not reached during the current experimental periods. The most common grade 3/4 adverse event was neutropenia (68.8%). CONCLUSIONS: The combination of eribulin and S-1 is safe and effective for treatment in patients with ABC and poor prognosis. TRIAL REGISTRATION: Current Controlled Trials UMIN000015049 , date of registration: September 5th 2014.
  • Tatsuo Kimura; Tomoya Kawaguchi; Yasutaka Chiba; Hiroshige Yoshioka; Katsuya Watanabe; Takashi Kijima; Yoshihito Kogure; Tetsuya Oguri; Naruo Yoshimura; Takashi Niwa; Takashi Kasai; Hidetoshi Hayashi; Akira Ono; Kazuhisa Asai; Hiroshi Tanaka; Seiji Yano; Nobuyuki Yamamoto; Yoichi Nakanishi; Kazuhiko Nakagawa
    Japanese journal of clinical oncology 49 10 947 - 955 2019年10月 [査読有り]
     
    BACKGROUND: Preclinical data suggest sequential administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) following chemotherapy may improve efficacy. We hypothesized that intermittent delivery of EGFR-TKI following chemotherapy may increase efficacy. METHODS: This was a multicenter, single-arm phase I/II study to evaluate the efficacy of intermitted erlotinib in combination with docetaxel in patients with EGFR-negative NSCLC who failed one prior chemotherapy. The phase I primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of erlotinib. Erlotinib was administered orally once per day on days 2-16 in combination with 60 mg/m2 docetaxel on day1 for 21 days. A standard 3 + 3 dose escalation design was employed for erlotinib from 100 to 150 mg/dose. The phase II primary endpoint was the objective response rate (ORR). The ORR and 95% confidence interval (CI) were calculated using a binomial distribution. This study required 45 patients. RESULTS: In the phase I part, the planned dose escalation was completed without reaching MTD. The RD of erlotinib was determined as 150 mg/dose. In the phase II part, the ORR and disease control rate were 17.1% (95%CI: 7.2-32.1%) and 53.7% (95%CI: 37.4-69.3%), respectively. Median progression-free survival and overall survival were 3.5 (95%CI: 3.1-4.5) and 11.3 (95%CI: 8.6-16.6) months, respectively. The common non-hematological adverse event was febrile neutropenia (grade 3-4:19.6%). Two treatment-related deaths were occurred because of interstitial lung disease and pleural infection. CONCLUSIONS: Intermittent dosing of erlotinib plus docetaxel is clinically feasible in phase I part but did not significantly improve ORR in phase II part.
  • Satomi Watanabe; Tomoyuki Otani; Tsutomu Iwasa; Takayuki Takahama; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    Clinical breast cancer 19 5 e589-e592  2019年10月 [査読有り]
  • Yoshikane Nonagase; Masayuki Takeda; Koichi Azuma; Hidetoshi Hayashi; Koji Haratani; Kaoru Tanaka; Kimio Yonesaka; Hidenobu Ishii; Tomoaki Hoshino; Kazuhiko Nakagawa
    Thoracic cancer 10 10 1928 - 1935 2019年10月 [査読有り]
     
    BACKGROUND: Non-small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR-tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one-fifth of NSCLC patients with acquired resistance to EGFR-TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown. METHODS: Tumor tissue and plasma specimens were collected from 25 EGFR-mutated NSCLC patients before EGFR-TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme-linked immunosorbent assays. RESULTS: AXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR-TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue. CONCLUSION: Plasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR-mutated NSCLC.
  • Kimio Yonesaka; Kaoru Tanaka; Mutsukazu Kitano; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Katsumi Doi; Kazuhiko Nakagawa
    Oncogenesis 8 10 54 - 54 2019年09月 [査読有り]
     
    The anti-epidermal growth factor receptor (EGFR) antibody cetuximab is standard therapy for head and neck squamous cell carcinoma (HNSCC). However, most HNSCC tumors are resistant to it and require alternative treatments. Here, we explored the mechanism of cetuximab resistance and evaluated its clinical relevance in HNSCC. An unbiased comprehensive transcriptome analysis was performed on cetuximab-resistant HNSCC FaDuCR cells. The causative resistance genome was knocked down with siRNA, cell signaling was immunologically analyzed, and drug efficacy was evaluated in vitro and in vivo. The mRNA in situ hybridization (ISH) of the causative genome was performed using 28 excised HNSCC tumors and its relationship with cetuximab efficacy was analyzed. FaDuCR cells were resistant to cetuximab, whereas parental FaDu cells were susceptible to it. FaDuCR cells expressed consistently higher levels of phosphorylated Akt than FaDu cells despite cetuximab exposure. A comprehensive transcriptome analysis revealed that the HER3-ligand heregulin was upregulated in FaDuCR cells compared to FaDu cells. Heregulin knockdown in FaDuCR cells repressed HER3 and Akt phosphorylation and recovered cetuximab anticancer efficacy. In contrast, pan-HER family tyrosine kinase inhibitors such as afatinib decreased HER3 and Akt phosphorylation in FaDuCR cells and inhibited FaDuCR tumor growth. Two of the 28 HNSCC tumor samples presented aberrant heregulin expression comparable to that of FaDuCR cells and were resistant to cetuximab therapy. In HNSCC, heregulin-mediated HER3-Akt activation causes resistance to cetuximab but not to second-generation EGFR-tyrosine kinase inhibitors. Subpopulations with aberrant heregulin-expressing HNSCC might be resistant to cetuximab.
  • Morihito Okada; Takashi Kijima; Keisuke Aoe; Terufumi Kato; Nobukazu Fujimoto; Kazuhiko Nakagawa; Yuichiro Takeda; Toyoaki Hida; Kuninobu Kanai; Fumio Imamura; Satoshi Oizumi; Toshiaki Takahashi; Mitsuhiro Takenoyama; Hiroshi Tanaka; Jun Hirano; Yoshinobu Namba; Yuichiro Ohe
    Clinical cancer research : an official journal of the American Association for Cancer Research 25 18 5485 - 5492 2019年09月 [査読有り]
     
    PURPOSE: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. PATIENTS AND METHODS: Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated. RESULTS: Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs. CONCLUSIONS: Nivolumab met the primary endpoint as second- or third-line treatment for patients with MPM and showed promising efficacy with manageable toxicity.See related commentary by Mansfield and Zauderer, p. 5438.
  • Koji Haratani; Hidetoshi Hayashi; Takayuki Takahama; Yasushi Nakamura; Shuta Tomida; Takeshi Yoshida; Yasutaka Chiba; Takahiro Sawada; Kazuko Sakai; Yoshihiko Fujita; Yosuke Togashi; Junko Tanizaki; Hisato Kawakami; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Journal for immunotherapy of cancer 7 1 251 - 251 2019年09月 [査読有り]
     
    BACKGROUND: Immune checkpoint inhibitors (ICIs) confer a survival benefit in many cancer types. Given that the survival outcome for cancer of unknown primary site (CUP) remains poor, we investigated the potential of CUP for immunotherapy. METHODS: A total of 164 patients with CUP (favorable subset, 34 patients; unfavorable subset, 130 patients) who were treated between January 2009 and March 2017 was identified from a review of medical records at Kindai University Hospital. They included 92 patients for whom pretreatment tumor tissue was available both for determination of programmed cell death-ligand 1 expression and tumor-infiltrating lymphocyte (TIL) density by immunohistochemistry (IHC) and for immune-related gene expression profiling (irGEP). The results of irGEP for CUP were compared with published data for ICI-treated solid cancers classified into progressive disease (PD) and non-PD subsets according to their best response to ICIs. RESULTS: The median overall survival of all CUP patients was 29.3 months (95% confidence interval [CI], 15.7-not reached) and 7.1 months (95% CI, 5.0-9.4) for favorable and unfavorable subsets, respectively. IHC and irGEP revealed that pretreatment immune activity-including expression of immune checkpoint molecules-for CUP was similar to that for ICI-responsive malignancies (antitumor immune cell signatures: CUP versus PD, P = 0.002-0.067; CUP versus non-PD, P = 0.591-0.999), although VEGFA expression was associated with suppression of antitumor immunity in CUP (P = 0.008, false discovery rate = 0.010). In addition, one case of CUP in the unfavorable subset that was associated with prominent PD-L1 expression on TILs and showed a durable response to nivolumab is presented. CONCLUSIONS: The survival outcome of CUP remains unsatisfactory. However, our clinical and immune profiling of CUP has revealed a potential to benefit from immunotherapy, with ICIs thus being a potential option for CUP treatment.
  • Akifumi Nakamura; Minoru Esaki; Kazuo Nakagawa; Keisuke Asakura; Yoji Kishi; Satoshi Nara; Kazuaki Shimada; Shun-Ichi Watanabe
    General thoracic and cardiovascular surgery 67 9 782 - 787 2019年09月 [査読有り]
     
    OBJECTIVE: The outcomes of surgically treating pulmonary metastases from hepatocellular carcinoma remain unclear. Therefore, we aimed to evaluate patients with hepatocellular carcinoma who underwent pulmonary metastasectomy to assess their survival outcome and prognostic factors. METHODS: This retrospective single-center study included 30 patients who underwent pulmonary metastasectomy for hepatocellular carcinoma between January 1980 and December 2016 at the National Cancer Center Hospital. RESULTS: The 1-, 3-, and 5-year overall survival rates after pulmonary metastasectomy were 86.7%, 46.2%, and 33.6%, respectively (median survival time: 25.0 months). The univariate prognostic factors were viral hepatitis (P = 0.019), number of pulmonary metastases (P = 0.002), and other site recurrence before metastasectomy (P = 0.048). Multivariate analysis using a Cox proportional hazards model revealed viral hepatitis (hazard ratio: 3.611, 95% confidence interval: 1.226-10.64; P = 0.02) and ≥ 2 pulmonary metastases (hazard ratio: 4.031, 95% confidence interval: 1.594-10.19; P = 0.003) to be independent prognostic factors. Subgroup analyses of the three risk factors (viral hepatitis, number of pulmonary metastases, and other site recurrence before metastasectomy) revealed that the median survival times after pulmonary metastasectomy were 66.0 and 15.5 months for patients with 0-1 risk factors and those with 2-3 risk factors, respectively (P < 0.001). CONCLUSIONS: For patients who underwent pulmonary metastasectomy for hepatocellular carcinoma, median survival time was 25.0 months and decreased with three risk factors which included viral hepatitis, multiple number of pulmonary metastases, and the presence of other site recurrence before metastasectomy.
  • Hidehito Horinouchi; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Toshiaki Takahashi; Hideo Saka; Mitsuhiro Takenoyama; Nobuyuki Katakami; Hiroshi Tanaka; Koji Takeda; Miyako Satouchi; Hiroshi Isobe; Makoto Maemondo; Koichi Goto; Tomonori Hirashima; Koichi Minato; Naoki Sumiyoshi; Tomohide Tamura
    Cancer medicine 8 11 5183 - 5193 2019年09月 [査読有り]
     
    BACKGROUND: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials. METHODS: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed. RESULTS: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. CONCLUSION: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC. TRIAL REGISTRATION: JapicCTI-132072; JapicCTI-132073.
  • Hibiki Udagawa; Hiroaki Akamatsu; Kentaro Tanaka; Masayuki Takeda; Shintaro Kanda; Keisuke Kirita; Shunsuke Teraoka; Kazuhiko Nakagawa; Yutaka Fujiwara; Ikuko Yasuda; Sumiko Okubo; Masayuki Shintani; Matthew P Kosloski; Charity Scripture; Tomohide Tamura; Isamu Okamoto
    Lung cancer (Amsterdam, Netherlands) 135 145 - 150 2019年09月 [査読有り]
     
    OBJECTIVES: Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) on small cell lung cancer (SCLC) tumors, is internalized and releases the toxin pyrrolobenzodiazepine to induce cell death. This open label phase I study was the first study of Rova-T in Japanese patients. The aim of this study was to evaluate, safety, pharmacokinetics, and preliminary efficacy of Rova-T in Japanese patients with advanced recurrent SCLC. MATERIALS AND METHODS: Patients received Rova-T (0.2 or 0.3 mg/kg) by intravenous infusion on Day (D) 1 of each 6-week cycle for 2 doses and dexamethasone (8 mg BID oral) on D-1, D1, and D2 of each 6-week cycle. Retreatment with Rova-T was permitted for patients who tolerated their initial doses and then progressed after disease control (defined as stable disease or better) was observed for at least 12 weeks after their last dose of Rova-T. RESULTS: Rova-T exhibited toxicity that was generally manageable in Japanese patients (N = 29). No dose-limiting toxicities were experienced. The most common treatment-related adverse events (≥25% of patients, all grades) were platelet count decreased, pleural effusion, peripheral edema, aspartate aminotransferase increased, white blood cell count decreased, neutrophil count decreased, alanine aminotransferase increased, hypoalbuminaemia, anemia and decreased appetite. Safety and pharmacokinetics exposures were similar to previous observations in non-Japanese populations. Per investigator assessment of DLL3 high patients, 17% (3/18) had confirmed partial responses, and the disease control rate was 56%, mPFS was 2.9 months, and mOS was 7.4 months. CONCLUSIONS: These preliminary data support further exploration of Rova-T treatment in Japanese patients with SCLC in global studies. This trial was registered with ClinicalTrials.gov as NCT03086239.
  • Hidetoshi Hayashi; Kazuto Nishio; Kazuhiko Nakagawa
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 23 2090 - 2090 2019年08月 [査読有り]
  • Kazuko Sakai; Masayuki Takeda; Shigeki Shimizu; Takayuki Takahama; Takeshi Yoshida; Satomi Watanabe; Tsutomu Iwasa; Kimio Yonesaka; Shinichiro Suzuki; Hidetoshi Hayashi; Hisato Kawakami; Yoshikane Nonagase; Kaoru Tanaka; Junji Tsurutani; Kazumasa Saigoh; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Kazuto Nishio
    Scientific reports 9 1 11340 - 11340 2019年08月 [査読有り]
     
    Medical oncologists are challenged to personalize medicine with scientific evidence, drug approvals, and treatment guidelines based on sequencing of clinical samples using next generation sequencer (NGS). Knowledge-based curation systems have the potential to help address this challenge. We report here the results of examining the level of evidence regarding treatment approval and clinical trials between recommendations made by Watson for Genomics (WfG), QIAGEN Clinical Insight Interpret (QCII), and Oncomine knowledge-based reporter (OKR). The tumor samples obtained from the solid cancer patients between May to June 2018 at Kindai University Hospital. The formalin-fixed paraffin-embedded tumor samples (n = 31) were sequenced using Oncomine Comprehensive Assay v3. Variants including copy number alteration and gene fusions identified by the Ion reporter software were used commonly on three curation systems. Curation process of data were provided for 25 solid cancers using three curation systems independently. Concordance and distribution of curated evidence levels of variants were analyzed. As a result of sequencing analysis, nonsynonymous mutation (n = 58), gene fusion (n = 2) or copy number variants (n = 12) were detected in 25 cases, and subsequently subjected to knowledge-based curation systems (WfG, OKR, and QCII). The number of curated information in any systems was 51/72 variants. Concordance of evidence levels was 65.3% between WfG and OKR, 56.9% between WfG and QCII, and 66.7% between OKR and QCII. WfG provided great number of clinical trials for the variants. The annotation of resistance information was also observed. Larger differences were observed in clinical trial matching which could be due to differences in the filtering process among three curation systems. This study demonstrates knowledge-based curation systems (WfG, OKR, and QCII) could be helpful tool for solid cancer treatment decision making. Difference in non-concordant evidence levels was observed between three curation systems, especially in the information of clinical trials. This point will be improved by standardized filtering procedure and enriched database of clinical trials in Japan.
  • PD-L1発現陰性/TMB Highの肺腺癌に対して化学療法とペムブロリズマブの併用療法を施行した1例
    金村 宙昌; 林 秀敏; 武田 真幸; 高濱 隆幸; 田中 薫; 中川 和彦; 坂井 和子; 西尾 和人
    肺癌 59 4 413 - 414 (NPO)日本肺癌学会 2019年08月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌のPD-L1発現率への影響
    磯本 晃佑; 原谷 浩司; 林 秀敏; 清水 重喜; 冨田 秀太; 丹羽 崇; 横山 俊秀; 福田 泰; 千葉 康敬; 加藤 了資; 谷崎 潤子; 田中 薫; 武田 真幸; 小倉 高志; 石田 直; 伊藤 彰彦; 中川 和彦
    肺癌 59 4 419 - 419 (NPO)日本肺癌学会 2019年08月
  • Jesús Corral; Tony S Mok; Kazuhiko Nakagawa; Rafael Rosell; Ki Hyeong Lee; Maria Rita Migliorino; Adam Pluzanski; Rolf Linke; Geeta Devgan; Weiwei Tan; Susan Quinn; Tao Wang; Yi-Long Wu
    Future oncology (London, England) 15 24 2795 - 2805 2019年08月 [査読有り]
     
    Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement. Trial registration number: NCT01774721.
  • Keita Nakanishi; Kazuo Nakagawa; Keisuke Asakura; Yukihiro Yoshida; Hirokazu Watanabe; Shun-Ichi Watanabe
    World journal of surgery 43 7 1850 - 1856 2019年07月 [査読有り]
     
    BACKGROUND: Calcified lymph nodes (LNs) on computed tomography (CT) in patients with lung cancer are generally considered to be a benign feature. However, few studies have evaluated the pathological status of such calcified LNs. We investigated the clinicopathological findings of patients with calcified LNs on preoperative CT who underwent operation for lung cancer and assessed the frequency of metastasis to calcified LNs as well as the risk factors associated with such metastases. METHODS: This was a retrospective study of 72 consecutive patients with calcified LNs detected on preoperative CT who underwent pulmonary resection for primary lung cancer between 2011 and 2013. A total of 354 LN stations including 101 LN stations with calcified LNs were evaluated. RESULTS: The frequency of metastasis to calcified LNs was 19.4% (14 of 72 patients) on a per-person basis and 18.8% (19 of 101 stations) on a per-nodal station basis. When the size of calcification was major (>5 mm), the frequency of metastasis to such calcified LNs was significantly lower than when it was minor (≦5 mm) on a per-nodal station basis (11.1% vs 27.7%, P = 0.043). Furthermore, when the size of calcification was major and the status of LN stations with calcified LNs was single, there was no metastasis to such LN stations (0 of 26 stations). CONCLUSIONS: The frequency of metastasis to calcified LNs was about 20% on both a per-person and a per-nodal station basis. Although calcified LNs as well as non-calcified LNs should be dissected during operation, dissection of a single LN station with calcification, particularly major calcification, can be omitted.
  • Uchida S; Yoshida Y; Ohe Y; Nakayama Y; Motoi N; Kobayashi A; Asakura K; Nakagawa K; Watanabe SI
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 56 1 167 - 173 2019年07月 [査読有り]
  • Hiroaki Akamatsu; Shunsuke Teraoka; Satoshi Morita; Nobuyuki Katakami; Motoko Tachihara; Haruko Daga; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 20 4 e492-e494 - e494 2019年07月 [査読有り]
     
    Osimertinib is a standard treatment for epidermal growth factor receptor (EGFR)-mutated, T790M-positive patients with progression during EGFR-tyrosine kinase inhibitor (TKI) therapy. Osimertinib, a third-generation EGFR-TKI, allows progression-free survival of around 10 months, but its toxicity is well-tolerated compared with other EGFR-TKIs. Preclinical and clinical evidence suggests that EGFR-TKI may work synergistically with vascular endothelial growth factor inhibitors. We therefore plan a phase I/II study to investigate this possibility. In phase I, the primary endpoint is assessment of the tolerability of osimertinib and bevacizumab in 6 patients. Phase II then explores the efficacy of combined treatment compared with osimertinib monotherapy with progression-free survival as the primary endpoint. Secondary endpoints are overall response rate, time to treatment failure, overall survival, and safety. Eighty patients will be enrolled in phase II.
  • Satoshi Watanabe; Hiroshige Yoshioka; Hiroshi Sakai; Katsuyuki Hotta; Mitsuhiro Takenoyama; Kazuhiko Yamada; Shunichi Sugawara; Yuichi Takiguchi; Yukio Hosomi; Keisuke Tomii; Seiji Niho; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Terufumi Kato; Toshiaki Takahashi; Ami Kamada; Kazumi Suzukawa; Yukie Omori; Sotaro Enatsu; Kazuhiko Nakagawa; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 132 157 - 158 2019年06月 [査読有り]
  • Makoto Nishio; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Tomohiro Tanaka; Hiroshi Kuriki; Ali Zeaiter; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 132 160 - 160 2019年06月 [査読有り]
  • Keunchil Park; Jaafar Bennouna; Michael Boyer; Toyoaki Hida; Vera Hirsh; Terufumi Kato; Shun Lu; Tony Mok; Kazuhiko Nakagawa; Kenneth O'Byrne; Luis Paz-Ares; Martin Schuler; Denis Moro Sibilot; Eng-Huat Tan; Hiroshi Tanaka; Yi-Long Wu; James C-H Yang; Li Zhang; Caicun Zhou; Angela Märten; Wenbo Tang; Nobuyuki Yamamoto
    Lung cancer (Amsterdam, Netherlands) 132 126 - 131 2019年06月 [査読有り]
     
    OBJECTIVES: With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. METHODS: Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan-Meier estimates. RESULTS: Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years. CONCLUSIONS: Most patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.
  • Masayuki Takeda; Kazuko Sakai; Takayuki Takahama; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    Cancers 11 6 2019年05月 [査読有り]
     
    : Recent progress in understanding the molecular basis of cancer-including the discovery of cancer-associated genes such as oncogenes and tumor suppressor genes-has suggested that cancer can become a treatable disease. The identification of driver oncogenes such as EGFR, ALK, ROS1, BRAF and HER2 has already been successfully translated into clinical practice for individuals with solid tumor. Next-generation sequencing (NGS) technologies have led to the ability to test for multiple cancer-related genes at once with a small amount of cells and tissues. In Japan, several hospitals have started NGS-based mutational profiling screening in patients with solid tumor in order to guide patients to relevant clinical trials. The Ministry of Health, Labor, and Welfare of Japan has also approved several cancer gene panels for use in clinical practice. However, there is an urgent need to develop a medical curriculum of clinical variant interpretation and reporting. We review recent progress in the implementation of NGS in Japan.
  • Shunichi Sugawara; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Hiroshi Nokihara; Yuichiro Ohe; Makoto Nishio; Toshiaki Takahashi; Koichi Goto; Makoto Maemondo; Yukito Ichinose; Takashi Seto; Hiroshi Sakai; Akihiko Gemma; Fumio Imamura; Masato Shingyoji; Hideo Saka; Akira Inoue; Koji Takeda; Isamu Okamoto; Katsuyuki Kiura; Satoshi Morita; Tomohide Tamura
    International journal of clinical oncology 24 5 485 - 493 2019年05月 [査読有り]
     
    INTRODUCTION: The East Asia S-1 Trial in Lung Cancer (EAST-LC) was a randomized phase III study conducted in East Asia that demonstrated the non-inferiority of S-1 to docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC). Here, we reported the results of the Japanese subgroup treated with docetaxel 60 mg/m2, the standard dosage in Japan. PATIENTS AND METHODS: Patients were randomized 1:1 to receive either S-1 or docetaxel. The primary endpoint was overall survival (OS); the secondary endpoints included progression-free survival (PFS), response rate (RR), quality of life (QOL), and safety. RESULTS: Patient characteristics in the Japanese subgroup (n = 724) were similar to those in the overall EAST-LC population. Median OS was 13.4 months in the S-1 group and 12.6 months in the docetaxel group. In pemetrexed-pretreated patients, OS with S-1 was similar to that with docetaxel. Median PFS was 2.9 and 3.0 months in the S-1 and docetaxel groups, respectively. RR was 9.4% and 10.3% in the S-1 and docetaxel groups, respectively. The QOL of patients treated with S-1 was better compared with that of patients treated with docetaxel. Decreased appetite and diarrhea were more common in the S-1 group, whereas the frequency of neutropenia and febrile neutropenia was markedly higher in the docetaxel group. CONCLUSIONS: This Japanese subgroup analysis showed that S-1 had similar efficacy to docetaxel in patients with previously treated advanced NSCLC. These results are similar to those of the overall EAST-LC population.
  • Qing Zhou; Yi-Long Wu; Jesus Corral; Kazuhiko Nakagawa; Edward B Garon; Eric I Sbar; Tao Wang; Rickard Sandin; Kay Noonan; Diana Gernhardt; Tony S Mok
    Future oncology (London, England) 15 13 1481 - 1491 2019年05月 [査読有り]
     
    Aim: This pooled safety analysis was conducted to analyze incidence and management of key dacomitinib-associated adverse drug reactions (ADRs). Patients & methods: Patients with EGFR mutation-positive advanced non-small-cell lung cancer who received first-line dacomitinib at the 45 mg/day recommended starting dose were included. ADRs were identified based on reasonable association with EGFR tyrosine kinase inhibitors. Results: Overall, 251/255 patients (98%) experienced ADRs. The most common were diarrhea, rash, stomatitis, nail disorder and dry skin. Dose interruptions and dose reductions were reported in 47 and 52% of patients, respectively. Fewer grade 3 key ADRs were observed following dose reductions. Conclusion: Dacomitinib was generally tolerable. Most reported ADRs were known to be associated with EGFR tyrosine kinase inhibitors and were managed with standard medical management and dose modifications.
  • Hiroaki Akamatsu; Yasuhiro Koh; Isamu Okamoto; Daichi Fujimoto; Akihiro Bessho; Koichi Azuma; Satoshi Morita; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 131 128 - 133 2019年05月 [査読有り]
     
    BACKGROUND: Liquid biopsy has been approved as an optional method to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). However, the clinical significance of its utility for monitoring the disease remains elusive. WJOG8114LTR is a prospective, multi-institutional study of liquid biopsy in EGFR mutated patients with NSCLC. PATIENTS AND METHODS: Chemotherapy naïve, advanced NSCLC patients with EGFR -sensitizing mutation received afatinib 40 mg/body until progressive disease (PD). Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFR mutations (exon 19 deletion, exon 20 T790 M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, digital PCR assay. This study was registered at UMIN 000015847. RESULTS: Fifty-seven patients were registered in the study. At baseline, 62.5% of patients were positive for EGFR mutation in plasma, and systemic spread of the tumor seemed to correlate with higher detection rate. After treatment, negative conversion of sensitive mutation within four weeks was observed among 87.5% of the patients. These patients demonstrated statistically significant longer progression-free survival than those who did not achieve negative conversion (13.6 months versus 5.1 months, p < 0.0001). Regarding progression, 35.7% of the patients showed recurrence in plasma DNA earlier than radiological progression. However, PFS curve based on plasma recurrence did not show significant difference than that based on RECIST. CONCLUSION: To predict durable efficacy and progression, liquid biopsy was useful in a part of EGFR mutated NSCLC patients.
  • Hiroaki Akamatsu; Shunsuke Teraoka; Yasuhiro Koh; Takeharu Yamanaka; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 20 2 139 - 141 2019年03月 [査読有り]
     
    Immune-checkpoint inhibitors (ICIs) play an important role in treatment for advanced non-small-cell lung cancer. Over one-half of patients, however, have relapse. Although rechallenge treatment of anti-cancer drugs that showed efficacy in prior lines of therapy has been broadly accepted in lung cancer, evidence of efficacy of rechallenge of ICIs has been limited to anecdotal case series. We therefore plan a phase II study. The primary endpoint is to assess the overall response rate of nivolumab in patients with advanced non-small-cell lung cancer who responded to prior ICIs. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Sixty patients will be enrolled in this trial. Programmed death-ligand 1 expression level in circulating tumor cells will be evaluated as a surrogate biomarker for the prediction of the efficacy.
  • Makoto Nishio; Toshiaki Takahashi; Hiroshige Yoshioka; Kazuhiko Nakagawa; Tatsuro Fukuhara; Kazuhiko Yamada; Masao Ichiki; Hiroshi Tanaka; Takashi Seto; Hiroshi Sakai; Kazuo Kasahara; Miyako Satouchi; Shi Rong Han; Kazuo Noguchi; Takashi Shimamoto; Terufumi Kato
    Cancer science 110 3 1012 - 1020 2019年03月 [査読有り]
     
    Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).
  • Hidetoshi Hayashi; Takayasu Kurata; Yuichi Takiguchi; Makoto Arai; Koji Takeda; Kohei Akiyoshi; Koji Matsumoto; Takuma Onoe; Hirofumi Mukai; Nobuaki Matsubara; Hironobu Minami; Masanori Toyoda; Yusuke Onozawa; Akira Ono; Yoshihiko Fujita; Kazuko Sakai; Yasuhiro Koh; Ayano Takeuchi; Yasuo Ohashi; Kazuto Nishio; Kazuhiko Nakagawa
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37 7 570 - 579 2019年03月 [査読有り]
     
    PURPOSE: Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS: Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS: One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (20%). The 1-year survival rate was 44.0% and 54.9% for site-specific treatment and empirical PC ( P = .264), respectively. Median overall and progression-free survival were 9.8 and 5.1 months, respectively, for site-specific treatment versus 12.5 and 4.8 months for empirical PC ( P = .896 and .550, respectively). Median overall survival (16.7 v 10.6 months; P = .116) and progression-free survival (5.5 v 3.9 months; P = .018) were better for predicted more-responsive than less-responsive tumor types. CONCLUSION: Site-specific treatment that was based on microarray profiling did not result in a significant improvement in 1-year survival compared with empirical PC, although prediction of the original site seemed to be of prognostic value.
  • Satomi Watanabe; Kimio Yonesaka; Junko Tanizaki; Yoshikane Nonagase; Naoki Takegawa; Koji Haratani; Hisato Kawakami; Hidetoshi Hayashi; Masayuki Takeda; Junji Tsurutani; Kazuhiko Nakagawa
    Cancer medicine 8 3 1258 - 1268 2019年03月 [査読有り]
     
    HER2-targeted therapy, especially the anti-HER2 antibody trastuzumab, is standard for HER2-positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)-dependent HER2-HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2-positive breast cancer. The anti-HER2 antibody pertuzumab and anti-HER3 antibody patritumab both target this heregulin-HER3-HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab-resistant HER2-positive breast cancer. HER2-positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3-HRG, BT474-HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474-HRG and an intrinsic heregulin-expressing and HER2-positive JIMT-1 xenograft models. SKBR3-HRG and BT474-HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin-expressing BT474-HRG and JIMT-1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin-expressing and HER2-positive breast cancer, which could be exploited clinically.
  • Shinichiro Suzuki; Koji Haratani; Takayuki Takahama; Satomi Watanabe; Naoki Takegawa; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Kazuhiko Nakagawa
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 3 e50-e52 - e52 2019年03月 [査読有り]
  • Satoshi Watanabe; Hiroshige Yoshioka; Hiroshi Sakai; Katsuyuki Hotta; Mitsuhiro Takenoyama; Kazuhiko Yamada; Shunichi Sugawara; Yuichi Takiguchi; Yukio Hosomi; Keisuke Tomii; Seiji Niho; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Terufumi Kato; Toshiaki Takahashi; Ami Kamada; Kazumi Suzukawa; Yukie Omori; Sotaro Enatsu; Kazuhiko Nakagawa; Tomohide Tamura
    Lung cancer (Amsterdam, Netherlands) 129 55 - 62 2019年03月 [査読有り]
     
    OBJECTIVES: This open-label, multicenter, phase 1b/2 study assessed necitumumab plus gemcitabine and cisplatin (GC + N) in patients with previously untreated squamous non-small cell lung cancer in Japan. MATERIALS AND METHODS: The phase 1b part determined the gemcitabine dose for the phase 2 part, in which patients were randomized 1:1 to GC + N or gemcitabine and cisplatin (GC) (gemcitabine 1250 mg/m2 on days 1 and 8; cisplatin 75 mg/m2 on day 1 of maximum four 3-week cycles; nectimumab 800 mg on days 1 and 8 of a 3-week cycle continued until progressive disease or unacceptable toxicity). The primary endpoint of the phase 2 part was overall survival. RESULTS: In the phase 2 part, 181 patients received GC + N (N = 90) or GC (N = 91). Overall survival was significantly improved with GC + N versus GC (median, 14.9 months vs 10.8 months; hazard ratio [HR] = 0.66, 95% CI: 0.47 - 0.93, p = 0.0161). Improvements were also observed in progression-free survival (median, 4.2 months vs 4.0 months; HR = 0.56; p = 0.0004) and objective response rate (51% vs 21%; p < 0.0001). Survival was also significantly prolonged with GC + N versus GC for patients with epidermal growth factor receptor-positive tumors. Grade ≥3 treatment-emergent adverse events at ≥5% higher incidence with GC + N than GC were neutrophil count decreased (42% vs 35%), febrile neutropenia (12% vs 3%), decreased appetite (11% vs 4%), and dermatitis acneiform (6% vs 0%). CONCLUSION: GC + N is well tolerated and has significant and clinically meaningful treatment benefit in the first-line treatment of patients with squamous non-small cell lung cancer in Japan. Clinicaltrials.gov identifier: NCT01763788.
  • Kimio Yonesaka; Naoki Takegawa; Satomi Watanabe; Koji Haratani; Hisato Kawakami; Kazuko Sakai; Yasutaka Chiba; Naoyuki Maeda; Takashi Kagari; Kenji Hirotani; Kazuto Nishio; Kazuhiko Nakagawa
    Oncogene 38 9 1398 - 1409 2019年02月 [査読有り]
     
    EGFR tyrosine kinase inhibitors (TKIs) are standard therapy for EGFR-mutant non-small cell lung cancer (NSCLC); however, these tumours eventually acquire chemoresistance. U3-1402 is an anti-HER3 antibody-drug conjugate with a novel topoisomerase I inhibitor, DXd. In the current study, we evaluated the anticancer efficacy of U3-1402 in EGFR-mutant NSCLC cells with acquired resistance to EGFR-TKIs. HCC827GR5 and PC9AZDR7 are EGFR-TKI-resistant clones for gefitinib and osimertinib, respectively. U3-1402 alone or in combination with the EGFR-TKI erlotinib demonstrated potent anticancer efficacy in HCC827GR5 cells using an in vitro growth inhibition assay and in vivo xenograft mouse model. U3-1402 induced apoptosis in HCC827GR5 cells accompanying phosphorylation of histone H2A.X, a marker of DNA damage, but did not block HER3/PI3K/AKT signalling. Further, we found using flow cytometry that the cell surface HER3 expression level in HCC827GR5 cells was twice that found in HCC827 cells, indicating internalization of U3-1402 was increased in resistant cells. In addition, administration of U3-1402 notably repressed growth of EGFR-TKI osimertinib-resistant PC9AZDR7 xenograft tumours, and that PC9AZDR7 cells expressed five times greater cell surface HER3 than PC9 cells. Furthermore, using immunofluorescent microscopy, HER3 was observed predominantly in the nucleus of PC9 cells, but was localized in the cytoplasm of PC9AZDR7 cells. This finding indicates that altered trafficking of the HER3-U3-1402 complex may accelerate linker payload cleavage by cytoplasmic lysosomal enzymes, resulting in DNA damage. Our results indicate that administration of U3-1402 alone or in combination with an EGFR-TKI may have potential as a novel therapy for EGFR-TKI-resistant EGFR-mutant NSCLC.
  • Hiroto Ueda; Hisato Kawakami; Yoshikane Nonagase; Naoki Takegawa; Tatsuya Okuno; Takayuki Takahama; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa
    The oncologist 24 2 163-e76 - e76 2019年02月 [査読有り]
     
    LESSONS LEARNED: The 5-fluorouracil, docetaxel, and nedaplatin (UDON) regimen was well tolerated and showed promising antitumor activity in terms of both objective response rate and survival for patients with advanced or recurrent esophageal squamous cell carcinoma in the first-line setting.UDON may be an optimal treatment option for patients with advanced esophageal cancer who are unfit for docetaxel, cisplatin, and 5-fluorouracil regimens.The high response rate as well as the rapid and marked tumor shrinkage associated with UDON suggest that further evaluation of this regimen in the neoadjuvant setting is warranted. BACKGROUND: A phase II study was performed to evaluate the efficacy and safety of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for untreated recurrent or metastatic esophageal cancer. METHODS: Patients received intravenous nedaplatin (90 mg/m2) on day 1, docetaxel (35 mg/m2) on days 1 and 15, and 5-fluorouracil (800 mg/m2) on days 1-5 of a 4-week cycle. The primary endpoint was response rate, with secondary endpoints including overall survival (OS), progression-free survival (PFS), dysphagia score, and adverse events. RESULTS: Between March 2015 and July 2017, 23 patients were enrolled. Of 22 evaluable patients, 16 and 4 individuals experienced a partial response and stable disease, respectively, yielding a response rate of 72.7% (95% confidence interval [CI], 49.8%-89.3%) and disease control rate of 90.9% (95% CI, 70.8%-98.9%). Median OS and PFS were 11.2 months (95% CI, 9.1 months to not reached) and 6.0 months (95% CI, 2.5-10.6 months), respectively. Eleven (64.7%) of the 17 patients with a primary lesion showed amelioration of dysphagia after treatment. Frequent adverse events of grade 3 or 4 included neutropenia (87.0%) and leukopenia (39.1%). Febrile neutropenia was observed in two patients (8.7%). CONCLUSION: This phase II study demonstrated promising antitumor activity and good tolerability of UDON.
  • Kimio Yonesaka; Yoshihisa Kobayashi; Hidetoshi Hayashi; Yasutaka Chiba; Tetsuya Mitsudomi; Kazuhiko Nakagawa
    Oncology reports 41 2 1059 - 1066 2019年02月 [査読有り]
     
    Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKIs) are efficacious drugs for non‑small cell lung cancers (NSCLCs) with EGFR‑activating mutations. Afatinib, a second‑generation EGFR‑TKI and osimertinib, a third‑generation EGFR‑TKI, are both standard therapies for patients with these types of cancer. Each drug possesses distinct binding sites for the tyrosine kinase domain of EGFR. The present study examined the efficacy of single and combination TKI therapy using in vitro growth inhibition assays of Ba/F3 cells with an EGFR‑activating Del19 mutation. Afatinib or osimertinib treatment alone markedly inhibited cell proliferation in Ba/F3 cells, although drug‑resistant cells eventually appeared with secondary EGFR mutations (either T790M or C797S, respectively) as determined by direct sequencing. Notably a combination of afatinib and osimertinib eradicated Ba/F3 cells with no development of resistance. We also evaluated the efficacy of afatinib, osimertinib, and a combination of the two, using drug‑resistant cells with T790M or C797S mutations. Osimertinib was effective for treating Ba/F3 cells with the T790M mutation, whereas afatinib was moderately effective against C797S Ba/F3 cells. However, subsequent treatment, even when both drugs were used in combination, could not completely eradicate the Ba/F3 population and doubly resistant cells with a variety of triple mutations were generated, including Del19/T790M/C797S. In conclusion, an initial treatment with a combination of osimertinib and afatinib is potentially more effective for eradicating mutant EGFR‑dependent cells than sequential drug use. This should be tested in future clinical trials to establish whether such a combination would be effective for the treatment of NSCLC.
  • Hayashi H; Kurata T; Takiguchi Y; Arai M; Takeda K; Akiyoshi K; Matsumoto K; Onoe T; Mukai H; Matsubara N; Minami H; Toyoda M; Onozawa Y; Ono A; Fujita Y; Sakai K; Koh Y; Takeuchi A; Ohashi Y; Nishio K; Nakagawa K
    Journal of Clinical Oncology 37 7 JCO1800771 - 579 Journal of Clinical Oncology 2019年01月 
    © 2019 by American Society of Clinical Oncology. PURPOSE Although gene expression profiling is a promising diagnostic technique to determine the tissue of origin for patients with cancer of unknown primary site (CUP), no clinical trial has evaluated yet site-specific therapy directed by this approach compared with empirical chemotherapy. We therefore performed a randomized study to assess whether such site-specific therapy improves outcome compared with empirical chemotherapy in previously untreated patients with CUP. PATIENTS AND METHODS Comprehensive gene expression profiling was performed by microarray analysis, and an established algorithm was applied to predict tumor origin. Patients with CUP were randomly assigned (1:1) to receive standard site-specific therapy or empirical paclitaxel and carboplatin (PC). The primary end point was 1-year survival rate. RESULTS One hundred thirty patients were randomly assigned and had sufficient biopsy tissue for molecular analysis. Efficacy analysis was performed for 50 and 51 patients in the site-specific therapy and empirical PC arms, respectively. Cancer types most commonly predicted were pancreatic (21%), gastric (21%), and lymphoma (2
  • Masayuki Takeda; Kazuhiko Nakagawa
    International journal of molecular sciences 20 1 2019年01月 [査読有り]
     
    Activating mutations of the epidermal growth factor receptor gene (EGFR) are a driving force for some lung adenocarcinomas. Several randomized phase III studies have revealed that treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) results in an improved progression-free survival (PFS) compared to standard chemotherapy in chemonaive patients with advanced non⁻small cell lung cancer (NSCLC), selected based on the presence of EGFR mutations. Patients treated with second-generation EGFR-TKIs have also shown an improved PFS relative to those treated with first-generation EGRF-TKIs. Osimertinib is a third-generation EGFR-TKI that still irreversibly inhibits the activity of EGFR after it has acquired the secondary T790M mutation that confers resistance to first- and second-generation drugs. Its efficacy has been validated for patients whose tumors have developed T790M-mediated resistance, as well as for first-line treatment of those patients with EGFR mutation⁻positive NSCLC. Although there are five EGFR-TKIs (gefitinib, erlotinib, afatinib, dacomitinib, and osimertinib) currently available for the treatment of EGFR-mutated lung cancer, the optimal sequence for administration of these drugs remains to be determined. In this review, we addressed this issue with regard to maximizing the duration of the EGFR-TKI treatment.
  • Shinsuke Uchida; Shun-Ichi Watanabe; Yukihiro Yoshida; Aki Kobayashi; Keisuke Asakura; Kazuo Nakagawa
    Journal of surgical case reports 2019 1 rjy359  2019年01月 [査読有り]
     
    Anatomic variations of the pulmonary artery (PA) cause vascular injuries and result in critical mistakes. Here we report the first case of lung cancer with a fissureless left upper lobectomy, an aberrant mediastinal trunk of the lingular and basal segments of the PA. A 65-year-old man was referred to our hospital with a solid mass on the left upper lobe. A fissureless left upper lobectomy was performed due to severe incomplete lobulation. Intraoperative findings showed an extremely rare anatomic variation (left A5+A8+A9b) that arose as a common trunk from the left main PA. To prevent intraoperative injury, it is essential to consider the unexpected mediastinal inferior branch and perform a surgical procedure such as fissureless lobectomy upon encountering incomplete lobulation.
  • Watanabe Satomi; Hayashi Hidetoshi; Haratani Koji; Shimizu Shigeki; Tanizaki Junko; Sakai Kazuko; Kawakami Hisato; Yonesaka Kimio; Tsurutani Junji; Togashi Yosuke; Nishio Kazuto; Ito Akihiko; Nakagawa Kazuhiko
    Cancer Science 110 1 52 - 60 2019年01月 
    非小細胞肺癌の細胞株や患者由来検体を実験材料とし、上皮成長因子受容体(EGFR)チロシンキナーゼ阻害薬(TKI)がMHCクラスIの発現に及ぼす影響について調査した。EGFR遺伝子にT790M二次的突然変異などの変異がある細胞株を適切なEGFR-TKIで処理するとMHCクラスIのmRNA/蛋白質発現は亢進した。細胞外シグナル調節キナーゼ(ERK)キナーゼであるMEKの阻害薬で処理した場合もMHCクラスI発現が亢進したことから、EGFR活性化に応答してみられるMHCクラスI発現の下方制御はMEK-ERK経路が媒介していることが示唆された。EGFR-TKI治療を施行したEGFR変異非小細胞肺癌患者から得た検体の免疫組織化学解析からも、疾患進行後においては、リン酸化EGFRやリン酸化ERKの下方制御が、MHC-Iの上方制御、CD8+浸潤T細胞の増加、およびPD-1リガンド1発現亢進と関連していることが明らかになった。これらの結果から、非小細胞癌においてEGFRが変異活性化するとMEK-ERK経路を通じてMHCクラスI発現が阻害され、免疫療法に不応となるのに寄与することが示唆された。
  • Arai S; Okabayashi A; Tohda R; Nakagawa K; Taniguchi M; Yanagihara S; Oiso N; Tsuruta D
    J Dermatol 46 1 e35 - e36 2019年01月 [査読有り]
  • Hiroaki Akamatsu; Hideyuki Harada; Shoji Tokunaga; Naruo Yoshimura; Hiroko Ikeda; Satoshi Oizumi; Naotoshi Sugimoto; Toshimi Takano; Haruyasu Murakami; Yasumasa Nishimura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    Clinical lung cancer 20 1 e25-e27 - e27 2019年01月 [査読有り]
     
    Locally advanced non-small-cell lung cancer (NSCLC) is curable. Standard treatment is concurrent chemoradiotherapy, but its efficacy with cytotoxic agents seems to reach a plateau. Among patients with advanced NSCLC who have epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitor is the key drug. Thus, a similar strategy should be tested in patients with locally advanced NSCLC who have EGFR mutation. This single arm, phase II study aims to explore the efficacy and tolerability of gefitinib with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. The primary endpoint is progression-free survival rate at 2 years. The secondary endpoints are overall response rate, progression-free survival, overall survival, and safety. A total of 27 patients will be enrolled in this trial.
  • Naoyuki Nogami; Makoto Nishio; Isamu Okamoto; Sotaro Enatsu; Kazumi Suzukawa; Hiroki Takai; Kazuhiko Nakagawa; Tomohide Tamura
    Respiratory investigation 57 1 27 - 33 2019年01月 [査読有り]
     
    BACKGROUND: The combination of pemetrexed and carboplatin is commonly used for the treatment of advanced non-squamous non-small cell lung cancer (NSCLC), mainly because it is comparatively effective and less toxic than other platinum-doublet therapies. Using the JMII (JACAL) study, we report the efficacy and safety of this treatment followed by pemetrexed maintenance in the elderly population (≥70 years of age). METHODS: The JMII study was a multicenter, post-marketing study that assessed the efficacy and safety of carboplatin (AUC6) and pemetrexed (500 mg/m2, given on Day 1 of a 21-day cycle, 4 cycles) followed by pemetrexed (500 mg/m2) maintenance in advanced non-squamous NSCLC patients (n = 109). Retrospective subgroup analyses were performed in elderly patients aged ≥70. RESULTS: The study includes younger (<70 years, n = 84) and elderly (≥70 years, n = 25) patients who received induction therapy. Median progression-free survival and overall survival from the start of the induction phase were 5.2 (95% CI: 3.5, 8.2) and 16.8 (95% CI: 10.3, NC) months for the elderly patients compared with 5.8 (95% CI: 4.3, 7.4) and 20.5 (95% CI: 16.7, NC) months for the younger patients, respectively. Grade 3/4 hematologic toxicities were more frequent in the elderly patients. Non-hematologic toxicities in the elderly patients were comparable to those in younger patients. Dose reduction was more common in the elderly (44% vs 23%), due to hematologic toxicities. CONCLUSIONS: There was no difference in efficacy (evaluated by progression-free survival) between elderly and younger patients. Although grade 3/4 hematologic toxicities were frequently observed in the elderly patients, they were easily managed with dose adjustment.
  • Satomi Watanabe; Hidetoshi Hayashi; Koji Haratani; Shigeki Shimizu; Junko Tanizaki; Kazuko Sakai; Hisato Kawakami; Kimio Yonesaka; Junji Tsurutani; Yosuke Togashi; Kazuto Nishio; Akihiko Ito; Kazuhiko Nakagawa
    Cancer science 110 1 52 - 60 2019年01月 [査読有り]
     
    The efficacy of programmed cell death-1 (PD-1) blockade in patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC-I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC-I expression in NSCLC cell lines. Appropriate EGFR-TKIs increased MHC-I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also increased MHC-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK-ERK pathway mediates the down-regulation of MHC-I expression in response to EGFR activation. Immunohistochemical analysis of EGFR-mutated NSCLC specimens obtained before and after EGFR-TKI treatment also revealed down-regulation of phosphorylated forms of EGFR and ERK in association with up-regulation of MHC-I, an increased number of infiltrating CD8+ T cells, and increased PD-1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC-I expression through the MEK-ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR-MEK-ERK signaling in and the immune response to EGFR-mutated NSCLC. .
  • Kazuma Kishi; Hiroshi Sakai; Takashi Seto; Toshiyuki Kozuki; Makoto Nishio; Fumio Imamura; Hiroshi Nokihara; Miyako Satouchi; Shintaro Nakagawa; Takashi Tahata; Kazuhiko Nakagawa
    Cancer treatment and research communications 18 100113 - 100113 2019年 [査読有り]
     
    INTRODUCTION: The phase II JO28638 study evaluated first-line onartuzumab plus erlotinib in patients with MET-positive advanced, metastatic, or post-operative recurrent non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The study was stopped following termination of the global METLung study (OAM4971g), which showed lack of efficacy in the onartuzumab/erlotinib arm. We present immature efficacy and safety data from JO28638. MATERIALS AND METHODS: Chemotherapy-naïve patients aged ≥ 20 years were enrolled. Patients received onartuzumab (15 mg/kg every 3 weeks) plus erlotinib (150 mg once daily) until progression or unacceptable toxicity. The co-primary endpoints were investigator (INV)-assessed progression-free survival (PFS) and safety. Secondary endpoints: overall response rate (ORR), disease control rate (DCR), overall survival (OS), duration of response (DOR), and pharmacokinetics. Exploratory biomarker analyses were also conducted. RESULTS: 61 patients received treatment. Median age was 67 years and most patients had stage IV NSCLC (71%), MET-IHC score 2 (87%), and exon 19 deletion EGFR mutation (53%). Median PFS (INV) was 8.5 months (95% confidence interval [CI] 6.8-12.4); median OS was 15.6 months (95% CI 15.6-not evaluable); ORR was 68.9% (95% CI 55.7-80.1); median DOR was not reached; DCR was 88.5% (95% CI 77.8-95.3). Pharmacokinetics were similar to previous studies. All patients experienced an adverse event (AE); 26 patients discontinued treatment due to AEs; no grade 5 AEs were reported. No significant correlation was found between biomarkers and efficacy outcomes. CONCLUSION: The results presented are inconclusive due to the early termination of the study.
  • Yuichiro Ohe; Fumio Imamura; Naoyuki Nogami; Isamu Okamoto; Takayasu Kurata; Terufumi Kato; Shunichi Sugawara; Suresh S Ramalingam; Hirohiko Uchida; Rachel Hodge; Sarah L Vowler; Andrew Walding; Kazuhiko Nakagawa
    Japanese journal of clinical oncology 49 1 29 - 36 2019年01月 [査読有り]
     
    Background: The FLAURA study was a multicenter, double-blind, Phase 3 study in which patients with previously untreated epidermal growth factor receptor mutation-positive advanced non-small-cell lung carcinoma were randomized 1:1 to oral osimertinib 80 mg once daily or standard-of-care (gefitinib 250 mg or erlotinib 150 mg, once daily) to compare safety and efficacy. In the overall FLAURA study, significantly better progression-free survival was shown with osimertinib versus standard-of-care. Methods: Selected endpoints, including progression-free survival (primary endpoint), overall survival, objective response rate, duration of response and safety were evaluated for the Japanese subset of the FLAURA study. Results: In Japan, 120 eligible Japanese patients were randomized to osimertinib (65 patients) or gefitinib (55 patients) treatment from December 2014 to June 2017. Median progression-free survival was 19.1 (95% confidence interval, 12.6, 23.5) and 13.8 (95% confidence interval, 8.3, 16.6) months with osimertinib and gefitinib, respectively (hazard ratio, 0.61; 95% confidence interval, 0.38, 0.99). Median overall survival was not reached in either treatment arm (data were immature). In the osimertinib and gefitinib arms, objective response rate was 75.4% (49/65) and 76.4% (42/55), and median duration of response from onset was 18.4 (95% confidence interval, not calculated) and 9.5 (95% confidence interval, 6.2, 13.9) months, respectively. The incidence of adverse events was similar in the two groups. The frequency of Grade ≥3 interstitial lung disease and pneumonitis in the two groups were the same (one patient). Conclusions: As the first-line therapy, osimertinib showed significantly improved efficacy versus gefitinib in the Japanese population of the FLAURA study. No new safety concerns were raised. Clinical trial registration: NCT02296125 (ClinicalTrials.gov).
  • Hitomi Sakai; Masayuki Takeda; Kazuko Sakai; Yasushi Nakamura; Akihiko Ito; Hidetoshi Hayashi; Kaoru Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    Lung cancer (Amsterdam, Netherlands) 127 59 - 65 2019年01月 [査読有り]
     
    OBJECTIVES: Immune-checkpoint inhibitors (ICIs) are now an established therapeutic option for advanced non-small cell lung cancer (NSCLC). It has remained unclear, however, whether cytotoxic chemotherapy affects the immune microenvironment in NSCLC wild type for EGFR and ALK. MATERIALS AND METHODS: We retrospectively evaluated changes in programmed cell death 1-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), and CD8+ tumor-infiltrating lymphocyte (TIL) density in NSCLC patients who underwent rebiopsy at the site of recurrence after postoperative platinum-based adjuvant chemotherapy, or in those who underwent rebiopsy after one or more chemotherapeutic regimens at the advanced stage. The PD-L1 tumor proportion score (TPS) and CD8+ TIL density were determined by immunohistochemistry. TMB was estimated by next-generation sequencing with a cancer gene panel (409 genes). RESULTS: Seventeen patients with NSCLC wild type for EGFR and ALK were enrolled. Although PD-L1 TPS tended to be increased in rebiopsy samples compared with initial biopsy tissue, this difference was not significant (P =  0.113). Seven patients showed an increase in PD-L1 TPS, with this change being pronounced in four. Two cases in which PD-L1 TPS increased from 0 to 90% or from 0 to 95% after cytotoxic chemotherapy also showed a durable response to subsequent treatment with an ICI. No substantial correlation between PD-L1 TPS and TMB was apparent either before (R = 0.112) or after (R = 0.101) chemotherapy. A moderate correlation was detected between PD-L1 TPS and CD8+ TIL density before chemotherapy (R = 0.517) and a negligible correlation after (R = 0.0219). CONCLUSION: Cytotoxic chemotherapy may change the biological characteristics of tumors including PD-L1 expression level and TMB.
  • Masayuki Takeda; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    OncoTargets and therapy 12 5355 - 5358 2019年 [査読有り]
     
    The discovery of RET rearrangement in non-small cell lung cancer (NSCLC) has prompted development of molecularly targeted therapy for such tumors, with several clinical trials being under way to evaluate the therapeutic effects of multitargeted tyrosine kinase inhibitors. The sensitivity of RET fusion-positive NSCLC to cytotoxic chemotherapy has remained unclear, however. We here report a case of NSCLC positive for the CCDC6-RET fusion gene that benefited from treatment with pemetrexed over a period of 30 months, suggesting that thymidylate synthase-targeted drugs such as pemetrexed may show efficacy for NSCLC harboring RET fusions.
  • Toshiharu Sakurai; Yoriaki Komeda; Tomoyuki Nagai; Ken Kamata; Kosuke Minaga; Kentarou Yamao; Mamoru Takenaka; Satoru Hagiwara; Tomohiro Watanabe; Naoshi Nishida; Hiroshi Kashida; Kazuhiko Nakagawa; Masatoshi Kudo
    Digestion 1 - 9 2018年12月 [査読有り]
  • Yutaka Kimura; Osamu Shiraishi; Hisato Kawakami; Hiroto Ueda; Tatsuya Okuno; Yoko Hiraki; Hiroaki Kato; Mitsuru Iwama; Atsushi Yasuda; Masayuki Shinkai; Takaaki Chikugo; Motohiro Imano; Haruhiko Imamoto; Kazuhiko Nakagawa; Takushi Yasuda
    Gan to kagaku ryoho. Cancer & chemotherapy 45 13 1812 - 1814 2018年12月 [査読有り]
     
    A 71-year-old man with a history of hypertension, diabetes mellitus, and cerebral infarction was admitted to our hospital with dysphagia. Gastroduodenoscopy, thoracoabdominal CT, and PET-CT findings showed type 2 advanced esophageal cancer( squamous cell carcinoma)with upper mediastinal and cervical lymph node(LN)metastasis: cT3N2M1(LYM #104L), cStage Ⅳ. Two courses of neoadjuvant UDONchemotherapy containing 5-FU(640mg/m / 2, days 1-5), docetaxel(28mg/m2, days 1 and 15), and nedaplatin(72mg/m2, day 1)were administered every 4 weeks. UDONtherapy caused grade(Gr)3 febrile neutropenia, Gr 2 diarrhea, and Gr 1 thrombopenia; the tumor and LNs partially responded to the therapy. After 2 courses of UDONtherapy, esophagectomy with right thoracotomy, 3-field LNdissection, and reconstruction of the gastric tube were performed. The postoperative course was almost uneventful besides recurrent nerve palsy, aspiration, pneumonia, and delirium, and the patient was discharged 60 days after surgery. The pathological diagnosis was ypT0N0M0, ypStage 0, and the histological response of the primary tumor and LNs were evaluated as Gr 3. Neoadjuvant UDON therapy is feasible for elderly patients with advanced esophageal cancer and renal failure or comorbidities, for whom CDDP could not be administered. We are planning a clinical trial to assess the effectiveness of neoadjuvant UDONtherapy.
  • Kato R; Hayashi H; Sano K; Handa K; Kumode T; Ueda H; Okuno T; Kawakami H; Matsumura I; Kudo M; Nakagawa K
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 12 e239 - e241 2018年12月 [査読有り]
  • 高用量CDDPの使用が困難な進行食道癌患者に対する術前化学療法の検討
    木村 豊; 白石 治; 川上 尚人; 植田 勲人; 奥野 達哉; 岩間 密; 加藤 寛章; 平木 洋子; 安田 篤; 新海 政幸; 今野 元博; 今本 治彦; 中川 和彦; 安田 卓司
    日本消化器外科学会雑誌 51 Suppl.2 268 - 268 (一社)日本消化器外科学会 2018年11月
  • Hata A; Katakami N; Shimokawa M; Mitsudomi T; Yamamoto N; Nakagawa K
    Clinical lung cancer 19 6 e865 - e869 2018年11月 [査読有り]
     
    We exhibit our ongoing multicenter, prospective, single-arm, phase II trial of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor (PEG-G-CSF) support for chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (NSCLC) (University Hospital Medical Information Network database: UMIN000030598). Docetaxel monotherapy is the Japanese standard of care for chemotherapy-naive elderly patients with advanced NSCLC. Docetaxel plus ramucirumab showed superior survival benefit over docetaxel monotherapy in the second-line setting for NSCLC. A Japanese phase II study comparing docetaxel plus ramucirumab and docetaxel monotherapy in the second-line setting showed febrile neutropenia (FN) incidence of approximately one-third in the docetaxel plus ramucirumab arm. Docetaxel plus ramucirumab could be a promising candidate for elderly patients with NSCLC, but such high FN incidence is a clinically critical concern. To overcome this problem, we adopt a routine primary prophylactic PEG-G-CSF with docetaxel plus ramucirumab therapy. We hypothesize that primary prophylactic PEG-G-CSF reduces FN and maximizes the efficacy of docetaxel plus ramucirumab in Japanese elderly patients with NSCLC. Intravenous docetaxel (60 mg/m2, day 1) plus ramucirumab (10 mg/kg, day 1) with subcutaneous PEG-G-CSF (3.6 mg, day 2) every 3 weeks is administered until progression. The primary endpoint is overall response rate (ORR). We decided the threshold ORR to be 20%, and the expected ORR 35%. Taking statistical points (α/β errors: 0.05/0.80) and ineligible patients into account, the sample size was set at 65. When the study results are promising, we will conduct a phase III trial to compare docetaxel plus ramucirumab with PEG-G-CSF support versus docetaxel monotherapy for chemotherapy-naive elderly patients with NSCLC.
  • 加藤 晃史; 岡田 守人; 木島 貴志; 青江 啓介; 藤本 伸一; 中川 和彦; 竹田 雄一郎; 樋田 豊明; 金井 一修; 今村 文生; 大泉 聡史; 高橋 利明; 竹之山 光広; 田中 洋史; 大江 裕一郎
    肺癌 58 6 461 - 461 (NPO)日本肺癌学会 2018年10月
  • Fumihiro Tanaka; Hiroyasu Yokomise; Toshinori Soejima; Hidetaka Uramoto; Takeharu Yamanaka; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Yasumasa Nishimura; Hiroshi Niwa; Morihito Okada; Tatsuo Nakagawa; Motohiro Yamashita
    The Annals of thoracic surgery 106 4 1018 - 1024 2018年10月 [査読有り]
     
    BACKGROUND: The optimal therapeutic strategy for potentially resectable clinical (c-) stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial. This phase II multiinstitutional study (West Japan Oncology Group 5308L) was designed to evaluate the feasibility of induction chemotherapy with concurrent thoracic radiotherapy (50 Gy), followed by resection and postoperative consolidation chemotherapy, in IIIA-N2 NSCLC. METHODS: Patients with resectable c-stage IIIA-N2 were eligible, and pathologic confirmation of N2 disease was mandatory. Patients received chemotherapy consisting of weekly carboplatin plus paclitaxel with concurrent radiotherapy (50 Gy in 25 fractions). Unless disease progression was documented, patients underwent surgical resection, and thereafter received two courses of consolidation chemotherapy with carboplatin plus paclitaxel. The primary end point was the proportion of patients who achieved complete resection after induction chemoradiotherapy (R0 rate). RESULTS: From December 2011 to November 2013, 40 eligible patients were enrolled. All patients completed induction chemoradiotherapy with an overall response rate of 58%, and 32 patients achieved complete resection (R0 rate, 80%) mostly with lobectomy (n = 27). Twenty patients (50%) completed the study treatment, including postoperative chemotherapy. After the median follow-up period of 38 months, the progression-free survival, overall survival, and recurrence-free survival rates at 2 years were 63%, 75%, and 62%, respectively. The 30-day and 90-day mortality were 0%. CONCLUSIONS: Induction chemotherapy with concurrent radiotherapy (50 Gy), followed by resection, was a feasible and promising treatment option for resectable c-stage IIIA-N2 NSCLC.
  • Yamamoto N; Kenmotsu H; Goto K; Takeda K; Kato T; Takeda M; Horinouchi H; Saito I; Sarashina A; Tanaka T; Morsli N; Nakagawa K
    Cancer chemotherapy and pharmacology 82 4 685 - 694 2018年10月 [査読有り]
  • Hiroaki Iwasa; Aradhan Sarkar; Takanobu Shimizu; Takeru Sawada; Shakhawoat Hossain; Xiaoyin Xu; Junichi Maruyama; Kyoko Arimoto-Matsuzaki; Kanchanamala Withanage; Kentaro Nakagawa; Hidetake Kurihara; Hidehito Kuroyanagi; Yutaka Hata
    Cancer Sci. 109 9 2767 - 2780 2018年09月 [査読有り]
     
    Ras-association domain family 6 (RASSF6) is a tumor suppressor that interacts with MDM2 and stabilizes p53. Caenorhabditis elegans unc-119 encodes a protein that is required for normal development of the nervous system. Humans have 2 unc-119 homologues, UNC119 and UNC119B. We have identified UNC119 as a RASSF6-interacting protein. UNC119 promotes the interaction between RASSF6 and MDM2 and stabilizes p53. Thus, UNC119 induces apoptosis by RASSF6 and p53. UNC119 depletion impairs DNA repair after DNA damage and results in polyploid cell generation. These findings support that UNC119 is a regulator of the RASSF6-MDM2-p53 axis and functions as a tumor suppressor.
  • Sakai Hitomi; Tsurutani Junji; Iwasa Tsutomu; Komoike Yoshifumi; Sakai Kazuko; Nishio Kazuto; Nakagawa Kazuhiko
    Breast Cancer 25 5 605 - 613 2018年09月 
    循環腫瘍DNA(ctDNA)のゲノム解析とその他のヒト上皮成長因子受容体2(HER2)陽性進行性乳癌(ABC)患者の臨床病理学的特徴を合わせて、trastuzumab emtasine(T-DM1)に対する初期耐性を予測した。T-DM1による治療を受けたHER2陽性ABC患者34例(年齢中央値62歳)を対象とした。患者の臨床病理学的特徴とT-DM1に対する初期耐性との相関関係を調べ、T-DM1を投与する前の患者16例から採取した血漿ctDNA検体を用いてHER2遺伝子コピー数とPIK3CA遺伝子突然変異を解析した。初回有効性解析の時点で疾患進行がみられた患者は9例で、これらの患者はT-DM1に対する初期耐性を有するとみなした。2群の間でT-DM1に対する初期耐性率の有意差は認められなかった。ctDNAを解析した16例のうち、4例がT-DM1に対する初期耐性を示した。これらの4例は、ctDNAにおけるHER2遺伝子増幅が陰性で、免疫組織化学検査ではエストロゲン受容体陽性および/またはプロゲステロン受容体陽性であった。
  • Murakami H; Nokihara H; Hayashi H; Seto T; Park K; Azuma K; Tsai CM; Yang JC; Nishio M; Kim SW; Kiura K; Inoue A; Takeda K; Kang JH; Nakagawa T; Takeda K; Akazawa R; Kaneko Y; Shimazaki M; Morita S; Fukuoka M; Nakagawa K
    Cancer science 109 9 2852 - 2862 2018年09月 [査読有り]
     
    Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose-escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25-600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations.
  • Junji Furuse; Takayasu Kurata; Naohiro Okano; Yasuhito Fujisaka; Daisuke Naruge; Toshio Shimizu; Hiroshi Kitamura; Tsutomu Iwasa; Fumio Nagashima; Kazuhiko Nakagawa
    Cancer chemotherapy and pharmacology 82 3 511 - 519 2018年09月 [査読有り]
     
    PURPOSE: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. METHODS: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. RESULTS: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. Cmax and AUCinf were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373). CONCLUSION: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. CLINICAL TRIAL REGISTRATION: JAPIC Clinical Trials Information; JapicCTI-121751.
  • Tomonari Sasaki; Takashi Seto; Takeharu Yamanaka; Naonobu Kunitake; Junichi Shimizu; Takeshi Kodaira; Makoto Nishio; Takuyo Kozuka; Toshiaki Takahashi; Hideyuki Harada; Naruo Yoshimura; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Yukito Ichinose; Kazuhiko Nakagawa; Yasumasa Nishimura; Nobuyuki Yamamoto; Yoichi Nakanishi
    BRITISH JOURNAL OF CANCER 119 6 675 - 682 2018年09月 [査読有り]
     
    BACKGROUND: Cisplatin-based chemoradiotherapy is the standard treatment for unresectable, locally advanced non-small-cell lung cancer (NSCLC). This trial evaluated two experimental regimens that combine chemotherapy with concurrent radiotherapy.METHODS: Eligible patients with unresectable stage III NSCLC were randomised to either the SP arm (S-1 and cisplatin) or VP arm (vinorelbine and cisplatin), with early concurrent thoracic radiotherapy of 60 Gy, comprising 2 Gy per daily fraction. The primary endpoint was the overall survival rate at 2 years (2-year overall survival (OS)) (Study ID: UM1N000002420).RESULTS: From September 2009 to September 2012, 112 patients were enroled. Of the 108 eligible patients, the 2-year OS was 75.6% (80% confidence interval (CI), 67-82%) in the SP arm and 68.5% (80% CI: 60-76%) in the VP arm. The hazard ratio (HR) for death between the two arms was 0.85 (0.48-1.49). The median progression-free survival was 14.8 months for the SP arm and 12.3 months for the VP arm with an HR of 0.92 (0.58-1.44). There were four treatment-related deaths in the SP arm and five in the VP arm.CONCLUSIONS: The null hypotheses for 2-year OS were rejected in both arms. The West Japan Oncology Group will employ the SP arm as the investigational arm in a future phase III study.
  • Toshimi Takano; Junji Tsurutani; Masato Takahashi; Takeharu Yamanaka; Kazuko Sakai; Yoshinori Ito; Junya Fukuoka; Hideharu Kimura; Hidetaka Kawabata; Kenji Tamura; Koji Matsumoto; Kenjiro Aogi; Kazuhiko Sato; Kazuto Nishio; Kazuhiko Nakagawa; Toshiaki Saeki
    Breast (Edinburgh, Scotland) 40 67 - 75 2018年08月 [査読有り]
     
    BACKGROUND: For human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) with progression on trastuzumab-based therapy, continuing trastuzumab beyond progression and switching to lapatinib combined with chemotherapy are both valid options. We conducted an open-label, randomized phase II trial to compare the efficacy of these strategies. PATIENTS AND METHODS: Women with HER2-positive MBC previously treated with trastuzumab and taxanes were randomly assigned to receive trastuzumab plus capecitabine (HX) or lapatinib plus capecitabine (LX). The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and the objective response rate (ORR). To explore the predictive value of the differential benefit of anti-HER2 drugs, PIK3CA mutations were assessed using circulating tumor DNA. RESULTS: Eighty-six patients (43 in each arm) were enrolled. The median PFS was 6.1 months in the HX arm and 7.1 months in the LX arm (hazard ratio, 0.81; 90% CI, 0.55-1.21; p = 0.39); the median OS was 31.0 months in the HX arm and was not reached in the LX arm (hazard ratio, 0.58; 95% CI, 0.26-1.31; p = 0.18). The ORR was 40% in the HX arm and 41% in the LX arm. PIK3CA mutations were detected in 23% of the 35 analyzed patients, and in patients without PIK3CA mutations, LX yielded relatively longer PFS and OS than HX. CONCLUSION: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, no significant differences in PFS and OS were observed between patients treated with LX and HX. TRIAL REGISTRATION NUMBER: UMIN000005219.
  • Solomon BJ; Kim DW; Wu YL; Nakagawa K; Mekhail T; Felip E; Cappuzzo F; Paolini J; Usari T; Tang Y; Wilner KD; Blackhall F; Mok TS
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 36 22 2251 - 2258 2018年08月 [査読有り]
  • Azuma K; Nishio M; Hayashi H; Kiura K; Satouchi M; Sugawara S; Hida T; Iwamoto Y; Inoue A; Takeda K; Ikeda S; Nakagawa T; Takeda K; Asahina S; Komatsu K; Morita S; Fukuoka M; Nakagawa K
    Cancer science 109 8 2532 - 2538 2018年08月 [査読有り]
     
    Epidermal growth factor receptor (EGFR) activating mutations occur in approximately 50% of East Asian patients with non-small-cell lung cancer (NSCLC) and confer sensitivity to tyrosine kinase inhibitors (TKIs). ASP8273 is an irreversible EGFR-TKI, given orally, that inhibits EGFR activating mutations and has shown clinical activity in patients with EGFR mutation-positive NSCLC. Epidermal growth factor receptor-TKI-naïve Japanese adult patients (≥20 years) with NSCLC harboring EGFR mutations were enrolled in this open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT02500927). Patients received ASP8273 300 mg once daily until discontinuation criteria were met. The primary end-point was to determine the safety of ASP8273 300 mg; the secondary end-point was antitumor activity defined by RECIST version 1.1. Thirty-one patients (12 men and 19 women; median age, 64 years [range, 31-82 years]) with EGFR mutation-positive NSCLC were enrolled; as of 23 February 2016, 25 patients (81%) were still on study. Of the 31 patients, 27 (87%) had an exon 19 deletion (n = 13, 42%) or an L858R (n = 14, 45%) EGFR activating mutation, and two (7%) had an L861Q mutation. Five patients (16%) had other EGFR activating mutations, two had an activating mutation and the T790M resistance mutation. The most commonly reported treatment-emergent adverse event was diarrhea (n = 24, 77%). All patients had at least one post-baseline scan; one patient (3%) achieved a confirmed complete response, 13 (42%) had a confirmed partial response, and 15 (48%) had confirmed stable disease (disease control rate, 94% [n = 29/31]) per investigator assessment. Once-daily ASP8273 at 300 mg was generally well tolerated and showed antitumor activity in TKI-naïve Japanese patients with EGFR mutation-positive NSCLC.
  • Mok TS; Cheng Y; Zhou X; Lee KH; Nakagawa K; Niho S; Lee M; Linke R; Rosell R; Corral J; Migliorino MR; Pluzanski A; Sbar EI; Wang T; White JL; Wu YL
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 36 22 2244 - 2250 2018年08月 [査読有り]
  • Reungwetwattana T; Nakagawa K; Cho BC; Cobo M; Cho EK; Bertolini A; Bohnet S; Zhou C; Lee KH; Nogami N; Okamoto I; Leighl N; Hodge R; McKeown A; Brown AP; Rukazenkov Y; Ramalingam SS; Vansteenkiste J
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology JCO2018783118  2018年08月 [査読有り]
     
    Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.
  • 【分子標的薬の新しいバイオマーカー】 バイオマーカーの最近のtopics
    中川 和彦; 各務 博; 松村 到; 岩田 広治
    がん分子標的治療 16 2 146 - 153 (株)メディカルレビュー社 2018年07月 
    分子標的薬や免疫チェックポイント阻害薬ががん治療に浸透していくなかで、より適切で効果的な治療開発に向け、バイオマーカーの研究も進んでいる。たとえば、免疫チェックポイント阻害薬においては、腫瘍細胞におけるPD-L1発現が進行非小細胞肺がんに対するペムブロリズマブのコンパニオン診断として使われている。しかしながら、がん種によってPD-L1発現のバイオマーカーとしての臨床的意義が異なっていたり、腫瘍細胞に発現するPD-L1が重要なのか、それとも腫瘍組織に浸潤した細胞傷害性Tリンパ球(CTL)に発現されるPD-L1か、どちらをみるべきかといった議論もあり、今後解決すべき課題は多い。一方で、腫瘍細胞のtumor mutation burdenやCD62Lが新たなバイオマーカーとして注目されている。一方、分子標的薬のバイオマーカーとしては、肺がん領域において上皮成長因子受容体(EGFR)の遺伝子変異やALK、ROS1、BRAFの融合遺伝子の有無が治療方針の決定に用いられている。最近では第3世代のEGFRチロシンキナーゼ阻害薬(TKI)であるオシメルチニブのコンパニオン診断としてEGFR遺伝子変異T790Mの臨床導入も行われている。血液がんでは慢性骨髄性白血病(CML)のBCR-ABL融合遺伝子がイマチニブ治療の診断薬ならびに効果判定の指標として使用されている。乳がんでは古くからエストロゲン受容体(ER)やプロゲステロン(PG)の蛋白発現の有無がホルモン療法の有効性のバイオマーカーとして用いられてきた。トラスツズマブ治療の診断薬の指標としてのヒト上皮成長因子受容体(HER)2蛋白の過剰発現は固形がんの分子標的治療の先駆けとして有名である。近年はPI3Kの遺伝子変異や生殖細胞のBRCA変異による患者選択が臨床開発されている。本座談会では、がん治療各領域におけるトップリーダーをお招きしてバイオマーカー研究の最近のtopicsを総括した。(著者抄録)
  • Nishio M; Kim DW; Wu YL; Nakagawa K; Solomon BJ; Shaw AT; Hashigaki S; Ohki E; Usari T; Paolini J; Polli A; Wilner KD; Mok T
    Cancer research and treatment : official journal of Korean Cancer Association 50 3 691 - 700 2018年07月 [査読有り]
  • Haratani K; Hayashi H; Nakagawa K
    JAMA oncology 4 7 1017 - 1018 2018年07月 [査読有り]
  • Makoto Nishio; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Tomohiro Tanaka; Hiroshi Kuriki; Ali Zeaiter; Tomohide Tamura
    Lung Cancer 121 37 - 40 2018年07月 [査読有り]
     
    Objectives: We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study. Materials and methods: Japanese patients aged ≥20 years with ALK-positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method. Results: The hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16–1.64 P = 0.2502) and 0.19 (95% CI: 0.07–0.53 P = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases. Conclusion: Alectinib appears to avert the progression of CNS metastases in patients with ALK-positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease.
  • Kimio Yonesaka; Koji Haratani; Shiki Takamura; Hitomi Sakai; Ryoji Kato; Naoki Takegawa; Takayuki Takahama; Kaoru Tanaka; Hidetoshi Hayashi; Masayuki Takeda; Sigeki Kato; Osamu Maenishi; Kazuko Sakai; Yasutaka Chiba; Takafumi Okabe; Keita Kudo; Yoshikazu Hasegawa; Hiroyasu Kaneda; Michiko Yamato; Kenji Hirotani; Masaaki Miyazawa; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical Cancer Research 24 11 2653 - 2664 2018年06月 [査読有り]
  • Nonagase Y; Takeda M; Tanaka K; Hayashi H; Iwasa T; Nakagawa K
    Oncotarget 9 50 29532 - 29535 2018年06月 [査読有り]
     
    © Nonagase et al. Malignant tumors can induce a hypercoagulable state known as Trousseau syndrome that increases the risk for venous thromboembolism including disabling cerebral infarction. Anticoagulant therapy without anticancer treatment is not effective for amelioration of this coagulation abnormality. Most patients with lung cancer positive for activating mutations of the epidermal growth factor receptor (EGFR) are sensitive to EGFR tyrosine kinase inhibitors (TKIs), but the efficacy and safety of EGFR-TKIs in such patients with a poor performance status (PS) due to Trousseau syndrome has been unclear. We here describe a patient with EGFR mutation-positive lung cancer who developed disabling cerebral infarction due to Trousseau syndrome. Administration of the EGFR-TKI gefitinib and anticoagulant therapy resulted in a partial tumor response and recovery from both the coagulation abnormality and the severe neurological symptoms. After the development of resistance to gefitinib, the EGFR-TKI osimertinib was safely administered until disease progression without recurrence of the coagulation abnormality. This case suggests that gefitinib followed by osimertinib may be a safe and effective treatment option for patients with EGFR mutation-positive lung cancer who experience disabling cerebral infarction due to Trousseau syndrome.
  • 進行性/再発性乳癌に対するeribulin/S-1併用療法の第II相試験(Phase II trial of Eribulin/S-1 combination therapy for advanced/recurrent breast cancer)
    鶴谷 純司; 岩朝 勤; 水野 豊; 小島 康幸; 高島 勉; 松並 展輝; 森本 卓; 山村 順; 大谷 彰一郎; 田辺 裕子; 渡邉 諭美; 加藤 了資; 高野 利美; 菰池 佳史; 中川 和彦
    日本乳癌学会総会プログラム抄録集 26回 334 - 334 2018年05月
  • Martin Reck; Edward B. Garon; Luis Paz-Ares; Santiago Ponce; Jesus Corral Jaime; Oscar Juan; Ernest Nadal; Katsuyuki Kiura; Ryan C. Widau; Shuang He; Rita Dalal; Pablo Lee; Kazuhiko Nakagawa
    Clinical Lung Cancer 19 3 213 - 220.e4 2018年05月 [査読有り]
     
    We conducted safety, exposure, and progression-free survival analyses of patients in part A (phase 1b) of RELAY, a randomized, double-blind, phase Ib/III study investigating ramucirumab-erlotinib in treatment-naive epidermal growth factor receptor-mutant stage IV non–small-cell lung cancer. Overall, ramucirumab-erlotinib showed no unexpected safety concerns and encouraging clinical activity. Phase III enrollment was initiated, maintaining ramucirumab at 10 mg/kg every 2 weeks with erlotinib at 150 mg/d. Background: Despite the likelihood of an initial response to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), EGFR-mutant non–small-cell lung cancer (NSCLC) patients develop disease progression. Antiangiogenic agents in combination with an EGFR TKI might provide additional benefit in patients with EGFR-mutant NSCLC. In this article we report safety, exposure, and progression-free survival (PFS) results for part A (phase Ib) of RELAY, a randomized, double-blind, phase Ib/III study investigating safety and efficacy of erlotinib (EGFR TKI) with ramucirumab (anti-vascular endothelial growth factor receptor-2 antibody) or placebo in first-line EGFR-mutant stage IV NSCLC. Patients and Methods: Eligible patients had untreated stage IV NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and activating EGFR mutation (exon 19 deletion or exon 21 L858R substitution). Patients received ramucirumab 10 mg/kg on day 1 of a repeating 14-day cycle and erlotinib 150 mg/d. Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability, in terms of dose-limiting toxicities (DLTs), during the first 2 cycles. Results: Fourteen patients were treated and 12 were evaluable for DLTs. One patient experienced a DLT of Grade 3 elevated alanine aminotransferase during the DLT assessment period. Adverse events were reported in all patients, but were generally mild and manageable. The most common Grade 3 adverse events were hypertension, rash, and diarrhea. No serious or Grade 4 to 5 events occurred. Median PFS was 17.1 months (95% confidence interval, 8.8-not reached). Five patients continue receiving study treatment. Conclusion: Ramucirumab with erlotinib showed no unexpected toxicities and encouraging clinical activity in part A. Phase III enrollment has been initiated, maintaining ramucirumab 10 mg/kg every 2 weeks with erlotinib 150 mg/d.
  • Junko Tanizaki; Yasutaka Chiba; Koji Haratani; Hidetoshi Hayashi; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 13 5 e86 - e87 2018年05月 [査読有り]
  • Yosuke Makuuchi; Hidetoshi Hayashi; Koji Haratani; Junko Tanizaki; Kaoru Tanaka; Masayuki Takeda; Kazuko Sakai; Shigeki Shimizu; Akihiko Ito; Kazuto Nishio; Kazuhiko Nakagawa
    Oncotarget 9 33 23315 - 23319 2018年05月 [査読有り]
     
    The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and ceritinib are standard treatment options for patients with non-small cell lung cancer (NSCLC) positive for ALK fusion genes. However, almost all patients eventually develop resistance to these drugs. We here report a case of ALK-rearranged NSCLC that developed resistance to alectinib but remained sensitive to ceritinib. The L1196M mutation within the ALK fusion gene was detected after failure of consecutive treatment with crizotinib and alectinib, but no other mechanism underlying acquired resistance to ALK-TKIs was found to be operative. Given the increasing application of ALK-TKIs to the treatment of patients with ALK-rearranged NSCLC, further clinical evaluation is warranted to provide a better understanding of the mechanisms of acquired resistance to these agents and to inform treatment strategies for such tumors harboring secondary mutations.
  • Yutaka Fujiwara; Masayuki Takeda; Noboru Yamamoto; Kazuhiko Nakagawa; Kaname Nosaki; Ryo Toyozawa; Chihiro Abe; Ryota Shiga; Kenji Nakamaru; Takashi Seto
    Oncotarget 9 34 23729 - 23737 2018年05月 [査読有り]
     
    Oncogenic ROS1 and NTRK fusions were reported in solid tumors, including non-small cell lung cancer (NSCLC). DS-6051b is an oral, potent selective small molecule tyrosine kinase inhibitor. We report the safety, tolerability, efficacy, and pharmacokinetics of DS-6051b in 15 Japanese patients with NSCLC harboring ROS1 fusions. Patients received DS-6051b once daily (400 mg n = 6 600 mg n = 6 or 800 mg n = 3) for cycles of 3 weeks. Safety, tolerability, maximum-tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. Common treatment-related adverse events were increased: aspartate aminotransferase and alanine aminotransferase (80.0% each), diarrhea (53.3%), and nausea (46.7%). Dose-limiting toxicities (two grade-3 alanine aminotransferase increases) were seen in the 800 mg cohort. The maximum-tolerated dose and recommended phase II dose was 600 mg once daily. Plasma concentrations of free DS-6051b and DS- 6051a increased with dose. Compared with a US phase I study, AUC0-24 h on day 15 was higher but narrowed after body weight correction. Objective response rate was 58.3% in patients with target lesions (n = 12) and 66.7% in crizotinib-naïve patients (n = 9). Disease control rate was 100%. DS-6051b is well tolerated and effective in Japanese patients with NSCLC harboring ROS1 fusions and might be a targeted therapy for advanced NSCLC.
  • Hitomi Sakai; Junji Tsurutani; Tsutomu Iwasa; Yoshifumi Komoike; Kazuko Sakai; Kazuto Nishio; Kazuhiko Nakagawa
    Breast Cancer 25 5 1 - 9 2018年04月 [査読有り]
     
    Background: Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC. Methods: The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and HER2 gene copy number and PIK3CA gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration. Results: Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER-positive and/or PR-positive by immunohistochemistry. Conclusions: HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T-DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non-invasive way to predict whether a patient would exhibit primary resistance to T-DM1.
  • Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tanaka; Junko Tanizaki; Takayuki Takahama; Koji Haratani; Kazuto Nishio; Kazuhiko Nakagawa
    Oncotarget 9 30 21132 - 21140 2018年04月 [査読有り]
     
    Unlike common epidermal growth factor receptor gene (EGFR) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene (HER2) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited. Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon- 20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel. Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR), and 12 patients harbored EGFR exon- 20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2. Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2, and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations.
  • Yoshihisa Nakatani; Hisato Kawakami; Masashi Ichikawa; Sachiyo Yamamoto; Yasuo Otsuka; Akiko Mashiko; Yasutoshi Takashima; Akihiko Ito; Kazuhiko Nakagawa; Shuji Arima
    Investigational New Drugs 36 4 1 - 6 2018年04月 [査読有り]
     
    Summary: We here report a case of nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent gastric cancer developed acute kidney injury associated with kidney enlargement and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy findings. Immunohistochemistry revealed expression of programmed cell death–ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules. Among infiltrating immune cells, aggregation of T cells was more extensive than that of B cells, with CD4+ T cells outnumbering CD8+ T cells, consistent with the relative numbers of these cells in the circulation. Treatment with methylprednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function and reduction in the number of circulating CD4+ T cells. Prompt administration of high-dose corticosteroid is thus recommended after diagnosis of this adverse event of nivolumab treatment by kidney biopsy.
  • Kodaira T; Kagami Y; Shibata T; Shikama N; Nishimura Y; Ishikura S; Nakamura K; Saito Y; Matsumoto Y; Teshima T; Ito Y; Akimoto T; Nakata K; Toshiyasu T; Nakagawa K; Nagata Y; Nishimura T; Uno T; Kataoka M; Yorozu A; Hiraoka M
    Annals of oncology : official journal of the European Society for Medical Oncology 29 4 992 - 997 2018年04月 [査読有り]
     
    Background: We assessed the non-inferiority of accelerated fractionation (AF) (2.4 Gy/fraction) compared with standard fractionation (SF) (2 Gy/fraction) regarding progression-free survival (PFS) in patients with T1-2N0M0 glottic cancer (GC). Patients and methods: In this multi-institutional, randomized, phase III trial, patients were enrolled from 32 Japanese institutions. Key inclusion criteria were GC T1-2N0M0, age 20-80, Eastern Cooperative Oncology Group performance status of 0-1, and adequate organ function. Patients were randomly assigned to receive either SF of 66-70 Gy (33-35 fractions), or AF of 60-64.8 Gy (25-27 fractions). The primary end point was the proportion of 3-year PFS. The planned sample size was 360 with a non-inferiority margin of 5%. Results: Between 2007 and 2013, 370 patients were randomized (184/186 to SF/AF). Three-year PFS was 79.9% (95% confidence interval [CI] 73.4-85.4) for SF and 81.7% (95% CI 75.4-87.0) for AF (difference 1.8%, 91% CI-5.1% to 8.8% onesided P=0.047 > 0.045). The cumulative incidences of local failure at 3 years for SF/AF were 15.9%/10.3%. No significant difference was observed in 3-year overall survival (OS) between SF and AF. Grade 3 or 4 acute and late toxicities developed in 22 (12.4%)/21 (11.5%) and 2 (1.1%)/1 (0.5%) in the SF/AF arms. Conclusion: Although the non-inferiority of AF was not confirmed statistically, the similar efficacy and toxicity of AF compared with SF, as well as the practical convenience of its fewer treatment sessions, suggest the potential of AF as a treatment option for early GC.
  • Katsuyuki Kiura; Fumio Imamura; Hiroshi Kagamu; Shingo Matsumoto; Toyoaki Hida; Kazuhiko Nakagawa; Miyako Satouchi; Isamu Okamoto; Mitsuhiro Takenoyama; Yasuhito Fujisaka; Takayasu Kurata; Masayuki Ito; Kota Tokushige; Ben Hatano; Makoto Nishio
    Japanese journal of clinical oncology 48 4 367 - 375 2018年04月 [査読有り]
     
    Background: In the global, Phase 3, ASCEND-5 study, ceritinib improved progression-free survival (PFS) vs chemotherapy in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) who had previously progressed on crizotinib and platinum-based chemotherapy. Here, we report efficacy and safety in a subset of Japanese patients from the ASCEND-5 study. Methods: Patients with advanced ALK-rearranged NSCLC received oral ceritinib 750 mg/day or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator's choice], every 21 days). Results: Among the 231 patients, 29 were Japanese, of which, 11 were treated with ceritinib and 18 were treated with chemotherapy (5 with pemetrexed and 13 with docetaxel). All the patients received prior crizotinib and one or two lines of prior chemotherapy for advanced disease. Median follow-up time was 16.6 months for ceritinib arm and 16.4 months for chemotherapy arm in the overall population. The median PFS by blinded independent review committee was 9.8 months (95% CI, 4.3-14.0) in ceritinib arm vs 1.6 months (95% CI, 1.4-3.0) in chemotherapy arm. Grade 3 or 4 adverse events, suspected to be study drug related, were reported in 36.4% of ceritinib arm and 72.2% of chemotherapy arm, respectively. No Grade 3 or 4 events of diarrhea, nausea and vomiting were reported in both the treatment arms. Adverse events leading to study drug discontinuation were reported in one patient in each arm: Grade 3 central-nervous system metastases in ceritinib-treated patient and Grade 3 febrile neutropenia in chemotherapy-treated patient. Conclusions: Consistent with overall population, ceritinib demonstrated better efficacy compared with the standard second-line chemotherapy in Japanese patients with crizotinib-resistant ALK+ NSCLC. ClinicalTrials.gov identifier: NCT01828112.
  • Hideo Saka; Masahide Oki; Chiyoe Kitagawa; Yoshihito Kogure; Yuki Kojima; Akiko M. Saito; Atsuko Ishida; Teruomi Miyazawa; Koji Takeda; Kazuhiko Nakagawa; Shinji Sasada; Shunichi Negoro
    Japanese Journal of Clinical Oncology 48 4 376 - 381 2018年04月 [査読有り]
     
    Background: Malignant pleural effusion is a commonly seen complication of malignancies such as lung and breast cancers. In Western countries, talc is frequently used as a standard therapeutic agent (pleurodesis agent) with the aim of alleviating symptoms including dyspnea and chest pain. Talc is not recognized as a pleurodesis agent in Japan. The aim of this study was to verify the efficacy and safety of sterilized talc (NPC-05) for the introduction of talc in Japan. Methods: The study was a single-arm, open-label, investigator-initiated trial conducted jointly at six institutions. The subjects were 30 patients with malignant pleural effusions. A solution of 4 g NPC-05 suspended in 50 ml physiological saline was instilled into the pleural space to perform pleurodesis. Results: The efficacy of NPC-05 for pleural adhesion 30 days after pleurodesis was 83.3% (25/30 cases). Amelioration of dyspnea and pain (chest pain) was seen. Commonly seen adverse effects were increased C-reactive protein (CRP) and fever. Nearly all adverse events were phenomena previously reported as adverse effects of talc. No acute respiratory distress syndrome (ARDS) or other serious side effects occurred. Conclusion: The efficacy and safety of NPC-05 for malignant pleural effusion in Japanese patients was verified, and the clinical outcomes with talc were confirmed to be the same as previously reported in other countries. There is thought to be a high level of need for this agent in the treatment of malignant pleural effusion in Japan.
  • 木村 達郎; 川口 知哉; 工藤 新三; 千葉 康敬; 丹羽 崇; 渡部 克也; 木島 貴志; 小暮 啓人; 小栗 鉄也; 笠井 尚; 林 秀敏; 小野 哲; 田中 洋史; 吉岡 弘鎮; 矢野 聖二; 山本 信之; 中西 洋一; 中川 和彦
    日本呼吸器学会誌 7 増刊 149 - 149 (一社)日本呼吸器学会 2018年03月
  • 渡邉 諭美; 中川 和彦
    薬局 69 4 2104 - 2107 (株)南山堂 2018年03月
  • 悪性リンパ腫放射線治療後、2次発癌として進行食道癌を併発した1例
    奥野 達哉; 植田 勲人; 武川 直樹; 野長瀬 祥兼; 川上 尚人; 谷崎 潤子; 林 秀敏; 田中 薫; 武田 真幸; 鶴谷 純司; 中川 和彦
    日本消化器病学会雑誌 115 臨増総会 A328 - A328 (一財)日本消化器病学会 2018年03月
  • Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Keita Kudo; Kimio Yonesaka; Ryoji Kato; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    JAMA Oncology 4 3 374 - 378 2018年03月 [査読有り]
     
    IMPORTANCE Immune-related adverse events (irAEs) have been associated with the efficacy of PD-1 (programmed cell death protein 1) inhibitors in patients with melanoma, but whether such an association exists for non-small cell lung cancer (NSCLC) has remained unknown. OBJECTIVE To evaluate the relation of irAEs to nivolumab efficacy in NSCLC. DESIGN, SETTING, AND PARTICIPANTS In this study based on landmark and multivariable analyses, a total of 134 patients with advanced or recurrent NSCLC who were treated with nivolumab in the second-line setting or later between December 2015 and August 2016 were identified from a review of medical records from multiple institutions, including a university hospital and community hospitals. Data were updated as of December 31, 2016. EXPOSURES The absence or presence of any irAE before the landmark date. MAIN OUTCOMES AND MEASURES Kaplan-Meier curves of progression-free survival (PFS) according to the development of irAEs in 6-week landmark analysis were evaluated with the log-rank test as a preplanned primary objective. Overall survival (OS) was similarly evaluated. Multivariable analysis of both PFS and OS was performed with Cox proportional hazard regression models. RESULTS In a cohort of 134 patients (median [range] age, 68 [33-85] years 90 men [67%], 44 women [33%]), irAEs were observed in 69 of the 134 study patients (51%), including 12 patients (9%) with such events of grade 3 or 4, and 24 patients (18%) requiring systemic corticosteroid therapy. In 6-week landmark analysis, median PFS was 9.2 months (95% CI, 4.4 to not reached [NR]) and 4.8 months (95% CI, 3.0 to 7.5) (P = .04) whereas median OS was NR (95% CI, 12.3 to NR) and 11.1 months (95% CI, 9.6 to NR) (P = .01) for patients with or without irAEs, respectively. Multivariable analysis also revealed that irAEs were positively associated with survival outcome, with hazard ratios of 0.525 (95% CI, 0.287 to 0.937 P = .03) for PFS and 0.282 (95% CI, 0.101 to 0.667 P = .003) for OS. CONCLUSIONS AND RELEVANCE Development of irAEs was associated with survival outcome of nivolumab treatment in patients with advanced or recurrent NSCLC. Further studies are needed to confirm our findings.
  • Isamu Okamoto; Satoshi Morita; Naoki Tashiro; Fumio Imamura; Akira Inoue; Takashi Seto; Nobuyuki Yamamoto; Yuichiro Ohe; Kazuhiko Nakagawa; Masahiro Fukuoka
    Lung Cancer 117 14 - 19 2018年03月 [査読有り]
     
    Objectives Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been shown to be effective for the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) in clinical trials. However, there is a lack of data from routine clinical practice. This study determined treatment and outcomes in patients with EGFR mutation-positive NSCLC treated in a real world setting. Materials and methods Clinical characteristics, information about NSCLC treatment regimens and survival outcomes data were obtained retrospectively from 17 medical centers across Japan. In addition to overall survival (OS), subgroup analyses were conducted based on first- and second-line treatments and combinations, and for patients who had survived > 5 years from initiation of first-line treatment. Results The full analysis set comprised 1656 patients (mean 67 years, 80.6% with performance status 0 or 1). Median follow-up was 29.5 months and median OS was 29.7 months 3- and 5-year survival rates were 41.2% and 21.5%, respectively. Significant predictors of OS were younger age, no smoking history, histological diagnosis of adenocarcinoma, less advanced clinical stage, good performance status and major EGFR-activating mutation. Despite some imbalances in baseline characteristics, patients who received first-line chemotherapy had numerically higher 5-year survival rates than those who received first-line EGFR-TKIs. Conclusions This large, long-term analysis of EGFR mutation-positive NSCLC patients provides useful information about treatment outcomes in clinical practice. Updated analyses are required to determine real world outcomes for NSCLC patients treated with the latest available agents, including immunotherapies.
  • Junichi Maruyama; Kazutoshi Inami; Fumiyoshi Michishita; Xinliang Jiang; Hiroaki Iwasa; Kentaro Nakagawa; Mari Ishigami-Yuasa; Hiroyuki Kagechika; Norio Miyamura; Jun Hirayama; Hiroshi Nishina; Daichi Nogawa; Kouhei Yamamoto; Yutaka Hata
    Molecular Cancer Research 16 2 197 - 211 2018年02月 [査読有り]
     
    Yes-associated protein 1 (YAP1) interacts with numerous transcription factors, including TEA-domain family proteins (TEAD) and p73. YAP1 is negatively regulated by the tumor suppressor Hippo pathway. In human cancers, the deregulation of the Hippo pathway and YAP1 gene amplification lead to the activation of YAP1, which induces epithelial–mesenchymal transition (EMT) and drug resistance. YAP1 inhibitors are expected to be useful in cancer therapy. On the other hand, in certain cancers, YAP1 upregulates p73-dependent gene transcription and behaves as a tumor suppressor. Moreover, as YAP1 regulates self-renewal and differentiation of tissue stem cells and plays an important role in tissue homeostasis, YAP1 activators may contribute to the regenerative medicine. With this in our mind, we screened for YAP1 activators by using human retinal pigment epithelial ARPE-19 cells expressing the TEAD-responsive fluorescence reporter under the coexpression of YAP1. From an extensive chemical compound library (n ¼ 18,606) 47 candidate YAP1 activators were identified. These compounds were characterized to determine whether this assay provides bona fide YAP1 activators. Importantly, one YAP1 activator was effective against the human multiple myeloma IM-9 cells and chronic myeloid leukemia K562 cells. Implications: YAP1 activation limits growth, induces apoptosis, and may be useful at suppressing hematological cancers.
  • Miyako Satouchi; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa
    Japanese Journal of Cancer and Chemotherapy 45 2 257 - 264 2018年02月 [査読有り]
     
    The advent of anaplastic lymphoma kinase (ALK) inhibitors has revolutionized treatment of ALK fusion gene-positive nonsmall cell lung cancer (NSCLC). Nevertheless, it has become clear that cases refractory and resistant to ALK inhibitors occur at a certain incidence, and how to treat such cases is a current issue. Following crizotinib and alectinib, ceritinib (Zykadia® capsules) is the third ALK inhibitor approved in Japan, and it is expected to be useful for patients who have developed crizotinib resistance. However, ceritinib has been pointed out to have a high incidence of gastrointestinal adverse events that impact patients' quality of life. Accordingly, in this paper, we report the clinical results and incidence of gastrointestinal adverse reactions with ceritinib in treatment of ALK-positive NSCLC patients. We also present management methods of the adverse events.
  • Treatment of EGFR mutation-positive non-small cell lung cancer complicated by Trousseau syndrome with gefitinib followed by osimertinib: a case report.
    Nonagase Y; Takeda M; Tanaka K; Hayashi H; Iwasa T; Nakagawa K
    Oncotarget. 9 50 29532 - 29535 2018年 [査読有り]
  • Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study.
    Fujiwara Y; Takeda M; Yamamoto N; Nakagawa K; Nosaki K; Toyozawa R; Abe C; Shiga R; Nakamaru K; Seto T
    Oncotarget. 9 34 23729 - 23737 2018年 [査読有り]
  • Clinical characteristics of non-small cell lung cancer harboring mutations in exon 20 of EGFR or HER2.
    Takeda M; Sakai K; Hayashi H; Tanaka K; Tanizaki J; Takahama T; Haratani K; Nishio K; Nakagawa K
    Oncotarget. 9 30 21132 - 21140 2018年 [査読有り]
  • Saka H; Oki M; Kitagawa C; Kogure Y; Kojima Y; Saito AM; Ishida A; Miyazawa T; Takeda K; Nakagawa K; Sasada S; Negoro S
    Jpn J Clin Oncol. 48 4 376 - 381 2018年 [査読有り]
  • Garassino MC; Cho BC; Kim JH; Mazi?res J; Vansteenkiste J; Lena H; Corral Jaime J; Gray JE; Powderly J; Chouaid C; Bidoli P; Wheatley-Price P; Park K; Soo RA; Huang Y; Wadsworth C; Dennis PA; Rizvi NA; ATLANTIC Investigators
    Lancet Oncol. 19 4 521 - 536 2018年 [査読有り]
  • Crizotinib Versus Chemotherapy in Asian Patients with Advanced ALK-positive Non-small Cell Lung Cancer.
    Nishio M; Kim DW; Wu YL; Nakagawa K; Solomon BJ; Shaw AT; Hashigaki S; Ohki E; Usari T; Paolini J; Polli A; Wilner KD; Mok T
    Cancer Res Treat. 50 3 691 - 700 2018年 [査読有り]
  • Noma D; Inamura K; Matsuura Y; Hirata Y; Nakajima T; Yamazaki H; Hirai Y; Ichinose J; Nakao M; Ninomiya H; Mun M; Nakagawa K; Masuda M; Ishikawa Y; Okumura S
    Clinical lung cancer 19 1 e109 - e122 2018年01月 [査読有り]
     
    INTRODUCTION: Lymphovascular invasion (LVI) is a known adverse prognostic factor for early-stage non-small-cell lung cancer (NSCLC). Nonetheless, the prognostic effect of LVI on TNM staging of stage I NSCLC remains inconclusive. We thus hypothesized that it might be better to upstage pathologic stage IA NSCLC with LVI to pathologic stage IB NSCLC. PATIENTS AND METHODS: Using a Cox proportional hazards model, we examined the effect of LVI on disease-specific survival (DSS) in stage IA versus stage IB disease in 660 consecutive patients with stage I NSCLC (598 with adenocarcinoma, 62 with squamous cell carcinoma) who had undergone complete resection. RESULTS: On univariable analysis of stage IA cases, vascular invasion (VI) was significantly associated with inferior DSS (univariable hazard ratio [HR], 3.39; 95% confidence interval [CI], 1.46-7.89; P = .005). In contrast, lymphatic invasion exhibited a tendency toward inferior DSS (univariable HR, 2.90; 95% CI, 0.97-8.66; P = .056). Multivariable analysis of DSS in stage IA cases identified VI as an independent significant prognostic factor (multivariable HR, 2.86; 95% CI, 1.58-5.18; P = .007). With VI, DSS was significantly poorer for stage IB than for stage IA patients without VI (univariable HR, 3.44; 95% CI, 1.67-7.09; P < .001). In contrast, no difference was observed between patients with stage IA and VI and stage IB patients (P = .97). CONCLUSION: The presence of VI independently and significantly affects DSS in patients with stage IA NSCLC. We found that stage IA with VI and stage IB disease had equivalent prognostic outcomes. Our results suggest that stage IA with VI should be upstaged to IB in the TNM classification of NSCLC.
  • Takahama, T.; Azuma, K.; Shimokawa, M.; Kato, T.; Daga, H.; Okamoto, I.; Akamatsu, H.; Takahashi, T.; Ohira, T.; Yokoyama, T.; Hirano, K.; Shiraishi, Y.; Himeji, D.; Yamamoto, N.; Nishio, K.; Nakagawa, K.
    Annals of Oncology 29 2018年 [査読有り]
  • Junko Tanizaki; Koji Haratani; Hidetoshi Hayashi; Yasutaka Chiba; Yasushi Nakamura; Kimio Yonesaka; Keita Kudo; Hiroyasu Kaneda; Yoshikazu Hasegawa; Kaoru Tanaka; Masayuki Takeda; Akihiko Ito; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 13 1 97 - 105 2018年01月 [査読有り]
     
    Objective The aim of this study was to identify baseline peripheral blood biomarkers associated with clinical outcome in patients with NSCLC treated with nivolumab. Methods Univariable and multivariable analyses were performed retrospectively for 134 patients with advanced or recurrent NSCLC treated with nivolumab to evaluate the relationship between survival and peripheral blood parameters measured before treatment initiation, including absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count, and absolute eosinophil count (AEC), as well as serum C-reactive protein and lactate dehydrogenase levels. Progression-free survival, overall survival, and response rate were determined. Results Among the variables selected by univariable analysis, a low ANC, high ALC, and high AEC were significantly and independently associated with both better progression-free survival (p = 0.001, p = 0.04, and p = 0.02, respectively) and better overall survival (p = 0.03, p = 0.03, and p = 0.003, respectively) in multivariable analysis. Categorization of patients according to the number of favorable factors revealed that those with only one factor had a significantly worse outcome than those with two or three factors. A similar trend was apparent for patients with a programmed death 1 ligand tumor proportion score less than 50%, whereas all patients with a score of 50% or higher had at least two favorable factors. Conclusions A baseline signature of a low ANC, high ALC, and high AEC was associated with a better outcome of nivolumab treatment, with the number of favorable factors identifying subgroups of patients differing in survival and response rate.
  • Tomonori Mizutani; Masahiko Ando; Junki Mizusawa; Kenichi Nakamura; Haruhiko Fukuda; Hiroko Tsukada; Tetsuya Abe; Koji Takeda; Akira Yokoyama; Shinichiro Nakamura; Kazuhiko Nakagawa; Noboru Yamamoto; Yuichiro Ohe
    Journal of Geriatric Oncology 9 6 583 - 588 2018年 [査読有り]
     
    Objective: The Lung Cancer Subscale (LCS) of the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire is commonly used for evaluating lung cancer-specific symptoms. The objective of this study was to elucidate the prognostic value of the LCS in older patients with advanced non-small cell lung cancer (NSCLC). Material and Methods: We conducted an integrated analysis of data from two randomized phase III trials (JCOG0207, JCOG0803/WJOG4307L) including patients aged 70 years or older with advanced NSCLC to evaluate the prognostic value of LCS scores at baseline (Aim 1) and for symptom improvement (an increase in LCS of two points or more during treatment) (Aim 2). Multivariable analyses for survival, adjusted for baseline factors, were performed using a stratified Cox regression model with treatment regimen as a stratum. Results: A total of 327 patients were included in the analysis for Aim 1 and 373 patients for Aim 2. Approximately 70% of patients were aged 75 or older. In Aim 1, use of descriptive statistics determined a cutoff point for baseline LCS score of 21. Multivariable analysis showed that higher baseline LCS was associated with favorable overall survival (OS) (hazard ratio [HR]: 0.68 95% confidence interval [CI]: 0.52–0.89) and progression-free survival (HR: 0.68 95% CI: 0.52–0.89). In Aim 2, symptom improvement was not associated with favorable OS (HR: 0.97 95% CI: 0.72–1.23). Conclusion: It is recommended to consider baseline LCS scores while determining treatment strategies for older patients with advanced NSCLC.
  • Shinji Atagi; Junki Mizusawa; Satoshi Ishikura; Toshiaki Takahashi; Hiroaki Okamoto; Hiroshi Tanaka; Koichi Goto; Kazuhiko Nakagawa; Masao Harada; Yuichiro Takeda; Naoyuki Nogami; Yuka Fujita; Takashi Kasai; Kazuma Kishi; Toshiyuki Sawa; Koji Takeda; Keisuke Tomii; Miyako Satouchi; Takashi Seto; Yuichiro Ohe
    Clinical Lung Cancer 19 5 e619 - e627 2018年 [査読有り]
     
    We have previously reported on the superiority of combined chemoradiotherapy over radiotherapy alone in elderly patients with locally advanced non–small-cell lung cancer. The current long-term follow-up results reconfirmed that the significant survival benefit of combined chemoradiotherapy, previously observed, remained unchanged. There was no observed increase in late toxicity with chemoradiotherapy compared with radiotherapy alone. Introduction: In the phase III JCOG0301 trial, chemoradiotherapy (CRT) with daily low-dose carboplatin showed significant benefits in elderly patients with locally advanced non–small-cell lung cancer (NSCLC) compared with radiotherapy (RT) alone. However, the long-term patterns and cumulative incidences of toxicity associated with CRT and RT in elderly patients are not well elucidated. We report long-term survival data and late toxicities after a minimum follow-up of 6.4 years. Patients and Methods: Eligible patients were older than 70 years and had unresectable stage III NSCLC. They were randomly assigned to RT or CRT. Prognosis and adverse events data were collected beyond those in the initial report. Late toxicities were defined as occurring more than 90 days after RT initiation. Results: From September 2003 to May 2010, 200 patients (RT arm, n = 100 CRT arm, n = 100) were enrolled. Consistent with the initial report, the CRT arm had better overall survival than the RT arm (hazard ratio, 0.743 95% confidence interval, 0.552-0.998 1-sided P =.0239). The proportion of Grade 3/4 late toxicities were 7.4% (heart 2.1%, lung 5.3%) in the RT arm (n = 94) and 7.5% (esophagus 1.1%, lung 6.5%) in the CRT arm (n = 93). No additional cases of late toxicity (Grade 3/4) and treatment-related death have been seen since the initial report that was published. Conclusion: Long-term follow-up confirmed the survival benefits of CRT for elderly patients with locally advanced NSCLC. There was no observed increase in late toxicity with CRT compared with RT alone.
  • Tony S. K. Mok; Sang-We Kim; Yi-Long Wu; Kazuhiko Nakagawa; Jin-Ji Yang; Myung-Ju Ahn; Jie Wang; James Chih-Hsin Yang; You Lu; Shinji Atagi; Santiago Ponce; Xiaojin Shi; Yuri Rukazenkov; Vincent Haddad; Kenneth S. Thress; Jean-Charles Soria
    JOURNAL OF CLINICAL ONCOLOGY 35 36 4027 - + 2017年12月 [査読有り]
     
    Purpose The Iressa Mutation-Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS) compared the continuation of gefitinib plus chemotherapy with placebo plus chemotherapy in patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer with progression (Response Evaluation Criteria in Solid Tumors 1.1) after first-line gefitinib. Primary results indicated no difference between treatments in terms of progression-free survival (PFS). The current analysis presents final, mature, overall survival (OS) data, together with exploratory analyses that examined whether specific biomarkers, including T790M mutation status, were able to differentiate a relative treatment effect. Patients and Methods Patients were randomly assigned to gefitinib 250 mg or placebo, in addition to cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) (maximum of six cycles of chemotherapy). EGFR mutation status was determined from plasma-derived circulating free tumor-derived DNA samples (beads, emulsification, amplification, and magnetics digital polymerase chain reaction assay, allelic fraction analysis). Results A total of 265 patients with non-small-cell lung cancer were randomly assigned, and overall data maturity was 66%. Continuation of gefitinib plus cisplatin and pemetrexed was detrimental to OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio [HR], 1.44; 95% CI, 1.07 to 1.94; P = .016; median OS, 13.4 v 19.5 months). The detriment was statistically significant in patients with T790M mutation-positive plasma samples (HR, 1.49; 95% CI, 1.02 to 2.21), whereas statistical significance was not reached in T790M mutation-negative patients (HR, 1.15; 95% CI, 0.68 to 1.94). PFS in T790M mutation-positive patients was similar between treatments, and the difference observed in T790M mutation-negative patients did not reach statistical significance (HR, 0.67; 95% CI, 0.43 to 1.03; P = .0745). Conclusion Final OS data from IMPRESS are supportive of earlier PFS results and are sufficient to warn physicians against the continuation of treatment with first-generation EGFR tyrosine kinase inhibitors beyond radiologic disease progression when chemotherapy is initiated. Plasma biomarker analyses suggest that this effect may be driven by T790M-positive status. (c) 2017 by American Society of Clinical Oncology
  • H. Nokihara; S. Lu; T. S. K. Mok; K. Nakagawa; N. Yamamoto; Y. K. Shi; L. Zhang; R. A. Soo; J. C. Yang; S. Sugawara; M. Nishio; T. Takahashi; K. Goto; J. Chang; M. Maemondo; Y. Ichinose; Y. Cheng; W. T. Lim; S. Morita; T. Tamura
    ANNALS OF ONCOLOGY 28 11 2698 - 2706 2017年11月 [査読有り]
     
    Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. Patients with advanced NSCLC previously treated with >= 1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m(2) in Japan, 75 mg/m(2) at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. Japan Pharmaceutical Information Center, JapicCTI-101155.
  • Ryoji Kato; Hidetoshi Hayashi; Yasutaka Chiba; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 18 6 E449 - E455 2017年11月 [査読有り]
     
    Minimal (< 10 mm in thickness) pericardial effusion can be incidentally detected by computed tomography at diagnosis in patients with lung cancer. We retrospectively analyzed 428 patients diagnosed with advanced nonesmall-cell lung cancer. Our study found that 14.3% of patients presented with minimal pericardial effusion at first diagnosis, and its presence was an independent prognostic factor for reduced survival in patients with advanced nonesmall-cell lung cancer. Introduction: Minimal (< 10 mm in thickness) pericardial effusion (PCE) can be incidentally detected by computed tomography at the time of diagnosis in patients with lung cancer. Although malignant PCE is known to be associated with poor prognosis, the impact of minimal PCE on outcome has remained unclear. We therefore examined the prognostic relevance of minimal PCE in patients with advanced nonesmall-cell lung cancer (NSCLC). Patients and Methods: We retrospectively analyzed consecutive patients diagnosed with stage IV NSCLC at Kindai University Hospital between April 2009 and March 2015. The patients were classified into 3 groups on the basis of the presence and thickness of PCE: no PCE, minimal (< 10 mm) PCE, and malignant (< 10 mm) PCE. The relation between overall survival and PCE status was examined with a Cox proportional hazards model. Results: The total of 428 enrolled patients included 327 (76.4%) in the no PCE group, 61 (14.3%) in the minimal PCE group, and 40 (9.3%) in the malignant PCE group. Median overall survival was 15.0, 10.1, and 7.6 months in the no PCE, minimal PCE, and malignant PCE groups, respectively, with the survival of patients with minimal PCE thus being intermediate between that of the other 2 groups (P = .003). Multivariable analysis revealed that minimal PCE was independently associated with reduced survival (hazard ratio, 1.46; 95% confidence interval, 1.07-1.96; P = .019). Conclusions: The presence of minimal PCE was an independent prognostic factor for reduced survival in patients with advanced NSCLC. (C) 2017 Elsevier Inc. All rights reserved.
  • Hidetoshi Hayashi; Yasutaka Chiba; Kazuko Sakai; Tomonobu Fujita; Hiroshige Yoshioka; Daisuke Sakai; Chiyoe Kitagawa; Tateaki Naito; Koji Takeda; Isamu Okamoto; Tetsuya Mitsudomi; Yutaka Kawakami; Kazuto Nishio; Shinichiro Nakamura; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 18 6 719 - 723 2017年11月 [査読有り]
     
    Antibodies to programmed cell death-1 (PD-1), such as nivolumab, have shown promising clinical activity in patients with advanced non-small-cell lung cancer (NSCLC), but their efficacy appears to be less pronounced in patients with such tumors harboring epidermal growth factor receptor gene (EGFR) mutations. Recent findings suggest that patients with EGFR mutation-positive NSCLC who develop resistance to tyrosine kinase inhibitors (TKIs) due to mechanisms other than acquisition of the secondary T790M mutation of EGFR are more likely to benefit from nivolumab treatment, possibly as a result of a higher level of expression of the PD-1 ligand PD-L1, than are patients who are T790M-positive. The WJOG8515L study (UMIN ID: 000021133) is a randomized phase II trial to compare nivolumab with the combination of carboplatin and pemetrexed in patients with EGFR mutation-positive nonsquamous NSCLC who have developed resistance to EGFR-TKIs due to mechanisms other than T790M. Eligible patients are those with stage IV or recurrent EGFR mutation-positive NSCLC who experience disease progression after therapy with more than 1 EGFR-TKI, including gefitinib, erlotinib, or afatinib; they must show no evidence of the T790M mutation on analysis of a tumor biopsy specimen obtained after progression on such EGFR-TKI therapy, or, if T790M is detected, they must again experience progression on subsequent treatment with a third-generation EGFR-TKI. The primary endpoint is progression-free survival (PFS), and secondary end points include overall survival (OS), objective response rate, duration of response, safety, and OS and PFS according to PD-L1 expression level. Recruitment started in May 2016 and is ongoing.
  • Satomi Watanabe; Takeshi Yoshida; Hisato Kawakami; Naoki Takegawa; Junko Tanizaki; Hidetoshi Hayashi; Masayuki Takeda; Kimio Yonesaka; Junji Tsurutani; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 16 11 2563 - 2571 2017年11月 [査読有り]
     
    T790M mutation-selective EGFR tyrosine kinase inhibitors (EGFR-TKI) have demonstrated clinical benefits in non-small cell lung cancer (NSCLC) patients harboring T790M mutation, which is the major cause of resistance to EGFR-TKI. However, their efficacy is limited, possibly due to the emergence of apoptosis resistance in T790M-positive NSCLC. We previously identified Src family kinases as cooncogenic drivers along with T790M and found that the Src inhibitor dasatinib combined with an irreversible or a preclinical T790M-selective EGFR-TKI enhanced antitumor activity in T790M-positive cells. In the current study, we evaluated the efficacy of dasatinib combined with the clinically relevant T790M-selective EGFR-TKI ASP8273 or osimertinib in EGFR mutation-positive NSCLC with or without T790M mutation. A cell viability assay revealed that dasatinib had synergistic effects with these TKIs in T790M positive cells and simultaneously inhibited Src, Akt, and Erk, which remained activated upon single-agent treatment. Dasatinib also increased the rate of apoptosis in T790M-positive cells induced by T790M-selective EGFR-TKIs, as determined by the Annexin-V binding assay; this was associated with down-regulation of the antiapoptotic Bcl-2 family member Bcl-xL, a finding that was confirmed in mice bearing T790M-positive xenografts. Our results suggest that Bcl-xL plays a key role in the apoptosis resistance of T790M-positive NSCLC, and that dasatinib combined with clinically relevant T790M-selective EGFRTKIs is potentially effective in overcoming resistance to first-generation EGFR-TKIs in NSCLC patients with acquired T790M. (C) 2017 AACR.
  • Kaoru Kubota; Hiroshige Yoshioka; Fumihiro Oshita; Toyoaki Hida; Kiyotaka Yoh; Hidetoshi Hayashi; Terufumi Kato; Hiroyasu Kaneda; Kazuhiko Yamada; Hiroshi Tanaka; Yukito Ichinose; Keunchil Park; Eun Kyung Cho; Kyung-Hee Lee; Chih-Bin Lin; James Chih-Hsin Yang; Kaori Hara; Takayuki Asato; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 35 32 3662 - + 2017年11月 [査読有り]
     
    Purpose This phase III, randomized, placebo-controlled, double-blind study determined whether motesanib improved progression-free survival (PFS) compared with placebo in combination with paclitaxel and carboplatin (P/C) in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. Patients and Methods Patients were randomly assigned (1: 1) to receive oral motesanib 125 mg or placebo once daily plus paclitaxel 200 mg/m(2) IV and carboplatin area under the concentration-time curve 6 mg/mL . min IV for up to six 3-week cycles. Random assignment was stratified by epidermal growth factor receptor status, region, and weight loss in the 6 months before assignment. The primary end point was PFS, the key secondary end point was overall survival, and other secondary end points were objective response rate, time to tumor response, duration of response, and adverse events (AEs). Results Four hundred one patients were assigned to receive motesanib plus P/C (n = 197) or placebo plus P/C (n = 204). Median PFS was 6.1 v 5.6 months for motesanib versus placebo (stratified log-rank test P = .0825; stratified hazard ratio, 0.81; 95% CI, 0.64 to 1.03; P = .0820); median overall survival was not reached versus 21.6 months (P = .5514). In secondary analyses, the objective response rate was 60.1% v 41.6% (P < .001); median time to tumor response, 1.4 v 1.6 months, and median duration of response, 5.3 v 4.1 months. Incidence of grade >= 3 AEs (86.7% v 67.6%) and AEs that led to drug discontinuation (32.7% v 14.2%) were higher with motesanib than with placebo. AEs reported more frequently with motesanib were GI disorders, hypertension, and gallbladder related. Conclusion Motesanib plus P/C did not significantly improve PFS versus placebo plus P/C in East Asian patients with stage IV/recurrent nonsquamous non-small-cell lung cancer. (C) 2017 by American Society of Clinical Oncology
  • Yi-Long Wu; Ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Fumito Tsuji; Rolf Linke; Rafael Rosell; Jesus Corral; Maria Rita Migliorino; Adam Pluzanski; Eric I. Sbar; Tao Wang; Jane Liang White; Sashi Nadanaciva; Rickard Sandin; Tony S. Mok
    LANCET ONCOLOGY 18 11 1454 - 1466 2017年11月 [査読有り]
     
    Background Dacomitinib is a second-generation, irreversible EGFR tyrosine kinase inhibitor. We compared its efficacy and safety with that of the reversible EGFR tyrosine kinase inhibitor gefitinib in the first-line treatment of patients with advanced EGFR-mutation-positive non-small-cell lung cancer (NSCLC). Methods In this international, multicentre, randomised, open-label, phase 3 study (ARCHER 1050), we enrolled adults (aged >= 18 years or >= 20 years in Japan and South Korea) with newly diagnosed advanced NSCLC and one EGFR mutation (exon 19 deletion or Leu858Arg) at 71 academic medical centres and university hospitals in seven countries or special administrative regions. We randomly assigned participants (1: 1) to receive oral dacomitinib 45 mg/day (in 28-day cycles) or oral gefitinib 250 mg/day (in 28-day cycles) until disease progression or another discontinuation criterion was met. Randomisation, stratified by race and EGFR mutation type, was done with a computer-generated random code assigned by a central interactive web response system. The primary endpoint was progression-free survival assessed by masked independent review in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01774721, and is ongoing but no longer recruiting patients. Findings Between May 9, 2013, and March 20, 2015, 452 eligible patients were randomly assigned to receive dacomitinib (n=227) or gefitinib (n=225). Median duration of follow-up for progression-free survival was 22.1 months (95% CI 20.3-23.9). Median progression-free survival according to masked independent review was 14.7 months (95% CI 11.1-16.6) in the dacomitinib group and 9.2 months (9.1-11.0) in the gefitinib group (hazard ratio 0.59, 95% CI 0.47-0.74; p<0.0001). The most common grade 3-4 adverse events were dermatitis acneiform (31 [14%] of 227 patients given dacomitinib vs none of 224 patients given gefitinib), diarrhoea (19 [8%] vs two [1%]), and raised alanine aminotransferase levels (two [1%] vs 19 [8%]). Treatment-related serious adverse events were reported in 21 (9%) patients given dacomitinib and in ten (4%) patients given gefitinib. Two treatment-related deaths occurred in the dacomitinib group (one related to untreated diarrhoea and one to untreated cholelithases/liver disease) and one in the gefitinib group (related to sigmoid colon diverticulitis/rupture complicated by pneumonia). Interpretation Dacomitinib significantly improved progression-free survival over gefitinib in first-line treatment of patients with EGFR-mutation-positive NSCLC and should be considered as a new treatment option for this population.
  • Naoki Takegawa; Yoshikane Nonagase; Kimio Yonesaka; Kazuko Sakai; Osamu Maenishi; Yusuke Ogitani; Takao Tamura; Kazuto Nishio; Kazuhiko Nakagawa; Junji Tsurutani
    INTERNATIONAL JOURNAL OF CANCER 141 8 1682 - 1689 2017年10月 [査読有り]
     
    Anti-HER2 therapies are beneficial for patients with HER2-positive breast or gastric cancer. T-DM1 is a HER2-targeting antibody-drug conjugate (ADC) comprising the antibody trastuzumab, a linker, and the tubulin inhibitor DM1. Although effective in treating advanced breast cancer, all patients eventually develop T-DM1 resistance. DS-8201a is a new ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). DS-8201a has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of T-DM1 (3.5). Owing to these unique characteristics and unlike T-DM1, DS-8201a is effective against cancers with low-HER2 expression. In the present work, T-DM1-resistant cells (N87-TDMR), established using the HER2-positive gastric cancer line NCI-N87 and continuous T-DM1 exposure, were shown to be susceptible to DS-8201a. The ATP-binding cassette (ABC) transporters ABCC2 and ABCG2 were upregulated in N87-TDMR cells, but HER2 overexpression was retained. Furthermore, inhibition of ABCC2 and ABCG2 by MK571 restored T-DM1 sensitivity. Therefore, resistance to T-DM1 is caused by efflux of its payload DM1, due to aberrant expression of ABC transporters. In contrast to DM1, DXd payload of DS-8201a inhibited the growth of N87-TDMR cells in vitro. This suggests that either DXd may be a poor substrate of ABCC2 and ABCG2 in comparison to DM1, or the high DAR of DS8201a relative to T-DM1 compensates for increased efflux. Notably, N87-TDMR xenograft tumor growth was prevented by DS8201a. In conclusion, the efficacy of DS-8201a as a treatment for patients with T-DM1-resistant breast or gastric cancer merits investigation.
  • Hiromichi Matsuoka; Chihiro Makimura; Atsuko Koyama; Yoshihiko Fujita; Junji Tsurutani; Kiyohiro Sakai; Ryo Sakamoto; Kazuto Nishio; Kazuhiko Nakagawa
    Biomedical Reports 7 4 380 - 384 2017年10月 [査読有り]
     
    Genetic differences in humans cause clinical difficulties in opioid treatment. Previous studies indicate that a single nucleotide polymorphism in the catechol-O-methyltransferase (COMT) gene (rs4680 p.Val158Met) may present as a predictive biomarker for the response to morphine treatment. In our previous pilot exploratory study, patients with a G/G genotype were demonstrated to require a higher dose of morphine, compared with patients with A/A and A/G genotypes. In the present study, the aim was to replicate the findings in an independent cohort of opioid-treatment-naïve patients exhibiting various types of cancer. This prospective study was conducted from 2011 to 2012 at the Kindai University Faculty of Medicine. A total of 50 patients with opioid-treatment naïve and histologically confirmed malignant neoplasms who were scheduled to undergo opioid treatment were evaluated in the present study. Assessments were conducted pre-treatment (day 1), post-treatment (day 1), and one week after treatment (day 8). The required dose of morphine on day 1 was significantly higher for patients with the G/G genotype of COMT, compared with those with the A/A and A/G genotypes (P=0.013). The results of the present study provide additional evidence that the COMT genotype may be a predictive biomarker for the response to morphine treatment.
  • Hiromichi Matsuoka; Junji Tsurutani; Yasutaka Chiba; Yoshihiko Fujita; Masato Terashima; Takeshi Yoshida; Kiyohiro Sakai; Yoichi Otake; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    BMC CANCER 17 1 674  2017年10月 [査読有り]
     
    Background: Cancer patients experience pain that has physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Opioids are used in treatment of pain in patients with various types of cancer. We previously showed that the catechol-O-methyltransferase (COMT) genotype is related to the plasma level of morphine and the required dose of morphine in an exploratory prospective study. The findings showed that a group of patients with a GG single nucleotide polymorphism (SNP) rs4680 in COMT required a significantly higher dose of morphine than a non-GG group. A biomarker for selection of opioids for cancer pain relief would be particularly useful clinically, and therefore we have planned a randomized comparative study of morphine and oxycodone, using the COMT rs4680 SNP as a biomarker. This study is aimed at verifying the assumption that patients in the GG group require an increased morphine dose for pain relief. Methods: The RELIEF study is a randomized, multi-institutional, open-label trial with a primary endpoint of the proportion of subjects requiring high-dose opioids, as calculated from the dose of a rescue preparation administered on day 0. Secondary endpoints include the Hospital Anxiety and Depression Scale, Short form McGill Pain Questionnaire-2, European Organization for Research and Treatment of Cancer QLQ-C15-PAL, Pain Catastrophizing Scale, and adverse events, Eligibility criteria are patients with advanced carcinoma with non-daily use of opioids in initial screening for registration; and cancer pain targeted for daily opioid treatment, NSAIDs or acetaminophen, NRS = >= 3(average over 24 h), opioid-treatment naive within 30 h, no chemotherapy, radiotherapy, or bisphosphonate administration newly started within 2 weeks, and written informed consent at the time of second registration. Between November 2014 and June 2017, an estimated 110 patients from two sites in Japan were randomized (1:1) to morphine or oxycodone in GG and non-GG groups. Discussion: A method for selection of appropriate opioids in cancer patients is a high unmet medical need. This study was designed to evaluate the efficacy of different opioids in patients with cancer based on gene polymorphism, as the first potential multi-institutional registration trial to be conducted in cancer patients with pain.
  • Hiroto Ueda; Masayuki Takeda; Shinya Ueda; Hisato Kawakami; Tatsuya Okuno; Naoki Takegawa; Hidetoshi Hayashi; Junji Tsurutani; Takao Tamura; Kazuki Ishikawa; Yasumasa Nishimura; Kazuhiko Nakagawa
    ONCOTARGET 8 46 80286 - 80294 2017年10月 [査読有り]
     
    Platinum-based chemotherapy is considered a standard treatment option for patients with metastatic esophageal carcinoma. However, the overall survival of patients receiving such treatment is <1 year. A common presenting symptom of esophageal cancer is dysphagia, which has a substantial impact on quality of life. We have now retrospectively evaluated the efficacy and safety of palliative chemoradiotherapy for patients with stage IV esophageal cancer, most of whom are unfit for curative chemoradiotherapy. Fifty consecutive patients diagnosed with stage IV esophageal cancer were treated with concurrent chemoradiotherapy at Kindai University Hospital between April 2008 and December 2014. Most (90%) patients received a total radiation dose of at least 50 Gy, and the median number of treatment cycles per patient was four for the combination of 5-fluorouracil and cisplatin. The response of the primary tumor and the overall response were 80% and 44%, respectively. The dysphagia score was improved after chemoradiotherapy in 36 (72%) patients and did not change between before and after treatment in 14 (28%) patients. With a median follow-up time of 9.4 months from the start of chemoradiotherapy, the median progression-free survival and overall survival were 4.7 and 12.3 months, respectively. Three patients (T4b in two, T3 in one) developed esophagobronchial fistula after completion of chemoradiotherapy (n = 2) or after disease progression (n = 1), resulting in death in each case. Our results suggest that palliative chemoradioiotherapy was safe and contributed the improvement of dysphagia in patients with stage IV esophageal cancer.
  • 吉田 健史; 渡邉 諭美; 武川 直樹; 川上 尚人; 中川 和彦
    肺癌 57 5 377 - 377 (NPO)日本肺癌学会 2017年09月
  • Masashi Yanae; Shinichiro Fujimoto; Kaori Tane; Maki Tanioka; Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshiyuki Morishima; Yasutaka Chiba; Shintaro Takao; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Shozo Nishida
    Journal of Bone Oncology 8 18 - 22 2017年09月 [査読有り]
     
    Background Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. Methods We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. Results The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30–87) years. Eighty-seven patients were aged ≥60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647–9.481 p = 0.002). Conclusions Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
  • Nagashima Y; Yoshino S; Yamamoto S; Maeda N; Azumi T; Komoike Y; Okuno K; Iwasa T; Tsurutani J; Nakagawa K; Masaaki O; Hiroaki N
    Molecular and clinical oncology 7 3 359 - 366 2017年09月 [査読有り]
     
    Anthracycline-based chemotherapies for breast cancer are known to adversely affect patients' quality of life (QOL) and immune function. For that reason, adjuvants that improve those impairments are required. A randomized double-blind study was conducted to evaluate the effectiveness of Lentinula edodes mycelia extract (LEM), which is an oral biological response modifier (BRM) medicine for cancer patients as such an adjuvant. A total of 47 breast cancer patients who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, i.e., 5-fluorouracil (5-FU) + cyclophosphamide + epirubicin (FEC regimen), 5-FU + cyclophosphamide + doxorubicin/pirarubicin (FAC regimen), cyclophosphamide + doxorubicin/pirarubicin (AC regimen) and cyclophosphamide + epirubicin (EC regimen), were entered in the study. The patients were randomly divided into either an LEM or a placebo tablet group; the tablets were orally ingested daily over 2 courses of each therapy. In the placebo group, the total scores for QOL were lower on day 8 of the second course of chemotherapy compared with the baseline scores, whereas in the LEM group the scores had not decreased. In the placebo group, the QOL functional well-being score was lower on day 8 after both the first and second courses of chemotherapy compared with the baseline score, but it had not decreased in the LEM group. Evaluation of immunological parameters indicated that an increase in the proportion of regulatory T cells to peripheral blood CD4+ cells tended to be inhibited in the LEM group compared with the placebo group. Oral LEM that was coadministered with anthracycline-based chemotherapies was useful for maintaining patients' QOL and immune function. Thus, LEM appears to be a useful oral adjuvant for patients receiving anthracycline-based chemotherapy.
  • Masashi Yanaea; Shinichiro Fujimoto; Kaori Tane; Maki Tanioka; Kimiko Fujiwara; Masanobu Tsubaki; Yuzuru Yamazoe; Yoshiyuki Morishima; Yasutaka Chiba; Shintaro Takao; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Shozo Nishida
    JOURNAL OF BONE ONCOLOGY 8 18 - 22 2017年09月 [査読有り]
     
    Background: Bone represents one of the most common sites to which breast cancer cells metastasize. Patients experience skeletal related adverse events (pathological fractures, spinal cord compressions, and irradiation for deteriorated pain on bone) even during treatment with zoledronic acid (ZA). Therefore, we conducted a retrospective cohort study to investigate the predictive factors for symptomatic skeletal events (SSEs) in bone-metastasized breast cancer (b-MBC) patients. Methods: We retrospectively collected data on b-MBC patients treated with ZA. Patient characteristics, including age, subtype, the presence of non-bone lesions, the presence of multiple bone metastases at the commencement of ZA therapy, duration of ZA therapy, the time interval between breast cancer diagnosis and the initiation of ZA therapy, and type of systemic therapy, presence of previous SSE were analyzed using multivariable logistic regression analysis. Results: The medical records of 183 patients were reviewed and 176 eligible patients were analyzed. The median age was 59 (range, 30-87) years. Eighty-seven patients were aged >= 60 years and 89 patients were aged < 60 years. The proportions of patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-positive disease were 81.8%, 63.1%, and 17.6%, respectively. Fifty-three patients had bone-only MBC at the commencement of ZA therapy. SSEs were observed in 42 patients. In the multivariable logistic regression analysis, bone-only MBC but not a breast cancer subtype was an independent risk factor for an SSE during ZA therapy (odds ratio: 3.878, 95% confidence interval: 1.647-9.481; p = 0.002). Conclusions: Bone-only MBC patients are more likely to experience an SSE even after treatment with ZA.
  • Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Chihiro Makimura; Yoshihiko Fujita; Junji Tsurutani; Kiyohiro Sakai; Ryo Sakamoto; Kazuto Nishio; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF BEHAVIORAL MEDICINE 24 4 535 - 541 2017年08月 [査読有り]
     
    Purpose Cancer pain is a multidimensional experience that includes physiological, sensory, affective, cognitive, behavioral, and sociocultural dimensions. Few prospective studies have examined the relationship between a patient's expectation of pain improvement and the pain prognosis. The aim of this prospective study was to investigate whether patients' expectation to pain reduction was associated with pain intensity after morphine treatment in opioid treatment-na < ve patients with various types of cancer. The subjects were patients scheduled for cancer pain treatment with morphine who were taking nonsteroidal anti-inflammatory drugs daily. Morphine treatment was performed according to the standard method, including titration (NCCN Guidelines (TM), Adult Cancer Pain). Simple regression analysis was performed between pain intensity numerical rating scale (NRS) (day 8) as the dependent variable, expectation of pain decrease NRS (day 1), tumor types, and the following covariates as independent variables: patients' characteristics such as age, gender, PS (day 1), genotype of catechol-O-methyltransferase, total scores of Hospital Anxiety and Depression Scale (day 1), and pain intensity NRS (day 1). Multiple regression analysis was performed using forced entry methods with pain intensity NRS (day 8) as the dependent variable, and expectation of pain decrease NRS (day 1) and the covariates as independent variables that had a p value < 0.05 in the simple regression models. A total of 100 patients with baseline data were included, and 97 patients (51% female) met the inclusion criteria. Patients with a high expectation of pain decrease NRS had a significantly lower pain intensity NRS (day 8) (p = 0.001). Non-pharmacological factors such as expectations for pain treatment could also be important factors to treat cancer pain, which might be associated with communication skills in physicians.
  • Hisato Kawakami; Junko Tanizaki; Kaoru Tanaka; Koji Haratani; Hidetoshi Hayashi; Masayuki Takeda; Ken Kamata; Mamoru Takenaka; Masatomo Kimura; Takaaki Chikugo; Takao Sato; Masatoshi Kudo; Akihiko Ito; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 35 4 529 - 536 2017年08月 [査読有り]
     
    Background Nivolumab demonstrates promising efficacy for the treatment of non-small cell lung cancer and other malignancies. The clinical benefit of nivolumab, however, may be hampered by specific immune-related adverse events (irAEs), and little is known regarding nivolumab-related cholangitis. Methods A computerized search of our clinical database identified 3 metastatic non-small cell lung cancer patients with nivolumab-related cholangitis. All patients were treated with in-travenous nivolumab monotherapy (3.0 mg/kg) every 2 weeks until disease progression or irAEs occurred. Clinical data regarding the duration of nivolumab treatment, symptoms, laboratory abnormalities, pathological findings of liver parenchyma biopsy specimens, and management of nivolumab-related cholangitis were analyzed. Results Our analysis revealed that nivolumab-related cholangitis was characterized by (1) localized extrahepatic bile duct dilation without obstruction; (2) diffuse hypertrophy of the extrahepatic bile duct wall; (3) a dominant increase in the biliary tract enzymes alkaline phosphatase and gamma-glutamyl transpeptidase relative to the hepatic enzymes aspartate and alanine aminotransferase; (4) normal or reduced levels of the serum immunological markers antinuclear antibody, antimitochondrial antibody, smooth muscle antibody, and immunoglobulin G4; (5) the pathological finding of biliary tract cluster of differentiation 8-positive T cell infiltration from liver biopsy; and (6) amoderate to poor response to steroid therapy. Conclusions Nivolumab-related cholangitis is associated with distinct imaging and clinicopathological features that distinguish it from acute cholangitis of common etiologies and other immune-related cholangitis. Further studies are warranted to establish the optimal management of patients with this irAE.
  • Toyoaki Hida; Miyako Satouchi; Kazuhiko Nakagawa; Takashi Seto; Shingo Matsumoto; Katsuyuki Kiura; Hiroshi Nokihara; Haruyasu Murakami; Kota Tokushige; Ben Hatano; Makoto Nishio
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 47 7 618 - 624 2017年07月 [査読有り]
     
    ClinicalTrials.gov identifier: NCT01685060.Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib. Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated. All 24 Japanese patients had received a parts per thousand<yen>2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2-12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6-67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8-92.9]), time to response (median 1.9 months [range: 1.7-3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0-not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7-9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%). This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060.
  • Toyoaki Hida; Hiroshi Nokihara; Masashi Kondo; Young Hak Kim; Koichi Azuma; Takashi Seto; Yuichi Takiguchi; Makoto Nishio; Hiroshige Yoshioka; Fumio Imamura; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Miyako Satouchi; Toshiyuki Kozuki; Takehito Shukuya; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Takashi Asakawa; Ryoichi Asabe; Tomohiro Tanaka; Tomohide Tamura
    LANCET 390 10089 29 - 39 2017年07月 [査読有り]
     
    Background Alectinib, a potent, highly selective, CNS-active inhibitor of anaplastic lymphoma kinase (ALK), showed promising efficacy and tolerability in the single-arm phase 1/2 AF-001JP trial in Japanese patients with ALK-positive non-small-cell lung cancer. Given those promising results, we did a phase 3 trial to directly compare the efficacy and safety of alectinib and crizotinib. Methods J-ALEX was a randomised, open-label, phase 3 trial that recruited ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, who were chemotherapy-naive or had received one previous chemotherapy regimen, from 41 study sites in Japan. Patients were randomly assigned (1: 1) via an interactive web response system using a permuted-block method stratified by Eastern Cooperative Oncology Group performance status, treatment line, and disease stage to receive oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was progression-free survival assessed by an independent review facility. The efficacy analysis was done in the intention-to-treat population, and safety analyses were done in all patients who received at least one dose of the study drug. The study is ongoing and patient recruitment is closed. This study is registered with the Japan Pharmaceutical Information Center (number JapicCTI-132316). Findings Between Nov 18, 2013, and Aug 4, 2015, 207 patients were recruited and assigned to the alectinib (n=103) or crizotinib (n=104) groups. At data cutoff for the second interim analysis, 24 patients in the alectinib group had discontinued treatment compared with 61 in the crizotinib group, mostly due to lack of efficacy or adverse events. At the second interim analysis (data cutoff date Dec 3, 2015), an independent data monitoring committee determined that the primary endpoint of the study had been met (hazard ratio 0.34 [99.7% CI 0.17-0.71], stratified log-rank p< 0.0001) and recommended an immediate release of the data. Median progression-free survival had not yet been reached with alectinib (95% CI 20.3-not estimated) and was 10.2 months (8.2-12.0) with crizotinib. Grade 3 or 4 adverse events occurred at a greater frequency with crizotinib (54 [52%] of 104) than alectinib (27 [26%] of 103). Dose interruptions due to adverse events were also more prevalent with crizotinib (77 [74%] of 104) than with alectinib (30 [29%] of 103), and more patients receiving crizotinib (21 [20%]) than alectinib (nine [9%]) discontinued the study drug because of an adverse event. No adverse events with a fatal outcome occurred in either treatment group. Interpretation These results provide the first head-to-head comparison of alectinib and crizotinib and have the potential to change the standard of care for the first-line treatment of ALK-positive non-small-cell lung cancer. The dose of alectinib (300 mg twice daily) used in this study is lower than the approved dose in countries other than Japan; however, this limitation is being addressed in the ongoing ALEX study.
  • 大学病院における早期からの緩和ケア・地域連携の実践
    吉田 健史; 松岡 弘道; 小山 敦子; 鶴谷 純司; 中川 和彦; 三瀬 博之; 尾崎 公俊; 前田 宗之; 新田 隆
    肺癌 57 3 251 - 251 (NPO)日本肺癌学会 2017年06月
  • Masayuki Takeda; Kazuko Sakai; Kazuhiko Nakagawa; Kazuto Nishio
    Transl Cancer Res 6 3 633 - 638 2017年06月 [査読有り]
     
    The development of targeted therapies for lung cancer based on the presence of corresponding specific biomarkers has highlighted the need for molecular diagnostic tests capable of the analysis of multiple actionable genetic alterations in a single tumor sample. Amplicon-based next-generation sequencing (NGS)- as opposed to conventional Sanger-based sequencing-has been introduced to facilitate the performance of multiple genomic tests with small amounts of tissue. In Japan, several institutions including the National Cancer Center and university hospitals have initiated NGS-based clinical testing for cancer patients and are able to provide access to investigational drugs or approved targeted agents matched to detected molecular alterations. However, no NGS system has yet been approved for the detection of somatic mutations by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan. Further development of precision medicine in clinical practice in Japan will require changes to the medical curriculum to support the interpretation and annotation of NGS data. In this review, we introduce NGS-based clinical sequencing projects that are ongoing in Japan-in particular, those focusing on lung cancer-and we discuss issues relating to the integration of NGS into clinical practice.
  • Chee Khoon Lee; Lucy Davies; Yi-Long Wu; Tetsuya Mitsudomi; Akira Inoue; Rafael Rosell; Caicun Zhou; Kazuhiko Nakagawa; Sumitra Thongprasert; Masahiro Fukuoka; Sally Lord; Ian Marschner; Yu-Kang Tu; Richard J. Gralla; Val Gebski; Tony Mok; James Chih-Hsin Yang
    JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE 109 6 2017年06月 [査読有り]
     
    Background: We performed an individual patient data meta-analysis to examine the impact of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy on overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods: Data from trials comparing EGFR-TKI against chemotherapy in exon 19 deletion (del19) or exon 21 L858R (L858R) EGFR mutations patients were used. We performed Cox regression to obtain hazard ratios (HRs) and 95% confidence intervals (CIs). Impact of postprogression therapies was examined in exploratory analyses. All statistical tests were two-sided. Results: Six eligible trials (gefitinib = 3, erlotinib = 3) included 1231 patients; 632 received EGFR-TKI and 599 received chemotherapy. At a median 35.0 months follow-up, there were 780 deaths and 1004 progressions. There was no difference in OS between EGFR-TKI and chemotherapy (HR = 1.01, 95% CI = 0.88 to 1.17, P = .84). There was also no difference in OS for Del19 (n = 682, HR = 0.96, 95% CI = 0.79 to 1.16, P = .68) and L858R (n = 540, HR = 1.06, 95% CI = 0.86 to 1.32, P = .59) subgroups (Pinteraction = .47), or according to smoking status, sex, performance status, age, ethnicity, or histology. However, EGFR-TKI statistically significantly prolonged progression-free survival (PFS) overall (HR = 0.37, 95% CI = 0.32 to 0.42, P < .001) and in all subgroups. Following progression, 73.8% from the chemotherapy arm received EGFR-TKI, and 65.9% from the EGFR-TKI arm received chemotherapy. Nine percent from the EGFR-TKI arm received no further treatment vs 0.6% from the chemotherapy arm. Following disease progression, patients randomly assigned to EGFR-TKI had shorter OS than those randomly assigned to chemotherapy (12.8 months, 95% CI = 11.4 to 14.3, vs 19.8 months, 95% CI = 17.6 to 21.7). Conclusions: Despite statistically significant PFS benefit, there is no relative OS advantage with frontline gefitinib or erlotinib vs chemotherapy in EGFR-mutated NSCLC. This finding is likely due to the high rate of crossover at progression.
  • 西山 理; 山崎 亮; 西川 祐作; 佐野 安希子; 山縣 俊之; 佐野 博幸; 岩永 賢司; 東本 有司; 東田 有智; 中川 和彦
    気管支学 39 Suppl. S191 - S191 (NPO)日本呼吸器内視鏡学会 2017年05月
  • Toyoaki Hida; Makoto Nishio; Naoyuki Nogami; Yuichiro Ohe; Hiroshi Nokihara; Hiroshi Sakai; Miyako Satouchi; Kazuhiko Nakagawa; Mitsuhiro Takenoyama; Hiroshi Isobe; Shiro Fujita; Hiroshi Tanaka; Koichi Minato; Toshiaki Takahashi; Makoto Maemondo; Koji Takeda; Hideo Saka; Koichi Goto; Shinji Atagi; Tomonori Hirashima; Naoki Sumiyoshi; Tomohide Tamura
    CANCER SCIENCE 108 5 1000 - 1006 2017年05月 [査読有り]
     
    Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum- containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy.
  • Masayuki Nakao; Yosuke Matsuura; Hirofumi Uehara; Mingyon Mun; Ken Nakagawa; Makoto Nishio; Yuichi Ishikawa; Sakae Okumura
    Asian Cardiovascular and Thoracic Annals 25 4 281 - 286 2017年05月 [査読有り]
     
    Background Systemic examination for distant metastases is generally recommended for all lung cancer patients. However, this approach rarely detects distant metastases in typically resectable cT1-2N0 non-small-cell lung cancer. The aim of this study was to identify factors associated with distant metastases and develop indication criteria for preoperative systemic examination in patients with cT1-2N0 non-small-cell lung cancer, with a particular focus on computed tomography imaging of primary lesions. Methods We retrospectively reviewed non-small-cell lung cancer patients treated at our institute between 2005 and 2013. Data were extracted and compared between two groups: patients diagnosed as cT1-2N0M0 who underwent complete resection (M0 group, n = 1530) and those diagnosed as cT1-2N0M1b who received systemic chemotherapy (M1 group, n = 26). Results The median age at diagnosis was significantly lower in the M1 group (p = 0.015). Although carcinoembryonic antigen levels were significantly higher in the M1 group (p < 0.001), 42% had normal levels. Tumor diameters in lung and mediastinal windows on chest computed tomography were significantly larger, and the proportion (mediastinal/lung window tumor diameter ratio) was higher in the M1 group (p < 0.001). All 26 patients in the M1 group had a tumor diameter > 15 mm and mediastinal/lung window ratio > 0.75. Conclusions Preoperative systemic examination is not necessary in cT1-2N0 non-small-cell lung cancer patients when tumor diameters are ≤15 mm and mediastinal/lung window ratios are ≤0.75. According to these criteria, systemic examinations would have been reduced by 40% in our cohort.
  • Toyoaki Hida; Makoto Nishio; Naoyuki Nogami; Yuichiro Ohe; Hiroshi Nokihara; Hiroshi Sakai; Miyako Satouchi; Kazuhiko Nakagawa; Mitsuhiro Takenoyama; Hiroshi Isobe; Shiro Fujita; Hiroshi Tanaka; Koichi Minato; Toshiaki Takahashi; Makoto Maemondo; Koji Takeda; Hideo Saka; Koichi Goto; Shinji Atagi; Tomonori Hirashima; Naoki Sumiyoshi; Tomohide Tamura
    Cancer Science 108 5 1000 - 1006 2017年05月 [査読有り]
     
    Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4–25.4), 2.7 (range 1.2–5.5) and 4.2 (95% CI 1.4–7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or ‎discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. Clinical trial registration number: JapicCTI-132072.
  • Tomohide Tamura; Katsuyuki Kiura; Takashi Seto; Kazuhiko Nakagawa; Makoto Maemondo; Akira Inoue; Toyoaki Hida; Hiroshige Yoshioka; Masao Harada; Yuichiro Ohe; Naoyuki Nogami; Haruyasu Murakami; Hiroshi Kuriki; Tadashi Shimada; Tomohiro Tanaka; Kengo Takeuchi; Makoto Nishio
    JOURNAL OF CLINICAL ONCOLOGY 35 14 1515 - + 2017年05月 [査読有り]
     
    Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naive, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment. (C) 2017 by American Society of Clinical Oncology. Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/
  • Yuichi Tambo; Yukio Hosomi; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Yasutsuna Sasaki; Terufumi Kato; Toshiaki Takahashi; Takashi Seto; Makoto Maemondo; Hiroshi Nokihara; Ryo Koyama; Kazuhiko Nakagawa; Tomoya Kawaguchi; Yuta Okamura; Osamu Nakamura; Makoto Nishio; Tomohide Tamura
    INVESTIGATIONAL NEW DRUGS 35 2 217 - 226 2017年04月 [査読有り]
     
    Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m2. In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m2) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1- 5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m2 of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8- 5.7) months with docetaxel group and 4.1 (1.5- 5.4) months with DR group (hazard ratio HR]: 1.354, 95% CI: 0.835-2.195; p = 0.209). Grade >= 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.
  • Naoya Yamazaki; Tatsuya Takenouchi; Manabu Fujimoto; Hironobu Ihn; Hiroshi Uchi; Takashi Inozume; Yoshio Kiyohara; Hisashi Uhara; Kazuhiko Nakagawa; Hiroshi Furukawa; Hidefumi Wada; Kazuo Noguchi; Takashi Shimamoto; Kenji Yokota
    Cancer chemotherapy and pharmacology 79 4 651 - 660 2017年04月 [査読有り]
     
    PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.
  • 渡邉 諭美; 中川 和彦
    薬局 68 4 2090 - 2093 (株)南山堂 2017年03月
  • Toshio Shimizu; Kimio Yonesaka; Hidetoshi Hayashi; Tsutomu Iwasa; Koji Haratani; Hironori Yamada; Shoichi Ohwada; Emi Kamiyama; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 79 3 489 - 495 2017年03月 [査読有り]
     
    This phase 1 study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287) Process 2, a new formulation of fully human anti-HER3 monoclonal antibody in combination with erlotinib, an epidermal growth factor receptortyrosine kinase inhibitor (EGFR-TKI) in prior chemotherapy treated Japanese patients with advanced non-small cell lung cancer (NSCLC). Patients received intravenous patritumab Process 2 formulation at 9 mg/kg every 3 weeks after initiation of 18 mg/kg loading dose combined with continuous daily dose of erlotinib (150 mg QD) until any of the withdrawal criteria are met. Adverse events (AEs) were assessed using CTCAE v4.0 and tumor response was assessed using RECIST v1.1. Full pharmacokinetic sampling and serum biomarker analyses were mainly performed during cycle 1 and 2. Total of six EGFR-mutant NSCLC patients including one EGFR-TKI na < ve patient received patritumab Process 2 formulation combined with erlotinib. No dose-limiting toxicities were observed. The most frequent AEs were gastrointestinal or skin toxicities, which were generally mild and manageable. One patient discontinued from study due to reversible grade 3 interstitial lung disease. The mean area under the curve (AUC) value was 2640 mu g/day/mL; the Cmax value was 434 mu g/mL, respectively. The median progression-free survival (95% confidence interval) was 220.0 (100.0-363.0) days. HER3 ligand heregulin was detected in serum from only a patient that maintained most durable stable disease. Patritumab Process 2 formulation in combination with erlotinib was well tolerated compatible with favorable PK profile in Japanese patients with advanced NSCLC.
  • Kimio Yonesaka; Kenji Hirotani; Joachim von Pawel; Mircea Dediu; Shuquan Chen; Catherine Copigneaux; Kazuhiko Nakagawa
    LUNG CANCER 105 1 - 6 2017年03月 [査読有り]
     
    Objectives: Patritumab is a fully human anti-human epidermal growth factor receptor 3 (HER3) antibody that blocks activation by its ligand, heregulin (HRG). Preclinical studies have demonstrated the efficacy of patritumab in aberrantly high HRG-expressing non-small cell lung cancer (NSCLC). In the phase II randomized, placebo-controlled double-blind study HERALD (n = 212 patients with NSCLC), patritumab plus erlotinib did not improve progression-free survival (PFS) compared with placebo plus erlotinib. The current study examined whether soluble HRG (sHRG) level in serum correlated with the efficacy of patritumab plus erlotinib. Materials and methods: Serum was obtained from participants prior to treatment (n = 202). sHRG level was measured using a validated quantitative immune assay, and correlations with survival were blindly assessed. Results: sHRG level was various (-1346-11,772 pg/mL). Participants were divided into the sHRG-high or-low subgroups at the concentration defining near the third quartile, 980 pg/mL. Patritumab plus erlotinib significantly improved PFS relative to placebo in the sHRG-high subgroup (n = 46, hazard ratio 0.42 [0.19-0.96], p = 0.0327). In contrast, the HRG-low subgroup (n = 148) had no improvement in PFS with patritumab. Conclusion: sHRG seems to be a predictive biomarker for the efficacy of patritumab plus erlotinib in NSCLC patients. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Sakai K; Matsuoka H; Ohtake Y; Makimura C; Izumi H; Fujita Y; Otsuka M; Tsurutani J; Nishio K; Nakagawa K; Koyama A
    Molecular and clinical oncology 6 3 331 - 333 2017年03月 [査読有り]
     
    Carnitine deficiency is reportedly associated with increased pain sensation in diabetes mellitus and fibromyalgia, but the association between serum carnitine concentration and cancer pain has not been fully elucidated. We investigated the incidence of carnitine deficiency in patients with cancer pain, and examined the effect of the patients' demographic and clinical characteristics on pain intensity and carnitine deficiency. The serum carnitine concentration was measured in 50 patients with cancer pain receiving non-steroidal anti-inflammatory drugs, but not opioids. Multivariate regression analysis was used to determine the association of carnitine concentration, pain intensity, age and gender with hemoglobin and C-reactive protein (CRP) concentrations. Carnitine deficiency was detected in 9 of the patients (18.0%) and found to be significantly correlated with an elevated CRP concentration (P=0.039). In conclusion, although there does not appear to be an association between carnitine deficiency and cancer pain, it may be affected by inflammation or infection.
  • H. Yoshioka; N. Katakami; H. Okamoto; Y. Iwamoto; T. Seto; T. Takahashi; N. Sunaga; S. Kudoh; K. Chikamori; M. Harada; H. Tanaka; H. Saito; H. Saka; K. Takeda; N. Nogami; N. Masuda; T. Harada; H. Kitagawa; H. Horio; T. Yamanaka; M. Fukuoka; N. Yamamoto; K. Nakagawa
    ANNALS OF ONCOLOGY 28 2 285 - 291 2017年02月 [査読有り]
     
    Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35mg/m(2) on days 1-3 every 3 weeks) or docetaxel (60mg/m(2) on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade >= 3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade >= 3 leukopenia occurred in 63.3% and 70.7%, and grade >= 3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel.
  • Christian Manegold; Anne-Marie C. Dingemans; Jhanelle E. Gray; Kazuhiko Nakagawa; Marianne Nicolson; Solange Peters; Martin Reck; Yi-Long Wu; Odd Terje Brustugun; Lucio Crino; Enriqueta Felip; Dean Fennell; Pilar Garrido; Rudolf M. Huber; Aurelien Marabelle; Marcin Moniuszko; Francoise Mornex; Silvia Novello; Mauro Papotti; Maurice Perol; Egbert F. Smit; Kostas Syrigos; Jan P. van Meerbeeck; Nico van Zandwijk; James Chih-Hsin Yang; Caicun Zhou; Everett Vokes
    JOURNAL OF THORACIC ONCOLOGY 12 2 194 - 207 2017年02月 [査読有り]
     
    Over the past few years, there have been considerable advances in the treatments available to patients with metastatic or locally advanced NSCLC, particularly those who have progressed during first-line treatment. Some of the treatment options available to patients are discussed here, with a focus on checkpoint inhibitor immunotherapies (nivolumab and pembrolizumab) and antiangiogenic agents (bevacizumab, ramucirumab, and nintedanib). It is hypothesized that combining immunotherapy with antiangiogenic treatment may have a synergistic effect and enhance the efficacy of both treatments. In this review, we explore the theory and potential of this novel treatment option for patients with advanced NSCLC. We discuss the growing body of evidence that proangiogenic factors can modulate the immune response (both by reducing T-cell infiltration into the tumor microenvironment and through systemic effects on immune-regulatory cell function), and we examine the preclinical evidence for combining these treatments. Potential challenges are also considered, and we review the preliminary evidence of clinical efficacy and safety with this novel combination in a variety of solid tumor types. (C) 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
  • Taniguchi H; Takeuchi S; Fukuda K; Nakagawa T; Arai S; Nanjo S; Yamada T; Yamaguchi H; Mukae H; Yano S
    Cancer science 108 1 53 - 60 2017年01月 [査読有り]
     
    Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer.
  • Takashi Satoh; Katsuhiro Nakagawa; Fuminori Sugihara; Ryusuke Kuwahara; Motooki Ashihara; Fumihiro Yamane; Yosuke Minowa; Kiyoharu Fukushima; Isao Ebina; Yoshichika Yoshioka; Atsushi Kumanogoh; Shizuo Akira
    NATURE 541 7635 96 - + 2017年01月 [査読有り]
     
    Monocytes and macrophages comprise a variety of subsets with diverse functions(1-5). It is thought that these cells play a crucial role in homeostasis of peripheral organs, key immunological processes and development of various diseases. Among these diseases, fibrosis is a life-threatening disease of unknown aetiology. Its pathogenesis is poorly understood, and there are few effective therapies. The development of fibrosis is associated with activation of monocytes and macrophages(6-8). However, the specific subtypes of monocytes and macrophages that are involved in fibrosis have not yet been identified. Here we show that Ceacam1(+)Msr1(+)Ly6C(-)F4/80(-)Mac1(+) monocytes, which we term segregated-nucleus-containing atypical monocytes (SatM), share granulocyte characteristics, are regulated by CCAAT/enhancer binding protein beta (C/EBP beta), and are critical for fibrosis. Cebpb deficiency results in a complete lack of SatM. Furthermore, the development of bleomycin-induced fibrosis, but not inflammation, was prevented in chimaeric mice with Cebpb(-/-) haematopoietic cells. Adoptive transfer of SatM into Cebpb(-/-) mice resulted in fibrosis. Notably, SatM are derived from Ly6C(-)Fc epsilon RI+ granulocyte/macrophage progenitors, and a newly identified SatM progenitor downstream of Ly6C(-)Fc epsilon RI+ granulocyte/macrophage progenitors, but not from macrophage/dendritic-cell progenitors. Our results show that SatM are critical for fibrosis and that C/EBP beta licenses differentiation of SatM from their committed progenitor.
  • Masaya Yotsukura; Akihiko Yoshida; Aoi Sukeda; Keisuke Asakura; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Hisao Asamura; Noriko Motoi
    JOURNAL OF THORACIC ONCOLOGY 12 1 S1127 - S1128 2017年01月 [査読有り]
  • Kyohei Masai; Aoi Sukeda; Akihiko Yoshida; Keisuke Asakura; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Hisao Asamura; Noriko Motoi
    JOURNAL OF THORACIC ONCOLOGY 12 1 S1122 - S1122 2017年01月 [査読有り]
  • Takuro Mizukami; Yosuke Togashi; Saeko Naruki; Eri Banno; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Azusa Yoneshige; Hidetoshi Hayashi; Yoshihiko Fujita; Shuta Tomida; Takako Eguchi Nakajima; Takashi Fujino; Narikazu Boku; Akihiko Ito; Kazuhiko Nakagawa; Kazuto Nishio
    Molecular Carcinogenesis 56 1 106 - 117 2017年01月 [査読有り]
     
    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of > 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.
  • Haratani K; Hayashi H; Tanaka T; Kaneda H; Togashi Y; Sakai K; Hayashi K; Tomida S; Chiba Y; Yonesaka K; Nonagase Y; Takahama T; Tanizaki J; Tanaka K; Yoshida T; Tanimura K; Takeda M; Yoshioka H; Ishida T; Mitsudomi T; Nishio K; Nakagawa K
    Ann Oncol 28 7 1532 - 1539 2017年 [査読有り]
     
    Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR. Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B). Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of ≥1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of ≥10% and ≥50%. The proportion of tumors with a PD-L1 level of ≥10% or ≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden. Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
  • Tomoko Funazo; Kyohei Morita; Naoya Ikegami; Chisato Konishi; Satoshi Nakao; Ryo Ariyasu; Masato Taki; Kazuhiko Nakagawa; Moon Hee Hwang; Chie Yoshimura; Toshiaki Wakayama; Yasuo Nishizaka
    Internal Medicine 56 17 2317 - 2320 2017年 [査読有り]
     
    Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.
  • Chisato Konishi; Kazuhiko Nakagawa; Erika Nakai; Kenta Nishi; Ryoichi Ishikawa; Shinya Uematsu; Satoshi Nakao; Masato Taki; Kyohei Morita; Hwang Moon Hee; Chie Yoshimura; Toshiaki Wakayama; Yasuo Nishizaka
    Internal Medicine 56 19 2633 - 2637 2017年 [査読有り]
     
    Interstitial lung disease (ILD) has rarely been reported as a manifestation of giant cell arteritis (GCA). We herein report a unique case of GCA in a 76-year-old woman who presented with ILD as an initial manifestation of GCA. Ten years before admission, she had been diagnosed with granulomatous ILD of unknown etiology. Corticosteroid therapy induced remission. One year after the cessation of corticosteroid therapy, she was admitted with a persistent fever. After admission, she developed left oculomotor paralysis. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) proved extremely useful in establishing the diagnosis. Our case promotes awareness of GCA as a possible diagnosis for granulomatous ILD with unknown etiology.
  • Takuro Mizukami; Yosuke Togashi; Saeko Naruki; Eri Banno; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Azusa Yoneshige; Hidetoshi Hayashi; Yoshihiko Fujita; Shuta Tomida; Takako Eguchi Nakajima; Takashi Fujino; Narikazu Boku; Akihiko Ito; Kazuhiko Nakagawa; Kazuto Nishio
    MOLECULAR CARCINOGENESIS 56 1 106 - 117 2017年01月 [査読有り]
     
    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. (c) 2016 Wiley Periodicals, Inc.
  • Edward B. Garon; Martin Reck; Luis Paz-Ares; Santiago Ponce; Jesus Corral Jaime; Oscar Juan; Ernest Nadal; Pablo Lee; Rita Dalal; Jingyi Liu; Shuang He; Joseph Treat; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 18 1 96 - 99 2017年01月 [査読有り]
     
    Introduction: We present the treatment rationale and study design for the RELAY study (NCT02411448). This phase lb/III study will assess safety, tolerability, and efficacy of the combination of ramucirumab with erlotinib in previously untreated stage IV non small-cell lung cancer patients with an activating epidermal growth factor receptor (EGFR) mutation. Patients and Methods: The study is being conducted in approximately 120 sites in North America, Europe, and Asia and is currently open for enrollment. In part A (phase lb), approximately 12 patients will receive ramucirumab (10 mg/kg) every 2 weeks with erlotinib (150 mg) every day. Dose -limiting toxicity will be assessed during 2 cycles (4 weeks) of treatment. In part B (phase III), approximately 450 patients will be randomized in a 1:1 ratio to receive ramucirumab or placebo every 2 weeks with erlotinib daily until disease progression, unacceptable toxicity, or other withdrawal criteria are met. The primary end point is progression-free survival, on the basis of investigator assessment. Secondary end points include overall survival, objective response rate, disease control rate, duration of response, safety, and quality of life. Conclusion: Erlotinib with ramucirumab combination was chosen because the addition of an antiangiogenic agent, such as ramucirumab, would further improve the efficacy of erlotinib, which is a standard of care in the first-line treatment of patients with activating EGFR mutations. (C) 2016 Elsevier Inc. All rights reserved.
  • Takeda M; Nakagawa K
    Molecular and clinical oncology 6 1 3 - 6 2017年01月 [査読有り]
  • Hiromichi Matsuoka; Hiroyasu Kaneda; Kazuko Sakai; Atsuko Koyama; Kazuto Nishio; Kazuhiko Nakagawa
    Clinical Lung Cancer 18 1 e85 - e87 2017年01月 [査読有り]
  • Kato R; Hayashi H; Tanizaki J; Tanaka K; Takeda M; Nakagawa K
    ESMO open 2 1 e000145  2017年 [査読有り]
  • Sakai H; Hayashi H; Iwasa T; Hasegawa Y; Takeda M; Nakagawa K
    ESMO open 2 Suppl 1 e000104  2017年 [査読有り]
  • Crizotinib Versus Chemotherapy in Asian Patients with Advanced ALK-positive Non-small Cell Lung Cancer.
    Nishio M; Kim DW; Wu YL; Nakagawa K; Solomon BJ; Shaw AT; Hashigaki S; Ohki E; Usari T; Paolini J; Polli A; Wilner KD; Mok T
    Cancer Res Treat. 2017年 [査読有り]
  • Peritumoral ground-glass opacity associated with tumor pseudoprogression in a patient with non?small cell lung cancer treated with nivolumab.
    Kato R; ※Hayashi H; Tanizaki J; Tanaka K; Takeda M; Nakagawa K
    ESMO Open 2 1 e000145.  2017年 [査読有り]
  • ALK融合遺伝子陽性NSCLCに対するクリゾチニブ、アレクチニブ逐次療法の生存解析
    渡邉 諭美; 林 秀敏; 岡本 邦男; 田中 薫; 武田 真幸; 中川 和彦; 金田 裕靖; 藤原 季美子; 長谷川 喜一
    肺癌 56 7 1064 - 1064 (NPO)日本肺癌学会 2016年12月
  • Kyohei Masai; Koji Tsuta; Noriko Motoi; Kouya Shiraishi; Koh Furuta; Shigeki Suzuki; Keisuke Asakura; Kazuo Nakagawa; Hiroyuki Sakurai; Shun-Ichi Watanabe; Nobuyoshi Hiraoka; Hisao Asamura
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 11 12 2141 - 2149 2016年12月 [査読有り]
     
    INTRODUCTION: An association between usual interstitial pneumonia (UIP) and carcinogenesis has been well established. However, few detailed analyses have investigated the clinicopathological, immunohistochemical, and genetic features of patients with primary lung adenocarcinoma (ADC) with UIP (UIP-ADC). METHODS: We identified 44 patients with ADC in the setting of UIP (the UIP-ADC group) (1.9%) from 2309 patients with primary ADC and compared clinicopathological, immunohistochemical, and genetic features between the UIP-ADC group and patients with ADC without UIP (the non-UIP-ADC group). RESULTS: Clinicopathological features of UIP-ADC included an older age at occurrence; male predominance; smoking history; predilection for the lower lobe; large tumor size; high incidence of lymph vessel invasion, pleural invasion, and lymph node metastasis; and poor survival rate. However, the cause of death of patients with UIP-ADC was largely influenced by respiratory complications. Histologically, patients in the UIP-ADC group could be stratified according to invasive mucinous-predominant subtype. Genetically, patients in the UIP-ADC group had lower EGFR and higher KRAS mutation rates compared with patients in the non-UIP-ADC group. CONCLUSIONS: UIP-ADC was associated with a poor prognosis owing to the high frequency of perioperative complications rather than the malignancy of the tumor itself. There was a high prevalence of the invasive mucinous-predominant subtype in cases of UIP-ADC. UIP-ADC also had a low prevalence of EGFR mutations and a high prevalence of KRAS mutations. These findings suggest that UIP-ADC should be distinct from non-UIP-ADC.
  • Yoshikane Nonagase; Kimio Yonesaka; Hisato Kawakami; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Junko Tanizaki; Hidetoshi Hayashi; Takeshi Yoshida; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa; Junji Tsurutani
    ONCOTARGET 7 51 84860 - 84871 2016年12月 [査読有り]
     
    Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
  • Hiroto Ueda; Hidetoshi Hayashi; Keita Kudo; Masayuki Takeda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 6 797 - 799 2016年12月 [査読有り]
     
    Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient with EGFR mutation-positive lung adenocarcinoma who developed severe hepatotoxicity during treatment first with gefitinib and then with erlotinib, but who was subsequently able to continue treatment with afatinib for at least 44 weeks with no evidence of hepatotoxicity or disease progression. As far as we are aware, this is the first report of successful treatment with afatinib after the development of high-grade hepatotoxicity during both gefitinib and erlotinib therapy.
  • Hiroto Ueda; Hidetoshi Hayashi; Keita Kudo; Masayuki Takeda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 6 797 - 799 2016年12月 [査読有り]
     
    Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient with EGFR mutation-positive lung adenocarcinoma who developed severe hepatotoxicity during treatment first with gefitinib and then with erlotinib, but who was subsequently able to continue treatment with afatinib for at least 44 weeks with no evidence of hepatotoxicity or disease progression. As far as we are aware, this is the first report of successful treatment with afatinib after the development of high-grade hepatotoxicity during both gefitinib and erlotinib therapy.
  • Yoshikane Nonagase; Kimio Yonesaka; Hisato Kawakami; Satomi Watanabe; Koji Haratani; Takayuki Takahama; Naoki Takegawa; Hiroto Ueda; Junko Tanizaki; Hidetoshi Hayashi; Takeshi Yoshida; Masayuki Takeda; Yasutaka Chiba; Takao Tamura; Kazuhiko Nakagawa; Junji Tsurutani
    ONCOTARGET 7 51 84860 - 84871 2016年12月 [査読有り]
     
    Background: Overexpression of heregulin, a HER3 ligand, is one mechanism that confers resistance to the anti-HER2 agents trastuzumab and lapatinib. We investigated the impact of heregulin expression on the efficacy of HER2-targeted therapeutic agents, including trastuzumab, trastuzumab emtansine (T-DM1) and lapatinib, in vitro and in vivo and evaluated the heregulin messenger RNA (mRNA) levels in specimens from patients with HER2-positive breast or gastric cancer. Results: Cell proliferation and apoptosis assays demonstrated that heregulin conferred robust resistance to lapatinib and trastuzumab via HER3-Akt pathway activation followed by survivin overexpression; however, heregulin conferred minimal or no resistance to T-DM1 and paclitaxel. The heregulin mRNA level of one of 10 patients was up-regulated after the acquisition of resistance to trastuzumab-based therapy. Materials and Methods: SK-BR-3, NCI-N87, BT-474, MDA-MB-453, HCC1954, SNU-216 and 4-1ST cells were pharmacologically treated with recombinant heregulin or transfected with the heregulin gene. We also assessed the expression of heregulin mRNA in HER2-positive breast or gastric cancer samples before and after trastuzumab-based therapy using a RT-PCR-based method. Conclusions: mRNA up-regulation of heregulin was observed in clinical breast cancer specimens during trastuzumab-based treatment, but heregulin overexpression had a limited effect on the sensitivity to T-DM1 in vitro and in vivo.
  • Junko Tanizaki; Hidetoshi Hayashi; Masatomo Kimura; Kaoru Tanaka; Masayuki Takeda; Shigeki Shimizu; Akihiko Ito; Kazuhiko Nakagawa
    LUNG CANCER 102 44 - 48 2016年12月 [査読有り]
     
    The recent approval of nivolumab and other immune-checkpoint inhibitors for the treatment of certain solid tumors including non small cell lung cancer (NSCLC) has transformed cancer therapy. However, it will be important to characterize effects of such agents not seen with classical cytotoxic drugs or other targeted therapeutics. We here report two cases of NSCLC showing so-called pseudoprogression during nivolumab treatment. In both cases, imaging assessment revealed that liver metastatic lesions initially progressed but subsequently shrank during continuous nivolumab administration, with treatment also resulting in a decline in serum levels of carcinoembryonic antigen. Histological evaluation of the liver metastatic lesion of one case after regression revealed fibrotic tissue containing infiltrated lymphocytes positive for CD3, CD4, or CD8 but no viable tumor cells, suggestive of a durable immune reaction even after a pathological complete response. Given the increasing use of immune-checkpoint inhibitors in patients with NSCLC or other solid tumors, further clinical evaluation and pathological assessment are warranted to provide a better understanding of such pseudoprogression. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Joji Samejima; Mingyon Mun; Yosuke Matsuura; Masayuki Nakao; Hirofumi Uehara; Ken Nakagawa; Munetaka Masuda; Sakae Okumura
    JOURNAL OF THORACIC DISEASE 8 11 3105 - 3111 2016年11月 [査読有り]
     
    Background: Dealing with incomplete lung fissures during thoracoscopic surgery is difficult. Our objective was to evaluate the efficacy and safety of a thoracoscopic anterior 'fissure first' technique for dealing with incomplete left lung fissures. Methods: One hundred and seventy patients underwent left upper lobectomy or left lower lobectomy between April 2008 and July 2014. Of these, 34 patients underwent surgery using a thoracoscopic anterior 'fissure first' technique for incomplete fissures (group A) and 136 underwent surgery using a conventional thoracoscopic method for unfused fissures (group B). A four-port complete thoracoscopic approach was used in all patients. After completion of the fissure, hilar lymphadenectomy was performed in the conventional manner. Results: There were no significant differences between the two groups in operating time, blood loss, or duration of chest tube drainage. Patients in group A required more staple cartridges than those in group B (mean number of cartridges, 2.4 vs. 1.1; P<0.01). The two groups did not significantly differ with regard to the prevalence of air leaks (12% vs. 4%; P=0.11), either prolonged or delayed. Conclusions: We found that a thoracoscopic anterior 'fissure first' technique for left lung cancer with an incomplete fissure enabled hilar lymphadenectomy to be performed in the conventional manner without any increase in the prevalence of air leaks, operating time, or duration of chest tube drainage. This technique should be considered for use in left upper lobectomy or left lower lobectomy in patients with an incomplete fissure.
  • 米阪 仁雄; 前西 修; 廣谷 賢志; 金田 裕靖; 西尾 和人; 中川 和彦
    肺癌 56 6 530 - 530 (NPO)日本肺癌学会 2016年11月
  • Junko Tanizaki; Eri Banno; Yosuke Togashi; Hidetoshi Hayashi; Kazuko Sakai; Masayuki Takeda; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    LUNG CANCER 101 11 - 15 2016年11月 [査読有り]
     
    Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Masaaki Hibi; Hiroyasu Kaneda; Junko Tanizaki; Kazuko Sakai; Yosuke Togashi; Masato Terashima; Marco Antonio De Velasco; Yoshihiko Fujita; Eri Banno; Yu Nakamura; Masayuki Takeda; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Isamu Okamoto; Kazuto Nishio
    CANCER SCIENCE 107 11 1667 - 1676 2016年11月 [査読有り]
     
    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
  • Toyoaki Hida; Kazuhiko Nakagawa; Takashi Seto; Miyako Satouchi; Makoto Nishio; Katsuyuki Hotta; Toshiaki Takahashi; Yuichiro Ohe; Koji Takeda; Masahiro Tatsuno; Takashi Asakawa; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    CANCER SCIENCE 107 11 1642 - 1646 2016年11月 [査読有り]
     
    We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (20years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naive and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40mg vs 150mg; food effect with 150mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC(last)+/- standard deviation 3230 +/- 914h<bold>ng</bold>/mL vs 3710 +/- 1040h<bold>ng</bold>/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2months (95% CI 1.1-2.1). For the full analysis set (n=35) and crizotinib-failure subpopulations (n=23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9months (95% CI 11.1-not reached) and 12.9months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.
  • Martin Reck; Alexander Luft; Aleksandra Szczesna; Libor Havel; Sang-We Kim; Wallace Akerley; Maria Catherine Pietanza; Yi-long Wu; Christoph Zielinski; Michael Thomas; Enriqueta Felip; Kathryn Gold; Leora Horn; Joachim Aerts; Kazuhiko Nakagawa; Paul Lorigan; Anne Pieters; Teresa Kong Sanchez; Justin Fairchild; David Spigel
    JOURNAL OF CLINICAL ONCOLOGY 34 31 3740 - + 2016年11月 [査読有り]
     
    Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum(cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC. (C) 2016 by American Society of Clinical Oncology
  • Toyoaki Hida; Kazuhiko Nakagawa; Takashi Seto; Miyako Satouchi; Makoto Nishio; Katsuyuki Hotta; Toshiaki Takahashi; Yuichiro Ohe; Koji Takeda; Masahiro Tatsuno; Takashi Asakawa; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    CANCER SCIENCE 107 11 1642 - 1646 2016年11月 [査読有り]
     
    We report pharmacokinetics, efficacy and safety data for a new 150-mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (20years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naive and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300mg twice daily (comprising different schedules of 20/40-mg and 150-mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40mg vs 150mg; food effect with 150mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1months (range 1.1-15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUC(last)+/- standard deviation 3230 +/- 914h<bold>ng</bold>/mL vs 3710 +/- 1040h<bold>ng</bold>/mL, respectively, for 150-mg vs 20/40-mg capsules. Food effect with 150mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2months (95% CI 1.1-2.1). For the full analysis set (n=35) and crizotinib-failure subpopulations (n=23), the overall response rate was 70.0% (95% CI 50.6-85.3) and 65.0% (95% CI 40.8-84.6), and median progression-free survival was 13.9months (95% CI 11.1-not reached) and 12.9months (95% CI 3.9-not reached), respectively. The 150-mg capsule had a similar exposure profile to 20/40-mg capsules. Alectinib demonstrated promising efficacy and was well tolerated.
  • Masaaki Hibi; Hiroyasu Kaneda; Junko Tanizaki; Kazuko Sakai; Yosuke Togashi; Masato Terashima; Marco Antonio De Velasco; Yoshihiko Fujita; Eri Banno; Yu Nakamura; Masayuki Takeda; Akihiko Ito; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Isamu Okamoto; Kazuto Nishio
    CANCER SCIENCE 107 11 1667 - 1676 2016年11月 [査読有り]
     
    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
  • Satomi Watanabe; Hidetoshi Hayashi; Kunio Okamoto; Kimiko Fujiwara; Yoshikazu Hasegawa; Hiroyasu Kaneda; Kaoru Tanaka; Masayuki Takeda; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 17 6 528 - 534 2016年11月 [査読有り]
     
    We identified 11 patients with ALK-rearranged non-small cell lung cancer treated with sequential crizotinib and alectinib. The median combined progression-free survival and overall survival in the present study was 18.2 and 48.6 months, respectively. These findings suggest that this regimen produces durable survival and therefore warrants further investigation. Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first-and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Materials and Methods: Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. Results: The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 020.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Conclusion: Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.
  • Junko Tanizaki; Eri Banno; Yosuke Togashi; Hidetoshi Hayashi; Kazuko Sakai; Masayuki Takeda; Hiroyasu Kaneda; Kazuto Nishio; Kazuhiko Nakagawa
    LUNG CANCER 101 11 - 15 2016年11月 [査読有り]
     
    Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Kiyohiro Sakai; Masayuki Takeda; Hidetoshi Hayashi; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Tetsuya Mitsudomi; Atsuko Koyama; Kazuhiko Nakagawa
    THORACIC CANCER 7 6 670 - 675 2016年11月 [査読有り]
     
    IntroductionThe concept of oligometastasis has emerged as a basis on which to identify patients with stage IV non-small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. Patients and methodsConsecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node-negative disease and a limited number of metastatic lesions (5) per organ site and a limited number of affected organ sites (1 or 2) were eligible. ResultsEighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median overall survival for all patients was 15.9months, with that for EGFR mutation-positive patients tending to be longer than that for EGFR mutation-negative patients. ConclusionCure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC, especially negative for driver mutations.
  • Hidetoshi Hayashi; Kazuhiko Nakagawa
    JOURNAL OF THORACIC DISEASE 8 10 E1311 - E1316 2016年10月 [査読有り]
  • Takayuki Takahama; Kazuko Sakai; Masayuki Takeda; Koichi Azuma; Toyoaki Hida; Masataka Hirabayashi; Tetsuya Oguri; Hiroshi Tanaka; Noriyuki Ebi; Toshiyuki Sawa; Akihiro Bessho; Motoko Tachihara; Hiroaki Akamatsu; Shuji Bandoh; Daisuke Himeji; Tatsuo Ohira; Mototsugu Shimokawa; Yoichi Nakanishi; Kazuhiko Nakagawa; Kazuto Nishio
    ONCOTARGET 7 36 58492 - 58499 2016年09月 [査読有り]
     
    Introduction: Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic. Methods: We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. Results: A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M. Conclusions: Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
  • Kiyotaka Yoh; Yukio Hosomi; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Toshiko Koue; Takashi Nakamura; Sotaro Enatsu; Pablo Lee; David Ferry; Tomohide Tamura; Kazuhiko Nakagawa
    LUNG CANCER 99 186 - 193 2016年09月 [査読有り]
     
    Objectives: Ramucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methods: Patients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10 mg/kg or placebo, followed by docetaxel 60 mg/m(2) (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. Results: In the primary population (N = 160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52-6.97] months; n=76) than with placebodocetaxel (4.21 [2.83-5.62] months; n = 81); hazard ratio 0.83 (95% CI 0.59-1.16). Median (95% CI) overall survival was 15.15 (12.45-26.55) months with ramucirumab-docetaxel and 14.65 con (11.93-24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56-1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). Conclusion: Second-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang; Jianxing He; Kazuhiko Nakagawa; Jin Hyoung Kang; Joo-Hang Kim; Xin Wang; Sotaro Enatsu; Tarun Puri; Mauro Orlando; James Chih-Hsin Yang
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3258 - + 2016年09月 [査読有り]
     
    Purpose To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. Patients and Methods Chemotherapy-naive for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2: 1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-freesurvival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). Results PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P =.014; two-sided P =.029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+ G, but toxicities were manageable. Conclusion P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
  • Yoshiko Urata; Nobuyuki Katakami; Satoshi Morita; Reiko Kaji; Hiroshige Yoshioka; Takashi Seto; Miyako Satouchi; Yasuo Iwamoto; Masashi Kanehara; Daichi Fujimoto; Norihiko Ikeda; Haruyasu Murakami; Haruko Daga; Tetsuya Oguri; Isao Goto; Fumio Imamura; Shunichi Sugawara; Hideo Saka; Naoyuki Nogami; Shunichi Negoro; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3248 - + 2016年09月 [査読有り]
     
    Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. Patients and Methods Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). Results Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinibwere 6.5 and 7.5months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P =.257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P =.768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFRmutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P =.424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). Conclusion The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.
  • Yoshiko Urata; Nobuyuki Katakami; Satoshi Morita; Reiko Kaji; Hiroshige Yoshioka; Takashi Seto; Miyako Satouchi; Yasuo Iwamoto; Masashi Kanehara; Daichi Fujimoto; Norihiko Ikeda; Haruyasu Murakami; Haruko Daga; Tetsuya Oguri; Isao Goto; Fumio Imamura; Shunichi Sugawara; Hideo Saka; Naoyuki Nogami; Shunichi Negoro; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3248 - + 2016年09月 [査読有り]
     
    Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non-small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. Patients and Methods Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). Results Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinibwere 6.5 and 7.5months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P =.257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P =.768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFRmutation-positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P =.424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). Conclusion The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.
  • Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang; Jianxing He; Kazuhiko Nakagawa; Jin Hyoung Kang; Joo-Hang Kim; Xin Wang; Sotaro Enatsu; Tarun Puri; Mauro Orlando; James Chih-Hsin Yang
    JOURNAL OF CLINICAL ONCOLOGY 34 27 3258 - + 2016年09月 [査読有り]
     
    Purpose To determine whether the addition of pemetrexed to gefitinib (P+G) provides clinical benefit, compared with gefitinib monotherapy, in patients with advanced nonsquamous (NS) non-small-cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations. Patients and Methods Chemotherapy-naive for advanced NSCLC patients from China, Japan, Korea, and Taiwan (35 sites) with advanced, EGFR-mutant, NS NSCLC were randomly assigned (2: 1; computer-generated, interactive voice response) to open-label pemetrexed (500 mg/m(2) on day 1 of every 21-day cycle) plus gefitinib (250 mg/d [n = 129]) or gefitinib alone (n = 66). The primary end point was progression-freesurvival (PFS); secondary end points were time to progressive disease, overall survival, tumor response rates, duration of response, and safety. All end points were assessed in the intent-to-treat and safety population (P+G, n = 126; gefitinib alone, n = 65). Results PFS was significantly longer with P+G (median, 15.8 months; 95% CI, 12.6 to 18.3 months) than with gefitinib (median, 10.9 months; 95% CI, 9.7 to 13.8 months; adjusted hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; one-sided P =.014; two-sided P =.029). Results of EGFR exon 19 deletion and EGFR exon 21 L858R point mutation subgroup analyses were consistent with the intent-to-treat result. P+G, compared with gefitinib alone, resulted in significantly longer time to progressive disease (median, 16.2 v 10.9 months, respectively; HR, 0.66; 95% CI, 0.47 to 0.93) and numerically longer duration of response (median, 15.4 v 11.3 months, respectively; HR, 0.74; 95% CI, 0.50 to 1.08). Tumor response rates did not differ. Overall survival data are immature. Drug-related grade 3 or 4 adverse events were more common with P+ G, but toxicities were manageable. Conclusion P+G improved PFS compared with gefitinib alone in East Asian patients with advanced NS NSCLC and activating EGFR mutations. This combination may offer EGFR mutation-positive patients new treatment options and improved clinical outcomes compared with the current standard of care.
  • Takayuki Takahama; Kazuko Sakai; Masayuki Takeda; Koichi Azuma; Toyoaki Hida; Masataka Hirabayashi; Tetsuya Oguri; Hiroshi Tanaka; Noriyuki Ebi; Toshiyuki Sawa; Akihiro Bessho; Motoko Tachihara; Hiroaki Akamatsu; Shuji Bandoh; Daisuke Himeji; Tatsuo Ohira; Mototsugu Shimokawa; Yoichi Nakanishi; Kazuhiko Nakagawa; Kazuto Nishio
    ONCOTARGET 7 36 58492 - 58499 2016年09月 [査読有り]
     
    Introduction: Next-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance to earlier generations of such drugs mediated by a secondary T790M mutation of EGFR, but the performance of a second tumor biopsy to assess T790M mutation status can be problematic. Methods: We developed and evaluated liquid biopsy assays for detection of TKI-sensitizing and T790M mutations of EGFR by droplet digital PCR (ddPCR) in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with acquired EGFR-TKI resistance. Results: A total of 260 patients was enrolled between November 2014 and March 2015 at 29 centers for this West Japan Oncology Group (WJOG 8014LTR) study. Plasma specimens from all subjects as well as tumor tissue or malignant pleural effusion or ascites fluid from 41 patients were collected after the development of EGFR-TKI resistance. All plasma samples were genotyped successfully and the results were reported to physicians within 14 days. TKI-sensitizing and T790M mutations were detected in plasma of 120 (46.2%) and 75 (28.8%) patients, respectively. T790M was detected in 56.7% of patients with plasma positive for TKI-sensitizing mutations. For the 41 patients with paired samples obtained after acquisition of EGFR-TKI resistance, the concordance for mutation detection by ddPCR in plasma compared with tumor tissue or malignant fluid specimens was 78.0% for TKI-sensitizing mutations and 65.9% for T790M. Conclusions: Noninvasive genotyping by ddPCR with cell-free DNA extracted from plasma is a promising approach to the detection of gene mutations during targeted treatment.
  • Kiyotaka Yoh; Yukio Hosomi; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Nobuyuki Yamamoto; Makoto Nishio; Yuichiro Ohe; Toshiko Koue; Takashi Nakamura; Sotaro Enatsu; Pablo Lee; David Ferry; Tomohide Tamura; Kazuhiko Nakagawa
    LUNG CANCER 99 186 - 193 2016年09月 [査読有り]
     
    Objectives: Ramucirumab plus docetaxel prolongs survival in patients with non-small cell lung cancer (NSCLC) with disease progression after platinum-based therapy. This phase II, double-blind, randomized, placebo-controlled study assessed efficacy and safety of second-line ramucirumab-docetaxel in Japanese patients with NSCLC. Materials and methods: Patients with NSCLC with progression after platinum-based therapy (28 Japanese sites; 19 December, 2012 to 22 May, 2015) were randomized (computer-generated sequence) to ramucirumab 10 mg/kg or placebo, followed by docetaxel 60 mg/m(2) (Day 1, 21-day cycle). Prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) monotherapy was prohibited in the primary population, but EGFR mutation-positive NSCLC patients who were treated with EGFR-TKI were enrolled as a separate exploratory population. Primary endpoint was progression-free survival (PFS); secondary outcomes included overall survival, tumor response rates, and safety. Investigator tumor assessments were used for the efficacy endpoints. Results: In the primary population (N = 160 randomized, n=157 treated), median (95% CI) PFS was longer with ramucirumab-docetaxel (5.22 [3.52-6.97] months; n=76) than with placebodocetaxel (4.21 [2.83-5.62] months; n = 81); hazard ratio 0.83 (95% CI 0.59-1.16). Median (95% CI) overall survival was 15.15 (12.45-26.55) months with ramucirumab-docetaxel and 14.65 con (11.93-24.44) months with placebo-docetaxel (hazard ratio [95% CI] 0.86 [0.56-1.32]). Objective response rate (28.9% vs 18.5%) and disease control rate (78.9% vs 70.4%) were numerically greater with ramucirumab-docetaxel than with placebo-docetaxel. Incidence and severity of most adverse events were similar, but febrile neutropenia was more common with ramucirumab-docetaxel (34.2%) than with placebo-docetaxel (19.8%). Conclusion: Second-line ramucirumab-docetaxel improved PFS similar to that seen in the REVEL trial with a manageable safety profile in Japanese patients with NSCLC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Kazuhiko Nakagawa
    TRANSLATIONAL CANCER RESEARCH 5 3 S554 - S556 2016年09月 [査読有り]
  • Koichi Goto; Yuichiro Ohe; Taro Shibata; Takashi Seto; Toshiaki Takahashi; Kazuhiko Nakagawa; Hiroshi Tanaka; Koji Takeda; Makoto Nishio; Kiyoshi Mori; Miyako Satouchi; Toyoaki Hida; Naruo Yoshimura; Toshiyuki Kozuki; Fumio Imamura; Katsuyuki Kiura; Hiroaki Okamoto; Toshiyuki Sawa; Tomohide Tamura
    LANCET ONCOLOGY 17 8 1147 - 1157 2016年08月 [査読有り]
     
    Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1: 1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1.0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided a of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22.7 months (IQR 20.0-35.3). Overall survival was significantly longer in the combination chemotherapy group (median 18.2 months, 95% CI 15.7-20.6) than in the topotecan group (12.5 months, 10.8-14.9; hazard ratio 0.67, 90% CI 0.51-0.88; p=0.0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer.
  • Benjamin J. Solomon; Federico Cappuzzo; Enriqueta Felip; Fiona H. Blackhall; Daniel B. Costa; Dong-Wan Kim; Kazuhiko Nakagawa; Yi-Long Wu; Tarek Mekhail; Jolanda Paolini; Jennifer Tursi; Tiziana Usari; Keith D. Wilner; Paulina Selaru; Tony S. K. Mok
    JOURNAL OF CLINICAL ONCOLOGY 34 24 2858 - + 2016年08月 [査読有り]
     
    Purpose Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer. Patients and Methods Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3weeks for <= six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed. Results Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < . 001; median, 10.9v 7.0months, respectively). Conclusion Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
  • Benjamin J. Solomon; Federico Cappuzzo; Enriqueta Felip; Fiona H. Blackhall; Daniel B. Costa; Dong-Wan Kim; Kazuhiko Nakagawa; Yi-Long Wu; Tarek Mekhail; Jolanda Paolini; Jennifer Tursi; Tiziana Usari; Keith D. Wilner; Paulina Selaru; Tony S. K. Mok
    JOURNAL OF CLINICAL ONCOLOGY 34 24 2858 - + 2016年08月 [査読有り]
     
    Purpose Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer. Patients and Methods Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3weeks for <= six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed. Results Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < . 001; median, 10.9v 7.0months, respectively). Conclusion Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.
  • Koichi Goto; Yuichiro Ohe; Taro Shibata; Takashi Seto; Toshiaki Takahashi; Kazuhiko Nakagawa; Hiroshi Tanaka; Koji Takeda; Makoto Nishio; Kiyoshi Mori; Miyako Satouchi; Toyoaki Hida; Naruo Yoshimura; Toshiyuki Kozuki; Fumio Imamura; Katsuyuki Kiura; Hiroaki Okamoto; Toshiyuki Sawa; Tomohide Tamura
    LANCET ONCOLOGY 17 8 1147 - 1157 2016年08月 [査読有り]
     
    Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1: 1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1.0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided a of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22.7 months (IQR 20.0-35.3). Overall survival was significantly longer in the combination chemotherapy group (median 18.2 months, 95% CI 15.7-20.6) than in the topotecan group (12.5 months, 10.8-14.9; hazard ratio 0.67, 90% CI 0.51-0.88; p=0.0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer.
  • Kazuo Nakagawa; Hisao Asamura; Koji Tsuta; Kanji Nagai; Eiji Yamada; Genichiro Ishii; Tetsuya Mitsudomi; Akihiko Ito; Masahiko Higashiyama; Yasuhiko Tomita; Masayoshi Inoue; Eiichi Morii; Nariaki Matsuur; Meinoshin Okumura
    LUNG CANCER 97 1 - 7 2016年07月 [査読有り]
     
    Objectives: The precise and rapid diagnosis of the presence or absence of lymph node (LN) metastasis is essential for deciding upon an appropriate therapeutic strategy for patients with non-small cell lung cancer (NSCLC). We conducted a prospective multicenter clinical trial in Japan to evaluate a rapid, automated and objective assay system, the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp), which targets cytokeratin 19 mRNA, to detect LN metastasis of NSCLC. Materials and methods: A total of 410 Lymph nodes (LNs) from 111 patients with clinical stage IB to IIIA NSCLC who underwent lung resection with LN dissection were included in this study. The LNs were divided into 4 blocks and examined by either the OSNA assay or a 3-level histological examination. The results of each method were compared and further analyses were performed for discordant cases. The primary endpoint was a concordance rate of more than 85% between the two methods. Results: The concordance rate between the two methods was 92.7% (95% CI, 89.7-95.0%), with a sensitivity of 79.7% (95% CI, 67.2-89.0%). Discordant results were observed in 30 LNs (5.8%), and were mainly due to a tissue allocation bias and/or contamination by CK19-expressing alveolar cells in LNs. Conclusion: The OSNA assay gave a diagnosis that was as accurate as a 3-level histological examination, which is more detailed than a histological examination in routine clinical practice. The OSNA assay might be useful in intraoperative decision-making in personalized lung cancer surgery based on the LN status. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Takekazu Iwata; Ichiro Yoshino; Shigetoshi Yoshida; Norihiko Ikeda; Masahiro Tsuboi; Yuji Asato; Nobuyuki Katakami; Kazuhiro Sakamoto; Yoshinori Yamashita; Jiro Okami; Tetsuya Mitsudomi; Motohiro Yamashita; Hiroshi Yokouchi; Kenichi Okubo; Morihito Okada; Mitsuhiro Takenoyama; Masayuki Chida; Keisuke Tomii; Motoki Matsuura; Arata Azuma; Tae Iwasawa; Kazuyoshi Kuwano; Shuji Sakai; Kenzo Hiroshima; Junya Fukuoka; Kenichi Yoshimura; Hirohito Tada; Kazuhiko Nakagawa; Yoichi Nakanishi
    RESPIRATORY RESEARCH 17 1 90  2016年07月 [査読有り]
     
    Background: Idiopathic pulmonary fibrosis (IPF) often accompanies lung cancer, and life-threatening acute exacerbation (AE) of IPF (AE-IPF) is reported to occur in 20 % of IPF patients who undergo lung cancer surgery. Pirfenidone is an anti-fibrotic agent known to reduce disease progression in IPF patients. A phase II study was conducted to evaluate whether perioperative pirfenidone treatment could reduce the incidence of postoperative AE-IPF patients with lung cancer. Methods: Pirfenidone was orally administered to IPF patients who were candidates for lung cancer surgery; pirfenidone was dosed at 600 mg/day for the first 2 weeks, followed by 1200 mg/day. Surgery was performed after at least 2 weeks of 1200-mg/day administration. The primary endpoint was non-AE-IPF rate during postoperative days 0-30, compared to the null value of 80 %, and the secondary endpoint was safety. Radiologic and pathologic diagnoses of IPF and AE-IPF were confirmed by an independent review committee. Results: From June 2012 to January 2014, 43 cases were enrolled, and 39 were eligible (full analysis set [FAS]). Both pirfenidone treatment and surgery were performed in 36 patients (per protocol set [PPS]). AE-IPF did not occur in 37/39 patients (94.9 % [95 % confidential interval: 82.7-99.4 %, p = 0.01]) in the FAS, and in 38/39 patients (97.2 % [95 % confidential interval: 85.5-99.9 %, p = 0.004] in the PPS. A grade 5 adverse event (death) occurred in 1 patient, after AE-IPF; no other grade 3-5 adverse events were observed. Conclusions: Perioperative pirfenidone treatment is safe, and is promising for reducing AE-IPF after lung cancer surgery in IPF patients.
  • Iwata T; Yoshino I; Yoshida S; Ikeda N; Tsuboi M; Asato Y; Katakami N; Sakamoto K; Yamashita Y; Okami J; Mitsudomi T; Yamashita M; Yokouchi H; Okubo K; Okada M; Takenoyama M; Chida M; Tomii K; Matsuura M; Azuma A; Iwasawa T; Kuwano K; Sakai S; Hiroshima K; Fukuoka J; Yoshimura K; Tada H; Nakagawa K; Nakanishi Y; West Japan; Oncology Group
    Respiratory research 17 1 90  2016年07月 [査読有り]
  • Shunta Nagashima; Junichi Maruyama; Shodai Kawano; Hiroaki Iwasa; Kentaro Nakagawa; Mari Ishigami-Yuasa; Hiroyuki Kagechika; Hiroshi Nishina; Yutaka Hata
    CANCER SCIENCE 107 6 791 - 802 2016年06月 [査読有り]
     
    Transcriptional co-activator with PDZ-binding motif (TAZ) plays versatile roles in cell proliferation and differentiation. It is phosphorylated by large tumor suppressor kinases, the core kinases of the tumor-suppressive Hippo pathway. Phosphorylation induces the cytoplasmic accumulation of TAZ and its degradation. In human cancers, the deregulation of the Hippo pathway and gene amplification enhance TAZ activity. TAZ interacts with TEA domain family members (TEAD), and upregulates genes implicated in epithelial-mesenchymal transition. It also confers stemness to cancer cells. Thus, TAZ activation provides cancer cells with malignant properties and worsens the clinical prognosis. Therefore, TAZ attracts attention as a therapeutic target in cancer therapy. We applied 18 606 small chemical compounds to human osteosarcoma U2OS cells expressing GFP-fused TAZ (GFP-TAZ), monitored the subcellular localization of GFP-TAZ, and selected 33 compounds that shifted GFP-TAZ to the cytoplasm. Unexpectedly, only a limited number of compounds suppressed TAZ-mediated enhancement of TEAD-responsive reporter activity. Moreover, the compounds that weakened TEAD reporter activity did not necessarily decrease the unphosphorylated TAZ. In this study, we focused on three compounds that decreased both TEAD reporter activity and unphosphorylated TAZ, and treated several human cancer cells with these compounds. One compound did not show a remarkable effect, whereas the other two compounds compromised the cell viability in certain cancer cells. In conclusion, the GFP-TAZ-based assay can be used as the first screening for compounds that inhibit TAZ and show anticancer properties. To develop anticancer drugs, we need additional assays to select the compounds.
  • 大学病院における早期からの緩和ケア・地域連携の実践 腫瘍内科と緩和ケアの融合の試み
    吉田 健史; 和泉 宏昌; 牧村 ちひろ; 松岡 弘道; 三瀬 博之; 尾崎 公俊; 前田 宗之; 新田 隆; 鶴谷 純司; 小山 敦子; 中川 和彦
    Palliative Care Research 11 Suppl. S502 - S502 (NPO)日本緩和医療学会 2016年06月
  • Toshio Shimizu; Takashi Seto; Fumihiko Hirai; Mitsuhiro Takenoyama; Kaname Nosaki; Junji Tsurutani; Hiroyasu Kaneda; Tsutomu Iwasa; Hisato Kawakami; Kazuo Noguchi; Takashi Shimamoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 3 347 - 354 2016年06月 [査読有り]
     
    Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.
  • Satomi Watanabe; Masayuki Takeda; Takayuki Takahama; Tsutomu Iwasa; Junji Tsurutani; Junko Tanizaki; Toshio Shimizu; Kazuko Sakai; Yoshitaka Wada; Noritaka Isogai; Kazuto Nishio; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 3 394 - 396 2016年06月 [査読有り]
     
    Extramammary Paget's disease is a malignant intraepithelial carcinoma, which constitutes less than 1 % of all vulvar malignancies. Surgical resection is the first treatment of choice and standard chemotherapy has not been established for advanced or recurrent disease. Experimental and clinical studies have identified human epidermal growth receptor 2 as a potential therapeutic target. A 63-year-old male was referred for recurrent extramammary Paget's disease after surgery. Human epidermal growth receptor 2 was shown to be overexpressed and amplified by immunohistochemical analysis and fluorescence in situ hybridization analysis, respectively. After two cycles of trastuzumab monotherapy, all lymph node metastases decreased in size. However, he experienced recurrence in the lymph nodes during the seven courses of trastuzumab. As a subsequent treatment, trastuzumab was administered in combination with docetaxel and pertuzumab; clinical response was sustained for 12 months without significant adverse events.
  • Toshio Shimizu; Takashi Seto; Fumihiko Hirai; Mitsuhiro Takenoyama; Kaname Nosaki; Junji Tsurutani; Hiroyasu Kaneda; Tsutomu Iwasa; Hisato Kawakami; Kazuo Noguchi; Takashi Shimamoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 34 3 347 - 354 2016年06月 [査読有り]
     
    Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.
  • Satomi Watanabe; Hidetoshi Hayashi; Kazuhiko Nakagawa
    Annals of Translational Medicine 4 11 225  2016年06月 [査読有り]
  • Hidetoshi Hayashi; Masakazu Ogura; Takashi Niwa; Satoshi Ikeo; Takashi Yokoi; Yoshitaro Torii; Kunio Okamoto; Yosuke Tamura; Kaoru Tanaka; Yasuhito Fujisaka; Isao Goto; Hiroyasu Kaneda; Takayasu Kurata; Hiroshige Yoshioka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 34 15 2016年05月 [査読有り]
  • Toshio Shimizu; Kazuto Nishio; Kazuko Sakai; Hidetoshi Hayashi; Kunio Okamoto; Masayuki Takeda; Tsutomu Iwasa; Kaoru Tanaka; Koji Aoyama; Maiko Morishita; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 34 15 2016年05月 [査読有り]
  • Toshio Shimizu; Kazuya Fukuoka; Masayuki Takeda; Tutomu Iwasa; Takeshi Yoshida; Joanna Horobin; Mitchell Keegan; Lou Vaickus; Ajit Chavan; Mahesh Padval; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 77 5 997 - 1003 2016年05月 [査読有り]
     
    Purpose VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. Methods VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Results Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). Conclusions VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.
  • Akira Inoue; Kazushi Yoshida; Satoshi Morita; Fumio Imamura; Takashi Seto; Isamu Okamoto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Satoshi Muto; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 5 462 - 467 2016年05月 [査読有り]
     
    Background: The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. Methods: Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years x 100. Results: The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with >= 2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. Conclusion: Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.
  • Akira Inoue; Kazushi Yoshida; Satoshi Morita; Fumio Imamura; Takashi Seto; Isamu Okamoto; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Satoshi Muto; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 46 5 462 - 467 2016年05月 [査読有り]
     
    Background: The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. Methods: Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years x 100. Results: The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with >= 2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. Conclusion: Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.
  • Toshio Shimizu; Kazuya Fukuoka; Masayuki Takeda; Tutomu Iwasa; Takeshi Yoshida; Joanna Horobin; Mitchell Keegan; Lou Vaickus; Ajit Chavan; Mahesh Padval; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 77 5 997 - 1003 2016年05月 [査読有り]
     
    Purpose VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase and proline-rich tyrosine kinase-2. This phase 1 study evaluated the safety and tolerability, pharmacokinetics, and clinical activity of VS-6063 in Japanese subjects with advanced solid tumor malignancies in a first-in-Asian study setting. Methods VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three subjects each with a standard 3 + 3 dose-escalation design until disease progression or unacceptable toxicity. Blood samples for pharmacokinetics were collected on Day 1 and 15. The assessments were performed using CTCAE v4.0 for adverse events (AEs), and the Response Evaluation Criteria In Solid Tumors, version v1.1 (RECIST v1.1) for tumor response. Results Nine patients were treated across three dose levels (200-600 mg BID). No dose-limiting toxicities were observed at any dose level. Most frequent treatment-related AEs were Grade 1/2 unconjugated hyperbilirubinemia, fatigue, decreased appetite, and diarrhea. Only one subject in the 200 mg BID cohort experienced reversible and transient Grade 3 unconjugated hyperbilirubinemia. PK analyses confirmed that the exposure at the recommended Phase 2 dose (RP2D) of 400 mg BID was comparable with exposures previously reported in non-Japanese subjects. Durable stable disease of approximately 24 weeks was confirmed in two subjects (malignant mesothelioma and rectal cancer). Conclusions VS-6063 was well tolerated at all dose levels investigated in this first-in-Asian study. These data support the administration of VS-6063 to Japanese subjects at the RP2D in clinical trials involving solid tumor malignancies.
  • N. Takegawa; H. Hayashi; N. Iizuka; T. Takahama; H. Ueda; K. Tanaka; M. Takeda; K. Nakagawa
    ANNALS OF ONCOLOGY 27 5 953 - 955 2016年05月 [査読有り]
  • M. Takeda; K. Sakai; K. Okamoto; H. Hayashi; K. Tanaka; T. Shimizu; K. Nishio; K. Nakagawa
    ANNALS OF ONCOLOGY 27 4 748 - 750 2016年04月 [査読有り]
     
    RET fusion genes have recently been identified as new "druggable" drivers in 1% to 2% of lung adenocarcinomas, with several clinical trials now being under way to evaluate the therapeutic effects of RET tyrosine kinase inhibitors in patients with RET fusion-positive lung cancer. We here describe a case study of long-term efficacy of docetaxel plus nintedanib (BIBF 1120) that was manifest over 33 months in a female never-smoker with non-small cell lung cancer wild-type for EGFR and ALK. Multiplex genetic testing of lung biopsy specimens revealed a CCDC6-RET fusion gene but no other actionable mutations. Our findings suggest that RET rearrangement as identified by multiplex testing is a potential target for nintedanib therapy.
  • Masayuki Takeda; Takeharu Yamanaka; Takashi Seto; Hidetoshi Hayashi; Koichi Azuma; Morihito Okada; Shunichi Sugawara; Haruko Daga; Tomonori Hirashima; Kimio Yonesaka; Yoshiko Urata; Haruyasu Murakami; Haruhiro Saito; Akihito Kubo; Toshiyuki Sawa; Eiji Miyahara; Naoyuki Nogami; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto
    CANCER 122 7 1050 - 1059 2016年04月 [査読有り]
     
    BACKGROUNDBevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients. METHODSWest Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS). RESULTSOne hundred patients were randomly assigned to receive docetaxel (n=50) or docetaxel plus bevacizumab (n=50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P<.2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P=.11). No unexpected or severe adverse events were recorded. CONCLUSIONSFurther evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. Cancer 2016;122:1050-1059. (c) 2016 American Cancer Society There has been no evidence to support the use of bevacizumab beyond disease progression in patients with advanced nonsquamous non-small cell lung cancer whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. A randomized trial has now shown that the continuation of bevacizumab therapy beyond disease progression in such patients meets the predefined threshold of P<.2 for the primary endpoint of progression-free survival. See also pages 000-000.
  • Masayuki Takeda; Takeharu Yamanaka; Takashi Seto; Hidetoshi Hayashi; Koichi Azuma; Morihito Okada; Shunichi Sugawara; Haruko Daga; Tomonori Hirashima; Kimio Yonesaka; Yoshiko Urata; Haruyasu Murakami; Haruhiro Saito; Akihito Kubo; Toshiyuki Sawa; Eiji Miyahara; Naoyuki Nogami; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto
    CANCER 122 7 1050 - 1059 2016年04月 [査読有り]
     
    BACKGROUNDBevacizumab combined with platinum-based chemotherapy has been established as a standard treatment option in the first-line setting for advanced nonsquamous non-small cell lung cancer (NSCLC). However, there has been no evidence to support the use of bevacizumab beyond disease progression in such patients. METHODSWest Japan Oncology Group 5910L was designed as a multicenter, open-label, randomized, phase 2 trial of docetaxel versus docetaxel plus bevacizumab every 3 weeks for patients with recurrent or metastatic nonsquamous NSCLC whose disease had progressed after first-line treatment with bevacizumab plus a platinum-based doublet. The primary endpoint was progression-free survival (PFS). RESULTSOne hundred patients were randomly assigned to receive docetaxel (n=50) or docetaxel plus bevacizumab (n=50), and this yielded median PFS times of 3.4 and 4.4 months, respectively, with a hazard ratio (HR) of 0.71 and a stratified log-rank P value of .058, which met the predefined criterion for statistical significance (P<.2). The median overall survival also tended to be longer in the docetaxel plus bevacizumab group (13.1 months; 95% confidence interval [CI], 10.6-21.4 months) versus the docetaxel group (11.0 months; 95% CI, 7.6-16.1 months) with an HR of 0.74 (95% CI, 0.46-1.19; stratified log-rank P=.11). No unexpected or severe adverse events were recorded. CONCLUSIONSFurther evaluation of bevacizumab beyond disease progression is warranted for patients with advanced NSCLC whose disease has progressed after treatment with bevacizumab plus a platinum-based doublet. Cancer 2016;122:1050-1059. (c) 2016 American Cancer Society There has been no evidence to support the use of bevacizumab beyond disease progression in patients with advanced nonsquamous non-small cell lung cancer whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. A randomized trial has now shown that the continuation of bevacizumab therapy beyond disease progression in such patients meets the predefined threshold of P<.2 for the primary endpoint of progression-free survival. See also pages 000-000.
  • 渡邉 諭美; 中川 和彦
    薬局 67 4 1899 - 1902 (株)南山堂 2016年03月
  • Yoshikane Nonagase; Kunio Okamoto; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Toshio Shimizu; Junji Tsurutani; Kazuhiko Nakagawa
    ANTI-CANCER DRUGS 27 3 251 - 253 2016年03月 [査読有り]
     
    Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.
  • Yoshikane Nonagase; Kunio Okamoto; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Toshio Shimizu; Junji Tsurutani; Kazuhiko Nakagawa
    ANTI-CANCER DRUGS 27 3 251 - 253 2016年03月 [査読有り]
     
    Both afatinib and erlotinib are tyrosine kinase inhibitors that inhibit aberrant epidermal growth factor receptor (EGFR) signals in non-small-cell lung cancer (NSCLC). Afatinib is an irreversible inhibitor directed against EGFR, ErbB-2, and ErbB-4, whereas erlotinib is a reversible inhibitor directed against EGFR only. Although afatinib has been shown to be effective in the treatment for erlotinib-refractory and/or gefitinib-refractory central nervous system metastases from NSCLC, little is known about the efficacy of erlotinib for afatinib-refractory central nervous system metastases. In the present report we describe a case of EGFR mutation-positive NSCLC in which brain metastases developed during first-line afatinib treatment. Whole-brain radiation therapy and substitution of erlotinib for afatinib led to successful shrinkage of the brain metastases. Our report highlights the potential benefit of erlotinib for the management of brain metastases refractory over afatinib in patients with NSCLC.
  • Kazuo Nakagawa; Kohei Yokoi; Jun Nakajima; Fumihiro Tanaka; Yoshimasa Maniwa; Makoto Suzuki; Takeshi Nagayasu; Hisao Asamura
    ANNALS OF THORACIC SURGERY 101 2 520 - 526 2016年02月 [査読有り]
     
    Background. The optimal mode of resection for thymoma in nonmyasthenic patients remains unclear. The aim of this study was to explore whether or not thymomectomy alone is a relevant option for patients with stage I (T1N0M0) thymoma in the proposed TNM classification. Methods. We investigated 2,835 patients with thymic epithelial tumors treated at 32 institutions participating in the Japanese Association for Research on the Thymus (JART). A total of 1286 patients with thymomectomy: resection of thymoma with partial thymectomy (n = 289) or thymothymomectomy: resection of thymoma with total thymectomy (n = 997) for stage I thymoma were included. Surgical and oncologic outcomes were compared between the 2 groups. Results. Patients who underwent thymomectomy were older (61.1 versus 57.0 years; p = 0.000) and had smaller tumors (4.77 versus 5.99 cm; p = 0.000) than those who underwent thymothymomectomy. There was a significant difference in the distribution of histologic subtype (p = 0.007). After propensity-score matching, the matched cohort consisted of 276 patients in each group. Postoperative complications were seen more frequently in the thymothymomectomy group than in the thymomectomy group (8.3% versus 4.3%; p = 0.0397). The 5-year overall survival rate was 97.3% in the thymomectomy group and 96.9% in the thymothymomectomy group (p = 0.487). Patients who underwent thymomectomy tended to have local recurrence more frequently than did those who underwent thymothymomectomy (2.2% versus 0.4%; p = 0.0613). Conclusions. Thymomectomy alone is acceptable for stage I thymoma in regard to postoperative complications and prognosis. Further studies are needed to evaluate long-term outcomes. (C) 2016 by The Society of Thoracic Surgeons
  • K. Yonesaka; K. Hirotani; H. Kawakami; M. Takeda; H. Kaneda; K. Sakai; I. Okamoto; K. Nishio; P. A. Jaenne; K. Nakagawa
    ONCOGENE 35 7 878 - 886 2016年02月 [査読有り]
     
    Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
  • Hideki Takeuchi; Toshiaki Saeki; Keisuke Aiba; Kazuo Tamura; Kenjiro Aogi; Kenji Eguchi; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Makoto Wada; Tatsuo Akechi; Yasuhiro Udagawa; Yutaka Okawa; Yusuke Onozawa; Hidenori Sasaki; Yasuo Shima; Naohito Shimoyama; Masayuki Takeda; Toshihiko Nishidate; Akifumi Yamamoto; Tadashi Ikeda; Koichi Hirata
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 21 1 1 - 12 2016年02月 [査読有り]
     
    The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT(3)) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT(3) receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT(3) receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.
  • Hideki Takeuchi; Toshiaki Saeki; Keisuke Aiba; Kazuo Tamura; Kenjiro Aogi; Kenji Eguchi; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Makoto Wada; Tatsuo Akechi; Yasuhiro Udagawa; Yutaka Okawa; Yusuke Onozawa; Hidenori Sasaki; Yasuo Shima; Naohito Shimoyama; Masayuki Takeda; Toshihiko Nishidate; Akifumi Yamamoto; Tadashi Ikeda; Koichi Hirata
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 21 1 1 - 12 2016年02月 [査読有り]
     
    The purpose of this article is to disseminate the standard of antiemetic therapy for Japanese clinical oncologists. On the basis of the Appraisal of Guidelines for Research and Evaluation II instrument, which reflects evidence-based clinical practice guidelines, a working group of the Japanese Society of Clinical Oncology (JSCO) reviewed clinical practice guidelines for antiemesis and performed a systematic review of evidence-based domestic practice guidelines for antiemetic therapy in Japan. In addition, because health-insurance systems in Japan are different from those in other countries, a consensus was reached regarding standard treatments for chemotherapy that induce nausea and vomiting. Current evidence was collected by use of MEDLINE, from materials from meetings of the American Society of Clinical Oncology National Comprehensive Cancer Network, and from European Society of Medical Oncology/Multinational Association of Supportive Care in Cancer guidelines for antiemesis. Initially, 21 clinical questions (CQ) were selected on the basis of CQs from other guidelines. Patients treated with highly emetic agents should receive a serotonin (5-hydroxytryptamine; 5HT(3)) receptor antagonist, dexamethasone, and a neurokinin 1 receptor antagonist. For patients with moderate emetic risk, 5HT(3) receptor antagonists and dexamethasone were recommended, whereas for those receiving chemotherapy with low emetic risk dexamethasone only is recommended. Patients receiving high-emetic-risk radiation therapy should also receive a 5HT(3) receptor antagonist. In this paper the 2010 JSCO clinical practice guidelines for antiemesis are presented in English; they reveal high concordance of Japanese medical circumstances with other antiemetic guidelines that are similarly based on evidence.
  • K. Takeuchi; Y. Togashi; Y. Kamihara; T. Fukuyama; H. Yoshioka; A. Inoue; H. Katsuki; K. Kiura; K. Nakagawa; T. Seto; M. Maemondo; T. Hida; M. Harada; Y. Ohe; N. Nogami; N. Yamamoto; M. Nishio; T. Tamura
    ANNALS OF ONCOLOGY 27 1 185 - 192 2016年01月 [査読有り]
     
    Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated. In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore. ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity. Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection. JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
  • K. Haratani; H. Hayashi; S. Watanabe; H. Kaneda; T. Yoshida; M. Takeda; T. Shimizu; K. Nakagawa
    ANNALS OF ONCOLOGY 27 1 200 - 202 2016年01月 [査読有り]
  • Report of two cases of pseudoprogression in patients with non-small cell lung cancer treated with nivolumab-including histological analysis of one case after tumor regression.
    Tanizaki J; Hayashi H; Kimura M; Tanaka K; Takeda M; Shimizu S; Ito A; Nakagawa K
    Lung Cancer. 102 44 - 48 2016年 [査読有り]
  • Treatment Rationale and Study Design for the RELAY Study: A Multicenter, Randomized, Double-Blind Study of Erlotinib With Ramucirumab or Placebo in Patients With Epidermal Growth Factor Receptor Mutation-Positive Metastatic Non-Small-Cell Lung Cancer.
    Garon EB; Reck M; Paz-Ares L; Ponce S; Jaime JC; Juan O; Nadal E, Lee P; Dalal R; Liu J; He S; Treat J; Nakagawa K
    Clin Lung Cancer. 16 30 139 - 405 2016年 [査読有り]
  • Current evidence in support of the second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor alectinib for the treatment of non-small cell lung cancer positive for ALK translocation.
    Hayashi H; Nakagawa K
    J Thorac Dis. 8 10 E1311 - E1316 2016年 [査読有り]
  • Clinical outcome of node-negative oligometastatic non-small cell lung cancer.
    Sakai K; Takeda M; Hayashi H; Tanaka K; Okuda T; Kato A; Nishimura Y; Mitsudomi T; Koyama A; Nakagawa K
    Thorac Cancer. 7 6 670 - 675 2016年 [査読有り]
  • Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib.
    Watanabe S; Hayashi H; Okamoto K; Fujiwara K; Hasegawa Y; Kaneda H; Tanaka K; Takeda M; Nakagawa K
    Clin Lung Cancer. 17 6 528 - 534 2016年 [査読有り]
  • Is afatinib a treatment option for brain metastases in patients with EGFR mutation-positive non-small cell lung cancer?
    Watanabe S; Hayashi H; Nakagawa K
    Ann Transl Med. 4 11 225  2016年 [査読有り]
  • Successful human epidermal growth receptor 2-targeted therapy beyond disease progression for extramammary Paget's disease.
    Watanabe S; Takeda M; Takahama T; Iwasa T; Tsurutani J; Tanizaki J; Shimizu T; Sakai K; Wada Y; Isogai N; Nishio K; Nakagawa K
    Invest New Drugs. 34 3 394 - 396 2016年 [査読有り]
  • Naoki Takegawa; Kimio Yonesaka; Kazuko Sakai; Hiroto Ueda; Satomi Watanabe; Yoshikane Nonagase; Tatsuya Okuno; Masayuki Takeda; Osamu Maenishi; Junji Tsurutani; Taroh Satoh; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ONCOTARGET 7 3 3443 - 3450 2016年01月 [査読有り]
     
    Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.
  • Motohiro Tamiya; Akihiro Tamiya; Hiroyasu Kaneda; Kazuhiko Nakagawa; Kiyotaka Yoh; Koichi Goto; Hiroaki Okamoto; Tsuneo Shimokawa; Tetsuya Abe; Hiroshi Tanaka; Haruko Daga; Koji Takeda; Tomonori Hirashima; Shinji Atagi
    MEDICAL ONCOLOGY 33 1 2  2016年01月 [査読有り]
     
    A phase I study recommended carboplatin (CBDCA, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m(2)) for elderly patients (>= 75-years old) with non-squamous non-small cell lung cancer (NSCLC). PEM maintenance therapy was well tolerated. We conducted a multicenter phase II trial to evaluate the efficacy and safety of this regimen in elderly patients with NSCLC. Four courses of CBDCA plus PEM, followed by PEM, were administered. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression-free survival (PFS), response rate (RR), and safety. Thirty-four patients (median age, 77 years) were enrolled between June 2012 and May 2013. The median observation time was 22.7 months. The primary endpoint of the 1-year OS rate was 58.0 % (95 % confidence interval (CI) 42.9-78.4 %), and RR and disease control rate were 41.2 and 85.3 %, respectively. Fourteen patients had partial responses, 15 had stable disease, 4 had disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8 %. The median PFS was 5.7 months (95 % CI 3.9-8.9 months), and median OS was 20.5 months (95 % CI 10.0-infinity months). Grade >= 3 hematological adverse events included leucopenia (23.5 % of patients), neutropenia (55.9 %), anemia (35.3 %), and thrombocytopenia (20.6 %). Grade >= 3 non-hematological adverse events included febrile neutropenia (8.8 %), elevated aminotransferases (5.9 %), infection (23.5 %), and anorexia/fatigue (5.9 %). Four patients had interstitial lung diseases (ILD) and one died due to ILD. CBDCA plus PEM, followed by PEM, was effective and reasonably tolerated in chemotherapy-naive elderly patients with non-squamous NSCLC.
  • Motohiro Tamiya; Akihiro Tamiya; Hiroyasu Kaneda; Kazuhiko Nakagawa; Kiyotaka Yoh; Koichi Goto; Hiroaki Okamoto; Tsuneo Shimokawa; Tetsuya Abe; Hiroshi Tanaka; Haruko Daga; Koji Takeda; Tomonori Hirashima; Shinji Atagi
    MEDICAL ONCOLOGY 33 1 2  2016年01月 [査読有り]
     
    A phase I study recommended carboplatin (CBDCA, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m(2)) for elderly patients (>= 75-years old) with non-squamous non-small cell lung cancer (NSCLC). PEM maintenance therapy was well tolerated. We conducted a multicenter phase II trial to evaluate the efficacy and safety of this regimen in elderly patients with NSCLC. Four courses of CBDCA plus PEM, followed by PEM, were administered. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression-free survival (PFS), response rate (RR), and safety. Thirty-four patients (median age, 77 years) were enrolled between June 2012 and May 2013. The median observation time was 22.7 months. The primary endpoint of the 1-year OS rate was 58.0 % (95 % confidence interval (CI) 42.9-78.4 %), and RR and disease control rate were 41.2 and 85.3 %, respectively. Fourteen patients had partial responses, 15 had stable disease, 4 had disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8 %. The median PFS was 5.7 months (95 % CI 3.9-8.9 months), and median OS was 20.5 months (95 % CI 10.0-infinity months). Grade >= 3 hematological adverse events included leucopenia (23.5 % of patients), neutropenia (55.9 %), anemia (35.3 %), and thrombocytopenia (20.6 %). Grade >= 3 non-hematological adverse events included febrile neutropenia (8.8 %), elevated aminotransferases (5.9 %), infection (23.5 %), and anorexia/fatigue (5.9 %). Four patients had interstitial lung diseases (ILD) and one died due to ILD. CBDCA plus PEM, followed by PEM, was effective and reasonably tolerated in chemotherapy-naive elderly patients with non-squamous NSCLC.
  • Naoki Takegawa; Kimio Yonesaka; Kazuko Sakai; Hiroto Ueda; Satomi Watanabe; Yoshikane Nonagase; Tatsuya Okuno; Masayuki Takeda; Osamu Maenishi; Junji Tsurutani; Taroh Satoh; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ONCOTARGET 7 3 3443 - 3450 2016年01月 [査読有り]
     
    Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy. Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy. Conclusion: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.
  • Koichi Azuma; Tomonori Hirashima; Nobuyuki Yamamoto; Isamu Okamoto; Toshiaki Takahashi; Makoto Nishio; Taizo Hirata; Kaoru Kubota; Kazuo Kasahara; Toyoaki Hida; Hiroshige Yoshioka; Kaoru Nakanishi; Shiro Akinaga; Kazuto Nishio; Tetsuya Mitsudomi; Kazuhiko Nakagawa
    ESMO open 1 4 e000063  2016年 [査読有り]
     
    BACKGROUND: Patients with epidermal growth factor receptor (EGFR) activation mutation-positive non-small-cell lung cancer (NSCLC) respond well to EGFR tyrosine kinase inhibitors (EGFR-TKIs), but eventually become resistant in most cases. The hepatocyte growth factor/c-Met (HGF/c-Met) pathway is reported as a poor prognostic factor in various cancers. As c-Met is involved in EGFR-TKI resistance, a c-Met inhibitor and EGFR-TKI combination may reverse the resistance. This study evaluated the efficacy and safety of a c-Met selective inhibitor, tivantinib (ARQ 197), in combination with erlotinib, in Japanese EGFR mutation-positive patients with NSCLC who progressed while on EGFR-TKIs. METHODS: This study enrolled 45 patients with NSCLC with acquired resistance to EGFR-TKIs, who were orally administered a daily combination of tivantinib/erlotinib. The primary end point was the overall response rate (ORR) and secondary end points included disease control rate, progression-free survival (PFS) and overall survival (OS). The patients underwent a mandatory second biopsy just after progression on EGFR-TKIs. The predictive biomarkers were extensively analysed using tumour and blood samples. RESULTS: The ORR was 6.7% (95% CI 1.4% to 18.3%), and the lower limit of 95% CI did not exceed the target of 5%. The median PFS (mPFS) and median OS (mOS) were 2.7 months (95% CI 1.4 to 4.2) and 18.0 months (95% CI 13.4 to 22.2), respectively. Both were longer in c-Met high patients (c-Met high vs low: mPFS 4.1 vs 1.4 months; mOS 20.7 vs 13.9 months). Partial response was observed in three patients, all of whom were c-Met and HGF high. The common adverse events and their frequencies were similar to those known to occur with tivantinib or erlotinib alone. CONCLUSIONS: Although this study did not prove clinical benefit of tivantinib in patients with acquired resistance to EGFR-TKIs, activated HGF/c-Met signalling, a poor prognostic factor, may define a patient subset associated with longer survival by the tivantinib/erlotinib combination. TRIAL REGISTRATION NUMBER: NCT01580735.
  • Nishio M; Hida T; Atagi S; Sakai H; Nakagawa K; Takahashi T; Nogami N; Saka H; Takenoyama M; Maemondo M; Ohe Y; Nokihara H; Hirashima T; Tanaka H; Fujita S; Takeda K; Goto K; Satouchi M; Isobe H; Minato K; Sumiyoshi N; Tamura T
    ESMO open 1 4 e000108  2016年 [査読有り]
     
    OBJECTIVE: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC. METHODS: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3 mg/kg, intravenously every 2 weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety. RESULTS: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8 months (95% CI 1.4 to 3.4) and 17.1 months (95% CI 13.3 to 23.0), respectively. The OS rate at 1 year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab. CONCLUSIONS: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression. TRIAL REGISTRATION NUMBER: JapicCTI-132073.
  • Shinichiro Ryuge; Noriyuki Masuda; Nobuyuki Yamamoto; Toshiaki Takahashi; Haruyasu Murakami; Koji Takeda; Haruko Daga; Kimio Yonesaka; Hiroshi Tsukuda; Kazuhiko Nakagawa; Kaoru Tanaka; Katsuyuki Kiura; Nagio Takigawa; Toyoaki Hida; Takashi Seto; Masanori Yokoba; Shinzoh Kudoh; Takeshi Takagaki; Kazushige Shono; Hideo Kitagawa; Takeshi Kurihara; Masahiro Fukuoka
    Cancer Treatment and Research Communications 9 81 - 87 2016年 [査読有り]
     
    Objective The pharmacokinetics of amrubicin in patients with impaired hepatic function have not been reported. The aim of this study was to compare the pharmacokinetics of amrubicin and its major metabolite, amrubicinol, and to assess the safety of amrubicin in lung cancer patients with impaired hepatic function and those with normal hepatic function. Materials and methods Five patients with impaired hepatic function (arm I) and 10 patients with normal hepatic function (arm N) with small or non-small cell lung carcinoma were enrolled. Liquid chromatography with tandem mass spectrometry was used to determine the amrubicin and amrubicinol concentrations. Pharmacokinetic parameters were estimated by non-compartmental analysis. Results The terminal half-lives of amrubicin and amrubicinol in whole blood and plasma were slightly longer in arm I than in arm N. The area under the concentration–time curve (AUC0–24h) values of amrubicin in plasma and AUC0–120h of amrubicinol in whole blood in arm I were not larger than those in arm N because of dose adjustments based on prior treatment history and baseline values of total bilirubin, aspartate aminotransferase and alanine aminotransferase. The dose-normalized AUCs (dose 40 mg/m2) of amrubicin and amrubicinol in arm I were slightly larger than those in arm N. There were two deaths in arm I, one related to disease progression and one from an unknown cause. Conclusion If an adjusted dose of amrubicin is used in patients with impaired hepatic function, the exposure of amrubicin and amrubicinol would be within the range of variation observed in patients with normal hepatic function.
  • Succsessful osimertinib treatment for leptomeningeal carcinomatosis from lung adenocarcinoma with the T790M mutation of EGFR.
    Hitomi Sakai; Hidetoshi Hayashi; Tsutomu Iwasa; Yoshikazu Hasegawa; Masayuki Takeda; Kazuhiko Nakagawa
    ESMO Open. 1 - 4 2016年 [査読有り]
  • The Efficacy and Safety of Sterile Graded Talc in Pleurodesis for Malignant Pleural Effusion:Phase II study
    Hideo Saka; Masahide Oki; Chiyoe Kitagawa; Yoshihito Kogure; Yuki Kojima; Akiko M. Siato; Atsuko Ishida; Terunao Miyazawa; Koji Takeda; Kazuhiko Nakagawa; Shinji Sasada; Shunishi Negoro
    Journal of Clinical Trials 6 6 279 - 281 2016年 [査読有り]
  • Takayuki Takahama; Masayuki Takeda; Shinichi Nishina; Kazuhiko Nakagawa
    BMC Research Notes 8 1 100  2015年12月 [査読有り]
     
    Background: Trastuzumab∈+∈chemotherapy is considered the standard therapy for advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer with mild manageable toxicity, on the basis of the results of a pivotal phase-III trial. Cerebrovascular events are not recognized as expected adverse effects of such therapy. Case presentation: We report the case of a 67-year-old, current-smoking male with stage-IV HER2-positive gastric cancer who suffered right middle cerebral artery (MCA) embolism after trastuzumab∈+∈chemotherapy. He received trastuzumab and cisplatin on Day 1, followed by a continuous 5-fluorouracil infusion for 5 days as a first-line treatment. Four days after chemotherapy initiation, he presented with left hemiplegia, and brain magnetic resonance imaging and magnetic resonance angiography revealed a right MCA occlusion. No further chemotherapy was administered because of worsening performance status. Conclusion: The present case, possibly the first such reported case, suggests the risk of development of embolism after trastuzumab∈+∈chemotherapy in HER2-positive advanced gastric cancer, although other factors should be considered.
  • M. Takeda; K. Sakai; M. Terashima; H. Kaneda; H. Hayashi; K. Tanaka; K. Okamoto; T. Takahama; T. Yoshida; T. Iwasa; T. Shimizu; Y. Nonagase; K. Kudo; S. Tomida; T. Mitsudomi; K. Saigo; A. Ito; K. Nakagawa; K. Nishio
    ANNALS OF ONCOLOGY 26 12 2477 - 2482 2015年12月 [査読有り]
     
    The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. Multiplex genomic testing can assist physicians in matching patients with approved or experimental targeted treatments. Background: The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer. Patients and methods: We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS). Results: Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027). Conclusions: Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of >= 95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments. Clinical trial registration: The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.
  • Haruko Daga; Koji Takeda; Hideaki Okada; Masaki Miyazaki; Shinya Ueda; Hiroyasu Kaneda; Isamu Okamoto; Kiyotaka Yoh; Koichi Goto; Koichi Konishi; Akiko Sarashina; Tetsuya Tanaka; Rolf Kaiser; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 6 1225 - 1233 2015年12月 [査読有り]
     
    This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After a parts per thousand yen4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was < 33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade a parts per thousand yen3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.
  • Takehito Shukuya; Takeharu Yamanaka; Takashi Seto; Haruko Daga; Koichi Goto; Hideo Saka; Shunichi Sugawara; Toshiaki Takahashi; Soichiro Yokota; Hiroyasu Kaneda; Tomoya Kawaguchi; Seisuke Nagase; Tetsuya Oguri; Yasuo Iwamoto; Takashi Nishimura; Yoshihiro Hattori; Kazuhiko Nakagawa; Yoichi Nakanishi; Nobuyuki Yamamoto
    LANCET ONCOLOGY 16 16 1630 - 1638 2015年12月 [査読有り]
     
    Background The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. Methods We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1: 1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. Findings Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13.6 months, 95% CI 11.6-15.6) than in the cisplatin group (11.4 months, 10.2-12.2; hazard ratio 0.81, 95% CI 0.65-1.02; p=0.037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. Interpretation Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.
  • Yasuo Iwamoto; Tetsuya Mitsudomi; Kazuko Sakai; Takeharu Yamanaka; Hiroshige Yoshioka; Makoto Takahama; Masahiro Yoshimura; Ichiro Yoshino; Masayuki Takeda; Shunichi Sugawara; Tomoya Kawaguchi; Toshiaki Takahashi; Mitsunori Ohta; Yukito Ichinose; Shinji Atagi; Morihito Okada; Hideo Saka; Kazuhiko Nakagawa; Yoichi Nakanishi; Kazuto Nishio
    CLINICAL CANCER RESEARCH 21 23 5245 - 5252 2015年12月 [査読有り]
     
    Purpose: The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. Experimental Design: A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m2) on day 1 plus oral S-1 (40 mg/m2 twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. Results: The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7-67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. Conclusions: Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy. (C) 2015 AACR.
  • Yasuo Iwamoto; Tetsuya Mitsudomi; Kazuko Sakai; Takeharu Yamanaka; Hiroshige Yoshioka; Makoto Takahama; Masahiro Yoshimura; Ichiro Yoshino; Masayuki Takeda; Shunichi Sugawara; Tomoya Kawaguchi; Toshiaki Takahashi; Mitsunori Ohta; Yukito Ichinose; Shinji Atagi; Morihito Okada; Hideo Saka; Kazuhiko Nakagawa; Yoichi Nakanishi; Kazuto Nishio
    CLINICAL CANCER RESEARCH 21 23 5245 - 5252 2015年12月 [査読有り]
     
    Purpose: The aims of this study were to evaluate the efficacy and safety of S-1 versus cisplatin (CDDP)+S-1 in patients with completely resected stage II and IIIA non-small cell lung cancer, and to identify predictive biomarkers whose expression in the tumors was significantly associated with patient outcome. Experimental Design: A total of 200 patients were randomly assigned to receive either S-1 (40 mg/m(2) twice per day) for 2 consecutive weeks repeated every 3 weeks for 1 year (S group) or CDDP (60 mg/m2) on day 1 plus oral S-1 (40 mg/m2 twice per day) for 2 consecutive weeks repeated every 3 weeks for four cycles (CS group) within 8 weeks after surgery. The primary endpoints were relapse-free survival (RFS) at 2 years and identification of predictive biomarkers whose expressions have been reported to be associated with CDDP or fluoropyrimidine sensitivity. Results: The RFS rate at 2 years was 65.6% (95% confidence intervals; CI, 55.3-74.0%) in the S group and 58.1% (95% CI, 47.7-67.2%) in the CS group. The only gene with interaction of P < 0.05 was uridine monophosphate synthase (UMPS; P = 0.0348). The benefit that members of the S group had over members of the CS group was higher expression of UMPS. In vitro and in vivo experiments confirmed that overexpression of UMPS enhanced the antitumor effect of fluoropyrimidine. Conclusions: Adjuvant S-1 monotherapy might be preferable to CDDP+S-1 for patients with completely resected NSCLC. UMPS expression may define a patient subset that would benefit from long-term postoperative S-1 monotherapy. (C) 2015 AACR.
  • Takehito Shukuya; Takeharu Yamanaka; Takashi Seto; Haruko Daga; Koichi Goto; Hideo Saka; Shunichi Sugawara; Toshiaki Takahashi; Soichiro Yokota; Hiroyasu Kaneda; Tomoya Kawaguchi; Seisuke Nagase; Tetsuya Oguri; Yasuo Iwamoto; Takashi Nishimura; Yoshihiro Hattori; Kazuhiko Nakagawa; Yoichi Nakanishi; Nobuyuki Yamamoto
    LANCET ONCOLOGY 16 16 1630 - 1638 2015年12月 [査読有り]
     
    Background The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1-2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. Methods We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20-74 years, Eastern Cooperative Oncology Group performance status of 0-1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1: 1) to 100 mg/m(2) nedaplatin and 60 mg/m(2) docetaxel intravenously, or 80 mg/m(2) cisplatin and 60 mg/m(2) docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. Findings Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13.6 months, 95% CI 11.6-15.6) than in the cisplatin group (11.4 months, 10.2-12.2; hazard ratio 0.81, 95% CI 0.65-1.02; p=0.037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. Interpretation Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer.
  • Haruko Daga; Koji Takeda; Hideaki Okada; Masaki Miyazaki; Shinya Ueda; Hiroyasu Kaneda; Isamu Okamoto; Kiyotaka Yoh; Koichi Goto; Koichi Konishi; Akiko Sarashina; Tetsuya Tanaka; Rolf Kaiser; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 6 1225 - 1233 2015年12月 [査読有り]
     
    This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy. A fixed dose of pemetrexed (500 mg/m(2) iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2-21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After a parts per thousand yen4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was < 33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade a parts per thousand yen3 non-hematologic or grade 4 hematologic AEs. Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease. Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid. Clinical trial information NCT00979576.
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    Therapeutics and Clinical Risk Management 11 1701 - 1706 2015年11月 [査読有り]
     
    Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. Several angiogenesis inhibitors have been developed as potential therapies for non-small-cell lung cancer (NSCLC). Nintedanib is a small-molecule tyrosine kinase inhibitor that targets receptors for vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor as well as RET (rearranged during transfection) and Flt3. When administered as monotherapy, nintedanib was well tolerated at doses up to 250 mg or 200 mg twice daily in European and Japanese patients, respectively, with liver toxicity featuring prominently among dose-limiting toxicities in both populations. A recent Phase III trial demonstrated that treatment with the combination of nintedanib and docetaxel resulted in a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with docetaxel alone in predefined NSCLC patients with adenocarcinoma tumor histology. Although the incidence of elevated alanine aminotransferase or aspartate aminotransferase as well as of diarrhea was higher in patients treated with nintedanib plus docetaxel, most of these adverse events were manageable with supportive treatment or dose reduction. The results of completed and ongoing clinical trials of nintedanib monotherapy and combination therapy for the treatment of NSCLC are summarized in this study.
  • Shodai Kawano; Junichi Maruyama; Shunta Nagashima; Kazutoshi Inami; Wenzhe Qiu; Hiroaki Iwasa; Kentaro Nakagawa; Mari Ishigami-Yuasa; Hiroyuki Kagechika; Hiroshi Nishina; Yutaka Hata
    JOURNAL OF BIOCHEMISTRY 158 5 413 - 423 2015年11月 [査読有り]
     
    Transcriptional co-activator with PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif (TAZ) regulates in cell proliferation and differentiation. In mesenchymal stem cells it promotes osteogenesis and myogenesis, and suppresses adipogenesis. TAZ activators are expected to prevent osteoporosis, obesity and muscle atrophy. TAZ activation induces epithelial-mesenchymal transition, confers stemness to cancer cells and leads to poor clinical prognosis in cancer patients. In this point of view, TAZ inhibitors should contribute to cancer therapy. Thus, TAZ attracts attention as a two-faced drug target. We screened for TAZ modulators by using human lung cancer A549 cells expressing the fluorescent reporter. Through this assay, we obtained TAZ activator candidates. We unexpectedly found that ethacridine, a widely used antiseptic and abortifacient, enhances the interaction of TAZ and protein phosphatases and increases unphosphorylated and nuclear TAZ. Ethacridine inhibits adipogenesis in mesenchymal C3H10T1/2 cells through the activation of TAZ. This finding suggests that ethacridine is a bona fide TAZ activator and supports that our assay is useful to discover TAZ activators.
  • 日本発の抗悪性腫瘍薬をいち早く患者へ届けるには アジアの中の日本 これからの"日亜主導的"グローバルがん早期新薬開発
    清水 俊雄; Lin Chia-Chi Josh; 中川 和彦
    臨床薬理 46 Suppl. S83 - S84 (一社)日本臨床薬理学会 2015年11月
  • Masayuki Takeda; Kazuhiko Nakagawa
    Current Cancer Drug Targets 15 9 792 - 802 2015年11月 [査読有り]
     
    Dysregulation of epidermal growth factor receptor (EGFR) signaling due to receptor overexpression or activating mutation is associated with cancer cell proliferation, metastasis, and survival. EGFR has become an important therapeutic target for non–small cell lung cancer (NSCLC), and several EGFR-targeted agents, such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), have been developed. The EGFR-TKIs gefitinib, erlotinib, and afatinib have been approved for the treatment of advanced NSCLC, and sensitivity to these drugs has been shown to be associated with the presence of EGFR mutations. Various mAbs to EGFR have also been evaluated in preclinical and clinical studies. In particular, phase III trials have shown a clinically significant survival benefit for addition of the anti-EGFR mAbs cetuximab or necitumumab to a platinum doublet in chemotherapy-naïve patients with advanced NSCLC. We here summarize the results of completed and ongoing clinical trials of EGFR-targeted mAbs for the treatment of NSCLC.
  • Kimio Yonesaka; Naoki Takegawa; Taroh Satoh; Hiroto Ueda; Takeshi Yoshida; Masayuki Takeda; Toshio Shimizu; Yasutaka Chiba; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    PLOS ONE 10 11 e0143132  2015年11月 [査読有り]
     
    Background Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC. Methods Plasma levels of amphiregulin and heregulin were measured by enzyme-linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis. Results Overall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort. Conclusion A subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients.
  • 武田 晃司; 阿部 徹哉; 大江 裕一郎; 川口 知哉; 一瀬 幸人; 岡本 浩明; 山本 信之; 吉岡 弘鎮; 湊 浩一; 澤 祥幸; 岩本 康男; 坂 英雄; 水谷 友紀; 中村 慎一郎; 安藤 昌彦; 横山 晶; 中川 和彦; 西條 長宏; 田村 友秀
    肺癌 55 5 394 - 394 (NPO)日本肺癌学会 2015年10月
  • 安宅 信二; 西尾 誠人; 樋田 豊明; 中川 和彦; 酒井 洋; 野上 尚之; 高橋 利明; 軒原 浩; 坂 英雄; 竹之山 光広; 藤田 史郎; 田中 洋史; 武田 晃司; 里内 美弥子; 磯部 宏; 前門戸 任; 後藤 功一; 平島 智徳; 湊 浩一; 田村 友秀
    肺癌 55 5 392 - 392 (NPO)日本肺癌学会 2015年10月
  • 林 秀敏; 武田 真幸; 山中 竹春; 瀬戸 貴司; 岡田 守人; 東 公一; 菅原 俊一; 駄賀 晴子; 平島 智徳; 米阪 仁雄; 浦田 佳子; 村上 晴泰; 齋藤 春洋; 久保 昭仁; 澤 祥幸; 宮原 栄治; 野上 尚之; 中川 和彦; 中西 洋一; 岡本 勇
    肺癌 55 5 430 - 430 (NPO)日本肺癌学会 2015年10月
  • H. Yoshioka; K. Azuma; N. Yamamoto; T. Takahashi; M. Nishio; N. Katakami; M. J. Ahn; T. Hirashima; M. Maemondo; S. W. Kim; M. Kurosaki; S. Akinaga; K. Park; C. M. Tsai; T. Tamura; T. Mitsudomi; K. Nakagawa
    ANNALS OF ONCOLOGY 26 10 2066 - 2072 2015年10月 [査読有り]
     
    Background: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). Methods: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. Results: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade >= 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). Conclusions: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR.
  • Akiyoshi Kasuga; Kazuhiko Nakagawa; Fumio Nagashima; Toshio Shimizu; Daisuke Naruge; Shinichi Nishina; Hiroshi Kitamura; Takayasu Kurata; Atsuko Takasu; Yasuhito Fujisaka; Wataru Okamoto; Yuichiro Nishimura; Akihira Mukaiyama; Hideki Matsushita; Junji Furuse
    INVESTIGATIONAL NEW DRUGS 33 5 1058 - 1067 2015年10月 [査読有り]
     
    Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single- agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)
  • Akiyoshi Kasuga; Kazuhiko Nakagawa; Fumio Nagashima; Toshio Shimizu; Daisuke Naruge; Shinichi Nishina; Hiroshi Kitamura; Takayasu Kurata; Atsuko Takasu; Yasuhito Fujisaka; Wataru Okamoto; Yuichiro Nishimura; Akihira Mukaiyama; Hideki Matsushita; Junji Furuse
    INVESTIGATIONAL NEW DRUGS 33 5 1058 - 1067 2015年10月 [査読有り]
     
    Background Trametinib is an inhibitor of MEK1/MEK2 activation and kinase activity. In order to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of single- agent trametinib (part 1) and trametinib in combination with gemcitabine (part 2), we undertook the first clinical study of this combination in Japanese patients with cancer and herein report our results. Methods In part 1, 13 patients with advanced solid tumors were enrolled into 3 dose cohorts, receiving trametinib once daily at a dose of 1.0, 2.0, or 3.0 mg. In part 2, 5 patients with pancreatic cancer received trametinib (2.0 mg once daily) in combination with gemcitabine (1000 mg/m(2)). Results In part 1, a dose-limiting toxicity was observed in a patient in the 2.0-mg dose cohort, but the maximum tolerated dose was not reached at doses up to 3.0 mg daily. The best overall response was a PR in 1 patient, and 6 patients had SD. In part 2, the combination of trametinib and gemcitabine was tolerated for a short period of time. However, serious interstitial lung disease (ILD) was observed in 3 of 5 patients 4 weeks or more after the start of the treatment, including 1 fatal case. Three patients achieved a PR, and 2 patients had SD. The most common adverse event was rash (85 % in part 1 and 100 % in part 2). Conclusions Trametinib monotherapy was tolerable in Japanese patients with cancer. However, the combination of trametinib plus gemcitabine carried a higher risk as compared with monotherapy, during which no ILD was observed. (ClinicalTrials.gov number, NCT01324258.)
  • Kimio Yonesaka; Keita Kudo; Satomi Nishida; Takayuki Takahama; Tsutomu Iwasa; Takeshi Yoshida; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Isamu Okamoto; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOTARGET 6 32 33602 - 33611 2015年10月 [査読有り]
     
    Afatinib is a second generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) characterized as an irreversible pan-human EGFR (HER) family inhibitor. Afatinib remains effective for a subpopulation of patients with non-small cell lung cancer (NSCLC) with acquired resistance to first generation EGFF-TKIs such as erlotinib. Heregulin activates HER3 in an autocrine fashion and causes erlotinib resistance in NSCLC. Here we examine whether afatinib is effective against heregulin-overexpressing NSCLCs harboring EGFR activating mutations. Afatinib but not erlotinib decreased EGFR mutant NSCLC PC9HRG cell proliferation in vitro and in mouse xenografts. Afatinib inhibited phosphorylation of the cell signaling pathway proteins HER3, EGFR, HER2, and HER4, likely by prevention of trans-phosphorylation as HER3 kinase activity is inadequate for auto-phosphorylation. Afatinib, unlike erlotinib, inhibited AKT activation, resulting in elevated apoptosis in PC9HRG cells. Clinically, a subpopulation of 33 patients with EGFR mutations and NSCLC who had received first generation EGFR-TKIs exhibited elevated plasma heregulin levels compared to healthy volunteers; one of these achieved a response with afatinib therapy despite having previously developed erlotinib resistance. Afatinib can overcome heregulin-mediated resistance to erlotinib in EGFR mutant NSCLC. Further studies are necessary to determine whether heregulin can predict afatinib efficacy after development offirst generation EGFR-TKI resistance.
  • Masayuki Takeda; Kazuko Sakai; Masato Terashima; Hiroyasu Kaneda; Hidetoshi Hayashi; Kaoru Tanaka; Tsutomu Iwasa; Takeshi Yoshida; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 10 9 S700 - S701 2015年09月 [査読有り]
  • Junichi Shimizu; Takeshi Kodaira; Takashi Seto; Tomonari Sasaki; Takeharu Yamanaka; Naonobu Kunitake; Fumiyoshi Ohyanagi; Takuyo Kozuka; Masayuki Takeda; Kiyoshi Nakamatsu; Toshiaki Takahashi; Hideyuki Harada; Naruo Yoshimura; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Kazuhiko Nakagawa; Yasumasa Nishimura; Yoichi Nakanishi
    JOURNAL OF THORACIC ONCOLOGY 10 9 S286 - S286 2015年09月 [査読有り]
  • Manami Kodaka; Zeyu Yang; Kentaro Nakagawa; Junichi Maruyama; Xiaoyin Xu; Aradhan Sarkar; Ayana Ichimura; Yusuke Nasu; Takeaki Ozawa; Hiroaki Iwasa; Mari Ishigami-Yuasa; Shigeru Ito; Hiroyuki Kagechika; Yutaka Hata
    EXPERIMENTAL CELL RESEARCH 336 2 171 - 181 2015年08月 [査読有り]
     
    The development of the efficient screening system of detecting compounds that promote myogenesis and prevent muscle atrophy is important. Mouse C2C12 cells are widely used to evaluate myogenesis but the procedures of the assay are not simple and the quantification is not easy. We established C2C12 cells expressing the N-terminal green fluorescence protein (GFP) and the C-terminal GFP (GFP1-10 and GFP11 cells). GFP1-10 and GFP11 cells do not exhibit GFP signals until they are fused. The signal intensity correlates with the expression of myogenic markers and myofusion. Myogenesis-promoting reagents, such as insulin-like growth factor-1 (IGF1) and beta-guanidinopropionic acid (GPA), enhance the signals, whereas the poly-caspase inhibitor, z-VAD-FMK, suppresses it. GFP signals are observed when myotubes formed by GFP1-10 cells are fused with single nuclear GFP11 cells, and enhanced by IGF1, GPA, and 185008738, a recently-reported myogenesis-promoting reagent. Fusion between myotubes formed by GFP1-10 and GFP11 cells is associated with the appearance of GFP signals. IGF1 and CPA augment these signals, whereas NSC23766, Rac inhibitor, decreases them. The conditioned medium of cancer cells suppresses GFP signals during myogenesis and reduces the width of GFP-positive myotubes after differentiation. Thus the novel split GFP-based assay will provide the useful method for the study of myogenesis, myofusion, and atrophy. (C) 2015 Elsevier Inc. All rights reserved.
  • 清水 俊雄; 中川 和彦
    日本臨床 73 8 1342 - 1348 (株)日本臨床社 2015年08月
  • Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Masatomo Otsuka; Kazuhiko Nakagawa
    PALLIATIVE & SUPPORTIVE CARE 13 4 859 - 864 2015年08月 [査読有り]
     
    Objective: Delirium is a frequently encountered psychiatric disease in terminal cancer patients. However, the mechanism of delirium is unclear. The aim of our study was to investigate the relationship between administration of chemotherapy drugs that penetrate the blood-brain barrier (BBB) and the development of delirium in cancer patients. Method: We retrospectively analyzed 166 cancer patients (97 males, 69 females) continuously who died between September of 2007 and January of 2010 using a review of medical charts. Multiple logistic regression analysis was employed to investigate the effects of antineoplastic drugs penetrating the BBB on development of delirium in cancer patients with control for other risk factors. Results: In multivariate analysis, antineoplastic drugs that penetrated the BBB were significantly associated with development of delirium (OR = 18.92, CI95 = 1.08-333.04, p < 0.001). Significance of results: The use of chemotherapy drugs that penetrate the BBB may be a risk factor for delirium. This information may allow palliative care doctors and medical oncologists to predict which patients are at increased risk for delirium.
  • Jean-Charles Soria; Yi-Long Wu; Kazuhiko Nakagawa; Sang-We Kim; Jin-Ji Yang; Myung-Ju Ahn; Jie Wang; James Chih-Hsin Yang; You Lu; Shinji Atagi; Santiago Ponce; Dae Ho Lee; Yunpeng Liu; Kiyotaka Yoh; Jian-Ying Zhou; Xiaojin Shi; Alan Webster; Haiyi Jiang; Tony S. K. Mok
    LANCET ONCOLOGY 16 8 990 - 998 2015年08月 [査読有り]
     
    Background Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. Methods The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapynaive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1: 1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Findings Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0 . 86, 95% CI 0 . 65-1 . 13; p=0 . 27; median progression-free survival 5 . 4 months in both groups [95% CI 4 . 5-5 . 7 in the gefitinib group and 4 . 6-5 . 5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. Interpretation Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.
  • Shinya Ueda; Hisato Kawakami; Shinichi Nishina; Tsutomu Sakiyama; Yoshikane Nonagase; Takafumi Okabe; Takao Tamura; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 2 279 - 285 2015年08月 [査読有り]
     
    Purpose The aims of this dose-escalating phase I study were to determine the maximum tolerable dose (MTD) and recommended dose (RD) of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for future phase II studies, and to evaluate the safety and efficacy of this regimen in patients with untreated recurrent or metastatic esophageal cancer. Methods Patients were administered 5-FU on days 1-5, docetaxel on days 1 and 15, and nedaplatin on day 1 at 4-week intervals. The dose levels of 5-FU/docetaxel/nedaplatin were escalated as follows (mg/m(2)): level 1, 800/30/80; level 2, 800/30/90; and level 3, 800/35/90. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Results Overall, nine patients were enrolled in this study. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and were diagnosed with squamous cell carcinoma. No dose-limiting toxicity was observed at any level, and planned dose escalation was completed without reaching the MTD. No grade 4 or higher toxicity was observed in this study. The observed grade 3 hematological toxicities included neutropenia in five patients (55.6 %) and leukopenia in three patients (33.3 %). None of the patients developed febrile neutropenia, and no grade 3 or 4 non-hematological toxicities were observed. The overall response rate was 77.8 %, including two complete responses, and the disease control rate was 100 %. Conclusion The RD of UDON was identified as level 3. The good tolerability and high antitumor efficacy of this regimen warrant further evaluation in this setting.
  • Hiromichi Matsuoka; Kazuhiro Yoshiuchi; Atsuko Koyama; Masatomo Otsuka; Kazuhiko Nakagawa
    PALLIATIVE & SUPPORTIVE CARE 13 4 859 - 864 2015年08月 [査読有り]
     
    Objective: Delirium is a frequently encountered psychiatric disease in terminal cancer patients. However, the mechanism of delirium is unclear. The aim of our study was to investigate the relationship between administration of chemotherapy drugs that penetrate the blood-brain barrier (BBB) and the development of delirium in cancer patients. Method: We retrospectively analyzed 166 cancer patients (97 males, 69 females) continuously who died between September of 2007 and January of 2010 using a review of medical charts. Multiple logistic regression analysis was employed to investigate the effects of antineoplastic drugs penetrating the BBB on development of delirium in cancer patients with control for other risk factors. Results: In multivariate analysis, antineoplastic drugs that penetrated the BBB were significantly associated with development of delirium (OR = 18.92, CI95 = 1.08-333.04, p < 0.001). Significance of results: The use of chemotherapy drugs that penetrate the BBB may be a risk factor for delirium. This information may allow palliative care doctors and medical oncologists to predict which patients are at increased risk for delirium.
  • Shinya Ueda; Hisato Kawakami; Shinichi Nishina; Tsutomu Sakiyama; Yoshikane Nonagase; Takafumi Okabe; Takao Tamura; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 2 279 - 285 2015年08月 [査読有り]
     
    Purpose The aims of this dose-escalating phase I study were to determine the maximum tolerable dose (MTD) and recommended dose (RD) of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for future phase II studies, and to evaluate the safety and efficacy of this regimen in patients with untreated recurrent or metastatic esophageal cancer. Methods Patients were administered 5-FU on days 1-5, docetaxel on days 1 and 15, and nedaplatin on day 1 at 4-week intervals. The dose levels of 5-FU/docetaxel/nedaplatin were escalated as follows (mg/m(2)): level 1, 800/30/80; level 2, 800/30/90; and level 3, 800/35/90. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. Results Overall, nine patients were enrolled in this study. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and were diagnosed with squamous cell carcinoma. No dose-limiting toxicity was observed at any level, and planned dose escalation was completed without reaching the MTD. No grade 4 or higher toxicity was observed in this study. The observed grade 3 hematological toxicities included neutropenia in five patients (55.6 %) and leukopenia in three patients (33.3 %). None of the patients developed febrile neutropenia, and no grade 3 or 4 non-hematological toxicities were observed. The overall response rate was 77.8 %, including two complete responses, and the disease control rate was 100 %. Conclusion The RD of UDON was identified as level 3. The good tolerability and high antitumor efficacy of this regimen warrant further evaluation in this setting.
  • Jean-Charles Soria; Yi-Long Wu; Kazuhiko Nakagawa; Sang-We Kim; Jin-Ji Yang; Myung-Ju Ahn; Jie Wang; James Chih-Hsin Yang; You Lu; Shinji Atagi; Santiago Ponce; Dae Ho Lee; Yunpeng Liu; Kiyotaka Yoh; Jian-Ying Zhou; Xiaojin Shi; Alan Webster; Haiyi Jiang; Tony S. K. Mok
    LANCET ONCOLOGY 16 8 990 - 998 2015年08月 [査読有り]
     
    Background Optimum management strategies for patients with advanced non-small-cell lung cancer (NSCLC) with acquired resistance to EGFR tyrosine-kinase inhibitors are undefined. We aimed to assess the efficacy and safety of continuing gefitinib combined with chemotherapy versus chemotherapy alone in patients with EGFR-mutation-positive advanced NSCLC with acquired resistance to first-line gefitinib. Methods The randomised, phase 3, multicentre IMPRESS study was done in 71 centres in 11 countries in Europe and the Asia-Pacific region. Eligible patients were aged at least 18 years with histologically confirmed, chemotherapynaive, stage IIIB-IV EGFR-mutation-positive advanced NSCLC with previous disease control with first-line gefitinib and recent disease progression (Response Evaluation Criteria in Solid Tumors version 1.1). Participants were randomly assigned (1: 1) by central block randomisation to oral gefitinib 250 mg or placebo once daily in tablet form; randomisation did not include stratification factors. All patients also received the platinum-based doublet chemotherapy cisplatin 75 mg/m(2) plus pemetrexed 500 mg/m(2) on the first day of each cycle. After completion of a maximum of six chemotherapy cycles, patients continued their randomly assigned treatment until disease progression or another discontinuation criterion was met. All study investigators and participants were masked to treatment allocation. The primary endpoint was progression-free survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The study has completed enrolment, but patients are still in follow-up for overall survival. This trial is registered with ClinicalTrials.gov, number NCT01544179. Findings Between March 29, 2012, and Dec 20, 2013, 265 patients were randomly assigned: 133 to the gefitinib group and 132 to the placebo group. At the time of data cutoff (May 5, 2014), 98 (74%) patients had disease progression in the gefitinib group compared with 107 (81%) in the placebo group (hazard ratio 0 . 86, 95% CI 0 . 65-1 . 13; p=0 . 27; median progression-free survival 5 . 4 months in both groups [95% CI 4 . 5-5 . 7 in the gefitinib group and 4 . 6-5 . 5 in the placebo group]). The most common adverse events of any grade were nausea (85 [64%] of 132 patients in the gefitinib group and 81 [61%] of 132 patients in the placebo group) and decreased appetite (65 [49%] and 45 [34%]). The most common adverse events of grade 3 or worse were anaemia (11 [8%] of 132 patients in the gefitinib group and five [4%] of 132 patients in the placebo group) and neutropenia (nine [7%] and seven [5%]). 37 (28%) of 132 patients in the gefitinib group and 28 (21%) of 132 patients in the placebo group reported serious adverse events. Interpretation Continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival in patients who received platinum-based doublet chemotherapy as subsequent line of treatment. Platinum-based doublet chemotherapy remains the standard of care in this setting.
  • Shimizu T; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 73 8 1342 - 1348 2015年08月 [査読有り]
     
    Aberrant activation of the Wnt, Notch and Hedgehog pathways via mutations or ligand overexpression has been implicated in a large number of cancer types where they are involved in functions ranging from tumor initiation to cancer stem cell (CSC) maintenance and angiogenesis. Agents targeting each one of these three pathways have now reached clinical trials, and the first one of these, Vismodegib, a hedgehog pathway inhibitor, was approved in 2012 by US FDA for the treatment of advanced basal cell carcinoma. Development of agents that target critical steps in these pathways as novel signal transduction pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are being explored coupled with early phase I clinical studies.
  • 乳癌骨転移患者におけるゾレドロン酸治療に関する後ろ向きコホート研究
    田根 香織; 柳江 正嗣; 鶴谷 純司; 谷岡 真樹; 藤本 伸一郎; 藤原 季美子; 山添 譲; 千葉 康敬; 中川 和彦; 菰池 佳史; 高尾 信太郎
    日本乳癌学会総会プログラム抄録集 23回 358 - 358 (一社)日本乳癌学会 2015年07月
  • James Chin-Hsin Yang; Myung-Ju Ahn; Kazuhiko Nakagawa; Tomohide Tamura; Helen Barraclough; Sotaro Enatsu; Rebecca Cheng; Mauro Orlando
    CANCER RESEARCH AND TREATMENT 47 3 424 - 435 2015年07月 [査読有り]
     
    Purpose A recent phase III study (PARAMOUNT) demonstrated that pemetrexed continuation maintenance therapy is a new treatment paradigm for advanced nonsquamous non-small cell lung cancer (NSCLC). The majority of patients enrolled in PARAMOUNT were Caucasian (94%). We reviewed efficacy and safety data from two clinical trials, which enrolled East Asian (EA) patients, to supplement data from PARAMOUNT on pemetrexed continuation maintenance therapy in patients with nonsquamous NSCLC. Materials and Methods Study S110 was a phase II, multicenter, randomized, controlled, open-label trial in never-smoker, chemonaive, EA patients (n=31) with locally advanced or metastatic nonsquamous NSCLC (n=27). Study JMII was a multicenter, open-label, single-arm, post-marketing, clinical trial in Japanese patients (n=109) with advanced nonsquamous NSCLC. PARAMOUNT was a multicenter, randomized, double-blind, placebo-controlled trial in patients with advanced nonsquamous NSCLC. Results In EA patients with nonsquamous NSCLC, the median progression-free survival (PFS) for pemetrexed continuation maintenance therapy was 4.04 months (95% confidence interval [CI], 3.22 to 5.29 months) in study S110 and 3.9 months (95% CI, 3.2 to 5.2 months) in study JMII. The median PFS for pemetrexed continuation maintenance therapy in PARAMOUNT was 4.1 months (95% CI, 3.2 to 4.6 months). Pemetrexed continuation maintenance therapy in EA patients in studies S110 and JMII did not lead to any unexpected safety events, and was consistent with PARAMOUNT's safety profile. Conclusion The efficacy and safety data in the EA trials were similar to those in PARAMOUNT despite differences in patient populations and study designs. These data represent consistent evidence for pemetrexed continuation maintenance therapy in EA patients with advanced nonsquamous NSCLC.
  • James Chin-Hsin Yang; Myung-Ju Ahn; Kazuhiko Nakagawa; Tomohide Tamura; Helen Barraclough; Sotaro Enatsu; Rebecca Cheng; Mauro Orlando
    CANCER RESEARCH AND TREATMENT 47 3 424 - 435 2015年07月 [査読有り]
     
    Purpose A recent phase III study (PARAMOUNT) demonstrated that pemetrexed continuation maintenance therapy is a new treatment paradigm for advanced nonsquamous non-small cell lung cancer (NSCLC). The majority of patients enrolled in PARAMOUNT were Caucasian (94%). We reviewed efficacy and safety data from two clinical trials, which enrolled East Asian (EA) patients, to supplement data from PARAMOUNT on pemetrexed continuation maintenance therapy in patients with nonsquamous NSCLC. Materials and Methods Study S110 was a phase II, multicenter, randomized, controlled, open-label trial in never-smoker, chemonaive, EA patients (n=31) with locally advanced or metastatic nonsquamous NSCLC (n=27). Study JMII was a multicenter, open-label, single-arm, post-marketing, clinical trial in Japanese patients (n=109) with advanced nonsquamous NSCLC. PARAMOUNT was a multicenter, randomized, double-blind, placebo-controlled trial in patients with advanced nonsquamous NSCLC. Results In EA patients with nonsquamous NSCLC, the median progression-free survival (PFS) for pemetrexed continuation maintenance therapy was 4.04 months (95% confidence interval [CI], 3.22 to 5.29 months) in study S110 and 3.9 months (95% CI, 3.2 to 5.2 months) in study JMII. The median PFS for pemetrexed continuation maintenance therapy in PARAMOUNT was 4.1 months (95% CI, 3.2 to 4.6 months). Pemetrexed continuation maintenance therapy in EA patients in studies S110 and JMII did not lead to any unexpected safety events, and was consistent with PARAMOUNT's safety profile. Conclusion The efficacy and safety data in the EA trials were similar to those in PARAMOUNT despite differences in patient populations and study designs. These data represent consistent evidence for pemetrexed continuation maintenance therapy in EA patients with advanced nonsquamous NSCLC.
  • Junji Tsurutani; Katsumasa Kuroi; Tsutomu Iwasa; Masaki Miyazaki; Shinichi Nishina; Chihiro Makimura; Junko Tanizaki; Kunio Okamoto; Toshinari Yamashita; Tomoyuki Aruga; Takashi Shigekawa; Yoshifumi Komoike; Toshiaki Saeki; Kazuhiko Nakagawa
    CANCER SCIENCE 106 6 734 - 739 2015年06月 [査読有り]
     
    We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80mg/m(2)) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100mg/m(2)nab-paclitaxel on days 1, 8, and 15 with 80mg/m(2) S-1 daily for 14days, followed by 7days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.
  • Makoto Nishio; Atsushi Horiike; Haruyasu Murakami; Nobuyuki Yamamoto; Hiroyasu Kaneda; Kazuhiko Nakagawa; Hidehito Horinouchi; Masaki Nagashima; Masaru Sekiguchi; Tomohide Tamura
    LUNG CANCER 88 3 275 - 281 2015年06月 [査読有り]
     
    Objectives: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients and methods: This study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0-1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined. Results: Twenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0(22.0-133.0) days for the EGFR wild-type group (n = 9) and 107.0(74.0-224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues. Conclusion: Patritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Junji Tsurutani; Katsumasa Kuroi; Tsutomu Iwasa; Masaki Miyazaki; Shinichi Nishina; Chihiro Makimura; Junko Tanizaki; Kunio Okamoto; Toshinari Yamashita; Tomoyuki Aruga; Takashi Shigekawa; Yoshifumi Komoike; Toshiaki Saeki; Kazuhiko Nakagawa
    CANCER SCIENCE 106 6 734 - 739 2015年06月 [査読有り]
     
    We conducted a phase I study of a weekly nab-paclitaxel and S-1 combination therapy in patients with human epidermal growth factor receptor type 2-negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21days. Levels 1, 2a, 2b, and 3 were set depending on the S-1 dose (65 or 80mg/m(2)) and nab-paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose-limiting toxicity was observed in one patient at Level 3 (100mg/m(2)nab-paclitaxel on days 1, 8, and 15 with 80mg/m(2) S-1 daily for 14days, followed by 7days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3-4 treatment-related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression-free survival was 13.2 and 21.0months, respectively. The present results show the feasibility and potential for long-term administration of this combination therapy.
  • Makoto Nishio; Atsushi Horiike; Haruyasu Murakami; Nobuyuki Yamamoto; Hiroyasu Kaneda; Kazuhiko Nakagawa; Hidehito Horinouchi; Masaki Nagashima; Masaru Sekiguchi; Tomohide Tamura
    LUNG CANCER 88 3 275 - 281 2015年06月 [査読有り]
     
    Objectives: Human epidermal growth factor receptor 3 (HER3) is a key dimerization partner for HER family members and is associated with resistance to other HER family receptor-targeted therapeutics. This study evaluated the safety, tolerability, pharmacokinetics and efficacy of patritumab (U3-1287), a fully human anti-HER3 monoclonal antibody, in combination with erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with previously treated advanced non-small cell lung cancer (NSCLC). Patients and methods: This study enrolled patients with stage IIIB/IV NSCLC with Eastern Cooperative Oncology Group performance status 0-1, life expectancy >3 months and who had progressed after at least one prior course of chemotherapy (excluding erlotinib). This open-label study included two parts: dose escalation (Part 1) and dose expansion (Part 2). In Part 1, patients received intravenous patritumab 9 or 18 mg/kg every 3 weeks in addition to per-oral erlotinib 150 mg/day daily. In Part 2, patients received the recommended dose of patritumab as determined in Part 1. Adverse event rates, pharmacokinetics and tumor responses were determined. Results: Twenty-four Japanese patients received patritumab at 9 mg/kg (n = 3) or 18 mg/kg (n = 21), and erlotinib. No dose-limiting toxicities were reported, indicating the maximum-tolerated dose was not reached. The most frequent adverse events were gastrointestinal or skin toxicities, which were generally mild and manageable. Patritumab pharmacokinetics were similar to those reported in previous studies. The median progression-free survival (95% confidence interval) was 44.0(22.0-133.0) days for the EGFR wild-type group (n = 9) and 107.0(74.0-224.0) days for the EGFR-activating mutation group (n = 13). Evaluation of biomarkers by immunohistochemical analysis did not indicate a relationship between efficacy and HER3 expression in tumor tissues. Conclusion: Patritumab in combination with erlotinib was well tolerated and the efficacy of the combination was encouraging, especially in patients where prior gefitinib treatment failed. (C) 2015 The Authors. Published by Elsevier Ireland Ltd.
  • Hiroyuki Sakurai; Kazuo Nakagawa; Shun-ichi Watanabe; Hisao Asamura
    ANNALS OF THORACIC SURGERY 99 5 1731 - 1738 2015年05月 [査読有り]
     
    Background. Subcentimeter lung cancers are still rare, and their pathobiologic behavior and management have not yet been fully clarified. Methods. From 1993 through 2011, 291 patients with resected lung cancers 1.0 cm or less in diameter were studied regarding their clinicopathologic characteristics. According to appearance on high-resolution computed tomography (HRCT), the tumors were classified into four types: type 1 (n = 50), nonsolid ground-glass opacity (GGO) lesion; type 2 (n = 89), part-solid GGO lesion including 50% or more GGO within the lesion; type 3 (n = 62), part-solid GGO lesion including less than 50% GGO within the lesion, and type 4 (n = 90), solid lesion. Results. Although none of types 1 to 3 tumors had lymph node metastases, these were found in 10% of type 4 tumors. Recurrence was observed in 13 patients, almost all of whom had type 4 tumors. The lone exception was a patient with a type 3 tumor in whom local recurrence developed on a surgical staple line. The 5-year overall survival rates were 100% in type 1 and type 2, 98% in type 3, and 88% in type 4. Type 4 had a significantly worse prognosis than the other types. Conclusions. Subcentimeter lung cancers with a GGO component on HRCT (types 1 to 3) can be considered "early" lung cancers. In these cases, limited resection may be warranted to achieve a cure because they had no lymph node metastasis. By contrast, lobectomy should still be considered the standard operation of choice for type 4 tumors. (C) 2015 by The Society of Thoracic Surgeons
  • Yukio Hosomi; Kiyotaka Yoh; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Kaoru Tanaka; Toyoaki Hida; Hiroshige Yoshioka; Terufumi Kato; Koji Takeda; Makoto Nishio; Hiroshi Sakai; Makoto Maemondo; Mitsuhiro Takenoyama; Hiroshi Nokihara; Masumi Tatsumi; Takashi Nakamura; Sotaro Enatsu; Tomohide Tamura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 33 15 2015年05月 [査読有り]
  • Takashi Seto; Tomonari Sasaki; Takeharu Yamanaka; Naonobu Kunitake; Junichi Shimizu; Takeshi Kodaira; Makoto Nishio; Takuyo Kozuka; Toshiaki Takahashi; Hideyuki Harada; Naruo Yoshimura; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Kazuhiko Nakagawa; Yasumasa Nishimura; Yoichi Nakanishi
    JOURNAL OF CLINICAL ONCOLOGY 33 15 2015年05月 [査読有り]
  • Kazuko Sakai; Junji Tsurutani; Takeharu Yamanaka; Azusa Yoneshige; Akihiko Ito; Yosuke Togashi; Marco A. De Velasco; Masato Terashima; Yoshihiko Fujita; Shuta Tomida; Takao Tamura; Kazuhiko Nakagawa; Kazuto Nishio
    PLOS ONE 10 5 e0121891  2015年05月 [査読有り]
     
    Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (alpha = 2 x 10(-5)). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.
  • ALK陽性完全切除不能進行肺癌に対し化学療法および分子標的治療後にサルベージ手術を行った1例
    阪口 全宏; 須田 健一; 岩崎 拓也; 武本 智樹; 富沢 健二; 佐藤 克明; 水内 寛; 下治 正樹; 小林 祥久; 岡部 崇記; 金田 裕靖; 中川 和彦; 光冨 徹哉
    日本呼吸器外科学会雑誌 29 3 O2 - 4 (一社)日本呼吸器外科学会 2015年04月
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    LUNG CANCER 88 1 74 - 79 2015年04月 [査読有り]
     
    Objectives: Three epidermal growth factor receptor (EGER) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. Materials and methods: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Results: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade >= 3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade >= 3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade >= 3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Conclusion: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Yasuhito Fujisaka; Takayasu Kurata; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 33 2 380 - 388 2015年04月 [査読有り]
     
    Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
  • Yasuhito Fujisaka; Takayasu Kurata; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 33 2 380 - 388 2015年04月 [査読有り]
     
    Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5 %) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4 %) and pyrexia (23.5 %). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
  • Yosuke Togashi; Hidetoshi Hayashi; Kunio Okamoto; Soichi Fumita; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio
    LUNG CANCER 88 1 16 - 23 2015年04月 [査読有り]
     
    Background: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance. Materials and methods: PC-9 and 11-18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1 mu M nicotine for 3 months and were designated as PC-9/N and 11-18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib. Results: The PC-9/N and 11-18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment. Conclusions: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    LUNG CANCER 88 1 74 - 79 2015年04月 [査読有り]
     
    Objectives: Three epidermal growth factor receptor (EGER) tyrosine kinase inhibitors (TKIs) - afatinib, erlotinib, and gefitinib - are available for the treatment of patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Given the long-term exposure of such patients to EGFR-TKIs, the toxicological properties of these agents in these individuals may differ from those observed in unselected patients. We compared the frequencies of severe adverse events (AEs) among EGFR mutation-positive NSCLC patients treated with these three EGFR-TKIs. Materials and methods: We performed a pooled analysis of severe AEs according to the type of EGFR-TKI administered with the use of data extracted from prospective clinical trials that evaluated the clinical efficacy of gefitinib, erlotinib, or afatinib in NSCLC patients with EGFR mutations. Results: Twenty-one trials published between 2006 and 2014 and including 1468 patients were eligible for analysis. Patients in 13 trials (n = 457) received gefitinib, those in 5 trials (n = 513) received erlotinib, and those in 3 trials (n = 498) received afatinib. Rash and diarrhea of grade >= 3 were significantly more frequent with afatinib therapy than with erlotinib or gefitinib therapy. The frequency of interstitial lung disease (ILD) of grade >= 3 was low (0.6-2.2%) with all three EGFR-TKIs and did not differ significantly among them. Gefitinib was associated with a significantly higher frequency of hepatotoxicity of grade >= 3 compared with erlotinib or afatinib. The overall frequency of AEs leading to treatment withdrawal was 6.1% (83 of 1354 evaluable patients), with such AEs occurring significantly more often with afatinib or gefitinib than with erlotinib. The most common withdrawal AEs were skin toxicity, ILD, and hepatotoxicity. Conclusion: Such information on AEs should facilitate selection of the most appropriate EGFR-TKI for EGFR mutation-positive NSCLC patients with regard to mitigation of the risk for certain types of toxicity. (c) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Nanjo S; Nakagawa T; Takeuchi S; Kita K; Fukuda K; Nakada M; Uehara H; Nishihara H; Hara E; Uramoto H; Tanaka F; Yano S
    Cancer science 106 3 244 - 52 2015年03月 [査読有り]
     
    EML4-ALK lung cancer accounts for approximately 3-7% of non-small-cell lung cancer cases. To investigate the molecular mechanism underlying tumor progression and targeted drug sensitivity/resistance in EML4-ALK lung cancer, clinically relevant animal models are indispensable. In this study, we found that the lung adenocarcinoma cell line A925L expresses an EML4-ALK gene fusion (variant 5a, E2:A20) and is sensitive to the ALK inhibitors crizotinib and alectinib. We further established highly tumorigenic A925LPE3 cells, which also have the EML4-ALK gene fusion (variant 5a) and are sensitive to ALK inhibitors. By using A925LPE3 cells with luciferase gene transfection, we established in vivo imaging models for pleural carcinomatosis, bone metastasis, and brain metastasis, all of which are significant clinical concerns of advanced EML4-ALK lung cancer. Interestingly, crizotinib caused tumors to shrink in the pleural carcinomatosis model, but not in bone and brain metastasis models, whereas alectinib showed remarkable efficacy in all three models, indicative of the clinical efficacy of these ALK inhibitors. Our in vivo imaging models of multiple organ sites may provide useful resources to analyze further the pathogenesis of EML4-ALK lung cancer and its response and resistance to ALK inhibitors in various organ microenvironments.
  • Toshiaki Saeki; Kazuo Tamura; Keisuke Aiba; Kenjiro Aogi; Keiko Lino; Chiyo Imamura; Kenji Eguchi; Kenji Okita; Yoshikazu Kagami; Ryuhei Tanaka; Kazuhiko Nakagawa; Hirofumi Fujii; Narikazu Boku; Kazuo Matsuura; Makoto Wada; Tatsuo Akechi; Yuichi Kakudo; Yong-Il Kim; Hide-Nori Sasaki; Yasuo Shima; Masayuki Takeda; Eijiro Nagasaki; Toshihiko Nishidate; Mitsue Saito; Yukino Ashikaga; Yusuke Tanigawara; Koichi Hirata; Chikashi Ishioka; Masahiko Nishiyama
    Japanese Journal of Cancer and Chemotherapy 42 3 305 - 311 2015年03月 [査読有り]
     
    Background: Japan Society of Clinical Oncology published a guideline for anti-emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire. Material: Questionnaire analysis From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff for the anti-emetic guideline published by (JSCO). Results: Questionnaire 1,529 medical stuff responded to our questionnaire. 1,308 (85.5%) stuffs recognized JSCO guidelines, 586 (51%) had regard for guideline and 489 (42.6%) referred to the guideline. 899 (78.3%) changed their practice in clinic to recommended practice by the guideline. But 385 (33.5%) complained high medical cost of recommended anti-emetic therapy. Conclusions: Degree of recognition and penetration of our guideline for anti-emetic therapy were very high in Japan.
  • Nakagawa K
    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 104 3 449 - 455 2015年03月 [査読有り]
  • Kimio Yonesaka; Taroh Satoh; Shinya Ueda; Takeshi Yoshida; Masayuki Takeda; Toshio Shimizu; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ANTICANCER RESEARCH 35 3 1683 - 1689 2015年03月 [査読有り]
     
    Background/Aim: The epidermal growth factor family (EGF) has been suggested to influence the sensitivity to anti-epidermal growth factor receptor therapy. We examined the correlation between circulating levels of the epidermal growth factors amphiregulin and transforming growth factor-alpha (TGF-alpha) and the MET ligand hepatocyte growth factor and sensitivity to the anti-epidermal growth factor receptor antibody in colorectal cancer (CRC) patients. Materials and Methods: Plasma levels of each ligand were measured by enzyme-linked immunosorbent assay in 51 patients with wild-type KRAS CRC. Results: Patients with high hepatocyte growth factor (HGF) levels had a significantly lower disease control rate (DCR) and shorter median progression-free survival (PFS) and overall survival (OS) than those with low expression levels. Amphiregulin was correlated with objective response rate (ORR) but not with PFS or OS. Cetuximab response and survival were not associated with TGF-alpha. Conclusion: Circulating HGF may help identify CRC patients most likely to benefit from anti-epidermal growth factor receptor antibody therapy.
  • Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Eri Banno; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio
    INTERNATIONAL JOURNAL OF ONCOLOGY 46 3 1025 - 1030 2015年03月 [査読有り]
     
    Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.
  • Kimio Yonesaka; Taroh Satoh; Shinya Ueda; Takeshi Yoshida; Masayuki Takeda; Toshio Shimizu; Isamu Okamoto; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    ANTICANCER RESEARCH 35 3 1683 - 1689 2015年03月 [査読有り]
     
    Background/Aim: The epidermal growth factor family (EGF) has been suggested to influence the sensitivity to anti-epidermal growth factor receptor therapy. We examined the correlation between circulating levels of the epidermal growth factors amphiregulin and transforming growth factor-alpha (TGF-alpha) and the MET ligand hepatocyte growth factor and sensitivity to the anti-epidermal growth factor receptor antibody in colorectal cancer (CRC) patients. Materials and Methods: Plasma levels of each ligand were measured by enzyme-linked immunosorbent assay in 51 patients with wild-type KRAS CRC. Results: Patients with high hepatocyte growth factor (HGF) levels had a significantly lower disease control rate (DCR) and shorter median progression-free survival (PFS) and overall survival (OS) than those with low expression levels. Amphiregulin was correlated with objective response rate (ORR) but not with PFS or OS. Cetuximab response and survival were not associated with TGF-alpha. Conclusion: Circulating HGF may help identify CRC patients most likely to benefit from anti-epidermal growth factor receptor antibody therapy.
  • 佐伯 俊昭; 田村 和夫; 相羽 惠介; 青儀 健二郎; 飯野 京子; 今村 知世; 江口 研二; 沖田 憲司; 加賀美 芳和; 田中 竜平; 中川 和彦; 藤井 博文; 朴 成和; 松浦 一生; 和田 信; 明智 龍男; 角道 祐一; 金 容壱; 佐々木 秀法; 志真 泰夫; 武田 真幸; 永崎 栄次郎; 西舘 敏彦; 齊藤 光江; 足利 幸乃; 谷川原 祐介; 平田 公一; 石岡 千加史; 西山 正彦; 制吐薬適正使用ガイドライン改訂ワーキンググループ
    癌と化学療法 42 3 305 - 311 (株)癌と化学療法社 2015年03月 [査読有り]
     
    制吐薬適正使用ガイドラインが発刊されて2年経過し、わが国のがん医療現場で本ガイドラインがどのような評価を得ているか、がん関連5学会の協力を得てアンケート調査を行った。方法:2012年6月〜8月まで日本癌治療学会、日本臨床腫瘍学会、日本緩和医療学会、日本放射線腫瘍学会の所属会員を対象として、日本癌治療学会のホームページにアンケートを掲載しweb上で回答を受け付け、集計した。結果:1,529の回答を得た。回答者の職種は医師73.4%、看護師7.3%、薬剤師17.7%であった。回答した医師の診療科は消化器外科18.9%、血液内科10.1%、腫瘍内科8.3%、消化器内科6.6%、泌尿器科9.2%、婦人科8.0%、乳腺外科6.4%であった。回答者の所属施設のうち68.6%ががん診療拠点病院、31.4%は拠点病院以外の施設であり、200床以上の病院は88.4%であった。まず、がん医療におけるガイドラインは93.8%が重視していた。本ガイドラインの認知度は85.5%であり、56.9%は学会・研究会などから、また28.8%が医療関係者から情報を得ていた。本ガイドラインは30.6%が施設で所有しており、54%は個人で所有していた。さらに、ガイドラインは87.8%の人々に一部またはほぼ全体を読まれ、93.6%が診療現場で利用していると回答があった。また、診療アルゴリズムあるいはダイアグラムはそれぞれ87.7%、89.9%の回答者が有用であるとしていた。考察:医師を中心とした学会会員を対象としたアンケートであったが、会員数が少ないにもかかわらず看護師、薬剤師の回答率が高く、本ガイドラインが医師のみならずチーム医療として行われているがん化学療法の現場で重要視されていると思われた。また、医師の診療科別ではがん化学療法が重要な役割をしている診療科に幅広く認知されており、臓器横断的な支持療法のコンセンサス形成に役立っていると考えられた。(著者抄録)
  • 南 真弓; 國吉一樹; 櫻本宏之; 岡本邦男; 中川和彦; 下村嘉一
    眼科臨床紀要 8 3 145 - 150 眼科臨床紀要会 2015年03月 [査読有り]
  • T. Sakiyama; J. Tsurutani; T. Iwasa; H. Kawakami; Y. Nonagase; T. Yoshida; K. Tanaka; Y. Fujisaka; T. Kurata; Y. Komoike; K. Nishio; K. Nakagawa
    BRITISH JOURNAL OF CANCER 112 5 819 - 824 2015年03月 [査読有り]
     
    Background: We evaluated the safety, maximum-tolerated dose (MTD), pharmacokinetics, recommended dose for phase II (P2RD), and preliminary anticancer activity of a combination eribulin and S-1 therapeutic in metastatic breast cancer patients pretreated with anthracycline and taxane. Method: Patients aged 20-74 years were recruited. In level 1, patients received S-1 (65mgm(-2)) from day 1 to 14, and eribulin (1.1mgm(-2)) on day 1 and 8 in a 21-day cycle. In level 2, eribulin was increased to 1.4mgm(-2). In level 3, S-1 was increased to 80 mgm(-2). Results: Twelve patients were enrolled into three cohorts. Planned dose escalation was completed, with one case exhibiting doselimiting toxicity (grade 3 hypokalaemia) at level 3, without reaching the MTD. The P2RD was determined to be level 2 (eribulin 1.4mgm(-2) and S-1 65mgm(-2)). The most common grade 3 or 4 toxicity was neutropenia (83.3%), followed by febrile neutropenia (25.0%). Five of eleven patients (41.7%) with measurable disease had a partial response. Pharmacokinetics were characterised by dose-dependent elimination and nonlinear exposure. Conclusion: Dose level 3 was not tolerated owing to febrile neutropenia development. Thus, intermediate dose level 2 was recommended for further evaluation. Preliminary antitumour activity warrants further investigation in this setting.
  • F. Hirai; T. Yamanaka; K. Taguchi; H. Daga; A. Ono; K. Tanaka; Y. Kogure; J. Shimizu; T. Kimura; J. Fukuoka; Y. Iwamoto; H. Sasaki; K. Takeda; T. Seto; Y. Ichinose; K. Nakagawa; Y. Nakanishi
    ANNALS OF ONCOLOGY 26 2 363 - 368 2015年02月 [査読有り]
     
    Background: Thymic carcinoma (TC) is an exceptionally rare tumor, which has a very poor prognosis differing from thymoma. Till date, there has been no report of any results of clinical trials focusing on TC. The role of non-anthracycline-based chemotherapy has not been elucidated since the previous studies included a relatively small number of TC patients. This single-arm study evaluated carboplatin and paclitaxel (CbP) in chemotherapy-naive patients with advanced TC. Patients and methods: The study treatment consisted of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) every 3 weeks for a maximum of six cycles. The primary end point was objective response rate (ORR) by independent review. The secondary end points included overall survival (OS), progression-free survival (PFS), and safety. Based on the SWOG 2-stage design, the planned sample size of 40 patients was determined to reject the ORR of 20% under the expectation of 40% with a power of 0.85 and a type I error of 0.05. Results: Forty patients from 21 centers were enrolled for this study from May 2008 to November 2010. Of the 39 patients evaluable for analysis, 36 were pathologically diagnosed by independent review, and 97% patients were eventually TC. There was 1/13 complete/partial responses with an ORR of 36% (95% confidence interval 21%-53%; P = 0.031). The median PFS was 7.5 (6.2-12.3) months, while OS did not reach the median value. Major adverse event was grade 3-4 neutropenia in 34 patients (87%). There was no treatment-related death. Conclusions: In this largest trial with TC, CbP showed promising efficacy in advanced TC when compared with anthracycline-based chemotherapy, which is the current standard treatment of thymic neoplasm. Our results established that CbP, one of the standard treatments for non-small-cell lung cancer, might be an option as a chemotherapy regimen for TC.
  • Kudo K; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 73 Suppl 2 542 - 547 2015年02月 [査読有り]
  • Tetsuya Abe; Koji Takeda; Yuichiro Ohe; Shinzoh Kudoh; Yukito Ichinose; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Koichi Minato; Toshiyuki Sawa; Yasuo Iwamoto; Hideo Saka; Junki Mizusawa; Taro Shibata; Shinichiro Nakamura; Masahiko Ando; Akira Yokoyama; Kazuhiko Nakagawa; Nagahiro Saijo; Tomohide Tamura
    JOURNAL OF CLINICAL ONCOLOGY 33 6 575 - U65 2015年02月 [査読有り]
     
    Purpose This phase III trial aimed to confirm the superiority of weekly docetaxel and cisplatin over docetaxel monotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naive patients with stage III, stage IV, or recurrent NSCLC age >= 70 years with a performance status of 0 or 1 who were considered unsuitable for bolus cisplatin administration were randomly assigned to receive docetaxel 60 mg/m(2) on day 1, every 3 weeks, or docetaxel 20 mg/m(2) plus cisplatin 25 mg/m(2) on days 1, 8, and 15, every 4 weeks. The primary end point was overall survival (OS). Results In the first interim analysis, OS of the doublet arm was inferior to that of the monotherapy arm (hazard ratio [HR], 1.56; 95% CI, 0.98 to 2.49), and the predictive probability that the doublet arm would be statistically superior to the monotherapy arm on final analysis was 0.996%, which led to early study termination. In total, 276 patients with a median age of 76 years (range, 70 to 87 years) were enrolled. At the updated analysis, the median survival time was 14.8 months for the monotherapy arm and 13.3 months for the doublet arm (HR, 1.18; 95% CI, 0.83 to 1.69). The rates of grade 3 neutropenia and febrile neutropenia were higher in the monotherapy arm, and those of anorexia and hyponatremia were higher in the doublet arm. Conclusion This study failed to demonstrate any survival advantage of weekly docetaxel plus cisplatin over docetaxel monotherapy as first-line chemotherapy for advanced NSCLC in elderly patients.
  • Isamu Okamoto; Masaki Miyazaki; Masayuki Takeda; Masaaki Terashima; Koichi Azuma; Hidetoshi Hayashi; Hiroyasu Kaneda; Takayasu Kurata; Junji Tsurutani; Takashi Seto; Fumihiko Hirai; Koichi Konishi; Akiko Sarashina; Nobutaka Yagi; Rolf Kaiser; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 10 2 346 - 352 2015年02月 [査読有り]
     
    Background: This phase I, open-label study evaluated the safety/tolerability and maximum tolerated dose of second-line nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer. Methods: Eligible patients received docetaxel 60 or 75 mg/m(2) (day 1) plus nintedanib 100, 150, or 200 mg twice daily (bid; days 2-21) in 21-day cycles. Standard 3 + 3 dose escalations were performed separately in patient cohorts with a body surface area (BSA) of less than 1.5 m(2) (BSA < 1.5) and BSA greater than or equal to 1.5, respectively. Results: Forty-two patients (17 BSA < 1.5, 25 BSA >= 1.5) were treated. The maximum tolerated dose of nintedanib was 150 and 200 mg bid in patients with BSA less than 1.5 and BSA greater than or equal to 1.5 (BSA >= 1.5), respectively, in combination with 75 mg/m(2) of docetaxel. Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred in 12 patients (six per cohort). Drug-related adverse events included neutropenia (95%), leukopenia (83%), fatigue (76%), alopecia (71%), decreased appetite (67%), and elevations in alanine aminotransferase (64%) and aspartate aminotransferase (64%). All hepatic enzyme elevations were reversible and manageable with dose reduction or discontinuation. Among 38 evaluable patients, 10 (26%) had a partial response and 18 (47%) had stable disease. Conclusion: Continuous treatment with second-line nintedanib combined with docetaxel was manageable and showed promising signs of efficacy in Japanese patients with advanced non-small-cell lung cancer.
  • Isamu Okamoto; Masaki Miyazaki; Masayuki Takeda; Masaaki Terashima; Koichi Azuma; Hidetoshi Hayashi; Hiroyasu Kaneda; Takayasu Kurata; Junji Tsurutani; Takashi Seto; Fumihiko Hirai; Koichi Konishi; Akiko Sarashina; Nobutaka Yagi; Rolf Kaiser; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 10 2 346 - 352 2015年02月 [査読有り]
     
    Background: This phase I, open-label study evaluated the safety/tolerability and maximum tolerated dose of second-line nintedanib combined with docetaxel in Japanese patients with advanced non-small-cell lung cancer. Methods: Eligible patients received docetaxel 60 or 75 mg/m(2) (day 1) plus nintedanib 100, 150, or 200 mg twice daily (bid; days 2-21) in 21-day cycles. Standard 3 + 3 dose escalations were performed separately in patient cohorts with a body surface area (BSA) of less than 1.5 m(2) (BSA < 1.5) and BSA greater than or equal to 1.5, respectively. Results: Forty-two patients (17 BSA < 1.5, 25 BSA >= 1.5) were treated. The maximum tolerated dose of nintedanib was 150 and 200 mg bid in patients with BSA less than 1.5 and BSA greater than or equal to 1.5 (BSA >= 1.5), respectively, in combination with 75 mg/m(2) of docetaxel. Dose-limiting toxicities (all grade 3 hepatic enzyme elevations) occurred in 12 patients (six per cohort). Drug-related adverse events included neutropenia (95%), leukopenia (83%), fatigue (76%), alopecia (71%), decreased appetite (67%), and elevations in alanine aminotransferase (64%) and aspartate aminotransferase (64%). All hepatic enzyme elevations were reversible and manageable with dose reduction or discontinuation. Among 38 evaluable patients, 10 (26%) had a partial response and 18 (47%) had stable disease. Conclusion: Continuous treatment with second-line nintedanib combined with docetaxel was manageable and showed promising signs of efficacy in Japanese patients with advanced non-small-cell lung cancer.
  • Tetsuya Abe; Koji Takeda; Yuichiro Ohe; Shinzoh Kudoh; Yukito Ichinose; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Koichi Minato; Toshiyuki Sawa; Yasuo Iwamoto; Hideo Saka; Junki Mizusawa; Taro Shibata; Shinichiro Nakamura; Masahiko Ando; Akira Yokoyama; Kazuhiko Nakagawa; Nagahiro Saijo; Tomohide Tamura
    JOURNAL OF CLINICAL ONCOLOGY 33 6 575 - U65 2015年02月 [査読有り]
     
    Purpose This phase III trial aimed to confirm the superiority of weekly docetaxel and cisplatin over docetaxel monotherapy in elderly patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naive patients with stage III, stage IV, or recurrent NSCLC age >= 70 years with a performance status of 0 or 1 who were considered unsuitable for bolus cisplatin administration were randomly assigned to receive docetaxel 60 mg/m(2) on day 1, every 3 weeks, or docetaxel 20 mg/m(2) plus cisplatin 25 mg/m(2) on days 1, 8, and 15, every 4 weeks. The primary end point was overall survival (OS). Results In the first interim analysis, OS of the doublet arm was inferior to that of the monotherapy arm (hazard ratio [HR], 1.56; 95% CI, 0.98 to 2.49), and the predictive probability that the doublet arm would be statistically superior to the monotherapy arm on final analysis was 0.996%, which led to early study termination. In total, 276 patients with a median age of 76 years (range, 70 to 87 years) were enrolled. At the updated analysis, the median survival time was 14.8 months for the monotherapy arm and 13.3 months for the doublet arm (HR, 1.18; 95% CI, 0.83 to 1.69). The rates of grade 3 neutropenia and febrile neutropenia were higher in the monotherapy arm, and those of anorexia and hyponatremia were higher in the doublet arm. Conclusion This study failed to demonstrate any survival advantage of weekly docetaxel plus cisplatin over docetaxel monotherapy as first-line chemotherapy for advanced NSCLC in elderly patients.
  • Ebi H; Oze I; Nakagawa T; Ito H; Hosono S; Matsuda F; Takahashi M; Takeuchi S; Sakao Y; Hida T; Faber AC; Tanaka H; Yatabe Y; Mitsudomi T; Yano S; Matsuo K
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10 1 59 - 66 2015年01月 [査読有り]
     
    INTRODUCTION: The BIM deletion polymorphism in intron 2 was found in a significant percent of the Asian population. Patients with epidermal growth factor receptor (EGFR) mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to EGFR tyrosine kinase inhibitors. However, the association between the BIM deletion polymorphism and lung cancer risk is unknown. METHODS: The BIM deletion polymorphism was screened by polymerase chain reaction in 765 lung cancer cases and 942 healthy individuals. RESULTS: Carriers possessing one allele of the BIM polymorphism were observed in 13.0% of control cases and 12.8% of lung cancer cases, similar to incidence rates reported earlier in healthy individuals. Homozygote for the BIM polymorphism was observed in four of 942 healthy controls and three of 765 lung cancer cases. The frequency of the BIM deletion polymorphism in lung cancer patients was not related to age, sex, smoking history, or family history of lung cancer. The BIM deletion polymorphism was found in 30 of 212 patients with EGFR wild type lung cancers and 16 of 120 patients with EGFR mutant lung cancers. The frequency of the BIM polymorphism is similar between cancers with wild type EGFR and mutated EGFR (p = 0.78). CONCLUSION: The BIM deletion polymorphism was not associated with lung cancer susceptibility. Furthermore, the BIM polymorphism is not associated with EGFR mutant lung cancer.
  • Masato Taki; Naoya Ikegami; Chisato Konishi; Satoshi Nakao; Tomoko Funazou; Ryo Ariyasu; Masanori Yoshida; Kazuhiko Nakagawa; Kyouhei Morita; Moon Hee Hwang; Chie Yoshimura; Toshiaki Wakayama; Yasuo Nishizaka
    Internal Medicine 54 19 2483 - 2486 2015年
  • Hirofumi Uehara; Yosuke Matsuura; Masayuki Nakao; Mingyon Mun; Ken Nakagawa; Yuichi Ishikawa; Sakae Okumura
    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 21 4 338 - 344 2015年 [査読有り]
     
    Purpose: Although curative resection is expected to be effective in patients with clinical (c-) stage IA/pathological (p-) stage IA non-small-cell lung cancers, recurrence is often observed. Hence, the aim of this study was to identify predictors of recurrence. Methods: Between 2005 and 2009, 138 patients with c- stage IA/p-stage IA non-small-cell lung cancers underwent resection. Recurrence and recurrence-free survival (RFS) were compared with clinical, radiographic and pathological findings. Results: The 5-year cancer-specific survival rate was 97% and the RFS rate was 89% at a median follow-up time of 91 months. Recurrence was observed in 10 patients (7.2%). Significant differences were observed in RFS according to tumour dimensions on the mediastinal window image (>1.5 cm), serum carcinoembryonic antigen levels (>5.0 ng/mL), maximum standardised uptake values (SUVmax >2.5) and angiolymphatic invasion. Patients were grouped according to the number of risk factors for poor RFS. Patients with 0-1 of the identified risk factors had an RFS of 97%, where those with 2-4 factors had an RFS of 68% (p < 0.001). Conclusion: Prognosis of patients exhibiting more than two of these risk factors is considerably poor. Thus, close observation and individualised adjuvant therapy may be beneficial to these patients.
  • 中川 和彦
    日本内科学会雑誌 104 3 449 - 455 一般社団法人 日本内科学会 2015年
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    THERAPEUTICS AND CLINICAL RISK MANAGEMENT 11 1701 - 1706 2015年 [査読有り]
     
    Angiogenesis is an essential process in the development, growth, and metastasis of malignant tumors including lung cancer. Several angiogenesis inhibitors have been developed as potential therapies for non-small-cell lung cancer (NSCLC). Nintedanib is a small-molecule tyrosine kinase inhibitor that targets receptors for vascular endothelial growth factor, platelet-derived growth factor, and fibroblast growth factor as well as RET (rearranged during transfection) and Flt3. When administered as monotherapy, nintedanib was well tolerated at doses up to 250 mg or 200 mg twice daily in European and Japanese patients, respectively, with liver toxicity featuring prominently among dose-limiting toxicities in both populations. A recent Phase III trial demonstrated that treatment with the combination of nintedanib and docetaxel resulted in a significant and clinically meaningful improvement in both progression-free survival and overall survival compared with docetaxel alone in predefined NSCLC patients with adenocarcinoma tumor histology. Although the incidence of elevated alanine aminotransferase or aspartate aminotransferase as well as of diarrhea was higher in patients treated with nintedanib plus docetaxel, most of these adverse events were manageable with supportive treatment or dose reduction. The results of completed and ongoing clinical trials of nintedanib monotherapy and combination therapy for the treatment of NSCLC are summarized in this study.
  • Hirofumi Uehara; Masayuki Nakao; Mingyon Mun; Ken Nakagawa; Makoto Nishio; Yuichi Ishikawa; Sakae Okumura
    ANNALS OF THORACIC AND CARDIOVASCULAR SURGERY 21 4 345 - 353 2015年 [査読有り]
     
    Purpose: To identify prognostic factors for pathologic N2 (pN2) non-small cell lung cancer (NSCLC) treated by surgical resection. Methods: Between 1990 and 2009, 287 patients with pN2 NSCLC underwent curative resection at the Cancer Institute Hospital without preoperative treatment. Results: The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) rates were 46%, 55% and 24%, respectively. The median follow-up time was 80 months. Multivariate analysis identified four independent predictors for poor OS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.616; p = 0.003); ipsilateral intrapulmonary metastasis (HR, 1.042; p = 0.002); tumor size >30 mm (HR, 1.013; p = 0.002); and clinical stage N1 or N2 (HR, 1.051; p = 0.030). Multivariate analysis identified three independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (HR, 1.457; p = 0.011); ipsilateral intrapulmonary metastasis (HR, 1.040; p = 0.002); and tumor size >30 mm (HR, 1.008; p = 0.032). Conclusion: Multiple-zone mediastinal lymph node metastasis, ipsilateral intrapulmonary metastasis, and tumor size >30 mm were common independent prognostic factors of OS, CSS, and RFS in pN2 NSCLC.
  • Nagata Y; Hiraoka M; Shibata T; Onishi H; Kokubo M; Karasawa K; Shioyama Y; Onimaru R; Kozuka T; Kunieda E; Saito T; Nakagawa K; Hareyama M; Takai Y; Hayakawa K; Mitsuhashi N; Ishikura S
    Int J Radiat Oncol Biol Phys 93 5 989 - 96 2015年 [査読有り]
  • Kuroda H; Sakao Y; Mun M; Uehara H; Nakao M; Matsuura Y; Mizuno T; Sakakura N; Motoi N; Ishikawa Y; Yatabe Y; Nakagawa K; Okumura S
    PLoS One 10 8 e0134674  2015年 [査読有り]
  • Takayuki Tasaki; Takeshi Okuda; Kunio Okamoto; Hiromasa Yoshioka; Mitsugu Fujita; Shuichi Izumoto; Kazuhiko Nakagawa; Amami Kato
    Japanese Journal of Neurosurgery 24 3 192 - 197 2015年 [査読有り]
     
    Glioblastoma multiforme (GBM) often infiltrates surrounding tissues, an action which is known as a clinical characteristic of this deadly disease. In contrast, extracranial metastases of GBM rarely occur. Consequently, the underlying mechanisms and prognosis of GBM metastasis remain unclear. In this regard, we here present a case of GBM with pleural metastases and discuss the relevant literature. The patient was a 62-year-old male who was originally diagnosed with GBM in the right temporal lobe and underwent craniotomy for tumor removal. Gross total resection was successfully performed. The patient received postoperative chemoradiotherapy with temozolomide, followed by maintenance chemotherapy with temozolomide alone. He showed a good postoperative course until a small recurrence occurred in the resection cavity at 17 months after the surgery. At 21 months, the patient developed thoracodorsal pain due to a large volume of pleural effusion with pleural masses. An intrathoracic biopsy revealed that the pleural lesions were metastases of the GBM. Simultaneously, intracranial imaging studies indicated tumor spread into the right cavernous sinus. These findings suggest that the GBM may have infiltrated into the cavernous sinus via the dura surrounding the cavernous sinus adjacent to the resection cavity and metastasized hematogenously to the pleural cavity
  • The pan-HER family tyrosine kinase inhibitor afatinib overcomes HER3 ligand heregulin-mediated resistance to EGFR inhibitors in non-small cell lung cancer.
    Yonesaka K; Kudo K; Nishida S; Takahama T; Iwasa T; Yoshida T; Tanaka K; Takeda M; Kaneda H; Okamoto I; Nishio K; Nakagawa K
    Oncotarget. 6 32 33602 - 33611 2015年 [査読有り]
  • Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal.
    Togashi Y; Hayashi H; Okamoto K; Fumita S; Terashima M; de Velasco MA; Sakai K; Fujita Y; Tomida S; Nakagawa K; Nishio K
    Lung Cancer. 88 1 16 - 23 2015年 [査読有り]
  • A case of severe cerebral embolism after chemotherapy for HER2-positive gastric cancer.
    Takahama T; Takeda M; Nishina S; Nakagawa K
    BMC Res Notes. 8 100 1 - 3 2015年 [査読有り]
  • Multiple regulatory mechanisms of hepatocyte growth factor expression in malignant cells with a short poly(dA) sequence in the HGF gene promoter.
    Sakai K; Takeda M; Okamoto I; Nakagawa K; Nishio K
    Oncol Lett. 9 1 405 - 410 2015年 [査読有り]
  • Yosuke Togashi; Hidetoshi Hayashi; Masato Terashima; Marco A. de Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuhiko Nakagawa; Kazuto Nishio
    JOURNAL OF THORACIC ONCOLOGY 10 1 93 - 101 2015年01月 [査読有り]
     
    Introduction: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). beta-Catenin is a key component of the Wnt/beta-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells. Methods and Results: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of beta-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a beta-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the beta-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the beta-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that beta-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation. Conclusion: Our findings indicate that beta-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.
  • Kazuko Sakai; Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    ONCOLOGY LETTERS 9 1 405 - 410 2015年01月 [査読有り]
     
    Hepatocyte growth factor (HGF) expression is a poor prognostic factor in various types of cancer. Expression levels of HGF have been reported to be regulated by shorter poly(dA) sequences in the promoter region. In the present study, the poly(dA) mononucleotide tract in various types of human cancer cell lines was examined and compared with the HGF expression levels in those cells. Short deoxyadenosine repeat sequences were detected in five of the 55 cell lines used in the present study. The H69, IM95, CCK-81, Sui73 and H28 cells exhibited a truncated poly(dA) sequence in which the number of poly(dA) repeats was reduced by 5 bp. Two of the cell lines exhibited high HGF expression, determined by reverse transcription quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The CCK-81, Sui73 and H28 cells with shorter poly(dA) sequences exhibited low HGF expression. The cause of the suppression of HGF expression in the CCK-81, Sui73 and H28 cells was clarified by two approaches, suppression by methylation and single nucleotide polymorphisms in the HGF gene. Exposure to 5-Aza-dC, an inhibitor of DNA methyltransferase 1, induced an increased expression of HGF in the CCK-81 cells, but not in the other cells. Single-nucleotide polymorphism (SNP) rs72525097 in intron 1 was detected in the Sui73 and H28 cells. Taken together, it was found that the defect of poly(dA) in the HGF promoter was present in various types of cancer, including lung, stomach, colorectal, pancreas and mesothelioma. The present study proposes the negative regulation mechanisms by methylation and SNP in intron 1 of HGF for HGF expression in cancer cells with short poly(dA).
  • 田崎 貴之; 奥田 武司; 岡本 邦男; 吉岡 宏真; 藤田 貢; 泉本 修一; 中川 和彦; 加藤 天美
    脳神経外科ジャーナル 24 3 192 - 197 2015年 [査読有り]
     
    Glioblastoma multiforme (GBM) often infiltrates surrounding tissues, an action which is known as a clinical characteristic of this deadly disease. In contrast, extracranial metastases of GBM rarely occur. Consequently, the underlying mechanisms and prognosis of GBM metastasis remain unclear. In this regard, we here present a case of GBM with pleural metastases and discuss the relevant literature. The patient was a 62-year-old male who was originally diagnosed with GBM in the right temporal lobe and underwent craniotomy for tumor removal. Gross total resection was successfully performed. The patient received postoperative chemoradiotherapy with temozolomide, followed by maintenance chemotherapy with temozolomide alone. He showed a good postoperative course until a small recurrence occurred in the resection cavity at 17 months after the surgery. At 21 months, the patient developed thoracodorsal pain due to a large volume of pleural effusion with pleural masses. An intrathoracic biopsy revealed that the pleural lesions were metastases of the GBM. Simultaneously, intracranial imaging studies indicated tumor spread into the right cavernous sinus. These findings suggest that the GBM may have infiltrated into the cavernous sinus via the dura surrounding the cavernous sinus adjacent to the resection cavity and metastasized hematogenously to the pleural cavity
  • H. Hayashi; T. Arao; Y. Togashi; H. Kato; Y. Fujita; M. A. De Velasco; H. Kimura; K. Matsumoto; K. Tanaka; I. Okamoto; A. Ito; Y. Yamada; K. Nakagawa; K. Nishio
    ONCOGENE 34 2 199 - 208 2015年01月 [査読有り]
     
    POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.
  • 吉岡 弘鎮; 西尾 誠人; 木浦 勝行; 瀬戸 貴司; 中川 和彦; 前門戸 任; 井上 彰; 樋田 豊明; 田中 智宏; 田村 友秀
    肺癌 54 7 892 - 897 2014年12月 [査読有り]
     
    Purpose. We investigated the efficacy and safety of the long-term administration of a highly selective anaplastic lymphoma kinase (ALK) inhibitor with a novel scaffold, alectinib, in Japanese patients with ALKrearranged non-small cell lung cancer (NSCLC). Methods. ALK-rearranged NSCLC patients (Pts) naive to ALK inhibitors were treated with alectinib at a dose of 300 mg b.i.d until on the onset of progressive disease. We herein report the efficacy and safety of this treatment according to an independent review at the one-year time point after enrollment of the last patient (as of April 18, 2013). Results. Among the 46 pts in assessed in the phase II portion of this study, the overall response rate was 93.5%(95%CI: 82.1-98.6). The one-year progression free rate was 83% (95%CI: 68-92), although the median progression free survival (PFS) had not been reached at the time of cutoff date. Among the 58 pts treated with alectinib at a dose of 300 mg b.i.d in the phase I and II portions of the AF-001JP study, 42 (72%) remained on the study regimen, with a median treatment duration of 15.8 months. Major treatment-related adverse events included dysgeusia, rashes and increased AST and blood bilirubin levels, mostly of grade 1-2. Conclusions. Alectinib demonstrates long-term efficacy and a favorable benefit-risk profile in ALK inhibitor-naive patients with ALK-rearranged NSCLC.
  • T. Naito; T. Seto; K. Takeda; K. Goto; I. Okamoto; K. Nakagawa; T. Ohba; H. Murakami; T. Takahashi; T. Yamanaka; N. Yamamoto
    LUNG CANCER 86 3 339 - 343 2014年12月 [査読有り]
     
    Background: S-1, a novel oral fluoropyrimidine, has potent antitumor activity against non-small-cell lung cancer (NSCLC). Meanwhile, leucovorin enhances the efficacy of 5-fluorouracil by inhibiting thymidylate synthase. Therefore, this phase II clinical trial evaluated the safety and efficacy of S-1 plus leucovorin combination therapy for previously treated patients with NSCLC. Patients and methods: Patients with stage IIIB or IV NSCLC were prospectively enrolled if they received 1 or 2 prior chemotherapy regimens. S-1 (40-60 mg) and leucovorin (25 mg) were administered together orally twice per day for 7 consecutive days followed by 7 days of rest. This 2-week cycle was repeated for a maximum of 25 cycles until the onset of disease progression or unacceptable adverse events. Endpoints included objective tumor response, progression-free survival, overall survival, and safety. Results: Among 33 patients, 6 (18.2%), 14 (42.4%), and 11 (33.3%) had partial response, stable disease, and progressive disease, respectively. Median progression-free and overall survival times were 3.5 and 11.7 months, respectively. The common grade 3 toxicities included stomatitis (18.2%), anorexia (12.1%), and neutropenia (9.1%). One patient had pneumatosis cystoides intestinalis, and another experienced paralytic ileus. There were no treatment-related deaths. Conclusions: 5-1 plus leucovorin combination therapy demonstrated promising efficacy and an acceptable toxicity profile in previously treated patients with NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
  • Hisato Kawakami; Isamu Okamoto; Kimio Yonesaka; Kunio Okamoto; Kiyoko Shibata; Yume Shinkai; Haruka Sakamoto; Michiko Kitano; Takao Tamura; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOTARGET 5 23 11847 - 11856 2014年12月 [査読有り]
     
    We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.
  • Benjamin J. Solomon; Tony Mok; Dong-Wan Kim; Yi-Long Wu; Kazuhiko Nakagawa; Tarek Mekhail; Enriqueta Felip; Federico Cappuzzo; Jolanda Paolini; Tiziana Usari; Shrividya Iyer; Arlene Reisman; Keith D. Wilner; Jennifer Tursi; Fiona Blackhall; M. Boyer; V. Ganju; B. Hughes; N. Pavlakis; B. Solomon; S. Varma; T. Berghmans; J-L Canon; I. Demedts; A. Janssens; R. Louis; T. Pieters; D. Schallier; V. Surmont; C. Maciel da Silva; C-G Moreira Ferreira; V. Hirsh; A. Joy; F. Laberge; W. Morzycki; R. Wierzbicki; B. Han; X. Liu; S. Qin; Y. Shi; Y. Wang; G. Wu; Y-L Wu; C. Zhou; J. Ahvonen; F. Barlesi; J. Cadranel; E. Dansin; J. Fayette; J-F Morere; D. Moro-Sibilot; J-L Pujol; E. Quoix; G. Zalcman; N. Frickhofen; C-P Schneider; T. Wehler; T. Mok; P. So; S. Cuffe; A. Bearz; C. Boni; F. Cappuzzo; F. Cognetti; F. De Braud; T. De Pas; D. Galetta; M. Migliorino; D. Rocco; G. Scagliotti; P. Tagliaferri; M. Tiseo; K. Aoe; T. Hida; T. Kato; T. Kozuki; K. Nakagawa; S. Niho; M. Nishio; H. Nokihara; M. Satouchi; T. Seto; T. Takahashi; J-S Ahn; D-W Kim; S-W Kim; G. Berchem; O. Arrieta Rodriguez; B. Biesma; A-M Dingemans; E. Smit; A. Helland; F. Barata; V. Gorbunova; G. Manikhas; S. Orlov; S. Leong; H-L Lim; R. Soo; E-H Tan; A. Nosworthy; M. Codes Villena; E. Felip; P. Garrido Lopez; D. Isla Casado; N. Martinez Banaclocha; S. Ponce Aix; N. Reguart Aransay; D. Rodriguez Abreu; J. Trigo Perez; O. Gautschi; M. Pless; A. Zippelius; G-C Chang; Y-H Tsai; Y. Shparyk; F. Blackhall; N. Steele; V. Armenio; K. Dragnev; M. Dugan; S. Gadgeel; D. Gerber; S. Graziano; S. Gurubhagavatula; L. Horn; S. Jalal; R. Lauer; R. Mehra; T. Mekhail; H. Mirshahidi; S. Pakkala; J. Polikoff; H. Raftopoulos; M. Saleh; R. Salgia; S. Waqar
    NEW ENGLAND JOURNAL OF MEDICINE 371 23 2167 - 2177 2014年12月 [査読有り]
     
    BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P = 0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC.
  • Akihiko Gemma; Shoji Kudoh; Masahiko Ando; Yuichiro Ohe; Kazuhiko Nakagawa; Takeshi Johkoh; Naoya Yamazaki; Hiroaki Arakawa; Yoshikazu Inoue; Masahito Ebina; Masahiko Kusumoto; Kazuyoshi Kuwano; Fumikazu Sakai; Hiroyuki Taniguchi; Yuh Fukuda; Akihiro Seki; Tadashi Ishii; Masahiro Fukuoka
    CANCER SCIENCE 105 12 1584 - 1590 2014年12月 [査読有り]
     
    Interstitial lung disease (ILD) occurrence and risk factors were investigated in the Japanese non-small-cell lung cancer, post-marketing, large-scale surveillance study, POLARSTAR. All patients with unresectable, recurrent/advanced non-small-cell lung cancer who were treated with erlotinib in Japan between December 2007 and October 2009 were enrolled. Primary endpoints were patterns of ILD and risk factors for onset of ILD and ILD-related death. Overall survival, progression-free survival, and occurrence of adverse drug reactions were secondary endpoints. Interstitial lung disease was confirmed in 429 (4.3%) patients. Concurrent/previous ILD (hazard ratio, 3.19), emphysema or chronic obstructive pulmonary disease (hazard ratio, 1.86), lung infection (hazard ratio, 1.55), smoking history (hazard ratio, 2.23), and period from initial cancer diagnosis to the start of treatment (<360days; hazard ratio, 0.58) were identified as significant risk factors for developing ILD by Cox multivariate analysis. Logistic regression analysis identified Eastern Cooperative Oncology Group performance status 2-4 (odds ratio, 2.45 [95% confidence interval, 1.41-4.27]; P=0.0016), 50% remaining normal lung area (odds ratio, 3.12 [1.48-6.58]; P=0.0029), and concomitant honeycombing with interstitial pneumonia (odds ratio, 6.67 [1.35-32.94]; P=0.02) as poor prognostic factors for ILD death. Median overall survival was 277days; median progression-free survival was 67days. These data confirm the well-characterized safety profile of erlotinib. Interstitial lung disease is still an adverse drug reaction of interest in this population, and these results, including ILD risk factors, give helpful information for treatment selection and monitoring. Erlotinib efficacy was additionally confirmed in this population. (POLARSTAR trial ML21590.)
  • Hidetoshi Hayashi; Isamu Okamoto; Junko Tanizaki; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 32 36 E122 - E124 2014年12月 [査読有り]
  • Hidetoshi Hayashi; Isamu Okamoto; Junko Tanizaki; Kaoru Tanaka; Takeshi Okuda; Amami Kato; Yasumasa Nishimura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 32 36 E122 - E124 2014年12月 [査読有り]
  • Akihiko Gemma; Shoji Kudoh; Masahiko Ando; Yuichiro Ohe; Kazuhiko Nakagawa; Takeshi Johkoh; Naoya Yamazaki; Hiroaki Arakawa; Yoshikazu Inoue; Masahito Ebina; Masahiko Kusumoto; Kazuyoshi Kuwano; Fumikazu Sakai; Hiroyuki Taniguchi; Yuh Fukuda; Akihiro Seki; Tadashi Ishii; Masahiro Fukuoka
    CANCER SCIENCE 105 12 1584 - 1590 2014年12月 [査読有り]
     
    Interstitial lung disease (ILD) occurrence and risk factors were investigated in the Japanese non-small-cell lung cancer, post-marketing, large-scale surveillance study, POLARSTAR. All patients with unresectable, recurrent/advanced non-small-cell lung cancer who were treated with erlotinib in Japan between December 2007 and October 2009 were enrolled. Primary endpoints were patterns of ILD and risk factors for onset of ILD and ILD-related death. Overall survival, progression-free survival, and occurrence of adverse drug reactions were secondary endpoints. Interstitial lung disease was confirmed in 429 (4.3%) patients. Concurrent/previous ILD (hazard ratio, 3.19), emphysema or chronic obstructive pulmonary disease (hazard ratio, 1.86), lung infection (hazard ratio, 1.55), smoking history (hazard ratio, 2.23), and period from initial cancer diagnosis to the start of treatment (<360days; hazard ratio, 0.58) were identified as significant risk factors for developing ILD by Cox multivariate analysis. Logistic regression analysis identified Eastern Cooperative Oncology Group performance status 2-4 (odds ratio, 2.45 [95% confidence interval, 1.41-4.27]; P=0.0016), 50% remaining normal lung area (odds ratio, 3.12 [1.48-6.58]; P=0.0029), and concomitant honeycombing with interstitial pneumonia (odds ratio, 6.67 [1.35-32.94]; P=0.02) as poor prognostic factors for ILD death. Median overall survival was 277days; median progression-free survival was 67days. These data confirm the well-characterized safety profile of erlotinib. Interstitial lung disease is still an adverse drug reaction of interest in this population, and these results, including ILD risk factors, give helpful information for treatment selection and monitoring. Erlotinib efficacy was additionally confirmed in this population. (POLARSTAR trial ML21590.)
  • Benjamin J. Solomon; Tony Mok; Dong-Wan Kim; Yi-Long Wu; Kazuhiko Nakagawa; Tarek Mekhail; Enriqueta Felip; Federico Cappuzzo; Jolanda Paolini; Tiziana Usari; Shrividya Iyer; Arlene Reisman; Keith D. Wilner; Jennifer Tursi; Fiona Blackhall; M. Boyer; V. Ganju; B. Hughes; N. Pavlakis; B. Solomon; S. Varma; T. Berghmans; J-L Canon; I. Demedts; A. Janssens; R. Louis; T. Pieters; D. Schallier; V. Surmont; C. Maciel da Silva; C-G Moreira Ferreira; V. Hirsh; A. Joy; F. Laberge; W. Morzycki; R. Wierzbicki; B. Han; X. Liu; S. Qin; Y. Shi; Y. Wang; G. Wu; Y-L Wu; C. Zhou; J. Ahvonen; F. Barlesi; J. Cadranel; E. Dansin; J. Fayette; J-F Morere; D. Moro-Sibilot; J-L Pujol; E. Quoix; G. Zalcman; N. Frickhofen; C-P Schneider; T. Wehler; T. Mok; P. So; S. Cuffe; A. Bearz; C. Boni; F. Cappuzzo; F. Cognetti; F. De Braud; T. De Pas; D. Galetta; M. Migliorino; D. Rocco; G. Scagliotti; P. Tagliaferri; M. Tiseo; K. Aoe; T. Hida; T. Kato; T. Kozuki; K. Nakagawa; S. Niho; M. Nishio; H. Nokihara; M. Satouchi; T. Seto; T. Takahashi; J-S Ahn; D-W Kim; S-W Kim; G. Berchem; O. Arrieta Rodriguez; B. Biesma; A-M Dingemans; E. Smit; A. Helland; F. Barata; V. Gorbunova; G. Manikhas; S. Orlov; S. Leong; H-L Lim; R. Soo; E-H Tan; A. Nosworthy; M. Codes Villena; E. Felip; P. Garrido Lopez; D. Isla Casado; N. Martinez Banaclocha; S. Ponce Aix; N. Reguart Aransay; D. Rodriguez Abreu; J. Trigo Perez; O. Gautschi; M. Pless; A. Zippelius; G-C Chang; Y-H Tsai; Y. Shparyk; F. Blackhall; N. Steele; V. Armenio; K. Dragnev; M. Dugan; S. Gadgeel; D. Gerber; S. Graziano; S. Gurubhagavatula; L. Horn; S. Jalal; R. Lauer; R. Mehra; T. Mekhail; H. Mirshahidi; S. Pakkala; J. Polikoff; H. Raftopoulos; M. Saleh; R. Salgia; S. Waqar
    NEW ENGLAND JOURNAL OF MEDICINE 371 23 2167 - 2177 2014年12月 [査読有り]
     
    BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P = 0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC.
  • Hisato Kawakami; Isamu Okamoto; Kimio Yonesaka; Kunio Okamoto; Kiyoko Shibata; Yume Shinkai; Haruka Sakamoto; Michiko Kitano; Takao Tamura; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOTARGET 5 23 11847 - 11856 2014年12月 [査読有り]
     
    We previously showed that tumor-derived heregulin, a ligand for HER3, is associated with both de novo and acquired resistance to cetuximab. We have now examined whether patritumab, a novel neutralizing monoclonal antibody to HER3, is able to overcome such resistance. Human colorectal cancer (DiFi) cells that are highly sensitive to cetuximab were engineered to stably express heregulin by retroviral infection, and the effects of cetuximab and patritumab on the resulting DiFi-HRG cells were examined. DiFi-HRG cells released substantial amounts of heregulin and showed resistance to cetuximab. Cetuximab alone inhibited EGFR and ERK phosphorylation in DiFi-HRG cells, but it had no effect on the phosphorylation of HER2, HER3, or AKT, suggesting that sustained AKT activation by HER2 and HER3 underlies cetuximab resistance in these cells. In contrast, patritumab in combination with cetuximab markedly inhibited the phosphorylation of EGFR, HER2, HER3, ERK, and AKT. The combination therapy also inhibited the growth of DiFi-HRG tumor xenografts in nude mice to a greater extent than did treatment with either drug alone. Activation of HER2-HER3 signaling associated with the operation of a heregulin autocrine loop confers resistance to cetuximab, and patritumab is able to restore cetuximab sensitivity through inhibition of heregulin-induced HER3 activation.
  • Yuko Kawano; Isamu Okamoto; Haruhiko Fukuda; Yuichiro Ohe; Shinichiro Nakamura; Kazuhiko Nakagawa; Katsuyuki Hotta; Katsuyuki Kiura; Yuichi Takiguchi; Hideo Saka; Hiroaki Okamoto; Koichi Takayama; Hiroshi Semba; Kunihiko Kobayashi; Hirotsugu Kenmotsu; Masahiro Tsuboi; Nobuyuki Yamamoto; Toshihiro Nukiwa; Yoichi Nakanishi
    Respiratory Investigation 52 6 339 - 347 2014年11月 [査読有り]
     
    The performance of scientifically and ethically valid prospective clinical trials is the only means by which to obtain reliable clinical evidence that can improve clinical practice and thus the outcome of patients with lung cancer. The efficacy of treatment for advanced lung cancer remains limited many cooperative study groups for lung cancer have been established in Japan since 1990s, and they have completed several landmark investigator-initiated clinical trials. This review highlights eight active Japanese cooperative study groups for lung cancer and summarizes their achievements made through clinical trials. In addition to their benefits, the existence of multiple study groups for a single disease such as lung cancer presents several challenges including the provision of infrastructure to ensure the scientific integrity of trial results, the unnecessary duplication of effort and the wasting of limited resources, and the accrual and completion of large-scale phase III trials in the shortest possible time. Collaboration among Japanese cooperative groups has recently increased in order to overcome these challenges. Although institutional barriers to the performance of such large intergroup trials remain, further harmonization and collaboration among cooperative groups will be vital in allowing Japanese investigators to make further important contributions for the development of new lung cancer therapies.
  • 中西 洋一; 池田 徳彦; 江口 研二; 澤 祥幸; 永井 完治; 中川 和彦; 早川 和重; 光冨 徹哉; 山本 信之
    肺癌 54 5 301 - 301 (NPO)日本肺癌学会 2014年10月
  • 高橋 利明; 秋永 士朗; Park Keunchil; Tsai Chun-Ming; 田村 友秀; 山本 信之; 光冨 徹哉; 中川 和彦; ARQ 197 Study Group
    肺癌 54 5 353 - 353 (NPO)日本肺癌学会 2014年10月
  • 金田 裕靖; 清水 俊雄; 樋田 豊明; 村上 晴泰; 軒原 浩; Go Jowell; Jaw-Tsai Sarah; Rolfe Lindsey; 中川 和彦
    肺癌 54 5 351 - 351 2014年10月
  • 林 秀敏; 金田 裕靖; 吉田 健史; 清水 俊雄; 古下 義彦; 飯塚 徳重; Rolfe Lindsey; 加藤 元一; 中川 和彦
    肺癌 54 5 398 - 398 (NPO)日本肺癌学会 2014年10月
  • 原田 眞雄; 西尾 誠人; 木浦 勝行; 瀬戸 貴司; 中川 和彦; 前門戸 任; 井上 彰; 樋田 豊明; 吉岡 弘鎮; 大江 裕一郎; 野上 尚之; 村上 晴泰; 竹内 賢吾; 島田 忠; 田中 智宏; 田村 友秀
    肺癌 54 5 325 - 325 (NPO)日本肺癌学会 2014年10月
  • 野上 尚之; 安宅 信二; 瀬戸 貴司; 高橋 利明; 吉岡 弘鎮; 中川 和彦; 竹尾 貞徳; 藤田 結花; O'Connell Joseph; 大木 恵美子; Zhang Hui; 橋垣 学; Ramalingam Suresh S.
    肺癌 54 5 353 - 353 2014年10月
  • Tsutomu Iwasa; Tsutomu Sakiyama; Junji Tsurutani; Kaoru Tanaka; Takeshi Yoshida; Yoshikane Nonagase; Yasuhito Fujisaka; Takayasu Kurata; Yoshifumi Komoike; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 25 2014年10月 [査読有り]
  • Hiroyasu Kaneda; Masayuki Takeda; Kaoru Tanaka; Takeshi Yoshida; Tsutomu Iwasa; Kunio Okamoto; Hisato Kawakami; Takayuki Takahama; Toshio Shimizu; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 25 2014年10月 [査読有り]
  • Takashi Seto; Terufumi Kato; Makoto Nishio; Koichi Goto; Shinji Atagi; Yukio Hosomi; Noboru Yamamoto; Toyoaki Hida; Makoto Maemondo; Kazuhiko Nakagawa; Seisuke Nagase; Isamu Okamoto; Takeharu Yamanaka; Kosei Tajima; Ryosuke Harada; Masahiro Fukuoka; Nobuyuki Yamamoto
    LANCET ONCOLOGY 15 11 1236 - 1244 2014年10月 [査読有り]
     
    Background With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. Methods In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. Findings Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16.0 months (95% CI 13.9-18.1) with erlotinib plus bevacizumab and 9.7 months (5.7-11.1) with erlotinib alone (hazard ratio 0.54, 95% CI 0.36-0.79; log-rank test p=0.0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). Interpretation Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted.
  • Takayasu Kurata; Junji Tsurutani; Yasuhito Fujisaka; Wataru Okamoto; Hidetoshi Hayashi; Hisato Kawakami; Eisei Shin; Nobuya Hayashi; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 32 5 946 - 954 2014年10月 [査読有り]
     
    Background AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer. Methods Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle). Results Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade a parts per thousand yen3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively. Conclusion Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.
  • Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Shunsuke Sogabe; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio
    INTERNATIONAL JOURNAL OF ONCOLOGY 45 4 1430 - 1436 2014年10月 [査読有り]
     
    Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
  • Takayasu Kurata; Junji Tsurutani; Yasuhito Fujisaka; Wataru Okamoto; Hidetoshi Hayashi; Hisato Kawakami; Eisei Shin; Nobuya Hayashi; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 32 5 946 - 954 2014年10月 [査読有り]
     
    Background AZD8931 is an equipotent, reversible inhibitor of signaling by epidermal growth factor receptor (EGFR), human EGFR 2 (HER2) and HER3. This two-part Japanese study (NCT01003158) assessed the safety/tolerability of AZD8931 monotherapy in patients with advanced solid tumors and in combination with paclitaxel in female patients with advanced breast cancer. Methods Monotherapy part: ascending doses of AZD8931 (40/60/80 mg twice daily [bid]) for 21 consecutive days. Combination part: AZD8931 40 mg bid and paclitaxel 90 mg/m(2) (on days 1, 8 and 15 of a 28-day cycle). Results Seventeen patients received AZD8931: 11 received AZD8931 monotherapy (40/60/80 mg [n = 3/4/4]) and six AZD8931 40 mg bid plus paclitaxel. No dose-limiting toxicities were observed for AZD8931 alone or combined with paclitaxel. The most frequent adverse events (AEs) were diarrhea, paronychia, pustular rash and dry skin (each n = 8) with AZD8931 monotherapy and diarrhea, stomatitis, rash, alopecia, epistaxis and neutropenia (each n = 4) with combination therapy. Grade a parts per thousand yen3 AEs were reported for one, two and four patients in the 40 mg, 60 mg and combination groups, respectively. AZD8931 was rapidly absorbed with a half-life of 12 h. There was no evidence of pharmacokinetic interaction between AZD8931 and paclitaxel. Two patients (one in each part) had unconfirmed and confirmed partial responses, with a duration of 42 and 172 days, respectively. Conclusion Although maximum tolerated dose was not confirmed for AZD8931, based on overall incidence of rash and diarrhea AEs in the 80 mg group, doses up to 60 mg bid as monotherapy and 40 mg bid combined with paclitaxel are the feasible AZD8931 doses in Japanese patients.
  • Akihiro Kogita; Yosuke Togashi; Hidetoshi Hayashi; Shunsuke Sogabe; Masato Terashima; Marco A. De Velasco; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Yoshifumi Takeyama; Kiyotaka Okuno; Kazuhiko Nakagawa; Kazuto Nishio
    INTERNATIONAL JOURNAL OF ONCOLOGY 45 4 1430 - 1436 2014年10月 [査読有り]
     
    Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.
  • Takashi Seto; Terufumi Kato; Makoto Nishio; Koichi Goto; Shinji Atagi; Yukio Hosomi; Noboru Yamamoto; Toyoaki Hida; Makoto Maemondo; Kazuhiko Nakagawa; Seisuke Nagase; Isamu Okamoto; Takeharu Yamanaka; Kosei Tajima; Ryosuke Harada; Masahiro Fukuoka; Nobuyuki Yamamoto
    LANCET ONCOLOGY 15 11 1236 - 1244 2014年10月 [査読有り]
     
    Background With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. Methods In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. Findings Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16.0 months (95% CI 13.9-18.1) with erlotinib plus bevacizumab and 9.7 months (5.7-11.1) with erlotinib alone (hazard ratio 0.54, 95% CI 0.36-0.79; log-rank test p=0.0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). Interpretation Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted.
  • M. Tanioka; K. Sakai; T. Sudo; T. Sakuma; K. Kajimoto; K. Hirokaga; S. Takao; S. Negoro; H. Minami; K. Nakagawa; K. Nishio
    BREAST CANCER RESEARCH AND TREATMENT 147 3 513 - 525 2014年10月 [査読有り]
     
    Several trials have confirmed that the pathological complete response (pCR) rates after neoadjuvant chemotherapy (NAC) are significantly lower in HER2-positive/ER-positive patients than in HER2-positive/ER-negative patients. To understand this phenomenon, we investigated the association between NAC resistance and CCND1, which is frequently overexpressed in ER-positive tumors. Pretreatment formalin-fixed tumor tissues were collected from 75 HER2-positive patients receiving NAC comprised anthracyclines, taxanes, and trastuzumab. Seventeen gene transcripts along with PIK3CA mutations were detected using MassARRAY (Sequenom, San Diego, CA). The gene expression levels were dichotomized according to the median values. The immunohistochemical expression of ER, PTEN, BCL-2, and cyclin D1 was scored. The relationship between the variables was assessed using the Spearman correlation. A logistic regression analysis was performed to detect predictors of pCR, which was defined as no invasive tumor in the breast or axilla. Forty-seven percent of the cases were ER-positive and 52 % (40/63 % in ER-positive/ER-negative) achieved a pCR. Among the ER-positive patients, the CCND1 gene expression level was 2.1 times higher than that in ER-negative patients and was significantly correlated with the expression of cyclin D1 protein. In a univariate analysis, a pCR was associated with high mRNA levels of ESR1, PGR, LMTK3, HER2, IGF1R, INPP4B, PDL-1, BCL-2, and CCND1 (P a parts per thousand currency sign 0.05). In contrast, none of these genes were significantly correlated with a pCR among the ER-negative tumors and only EGFR was significantly correlated with a pCR. PIK3CA mutations or PTEN loss were not associated with a pCR in either group. After excluding ESR1 (r = 0.58), PGR (r = 0.64), and IGF1R (r = 0.59), the expressions of which were correlated with CCND1, a multivariate analysis revealed that CCND1 [P = 0.043; OR, 0.16] and HER2 [P = 0.012; OR, 11.2] retained its predictive value for pCR among ER-positive patients, but not among ER-negative patients. A High Level of CCND1 gene expression is a poor predictor of a pCR and provides a rationale for evaluating CDK4/6 inhibitors in HER2-positive/ER-positive breast cancer patients.
  • 進行固形がん患者に対する焦点接着班キナーゼ(FAK)阻害薬VS-6063のファーストインアジア第1相試験(A first-in-Asian phase I study of VS-6063, a focal adhesion kinase inhibitor in subjects with advanced solid tumors)
    清水 俊雄; 曾田 秀巳; 橋井 千晶; Horobin Joanna; Keegan Mitchell; Padval Mahesh; Poli Anne; 中川 和彦
    日本癌学会総会記事 73回 IS6 - 2 2014年09月
  • Hisato Kawakami; Isamu Okamoto; Wataru Okamoto; Junko Tanizaki; Kazuhiko Nakagawa; Kazuto Nishio
    CANCERS 6 3 1540 - 1552 2014年09月 [査読有り]
     
    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as oncogene addiction. A new generation of drugs that selectively target such driver oncogenes manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an oncogenic driver and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.
  • Hisato Kawakami; Isamu Okamoto; Wataru Okamoto; Junko Tanizaki; Kazuhiko Nakagawa; Kazuto Nishio
    CANCERS 6 3 1540 - 1552 2014年09月 [査読有り]
     
    Certain genetically defined cancers are dependent on a single overactive oncogene for their proliferation and survival, a phenomenon known as oncogene addiction. A new generation of drugs that selectively target such driver oncogenes manifests a clinical efficacy greater than that of conventional chemotherapy in appropriate genetically defined patients. MET is a proto-oncogene that encodes a receptor tyrosine kinase, and aberrant activation of MET signaling occurs in a subset of advanced cancers as result of various genetic alterations including gene amplification, polysomy, and gene mutation. Our preclinical studies have shown that inhibition of MET signaling either with the small-molecule MET inhibitor crizotinib or by RNA interference targeted to MET mRNA resulted in marked antitumor effects in cancer cell lines with MET amplification both in vitro and in vivo. Furthermore, patients with non-small cell lung cancer or gastric cancer positive for MET amplification have shown a pronounced clinical response to crizotinib. Accumulating preclinical and clinical evidence thus suggests that MET amplification is an oncogenic driver and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification. In this review, we provide a rationale for targeting this genetic alteration in cancer therapy.
  • 目崎 久美; 花岡 俊仁; 中川 和彦; 小林 成行; 福原 哲治; 小林 一泰; 白川 敦子
    日本臨床外科学会雑誌 75 9 2247 - 2451 2014年09月 [査読有り]
  • Takeshi Yoshida; Guolin Zhang; Matthew A. Smith; Alex S. Lopez; Yun Bai; Jiannong Li; Bin Fang; John Koomen; Bhupendra Rawal; Kate J. Fisher; Ann Y. Chen; Michiko Kitano; Yume Morita; Haruka Yamaguchi; Kiyoko Shibata; Takafumi Okabe; Isamu Okamoto; Kazuhiko Nakagawa; Eric B. Haura
    CLINICAL CANCER RESEARCH 20 15 4059 - 4074 2014年08月 [査読有り]
     
    Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non-small cell lung cancer (NSCLC), yet they display limited clinical efficacy. Wehypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI-resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry-based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib-treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced antitumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M-mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both codrivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in patients with NSCLC with acquired T790M. (C) 2014 AACR.
  • Kunio Okamoto; Isamu Okamoto; Masayuki Takeda; Shinya Kobayashi; Koji Takeda; Kiyoshi Nakamatsu; Yasumasa Nishimura; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 8 743 - 748 2014年08月 [査読有り]
     
    Objective: The optimal treatment for elderly patients with limited-disease small cell lung cancer has not been defined. We therefore performed a Phase I study for split-dose cisplatin plus etoposide combined with early concurrent accelerated hyperfractionated thoracic radiotherapy in elderly (70 years of age or older) patients with limited-disease small cell lung cancer. Methods: Chemotherapy consisted of cisplatin at 20 or 25 mg/m(2) and etoposide at 80 mg/m(2), both administered on Days 1-3 of a 28-day cycle. Radiotherapy was initiated at the onset of chemotherapy and administered at a dose of 1.5 Gy twice daily over 3 weeks up to a total dose of 45 Gy. Results: Twelve patients with a median age of 76 years (range, 70-85) were enrolled. Dose-limiting toxicities occurred in two (hyponatremia of Grade 4 or cardiac ischemia of Grade 3) of the six patients treated at dose Level 1 as well as in three (perforation of the sigmoid colon of Grade 3, febrile neutropenia of Grade 3, or hyponatremia of Grade 3) of the six patients treated at dose Level 2. The most frequent non-hematologic adverse events included anorexia, fatigue, esophagitis and pneumonitis, but most of these events were of Grade 1 or 2. Conclusions: The recommended dose for cisplatin and etoposide chemotherapy administered on Days 1-3 was determined to be 20 and 80 mg/m(2), respectively. Our results indicate that split-dose cisplatin plus etoposide chemotherapy combined with early concurrent accelerated hyperfractionated thoracic radiotherapy is well tolerated by elderly patients with limited-disease small cell lung cancer.
  • Haruyasu Murakami; Takeharu Yamanaka; Takashi Seto; Kenji Sugio; Isamu Okamoto; Toshiyuki Sawa; Tomonori Hirashima; Koji Takeda; Shinji Atagi; Masahiro Fukuoka; Yoichi Nakanishi; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    CANCER SCIENCE 105 8 989 - 995 2014年08月 [査読有り]
     
    The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60mg/m2) with (groupDZ) or without (groupD) zoledronic acid every 21days. There were 50patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94patients (DZ, 48; D, 46), the median progression-free survival was 2.7months (95% confidence interval [CI], 1.5-3.5months) for the DZ group and 2.6months (95% CI, 1.5-3.4months) for the Dgroup (stratified log-rank test, P=0.89). The median overall survival was 10.4months (95% CI, 7.0-15.8months) for the DZ group and 9.7months (95% CI, 6.1-12.5months) for the Dgroup (stratified log-rank test, P=0.62). There were no clinically relevant differences in the frequencies of grade3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).
  • Haruyasu Murakami; Takeharu Yamanaka; Takashi Seto; Kenji Sugio; Isamu Okamoto; Toshiyuki Sawa; Tomonori Hirashima; Koji Takeda; Shinji Atagi; Masahiro Fukuoka; Yoichi Nakanishi; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    CANCER SCIENCE 105 8 989 - 995 2014年08月 [査読有り]
     
    The aim of this open-label, multicenter, randomized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non-small-cell lung cancer (NSCLC) and bone metastases. In this study, patients randomly received docetaxel (60mg/m2) with (groupDZ) or without (groupD) zoledronic acid every 21days. There were 50patients in each group, and the primary endpoint was progression-free survival. In an efficacy analysis of 94patients (DZ, 48; D, 46), the median progression-free survival was 2.7months (95% confidence interval [CI], 1.5-3.5months) for the DZ group and 2.6months (95% CI, 1.5-3.4months) for the Dgroup (stratified log-rank test, P=0.89). The median overall survival was 10.4months (95% CI, 7.0-15.8months) for the DZ group and 9.7months (95% CI, 6.1-12.5months) for the Dgroup (stratified log-rank test, P=0.62). There were no clinically relevant differences in the frequencies of grade3 or 4 adverse events between the two groups. No treatment-related deaths occurred in the DZ group. Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression-free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone. This trial was registered with the University Hospital Medical Information Network (UMIN000001098).
  • Kunio Okamoto; Isamu Okamoto; Masayuki Takeda; Shinya Kobayashi; Koji Takeda; Kiyoshi Nakamatsu; Yasumasa Nishimura; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 8 743 - 748 2014年08月 [査読有り]
     
    Objective: The optimal treatment for elderly patients with limited-disease small cell lung cancer has not been defined. We therefore performed a Phase I study for split-dose cisplatin plus etoposide combined with early concurrent accelerated hyperfractionated thoracic radiotherapy in elderly (70 years of age or older) patients with limited-disease small cell lung cancer. Methods: Chemotherapy consisted of cisplatin at 20 or 25 mg/m(2) and etoposide at 80 mg/m(2), both administered on Days 1-3 of a 28-day cycle. Radiotherapy was initiated at the onset of chemotherapy and administered at a dose of 1.5 Gy twice daily over 3 weeks up to a total dose of 45 Gy. Results: Twelve patients with a median age of 76 years (range, 70-85) were enrolled. Dose-limiting toxicities occurred in two (hyponatremia of Grade 4 or cardiac ischemia of Grade 3) of the six patients treated at dose Level 1 as well as in three (perforation of the sigmoid colon of Grade 3, febrile neutropenia of Grade 3, or hyponatremia of Grade 3) of the six patients treated at dose Level 2. The most frequent non-hematologic adverse events included anorexia, fatigue, esophagitis and pneumonitis, but most of these events were of Grade 1 or 2. Conclusions: The recommended dose for cisplatin and etoposide chemotherapy administered on Days 1-3 was determined to be 20 and 80 mg/m(2), respectively. Our results indicate that split-dose cisplatin plus etoposide chemotherapy combined with early concurrent accelerated hyperfractionated thoracic radiotherapy is well tolerated by elderly patients with limited-disease small cell lung cancer.
  • Takeshi Yoshida; Guolin Zhang; Matthew A. Smith; Alex S. Lopez; Yun Bai; Jiannong Li; Bin Fang; John Koomen; Bhupendra Rawal; Kate J. Fisher; Ann Y. Chen; Michiko Kitano; Yume Morita; Haruka Yamaguchi; Kiyoko Shibata; Takafumi Okabe; Isamu Okamoto; Kazuhiko Nakagawa; Eric B. Haura
    CLINICAL CANCER RESEARCH 20 15 4059 - 4074 2014年08月 [査読有り]
     
    Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non-small cell lung cancer (NSCLC), yet they display limited clinical efficacy. Wehypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI-resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry-based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib-treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced antitumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M-mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both codrivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in patients with NSCLC with acquired T790M. (C) 2014 AACR.
  • Naruyuki Kobayashi; Tetsuji Fukuhara; Kumi Mesaki; Kazuhiko Nakagawa; Kazuyasu Kobayashi; Toshihito Hanaoka; Satoshi Uchinomura; Tsutomu Kato
    Japanese Journal of Cancer and Chemotherapy 41 7 905 - 907 2014年07月 [査読有り]
     
    A 51-year-old man with a history of an abdominoperineal resection of the rectum and colostomy for rectal cancer underwent chemotherapy for multiple liver metastases. Twenty-two courses of the folinic acid, 5-fluorouracil (5-FU) and oxalipla-tin (FOLFOX4)/bevacizumab (BEV) regimen and 39 courses of 5-FU/Leucovorin/BEV were administered. Progressive splenomegaly and stomal varices were observed during the course of chemotherapy. The patient was admitted due to excessive bleeding after colostomy. Angiography revealed bleeding stomal varices secondary to portal hypertension. Splenectomy was performed with subsequent reduction in the size of the stomal varices and no rebleeding was observed. Oxaliplatin-based chemotherapy could lead to hepatic sinusoidal dilation and induce splenomegaly and varix formation secondary to portal hypertension. Our experience with this case suggests that careful attention should be paid to stomal varices in colostomy patients receiving oxaliplatin-based chemotherapy.
  • Hidehito Horinouchi; Noboru Yamamoto; Hiroshi Nokihara; Takeshi Horai; Makoto Nishio; Fumiyoshi Ohyanagi; Atsushi Horiike; Kazuhiko Nakagawa; Masaaki Terashima; Takafumi Okabe; Hiroyasu Kaneda; Mark D. McKee; Dawn M. Carlson; Hao Xiong; Tomohide Tamura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 74 1 37 - 43 2014年07月 [査読有り]
     
    Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC. Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m(2)) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients. Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib C (max) was 0.32 mu g/mL and AUC(24) was 4.29 mu g h/mL. Linifanib C (max) occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients. Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.
  • Hidehito Horinouchi; Noboru Yamamoto; Hiroshi Nokihara; Takeshi Horai; Makoto Nishio; Fumiyoshi Ohyanagi; Atsushi Horiike; Kazuhiko Nakagawa; Masaaki Terashima; Takafumi Okabe; Hiroyasu Kaneda; Mark D. McKee; Dawn M. Carlson; Hao Xiong; Tomohide Tamura
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 74 1 37 - 43 2014年07月 [査読有り]
     
    Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC. Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m(2)) were administered on day 1 of each 21-day cycle up to a maximum of six cycles. Oral linifanib (7.5 mg) was given to six patients once daily throughout all cycles and escalated to 12.5 mg/day in a second cohort of six patients. Twelve patients received at least one dose of linifanib. The most common adverse events were hematologic and consistent with expected toxicities with carboplatin/paclitaxel. With 12.5 mg linifanib, grade 3/4 neutropenia, leukopenia, and thrombocytopenia occurred in 100, 83, and 83 % of patients, respectively. Dose-limiting grade 4 thrombocytopenia occurred in one patient at each dose level. Linifanib pharmacokinetics was similar to that in non-Japanese patients. At 12.5 mg, linifanib C (max) was 0.32 mu g/mL and AUC(24) was 4.29 mu g h/mL. Linifanib C (max) occurred at 2-3 h with both doses and when given alone or in combination with carboplatin/paclitaxel. Exposure to linifanib appeared to be increased by carboplatin/paclitaxel, and exposure to paclitaxel appeared to be increased by linifanib. Partial responses were observed in nine patients. Linifanib added to carboplatin/paclitaxel is well tolerated in Japanese patients with advanced/metastatic NSCLC. The recommended dose of linifanib with carboplatin/paclitaxel is 12.5 mg, same as for US patients.
  • Yasuhiro Kidera; Hisato Kawakami; Tsutomu Sakiyama; Kunio Okamoto; Kaoru Tanaka; Masayuki Takeda; Hiroyasu Kaneda; Shin-ichi Nishina; Junji Tsurutani; Kimiko Fujiwara; Morihiro Nomura; Yuzuru Yamazoe; Yasutaka Chiba; Shozo Nishida; Takao Tamura; Kazuhiko Nakagawa
    PLOS ONE 9 7 e101902  2014年07月 [査読有り]
     
    Background: Nephrotoxicity remains a problem for patients who receive cisplatin chemotherapy. We retrospectively evaluated potential risk factors for cisplatin-induced nephrotoxicity as well as the potential impact of intravenous magnesium supplementation on such toxicity. Patients and Methods: We reviewed clinical data for 401 patients who underwent chemotherapy including a high dose (>= 60 mg/m(2)) of cisplatin in the first-line setting. Nephrotoxicity was defined as an increase in the serum creatinine concentration of at least grade 2 during the first course of cisplatin chemotherapy, as assessed on the basis of National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The severity of nephrotoxicity was evaluated on the basis of the mean change in the serum creatinine level. Magnesium was administered intravenously to 67 patients (17%). Results: Cisplatin-induced nephrotoxicity was observed in 127 patients (32%). Multivariable analysis revealed that an Eastern Cooperative Oncology Group performance status of 2 (risk ratio, 1.876; P = 0.004) and the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) (risk ratio, 1.357; P = 0.047) were significantly associated with an increased risk for cisplatin nephrotoxicity, whereas intravenous magnesium supplementation was associated with a significantly reduced risk for such toxicity (risk ratio, 0.175; P = 0.0004). The development of hypomagnesemia during cisplatin treatment was significantly associated with a greater increase in serum creatinine level (P = 0.0025). Magnesium supplementation therapy was also associated with a significantly reduced severity of renal toxicity (P = 0.012). Conclusions: A relatively poor performance status and the regular use of NSAIDs were significantly associated with cisplatin-induced nephrotoxicity, although the latter association was marginal. Our findings also suggest that the ability of magnesium supplementation to protect against the renal toxicity of cisplatin warrants further investigation in a prospective trial.
  • 尿タンパク試験紙にBence Jonesタンパクが反応することの検証
    井本真由美; 松村 到; 船内正憲; 中川和彦; 鮫島謙一; 前田裕弘; 森嶋祥之; 中江健市; 上硲俊法; 工藤正俊; 櫻林郁之介
    臨床化学 43 3 217 - 225 2014年07月 [査読有り]
  • Yasuhito Fujisaka; Kazuhiko Nakagawa
    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 103 6 1267 - 72 2014年06月 [査読有り]
  • 洪 泰浩; 西尾 和人; 中川 和彦
    近畿大学医学雑誌 39 1-2 27 - 37 近畿大学医学会 2014年06月 [査読有り]
     
    ドセタキセルは進行非小細胞肺がん治療におけるキードラッグのひとつであり、白金製剤との併用もしくは単剤にて用いられている。しかしながら、薬剤耐性の獲得は必至であり、ドセタキセル耐性非小細胞肺がんに対する有効な薬剤の開発が必要である。我々は、細胞分裂時の紡錘体形成において重要な役割を担うモータープロテインの一つであるEg5を標的とした、新規S-trityl-L-cystein誘導体Compound3の、ドセタキセル耐性非小細胞肺がんにおける有効性について基礎的検討を行った。MTTアッセイによりその細胞増殖抑制効果が、非小細胞肺がん細胞株である、PC-14細胞およびドセタキセル耐性PC-14/TXT細胞において同等であることを確認した。また、その作用機序は、G2/M期における細胞周期の停止およびアポトーシスの誘導であることが示唆された。Eg5阻害剤処理時に観察される典型的なmonoastral spindle formationの誘導についても免疫染色にて、耐性細胞において親株と同様に観察された。アポトーシスの誘導について、耐性株において親株と同等であることをウェスタンブロット及びAPO-BRDUアッセイにより確認した。新規Eg5阻害剤であるCompound3はドセタキセル耐性非小細胞肺がんにおいて有効であることが示唆された。(著者抄録)
  • Zeyu Yang; Kentaro Nakagawa; Aradhan Sarkar; Junichi Maruyama; Hiroaki Iwasa; Yijun Bao; Mari Ishigami-Yuasa; Shigeru Ito; Hiroyuki Kagechika; Shoji Hata; Hiroshi Nishina; Shinya Abe; Masanobu Kitagawa; Yutaka Hata
    MOLECULAR AND CELLULAR BIOLOGY 34 9 1607 - 1621 2014年05月 [査読有り]
     
    The transcriptional coactivator with a PDZ-binding motif (TAZ) cooperates with various transcriptional factors and plays various roles. Immortalized human mammalian epithelial MCF10A cells form spheres when TAZ is overexpressed and activated. We developed a cell-based assay using sphere formation by TAZ-expressing MCF10A cells as a readout to screen 18,458 chemical compounds for TAZ activators. Fifty compounds were obtained, and 47 were confirmed to activate the TAZ-dependent TEAD-responsive reporter activity in HEK293 cells. We used the derived subset of compounds as a TAZ activator candidate minilibrary and searched for compounds that promote myogenesis in mouse C2C12 myoblast cells. In this study, we focused on one compound, IBS008738. IBS008738 stabilizes TAZ, increases the unphosphorylated TAZ level, enhances the association of MyoD with the myogenin promoter, upregulates MyoD-dependent gene transcription, and competes with myostatin in C2C12 cells. TAZ knockdown verifies that the effect of IBS008738 depends on endogenous TAZ in C2C12 cells. IBS008738 facilitates muscle repair in cardiotoxin- induced muscle injury and prevents dexamethasone-induced muscle atrophy. Thus, this cell-based assay is useful to identify TAZ activators with a variety of cellular outputs. Our findings also support the idea that TAZ is a potential therapeutic target for muscle atrophy.
  • Hidetoshi Hayashi; Tokuzo Arao; Kazuko Matsumoto; Hideharu Kimura; Yosuke Togashi; Yoshinori Hirashima; Yosuke Horita; Satoru Iwasa; Natsuko Tsuda Okita; Yoshitaka Honma; Atsuo Takashima; Ken Kato; Tetsuya Hamaguchi; Yasuhiro Shimada; Kazuhiko Nakagawa; Kazuto Nishio; Yasuhide Yamada
    ONCOTARGET 5 9 2588 - 2595 2014年05月 [査読有り]
     
    Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.
  • Hidetoshi Hayashi; Tokuzo Arao; Kazuko Matsumoto; Hideharu Kimura; Yosuke Togashi; Yoshinori Hirashima; Yosuke Horita; Satoru Iwasa; Natsuko Tsuda Okita; Yoshitaka Honma; Atsuo Takashima; Ken Kato; Tetsuya Hamaguchi; Yasuhiro Shimada; Kazuhiko Nakagawa; Kazuto Nishio; Yasuhide Yamada
    ONCOTARGET 5 9 2588 - 2595 2014年05月 [査読有り]
     
    Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.
  • Isamu Okamoto; Kazuko Sakai; Satoshi Morita; Hiroshige Yoshioka; Hiroyasu Kaneda; Koji Takeda; Tomonori Hirashima; Yoshihito Kogure; Tatsuo Kimura; Toshiaki Takahashi; Shinji Atagi; Takashi Seto; Toshiyuki Sawa; Masashi Yamamoto; Miyako Satouchi; Motoyasu Okuno; Seisuke Nagase; Koichi Takayama; Keisuke Tomii; Tadashi Maeda; Satoshi Oizumi; Shinji Fujii; Yusaku Akashi; Kazumi Nishino; Noriyuki Ebi; Kazuhiko Nakagawa; Yoichi Nakanishi; Kazuto Nishio
    ONCOTARGET 5 8 2293 - 2304 2014年04月 [査読有り]
     
    Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from advanced NSCLC patients enrolled in LETS phase III trial comparing first-line S-1/carboplatin with paclitaxel/carboplatin and subjected to multiplex genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel) with the Sequenom MassARRAY platform. MET amplification was evaluated by fluorescence in situ hybridization. A somatic mutation in at least one gene was identified in 48% of non-squamous cell carcinoma and 45% of squamous cell carcinoma specimens, with EGFR (17%), TP53 (11%), STK11 (9.8%), MET (7.6%), and KRAS (6.2%). Mutations in EGFR or KRAS were associated with a longer or shorter median overall survival, respectively. The LungFusion Panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and a RET fusion in one case (0.4%), with these three types of rearrangement being mutually exclusive. Nine (3.9%) of 229 patients were found to be positive for de novo MET amplification. This first multiplex genotyping of NSCLC associated with a phase III trial shows that MassARRAY-based genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE specimens of NSCLC tissue.
  • Miyako Satouchi; Yoshikazu Kotani; Taro Shibata; Masahiko Ando; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Yukito Ichinose; Yuichiro Ohe; Makoto Nishio; Toyoaki Hida; Koji Takeda; Tatsuo Kimura; Koichi Minato; Akira Yokoyama; Shinji Atagi; Haruhiko Fukuda; Tomohide Tamura; Nagahiro Saijo
    JOURNAL OF CLINICAL ONCOLOGY 32 12 1262 - + 2014年04月 [査読有り]
     
    Purpose This randomized phase III trial was conducted to confirm noninferiority of amrubicin plus cisplatin (AP) compared with irinotecan plus cisplatin (IP) in terms of overall survival (OS) in chemotherapy-naive patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Chemotherapy-naive patients with ED-SCLC were randomly assigned to receive IP, composed of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 every 4 weeks, or AP, composed of amrubicin 40 mg/m(2) on days 1, 2, and 3 and cisplatin 60 mg/m(2) on day 1 every 3 weeks. Results A total of 284 patients were randomly assigned to IP (n = 142) and AP (n = 142) arms. The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. In updated analysis, median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85), median progression-free survival was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was 72.3% (IP) versus 77.9% (AP; P = .33). Adverse events observed in IP and AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). Conclusion AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan.
  • Miyako Satouchi; Yoshikazu Kotani; Taro Shibata; Masahiko Ando; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Yukito Ichinose; Yuichiro Ohe; Makoto Nishio; Toyoaki Hida; Koji Takeda; Tatsuo Kimura; Koichi Minato; Akira Yokoyama; Shinji Atagi; Haruhiko Fukuda; Tomohide Tamura; Nagahiro Saijo
    JOURNAL OF CLINICAL ONCOLOGY 32 12 1262 - + 2014年04月 [査読有り]
     
    Purpose This randomized phase III trial was conducted to confirm noninferiority of amrubicin plus cisplatin (AP) compared with irinotecan plus cisplatin (IP) in terms of overall survival (OS) in chemotherapy-naive patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Chemotherapy-naive patients with ED-SCLC were randomly assigned to receive IP, composed of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 every 4 weeks, or AP, composed of amrubicin 40 mg/m(2) on days 1, 2, and 3 and cisplatin 60 mg/m(2) on day 1 every 3 weeks. Results A total of 284 patients were randomly assigned to IP (n = 142) and AP (n = 142) arms. The point estimate of OS hazard ratio (HR) for AP to IP in the second interim analysis exceeded the noninferior margin (HR, 1.31), resulting in early publication because of futility. In updated analysis, median survival time was 17.7 (IP) versus 15.0 months (AP; HR, 1.43; 95% CI, 1.10 to 1.85), median progression-free survival was 5.6 (IP) versus 5.1 months (AP; HR, 1.42; 95% CI, 1.16 to 1.73), and response rate was 72.3% (IP) versus 77.9% (AP; P = .33). Adverse events observed in IP and AP arms were grade 4 neutropenia (22.5% v 79.3%), grade 3 to 4 febrile neutropenia (10.6% v 32.1%), and grade 3 to 4 diarrhea (7.7% v 1.4%). Conclusion AP proved inferior to IP in this trial, perhaps because the efficacy of amrubicin as a salvage therapy was differentially beneficial to IP. IP remains the standard treatment for extensive-stage SCLC in Japan.
  • Isamu Okamoto; Kazuko Sakai; Satoshi Morita; Hiroshige Yoshioka; Hiroyasu Kaneda; Koji Takeda; Tomonori Hirashima; Yoshihito Kogure; Tatsuo Kimura; Toshiaki Takahashi; Shinji Atagi; Takashi Seto; Toshiyuki Sawa; Masashi Yamamoto; Miyako Satouchi; Motoyasu Okuno; Seisuke Nagase; Koichi Takayama; Keisuke Tomii; Tadashi Maeda; Satoshi Oizumi; Shinji Fujii; Yusaku Akashi; Kazumi Nishino; Noriyuki Ebi; Kazuhiko Nakagawa; Yoichi Nakanishi; Kazuto Nishio
    ONCOTARGET 5 8 2293 - 2304 2014年04月 [査読有り]
     
    Archival formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected from advanced NSCLC patients enrolled in LETS phase III trial comparing first-line S-1/carboplatin with paclitaxel/carboplatin and subjected to multiplex genotyping for 214 somatic hotspot mutations in 26 genes (LungCarta Panel) and 20 major variants of ALK, RET, and ROS1 fusion genes (LungFusion Panel) with the Sequenom MassARRAY platform. MET amplification was evaluated by fluorescence in situ hybridization. A somatic mutation in at least one gene was identified in 48% of non-squamous cell carcinoma and 45% of squamous cell carcinoma specimens, with EGFR (17%), TP53 (11%), STK11 (9.8%), MET (7.6%), and KRAS (6.2%). Mutations in EGFR or KRAS were associated with a longer or shorter median overall survival, respectively. The LungFusion Panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and a RET fusion in one case (0.4%), with these three types of rearrangement being mutually exclusive. Nine (3.9%) of 229 patients were found to be positive for de novo MET amplification. This first multiplex genotyping of NSCLC associated with a phase III trial shows that MassARRAY-based genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE specimens of NSCLC tissue.
  • Tomohiro Maniwa; Masahiro Endo; Mitsuhiro Isaka; Kazuo Nakagawa; Yasuhisa Ohde; Takehiro Okumura; Haruhiko Kondo
    SURGERY TODAY 44 3 494 - 498 2014年03月 [査読有り]
     
    Interstitial lung disease (ILD) has been associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). The effectiveness of 2-[18]-fluoro-2-deoxy-d-glucose (F-18-FDG) positron emission tomography (PET) for staging lung cancer is well established. This study investigates the association of FDG uptake on PET in patients with AE of ILD. The subjects of this retrospective study were 1309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September, 2002 and January, 2011. ILD was diagnosed with chest computed tomography in 95 patients, 81 of whom underwent F-18-FDG PET before surgery. Six patients suffered from AE after surgery (AE group), while the remaining 75 (non-AE group) did not. We investigated the clinico-pathological findings and the results of FDG uptake on PET using the value of the I/M ratio, which is the ratio of the peak of standardized uptake value (SUV) of the ILD area to the mean SUV of the mediastinum. There was no significant difference in clinico-pathological findings, but a significance difference in the I/M ratio (P = 0.0102). The FDG uptake in PET may be a predictive factor for AE of ILD in patients who have undergone lung cancer surgery.
  • Ikuo Sekine; Hiroaki Okamoto; Takeshi Horai; Kazuhiko Nakagawa; Hironobu Ohmatsu; Akira Yokoyama; Nobuyuki Katakami; Masahiko Shibuya; Nagahiro Saijo; Masahiro Fukuoka
    CLINICAL LUNG CANCER 15 2 96 - 102 2014年03月 [査読有り]
     
    This study compared amrubicin monotherapy with carboplatin/etoposide combination therapy in elderly Japanese patients with extensive-disease small-cell lung cancer (ED-SCLC). The trial was prematurely closed owing to 3 treatment-related deaths in the amrubicin arm. Overall survival in the amrubicin and carboplatin/etoposide arms was 10.9 months and 11.3 months, respectively. Amrubicin monotherapy at 40 to 45 mg/m(2) was toxic and intolerable in elderly Japanese patients with ED-SCLC. Introduction: The efficacy and safety of amrubicin, a third-generation synthetic anthracycline, were evaluated by comparison with carboplatin/etoposide combination therapy in elderly Japanese patients with extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods: Eligibility included histologically or cytologically proven SCLC, no previous systemic chemotherapy, performance status of 0 to 2, and age >= 70 years. Patients received amrubicin (70-74 years old, 40-45 mg/m(2); >= 75 years old, 40 mg/m(2)) intravenously on days 1 to 3 every 3 weeks for 4 to 6 cycles or carboplatin (area under the curve of 5 intravenously on day 1) and etoposide (80 mg/m(2) intravenously on days 1 to 3) every 3 weeks for 4 to 6 cycles. Results: The target number of patients was 130 with 65 in each arm. However, the study was terminated early owing to 3 treatment-related deaths in the amrubicin arm, and only 62 patients (median age, 76 years; range, 70-88 years) were enrolled. The characteristics of the patients in the amrubicin and carboplatin/etoposide arms did not differ significantly. Overall survival, time to progression, and objective response rate were 10.9 vs. 11.3 months (P = .7353), 4.7 vs. 4.4 months, and 74.2% (23 of 31) vs. 60.0% (18 of 30), respectively, and quality of life showed no significant difference between the 2 arms. Higher incidences of febrile neutropenia and interstitial lung disease of grade 3 or worse occurred with amrubicin (34.4% vs. 3.3% and 12.5% vs. 0%, respectively). Conclusion: These results indicate that amrubicin monotherapy at 40 to 45 mg/m(2) is toxic and intolerable in elderly Japanese patients with ED-SCLC. (C) 2014 Elsevier Inc. All rights reserved.
  • H. Murakami; T. Kurata; Y. Onozawa; J. Watanabe; A. Ono; T. Takahashi; N. Yamamoto; Y. Fujisaka; H. Kiyota; H. Hayashi; K. Tanaka; K. Nakagawa; S. Kuroda
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 73 3 623 - 630 2014年03月 [査読有り]
     
    To determine ombrabulin's maximum tolerated dose and dose recommended for Japanese patients with advanced solid tumors and to assess its antitumor activity and overall safety and pharmacokinetic profiles. This was a multi-center, open-label, sequential-cohort, dose-escalation phase I study of ombrabulin, a vascular disrupting agent, administered once every 3 weeks. Patients were treated with 15.5, 25, 35, or 50 mg/m(2) ombrabulin over a 30-min intravenous infusion. The recommended dose was the highest dose at which < 33 % of all evaluable patients experienced dose-limiting toxicities (DLTs) during the first treatment cycle or 50 mg/m(2) (recommended in Caucasian patients) if the previous definition was not met. Fifteen patients were treated. No DLT occurred with 15.5, 25, or 35 mg/m(2) ombrabulin. In the 50 mg/m(2) group, one patient had Grade 3 lymphopenia, and another experienced Grade 2 hypertension and Grade 3 diarrhea judged as DLTs. The most frequent related adverse events in this group were diarrhea, nausea, and hypertension. Two patients had Grade 3 anemia, one at the 15.5 mg/m(2) and the other at the 50 mg/m(2). No AEs necessitating dose reduction or Grade 4 AEs were observed. Overall, five patients had stable disease. Pharmacokinetic parameters were comparable to those in non-Japanese patients. Ombrabulin treatment once every 3 weeks was well tolerated in Japanese patients with advanced solid tumors. The dose recommended is 50 mg/m(2), as in Caucasian patients. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients (funded by Sanofi; ClinicalTrials.gov number, NCT00968916).
  • T. Harada; A. Hamada; M. Shimokawa; K. Takayama; S. Kudoh; K. Maeno; S. Saeki; H. Miyawaki; A. Moriyama; K. Nakagawa; Y. Nakanishi
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 2 127 - 133 2014年02月 [査読有り]
     
    This study reports the findings of a Phase I/II, cohort, dose-escalation trial of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor. This study aimed to determine the dose-limiting toxicity of the combination and to define the maximum-tolerated dose, as a recommended dose for Phase II trials. We also sought to obtain preliminary data on the efficacy of this combination as a frontline therapy for extensive-disease small-cell lung cancer. We included 23 chemo-nave patients with extensive-disease small-cell lung cancer in the trial. The amrubicin dose was escalated from 35 to 40 mg/m(2) (Levels 1 and 2, respectively) to determine the dose-limiting toxicity, with an unchanged dose of irinotecan at 50 mg/m(2). Of nine patients, three experienced dose-limiting toxicities at Level 1 of prolonged Grade 4 neutropenia, Grade 3 febrile neutropenia and Grade 3 febrile neutropenia with Grade 3 diarrhea. At Level 2, two patients experienced dose-limiting toxicities of Grade 4 neutropenia and Grade 3 neutropenia with Grade 4 diarrhea. The maximum-tolerated doses and recommended doses for amrubicin and irinotecan were therefore determined to be 35 and 50 mg/m(2), respectively. The Level 1 trial was then expanded to 21 patients, 14 (70) of whom showed partial responses to the recommended dose. The median progression-free and overall survival times were 6.37 and 15.21 months, respectively. The combination of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor produced a potent effect in chemo-nave extensive-disease small-cell lung cancer patients. The use of biomarkers for this regimen may identify patients who are likely to suffer from treatment-ending severe adverse effects.
  • James Chih-Hsin Yang; Yi-Long Wu; Valorie Chan; Johan Kurnianda; Kazuhiko Nakagawa; Nagahiro Saijo; Masahiro Fukuoka; Gael McWalter; Rose McCormack; Tony S. K. Mok
    LUNG CANCER 83 2 174 - 181 2014年02月 [査読有り]
     
    Objectives: Epidermal growth factor receptor (EGFR) mutation testing is standard practice after lung adenocarcinoma diagnosis, and provision of high-quality tumor tissue is ideal. However, there are knowledge gaps regarding the utility of cytology or low tumor content histology samples to establish EGFR mutation status, particularly with regard to the proportion of testing performed using these sample types, and the lack of an established link with efficacy of treatment. Methods: The randomized phase III Iressa Pan-ASia Study (IPASS; ClinicalTrials.gov identifier NCT00322452) of first-line gefitinib versus chemotherapy analyzed samples meeting preplanned specifications (n = 437 evaluable for EGFR mutation; n = 261 mutation-positive). This supplementary analysis assessed tumor content and mutation status of histology (n = 99) and cytology samples (n = 116) which were previously unanalyzed due to sample quality, type, and tumor content (<100 cells). Objective response rate (ORR) and change in tumor size with gefitinib treatment were assessed. Results: EGFR mutation testing was successful in 80% and 19% of previously unanalyzed histology and cytology samples, respectively. Mutations were detected in 54 tumors previously described as mutation-unknown (histology, n = 45; cytology, n = 9). ORRs in mutation-positive cytology (83%) and histology (74%) subgroups were consistent with previous analyses (71%). Tumor size decrease was consistent across previously analyzed and unanalyzed samples (all mutation subgroups), with less consistency across ORRs in mutation-negative cytology (16%) and histology (25%) subgroups versus the previous analysis (1%). Conclusions: Histology samples with low tumor content and cytology samples can be used for EGFR mutation testing; patients whose mutation status was confirmed using these sample types achieved a response to treatment consistent with those confirmed using high-quality histology samples. Better sample quantity/quality can potentially reduce false-negative results. (C) 2013 The Authors. Published by Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 9 2 200 - 204 2014年02月 [査読有り]
     
    Introduction: Somatic mutations in the epidermal growth factor receptor gene (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). Clinical indicators of the likely survival benefit of EGFR-TKI treatment in NSCLC patients with EGFR mutations have not been identified, however. We therefore evaluated progression-free survival (PFS) and overall survival (OS) according to tumor response and tumor shrinkage pattern in such patients. Methods: Among 145 EGFR mutation-positive NSCLC patients treated with EGFR-TKIs, 68 individuals were selected for analysis. Results: Of the 68 selected patients, 6 achieved a complete response (CR), 42 a partial response (PR), and 14 stable disease (SD). Both PFS and OS were significantly longer in patients who achieved a CR or PR than in those who experienced SD. Multivariate analysis showed that a response (CR or PR) to EGFR-TKIs was significantly associated with both PFS and OS. Among the CR/PR group, the median maximal tumor shrinkage relative to baseline was 56%, and the median time to response (TTR) was 4.2 weeks. The subsets of these patients who experienced rapid tumor regression (TTR of 4.2 weeks) or a high degree of tumor shrinkage (56%) did not show a more favorable PFS or OS compared with those who experienced slow tumor regression or a low degree of tumor shrinkage. Conclusion: Response (CR or PR) may represent the optimal surrogate for efficacy among EGFR mutation-positive NSCLC patients treated with EGFR-TKIs.
  • Nakamura Y; Nishizaka Y; Ariyasu R; Okamoto N; Yoshida M; Taki M; Nagano H; Hanaoka K; Nakagawa K; Yoshimura C; Wakayama T; Amitani R
    Internal medicine (Tokyo, Japan) 53 2 139 - 143 2014年 [査読有り]
  • Asuki Fukatsu; Futoshi Ishiguro; Ichidai Tanaka; Takumi Kudo; Kentaro Nakagawa; Keiko Shinjo; Yutaka Kondo; Makiko Fujii; Yoshinori Hasegawa; Kenji Tomizawa; Tetsuya Mitsudomi; Hirotaka Osada; Yutaka Hata; Yoshitaka Sekido
    LUNG CANCER 83 1 23 - 29 2014年01月 [査読有り]
     
    Background: Ras-Association Family1A (RASSF1A) is a well-established tumor suppressor. Ten RASSF homologues comprise this family, and each member is considered a tumor suppressor. RASSF3 is one of the RASSF family members, but its function has not yet been clarified. Recently, we found that RASSF3 interacts with MDM2 and facilitates its ubiquitination, which induces apoptosis through p53 stabilization. However, the role of RASSF3 in human malignancies remains largely unknown. Patients and methods: Ninety-five non-small cell lung cancer (NSCLC) patients from Nagoya University Hospital and 45 NSCLC patients from Aichi Cancer Center Hospital underwent pulmonary resection at each hospital, and lung cancer and corresponding non-cancerous lung tissues were collected. The expression levels of RASSF3 were analyzed using quantitative real-time reverse transcription PCR. We performed statistical analysis to investigate the correlation with RASSF3 expression and the clinicopathological characteristics. We also transfected RASSF3-siRNA into NSCLC cells, and performed motility assays to evaluate the influence on migration ability. Results: RASSF3 expression levels were downregulated in 125 of a total 140 NSCLCs. In a multi-variate logistic regression analysis, the low RASSF3 expression group below the median value was independently correlated with progressive phenotypes (lymph node metastasis and pleural invasion), non-adenocarcinoma histology and wild-type epidermal growth factor receptor (EGFR) status. In motility assays, RASSF3-knockdown NSCLC cells increased the migration rate compared to the control cells. Conclusions: We found that the expression levels of RASSF3 were frequently downregulated in NSCLCs. Downregulation of RASSF3 strongly correlated with the progressive phenotypes of NSCLCs and EGFR wildtype status. In vitro studies also suggested that RASSF3 downregulation increases migration ability of lung cancer cells. Together, our findings indicate RASSF3 is a candidate tumor suppressor gene of NSCLCs. (C) 2013 Elsevier Ireland Ltd. All rights reserved.
  • Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer.
    Kogita A; Togashi Y; Hayashi H; Banno E; Terashima M; De Velasco MA; Sakai K; Fujita Y; Tomida S; Takeyama Y; Okuno K; Nakagawa K; Nishio K
    Int J Oncol. 46 3 1025 - 1030 2014年 [査読有り]
  • Pemetrexed Continuation Maintenance in Patients with Nonsquamous Non-small Cell Lung Cancer: Review of Two East Asian Trials in Reference to PARAMOUNT.
    Yang JC; Ahn MJ; Nakagawa K; Tamura T; Barraclough H; Enatsu S; Cheng R; Orlando M
    Cancer Res Treat. 2014年 [査読有り]
  • Current status and future perspectives of cooperative study groups for lung cancer in Japan.
    Kawano Y; Okamoto I; Fukuda H; Ohe Y; Nakamura S; Nakagawa K; Hotta K; Kiura K; Takiguchi Y; Saka H; Okamoto H; Takayama K; Semba H; Kobayashi K; Kenmotsu H; Tsuboi M; Yamamoto N; Nukiwa T; Nakanishi Y
    Respir Investig. 52 6 339 - 347 2014年 [査読有り]
  • Chemotherapeutic drugs that penetrate the blood-brain barrier affect the development of hyperactive delirium in cancer patients.
    Matsuoka H; Yoshiuchi K; Koyama A; Otsuka M; Nakagawa K
    Palliat Support Care. 1 - 6 2014年 [査読有り]
  • Survival outcome assessed according to tumor response and shrinkage pattern in patients with EGFR mutation-positive non-small-cell lung cancer treated with gefitinib or erlotinib.
    Takeda M; Okamoto I; Nakagawa K
    J Thorac Oncol. 9 2 200 - 204 2014年 [査読有り]
  • Kaoru Kubota; Toyoaki Hida; Satoshi Ishikura; Junki Mizusawa; Makoto Nishio; Masaaki Kawahara; Akira Yokoyama; Fumio Imamura; Koji Takeda; Shunichi Negoro; Masao Harada; Hiroaki Okamoto; Nobuyuki Yamamoto; Tetsu Shinkai; Hiroshi Sakai; Kaoru Matsui; Kazuhiko Nakagawa; Taro Shibata; Nagahiro Saijo; Tomohide Tamura
    LANCET ONCOLOGY 15 1 106 - 113 2014年01月 [査読有り]
     
    Background Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. Methods We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1: 1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. Findings 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). Interpretation Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC.
  • Kaoru Kubota; Toyoaki Hida; Satoshi Ishikura; Junki Mizusawa; Makoto Nishio; Masaaki Kawahara; Akira Yokoyama; Fumio Imamura; Koji Takeda; Shunichi Negoro; Masao Harada; Hiroaki Okamoto; Nobuyuki Yamamoto; Tetsu Shinkai; Hiroshi Sakai; Kaoru Matsui; Kazuhiko Nakagawa; Taro Shibata; Nagahiro Saijo; Tomohide Tamura
    LANCET ONCOLOGY 15 1 106 - 113 2014年01月 [査読有り]
     
    Background Four cycles of etoposide plus cisplatin and accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard of care for limited-stage small-cell lung cancer (SCLC). Irinotecan plus cisplatin significantly improved overall survival compared with etoposide plus cisplatin for extensive-stage SCLC. We compared these regimens for overall survival of patients with limited-stage SCLC. Methods We did this phase 3 study in 36 institutions in Japan. Eligibility criteria included age 20-70 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ functions. Eligible patients with previously untreated limited-stage SCLC received one cycle of etoposide plus cisplatin (intravenous etoposide 100 mg/m(2) on days 1-3; intravenous cisplatin 80 mg/m(2) on day 1) plus AHTRT (1.5 Gy twice daily, 5 days a week, total 45 Gy over 3 weeks). Patients without progressive disease following induction therapy were randomised (1: 1 ratio, using a minimisation method with biased-coin assignment balancing on ECOG performance status [0 vs 1], response to induction chemoradiotherapy [complete response plus near complete response vs partial response and stable disease], and institution) to receive either three further cycles of consolidation etoposide plus cisplatin or irinotecan plus cisplatin (intravenous irinotecan 60 mg/m(2) on days 1, 8, 15; intravenous cisplatin 60 mg/m(2) on day 1). Patients, physicians, and investigators were aware of allocation. The primary endpoint was overall survival after randomisation; primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00144989, and the UMIN Clinical Trials Registry, number C000000095. Findings 281 patients were enrolled between Sept 1, 2002, and Oct 2, 2006. After induction etoposide plus cisplatin and AHTRT, 258 patients were randomised to consolidation etoposide plus cisplatin (n=129) or irinotecan plus cisplatin (n=129). In the etoposide plus cisplatin group, median overall survival was 3.2 years (95% CI 2.4-4.1). In the irinotecan and cisplatin group, median overall survival was 2.8 years (95% CI 2.4-3.6); overall survival did not differ between the two groups (hazard ratio 1.09 [95% CI 0.80-1.46], one-sided stratified log-rank p=0.70). The most common adverse events of grade 3 or 4 were neutropenia (120 [95%] in the etoposide plus cisplatin group vs 101 [78%] in the irinotecan plus cisplatin group), anaemia (44 [35%] vs 50 [39%]), thrombocytopenia (26 [21%] vs six [5%]), febrile neutropenia (21 [17%] vs 18 [14%]), and diarrhoea (two [2%] vs 13 [10%]). There was one treatment-related adverse event leading to death in each group (radiation pneumonitis in the etoposide plus cisplatin group; brain infarction in the irinotecan plus cisplatin group). Interpretation Four cycles of etoposide plus cisplatin and AHTRT should continue to be the standard of care for limited-stage SCLC.
  • Yosuke Togashi; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuto Nishio
    DRUG DESIGN DEVELOPMENT AND THERAPY 8 1037 - 1046 2014年 [査読有り]
     
    Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood-brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted.
  • Takeshi Okuda; Hidetoshi Hayashi; Mitsugu Fujita; Hiromasa Yoshioka; Takayuki Tasaki; Kazuhiko Nakagawa; Amami Kato
    Metallography, Microstructure, and Analysis 3 4 211 - 214 2014年 [査読有り]
     
    Meningeal carcinomatosis (MC) is a refractory disease with a dismal prognosis, and no therapeutic strategy has been established to date. Herein we report a case of lung adenocarcinoma-derived MC in which the patient’s performance status was dramatically improved by administration of gefitinib suspension via a nasogastric tube. The patient was a 71-year-old woman who was originally admitted to our hospital for a progressive headache and subsequently presented with severe consciousness disturbance. Cerebrospinal fluid examination and systemic imaging studies revealed MC that was derived from lung adenocarcinoma. Moreover, epidermal growth factor receptor (EGFR) mutations were detected in the tumor cells. Since the patient suffered from hydrocephalus, a ventriculoperitoneal shunt was placed. Nevertheless, her consciousness disturbance persisted. Subsequently, gefitinib suspension was prepared and administered via nasogastric tube, which dramatically improved her consciousness level and enabled her to tolerate oral intake. She died 14 months after the disease onset. The observations in this case report suggest that gefitinib might be a therapeutic option for patients with MC derived from cancers harboring EGFR mutations even though the patient exhibited severe consciousness disturbance.
  • Hiromichi Matsuoka; Junji Tsurutani; Junko Tanizaki; Tsutomu Iwasa; Yoshifumi Komoike; Atsuko Koyama; Kazuhiko Nakagawa
    BMC Research Notes 6 1 541  2013年12月 [査読有り]
     
    Background: Eribulin is a recently approved new therapeutic option for patients with metastatic breast cancer. According to several reports, eribulin has limited ability to cross the blood brain barrier. Recently, capecitabine and eribulin have been recognized as drugs with similar application for patients with advanced breast cancer. Although there have been several case reports describing the efficacy of capecitabine against brain metastases, no report of eribulin demonstrating efficacy for brain metastases exists today. Case presentation. We describe a case of a 57-year-old Japanese woman who was diagnosed with breast cancer stage IV metastasized to multiple organs including liver and lung. After she received 3 regimens, she showed evidence of brain metastases, and whole brain radiation therapy was performed. Lapatinib and capecitabine was then administered as fourth-line chemotherapy, but the patient was hospitalized due to the exacerbation of interstitial pneumonitis and progression of brain and liver metastases. To control the systemic disease, eribulin was commenced as fifth-line chemotherapy. One month later, a significant response of brain metastases had been achieved, and this response has persisted for the last 4 months. We now describe a remarkable antitumor effect of eribulin against brain metastases from breast cancer. This case is the first report which indicates potential treatment of brain metastases using this medication. Conclusion: This report suggests that eribulin treatment may be beneficial for breast cancer patients with brain metastases progressing after whole brain radiation therapy. However, further clinical studies are warranted to determine the clinical effect of eribulin in brain metastases. © 2013 Matsuoka et al. licensee BioMed Central Ltd.
  • Hidetoshi Hayashi; Isamu Okamoto; Shinya Ueda; Kaoru Tanaka; Kunio Okamoto; Hisato Kawakami; Shinichi Nishina; Masayuki Takeda; Yasuhito Fujisaka; Taroh Satoh; Kyoichi Terao; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Anticancer research 33 12 5699 - 705 2013年12月 [査読有り]
     
    AIM: We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%. CONCLUSION: This combination was well-tolerated and manifested a promising activity against HNSCC.
  • Asuka Tsuya; Takayasu Kurata; Akihiro Tamiya; Isamu Okamoto; Shinya Ueda; Daisuke Sakai; Naotoshi Sugimoto; Koji Matsumoto; Isao Goto; Nobuyuki Yamamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 6 1568 - 1572 2013年12月 [査読有り]
     
    Background Carcinomas of unknown primary site (CUPs) are heterogeneous tumors associated with a poor prognosis. This phase II trial was designed to evaluate the efficacy and safety of a novel combination chemotherapy of S-1 and cisplatin (CDDP) in patients with CUP. Patients and Methods Patients with previously untreated CUPs were eligible for this trial. The treatment schedule consisted of oral S-1 (40 mg/m(2)) twice a day on days 1-21, and intravenous CDDP (60 mg/m(2)) on day 8. This schedule was repeated every 5 weeks. Results A total of 46 patients were enrolled. The overall response rate and the disease control rate were 41.3 % and 80.4 %, respectively. The median overall survival time was 17.4 months. Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3 %, 13.0 %, and 2.2 % of the patients, respectively. Conclusion CDDP plus S-1 combination chemotherapy is well tolerated and active first-line empiric therapies for patients with CUP.
  • Asuka Tsuya; Takayasu Kurata; Akihiro Tamiya; Isamu Okamoto; Shinya Ueda; Daisuke Sakai; Naotoshi Sugimoto; Koji Matsumoto; Isao Goto; Nobuyuki Yamamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 6 1568 - 1572 2013年12月 [査読有り]
     
    Background Carcinomas of unknown primary site (CUPs) are heterogeneous tumors associated with a poor prognosis. This phase II trial was designed to evaluate the efficacy and safety of a novel combination chemotherapy of S-1 and cisplatin (CDDP) in patients with CUP. Patients and Methods Patients with previously untreated CUPs were eligible for this trial. The treatment schedule consisted of oral S-1 (40 mg/m(2)) twice a day on days 1-21, and intravenous CDDP (60 mg/m(2)) on day 8. This schedule was repeated every 5 weeks. Results A total of 46 patients were enrolled. The overall response rate and the disease control rate were 41.3 % and 80.4 %, respectively. The median overall survival time was 17.4 months. Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3 %, 13.0 %, and 2.2 % of the patients, respectively. Conclusion CDDP plus S-1 combination chemotherapy is well tolerated and active first-line empiric therapies for patients with CUP.
  • Hidetoshi Hayashi; Isamu Okamoto; Shinya Ueda; Kaoru Tanaka; Kunio Okamoto; Hisato Kawakami; Shinichi Nishina; Masayuki Takeda; Yasuhito Fujisaka; Taroh Satoh; Kyoichi Terao; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Anticancer research 33 12 5699 - 705 2013年12月 [査読有り]
     
    AIM: We performed a pharmacokinetic phase I trial of the combination of S-1 granules and nedaplatin for head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients were treated with both nedaplatin on day 1 at a dose starting at 80 mg/m(2) (level 1) escalating up to 90 mg/m(2) (level 2), and S-1 granules at a daily dose of 80 mg/m(2) on days 1 to 14 every three weeks. The primary end-point was determination of the recommended dose. RESULTS: Twenty patients were enrolled. Dose-limiting toxicities occurred in one out of six patients at dose level 1 (neutropenia) and in all three patients at level 2 (neutropenia and thrombocytopenia). The recommended dose was determined as level 1. Pharmacokinetic parameters of S-1 granule did not differ from the capsula formulation. The response rate was 42.1%. CONCLUSION: This combination was well-tolerated and manifested a promising activity against HNSCC.
  • Hisato Kawakami; Isamu Okamoto; Kyoichi Terao; Kazuko Sakai; Minoru Suzuki; Shinya Ueda; Kaoru Tanaka; Kiyoko Kuwata; Yume Morita; Koji Ono; Kazuto Nishio; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    CANCER MEDICINE 2 6 933 - 941 2013年12月 [査読有り]
     
    Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immunohistochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214; 95% confidence interval, 0.074-0.614; P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese.
  • 鶴谷 純司; 中川 和彦
    外科 75 12 1403 - 1408 (株)南江堂 2013年11月
  • N. Yamamoto; H. Murakami; H. Hayashi; Y. Fujisaka; T. Hirashima; K. Takeda; M. Satouchi; K. Miyoshi; S. Akinaga; T. Takahashi; K. Nakagawa
    BRITISH JOURNAL OF CANCER 109 11 2803 - 2809 2013年11月 [査読有り]
     
    Background: A previous clinical study in non-small cell lung cancer (NSCLC) patients in Western countries suggested the potential for combination of a first-in-class non-ATP-competitive c-Met inhibitor tivantinib with an epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib. Polymorphisms of CYP2C19, the key metabolic enzyme for tivantinib, should be addressed to translate the previous Western study to Asian population, because higher incidence of poor metabolisers (PMs) is reported in Asian population. Methods: Japanese patients with advanced/metastatic NSCLC received tivantinib in combination with erlotinib to evaluate safety and pharmacokinetics. Doses of tivantinib were escalated separately for extensive metabolisers (EMs) and PMs. Results: Tivantinib, when combined with erlotinib, was well tolerated up to 360 mg BID for EMs and 240 mg BID for PMs, respectively. Among 25 patients (16 EMs and 9 PMs), the adverse events (AEs) related to tivantinib and/or erlotinib (420%, any grade) were rash, diarrhoea, dry skin and nausea. Grade >= 3 AEs were leukopenia, anaemia and neutropenia. No dose-limiting toxicity was observed. Pharmacokinetics profile of tivantinib was not clearly different between the combination and monotherapy. Three partial response and three long-term stable disease (>= 24 weeks) were reported. Conclusion: Two doses of tivantinib in combination with erlotinib were recommended based on CYP2C19 genotype: 360 mg BID for EMs and 240 mg BID for PMs.
  • Hiromichi Matsuoka; Chihiro Makimura; Atsuko Koyama; Masatomo Otsuka; Kiyohiro Sakai; Ryo Sakamoto; Kazuhiko Nakagawa
    PSYCHO-ONCOLOGY 22 229 - 229 2013年11月 [査読有り]
  • Junichi Shimizu; Fumihiko Hirai; Takeharu Yamanaka; Keni-chi Taguchi; Haruko Daga; Yoshihito Kogure; Tatsuo Kimura; Kaoru Tanaka; Yasuo Iwamoto; Akira Ono; Hidefumi Sasaki; Junya Fukuoka; Kenichi Nishiyama; Koji Takeda; Takashi Seto; Yukito Ichinose; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF THORACIC ONCOLOGY 8 S270 - S270 2013年11月 [査読有り]
  • Takayasu Kurata; Yasuhito Fujisaka; Kaoru Tanaka; Toshihiro Kudo; Kunio Okamoto; Junji Tsurutani; Hiroyasu Kaneda; Isamu Okamoto; Masayuki Namiki; Chifumi Kitamura; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 8 S935 - S935 2013年11月 [査読有り]
  • Wataru Okamoto; Takayuki Yoshino; Toshiaki Takahashi; Isamu Okamoto; Shinya Ueda; Asuka Tsuya; Narikazu Boku; Kazuto Nishio; Masahiro Fukuoka; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 72 5 1063 - 1071 2013年11月 [査読有り]
     
    Nimotuzumab is a humanized IgG(1) monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors. Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens. Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression. Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.
  • Wataru Okamoto; Takayuki Yoshino; Toshiaki Takahashi; Isamu Okamoto; Shinya Ueda; Asuka Tsuya; Narikazu Boku; Kazuto Nishio; Masahiro Fukuoka; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 72 5 1063 - 1071 2013年11月 [査読有り]
     
    Nimotuzumab is a humanized IgG(1) monoclonal antibody to the epidermal growth factor receptor (EGFR) and has demonstrated the absence of severe dermatological toxicity commonly caused by other EGFR-targeting antibodies. We conducted a phase I study to assess toxicities, pharmacokinetics, pharmacodynamics, and predictive biomarkers of nimotuzumab administered in Japanese patients with advanced solid tumors. Three dose levels, 100, 200, and 400 mg, of weekly i.v. nimotuzumab were given until disease progression or drug intolerability. Four patients with solid tumors were enrolled in each dose level. The expression and gene copy number of EGFR or its downstream transducers were investigated using skin biopsy samples and tumor specimens. Planned dose escalation was completed without dose-limiting toxicity, and maximum tolerated dose was not reached. No allergic reaction and hypomagnesaemia were observed, and grade 3 or 4 toxicity did not occur. The common toxicity was skin rash (58 %); however, all of them were grade 1 or 2. In skin biopsies, no correlation was shown between doses and the phosphorylation of EGFR or its downstream signal transducers. Of 11 evaluable patients, no objective response was obtained, while 8 patients had stable disease (73 %). Patients with a higher-EGFR gene copy number level measured by FISH showed a longer time to progression. Nimotuzumab administered weekly was feasible and well tolerated up to 400 mg in Japanese patients. A low dermatological toxicity could be a notable advantage as anti-EGFR mAb, and further evaluation is warranted.
  • Hiroaki Iwasa; Takumi Kudo; Sainawaer Maimaiti; Mitsunobu Ikeda; Junichi Maruyama; Kentaro Nakagawa; Yutaka Hata
    JOURNAL OF BIOLOGICAL CHEMISTRY 288 42 30320 - 30329 2013年10月 [査読有り]
     
    Ras association domain family (RASSF) 6 is a member of the C-terminal RASSF proteins such as RASSF1A and RASSF3. RASSF6 is involved in apoptosis in various cells under miscellaneous conditions, but it remains to be clarified how RASSF6 exerts tumor-suppressive roles. We reported previously that RASSF3 facilitates the degradation of MDM2, a major E3 ligase of p53, and stabilizes p53 to function as a tumor suppressor. In this study, we demonstrate that RASSF6 overexpression induces G(1)/S arrest in p53-positive cells. Its depletion prevents UV- and VP-16-induced apoptosis and G(1)/S arrest in HCT116 and U2OS cells. RASSF6-induced apoptosis partially depends on p53. RASSF6 binds MDM2 and facilitates its ubiquitination. RASSF6 depletion blocks the increase of p53 in response to UV exposure and up-regulation of p53 target genes. RASSF6 depletion delays DNA repair in UV- and VP-16-treated cells and increases polyploid cells after VP-16 treatment. These findings indicate that RASSF6 stabilizes p53, regulates apoptosis and the cell cycle, and functions as a tumor suppressor. Together with the previous reports regarding RASSF1A and RASSF3, the stabilization of p53 may be the common function of the C-terminal RASSF proteins.
  • 澤 祥幸; 安宅 信二; 横山 晶; 岡本 浩明; 高橋 利明; 大江 裕一郎; 千場 博; 武田 晃司; 野上 尚之; 森 清志; 中川 和彦; 原田 眞雄; 工藤 新三; 富澤 由雄; 竹田 雄一郎; 樋田 豊明; 片上 信之; 石倉 聡; 田村 友秀
    肺癌 53 5 390 - 390 (NPO)日本肺癌学会 2013年10月
  • 楠本 昌彦; 酒井 文和; 上甲 剛; 荒川 浩明; 福岡 正博; 工藤 翔二; 安藤 昌彦; 大江 裕一郎; 中川 和彦; 山崎 直也; 弦間 昭彦; 谷口 博之; 井上 義一; 海老名 雅仁; 桑野 和善; 福田 悠; 関 顕洋; エルロチニブ適正使用検討委員会
    肺癌 53 5 366 - 366 (NPO)日本肺癌学会 2013年10月
  • 海老名 雅仁; 福岡 正博; 工藤 翔二; 安藤 昌彦; 大江 裕一郎; 中川 和彦; 山崎 直也; 荒川 浩明; 井上 義一; 楠本 昌彦; 桑野 和善; 弦間 昭彦; 酒井 文和; 上甲 剛; 谷口 博之; 福田 悠; 関 顕洋
    肺癌 53 5 469 - 469 (NPO)日本肺癌学会 2013年10月
  • Isamu Okamoto; Keisuke Aoe; Terufumi Kato; Yukio Hosomi; Akira Yokoyama; Fumio Imamura; Katsuyuki Kiura; Tomonori Hirashima; Makoto Nishio; Naoyuki Nogami; Hiroaki Okamoto; Hideo Saka; Nobuyuki Yamamoto; Naoto Yoshizuka; Risa Sekiguchi; Kazuhiro Kiyosawa; Kazuhiko Nakagawa; Tomohide Tamura
    Investigational New Drugs 31 5 1395 - 1396 2013年10月 [査読有り]
  • Isamu Okamoto; Keisuke Aoe; Terufumi Kato; Yukio Hosomi; Akira Yokoyama; Fumio Imamura; Katsuyuki Kiura; Tomonori Hirashima; Makoto Nishio; Naoyuki Nogami; Hiroaki Okamoto; Hideo Saka; Nobuyuki Yamamoto; Naoto Yoshizuka; Risa Sekiguchi; Kazuhiro Kiyosawa; Kazuhiko Nakagawa; Tomohide Tamura
    Investigational New Drugs 31 5 1275 - 1282 2013年10月 [査読有り]
     
    Introduction This study prospectively evaluated the efficacy and safety of pemetrexed and carboplatin followed by maintenance pemetrexed in chemo-naïve patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Methods A total of 109 patients received pemetrexed (500 mg/m 2) and carboplatin (area under the curve = 6 mg/mL·min) every 21 days. For patients without disease progression after 4 cycles, pemetrexed was continued until disease progression or unacceptable toxicity. Pre-planned subgroup analysis results based on the presence of epidermal growth factor receptor (EGFR) mutations are also presented. Results The median number of treatment cycles was 5 (range: 1-30) in the entire study period. Most of the grade ≥3 toxicities observed were hematologic in nature, with no increase in the relative incidence associated with continuation maintenance therapy with pemetrexed. Among the 106 total patients assessable for efficacy, the objective response rate was 35.8 %, median progression free survival (PFS) 5.7 months, and median overall survival (OS) 20.2 months. Sixty patients received maintenance pemetrexed (median: 4 cycles, range: 1-26 cycles) median PFS from the beginning of induction treatment was 7.5 months. From the subgroup analysis for EGFR mutation status, the median OS of EGFR wild-type patients (n = 61) was 20.2 months. Conclusions Pemetrexed/carboplatin followed by pemetrexed was well tolerated and active for front-line treatment of advanced nonsquamous NSCLC. Encouraging survival outcomes were observed even in EGFR-wild type patients. © 2013 Springer Science+Business Media New York.
  • Kunio Okamoto; Isamu Okamoto; Masaki Miyazaki; Kaoru Tanaka; Hiroyasu Kaneda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 5 1364 - 1366 2013年10月 [査読有り]
     
    We report contemporaneous bronchoscopic findings for a case of bevacizumab-related pulmonary hemorrhage in a patient with advanced non-small cell lung cancer (NSCLC). Flexible bronchoscopy at diagnosis revealed abnormal capillary dilation that was suggestive of endobronchial involvement at the primary tumor location. The patient developed massive hemoptysis despite of marked tumor shrinkage achieved by bevacizumab-containing chemotherapy. Emergency flexible bronchoscopy for hemoptysis suggested that the location of the primary tumor was the source of bleeding. Subsequent follow-up flexible bronchoscopy revealed an ulcerative mucosal-like lesion associated with a white necrotic substance as well as attenuation of the dilation of submucosal vessels compared with that apparent at diagnosis. Our case report highlights the potential mechanistic insights into bevacizumab-related bleeding and importance of performing bronchoscopy at diagnosis in NSCLC patients, given that abnormal bronchoscopic findings may be a risk factor for bleeding.
  • Isamu Okamoto; Keisuke Aoe; Terufumi Kato; Yukio Hosomi; Akira Yokoyama; Fumio Imamura; Katsuyuki Kiura; Tomonori Hirashima; Makoto Nishio; Naoyuki Nogami; Hiroaki Okamoto; Hideo Saka; Nobuyuki Yamamoto; Naoto Yoshizuka; Risa Sekiguchi; Kazuhiro Kiyosawa; Kazuhiko Nakagawa; Tomohide Tamura
    Investigational New Drugs 31 5 1275 - 1282 2013年10月 [査読有り]
     
    Introduction This study prospectively evaluated the efficacy and safety of pemetrexed and carboplatin followed by maintenance pemetrexed in chemo-naïve patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Methods A total of 109 patients received pemetrexed (500 mg/m 2) and carboplatin (area under the curve = 6 mg/mL·min) every 21 days. For patients without disease progression after 4 cycles, pemetrexed was continued until disease progression or unacceptable toxicity. Pre-planned subgroup analysis results based on the presence of epidermal growth factor receptor (EGFR) mutations are also presented. Results The median number of treatment cycles was 5 (range: 1-30) in the entire study period. Most of the grade ≥3 toxicities observed were hematologic in nature, with no increase in the relative incidence associated with continuation maintenance therapy with pemetrexed. Among the 106 total patients assessable for efficacy, the objective response rate was 35.8 %, median progression free survival (PFS) 5.7 months, and median overall survival (OS) 20.2 months. Sixty patients received maintenance pemetrexed (median: 4 cycles, range: 1-26 cycles) median PFS from the beginning of induction treatment was 7.5 months. From the subgroup analysis for EGFR mutation status, the median OS of EGFR wild-type patients (n = 61) was 20.2 months. Conclusions Pemetrexed/carboplatin followed by pemetrexed was well tolerated and active for front-line treatment of advanced nonsquamous NSCLC. Encouraging survival outcomes were observed even in EGFR-wild type patients. © 2013 Springer Science+Business Media New York.
  • Kunio Okamoto; Isamu Okamoto; Masaki Miyazaki; Kaoru Tanaka; Hiroyasu Kaneda; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 5 1364 - 1366 2013年10月 [査読有り]
     
    We report contemporaneous bronchoscopic findings for a case of bevacizumab-related pulmonary hemorrhage in a patient with advanced non-small cell lung cancer (NSCLC). Flexible bronchoscopy at diagnosis revealed abnormal capillary dilation that was suggestive of endobronchial involvement at the primary tumor location. The patient developed massive hemoptysis despite of marked tumor shrinkage achieved by bevacizumab-containing chemotherapy. Emergency flexible bronchoscopy for hemoptysis suggested that the location of the primary tumor was the source of bleeding. Subsequent follow-up flexible bronchoscopy revealed an ulcerative mucosal-like lesion associated with a white necrotic substance as well as attenuation of the dilation of submucosal vessels compared with that apparent at diagnosis. Our case report highlights the potential mechanistic insights into bevacizumab-related bleeding and importance of performing bronchoscopy at diagnosis in NSCLC patients, given that abnormal bronchoscopic findings may be a risk factor for bleeding.
  • Yoshihito Kogure; Fumihiko Hirai; Takeharu Yamanaka; Kenichi Taguchi; Koji Takeda; Haruko Daga; Tatsuo Kimura; Junichi Shimizu; Kaoru Tanaka; Yasuo Iwamoto; Akira Ono; Hidefumi Sasaki; Junya Fukuoka; Kenichi Nishiyama; Takashi Seto; Yukito Ichinose; Kazuhiko Nakagawa; Yoichi Nakanishi
    JOURNAL OF THORACIC ONCOLOGY 8 22 - 22 2013年09月 [査読有り]
  • Hisato Kawakami; Isamu Okamoto; Hidetoshi Hayashi; Masataka Taguri; Satoshi Morita; Kazuhiko Nakagawa
    European Journal of Cancer 49 14 3003 - 3009 2013年09月 [査読有り]
     
    Background With the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer. Patients and methods A literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated. Results The average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365). Conclusion An increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer. © 2013 Elsevier Ltd. All rights reserved.
  • Hisato Kawakami; Isamu Okamoto; Hidetoshi Hayashi; Masataka Taguri; Satoshi Morita; Kazuhiko Nakagawa
    European Journal of Cancer 49 14 3003 - 3009 2013年09月 [査読有り]
     
    Background With the increasing availability of active agents, the importance of postprogression survival (PPS) has been recognised for several malignancies. However, little is known of PPS in advanced gastric cancer. Patients and methods A literature search identified 43 randomised trials in chemotherapy-naive patients with advanced gastric cancer. We partitioned overall survival (OS) into progression-free survival (PFS) and PPS, and then examined the correlation between median OS and either median PFS or median PPS. The correlation between differences in OS (ΔOS) and those in PFS (ΔPFS) between trial arms was also investigated. Results The average median OS was significantly longer in recent (2006 and later) trials than in older (2005 and earlier) trials (10.60 versus 8.64 months, P < 0.001), as was the average median PPS (5.34 versus 3.74 months, P = 0.001). Median PPS was correlated with median OS for all trials (r = 0.732), and this correlation was more pronounced in recent trials (r = 0.850). By contrast, the correlation between median PFS and median OS was less pronounced in recent trials (r = 0.282), as was that between ΔPFS and ΔOS (r = 0.365). Conclusion An increase in median PPS was found in accordance with an increase in median OS in recent trials compared with older trials for patients with advanced gastric cancer. © 2013 Elsevier Ltd. All rights reserved.
  • Sano T; Takeuchi S; Nakagawa T; Ishikawa D; Nanjo S; Yamada T; Nakamura T; Matsumoto K; Yano S
    International journal of cancer 133 2 505 - 13 2013年07月 [査読有り]
     
    Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical problem in the management of patients with EGFR mutant lung cancer. Several mechanisms have been reported involved in this acquired resistance, including hepatocyte growth factor (HGF) activation of an alternative pathway. PI3K and mTOR are downstream molecules of receptor tyrosine kinases, such as EGFR and Met, and are thought to be ideal targets for controlling various tumor types. We assessed whether BEZ235, a dual inhibitor of PI3K and mTOR, could overcome the EGFR-TKI resistance induced by HGF in an EGFR mutant lung cancer model. Exogenous and endogenous HGF triggered resistance to erlotinib in the PC-9 and HCC827, EGFR mutant lung cancer cell lines. BEZ235 alone inhibited the viability of PC-9 and HCC827 cells in vitro, irrespective of the presence or the absence of HGF. Using a xenograft model of severe combined immunodeficient mice with HGF-gene-transfected PC-9 cells (PC-9/HGF), we found that BEZ235 inhibited tumor growth, whereas erlotinib did not. BEZ235 monotherapy also inhibited the phosphorylation of Akt and p70S6K/S6RP, downstream molecules of PI3K and mTOR, respectively, as well as suppressing tumor-cell proliferation and angiogenesis of PC-9/HGF tumors. These results suggest that BEZ235, even as monotherapy, may be useful in managing HGF-induced EGFR-TKI resistance in EGFR mutant lung cancer.
  • Maniwa T; Okumura T; Isaka M; Nakagawa K; Ohde Y; Kondo H
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 44 1 e59 - 64 2013年07月 [査読有り]
  • Hiromichi Matsuoka; Takayasu Kurata; Isamu Okamoto; Hiroyasu Kaneda; Kaoru Tanaka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 31 19 E322 - E323 2013年07月 [査読有り]
  • Hiromichi Matsuoka; Takayasu Kurata; Isamu Okamoto; Hiroyasu Kaneda; Kaoru Tanaka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 31 19 E322 - E323 2013年07月 [査読有り]
  • 乳癌骨転移患者に対するゾレドロン酸使用における後方観察研究
    柳江 正嗣; 鶴谷 純司; 松岡 弘道; 藤島 成; 安積 達也; 橋本 幸彦; 菰池 佳史; 藤原 季美子; 木寺 康裕; 野村 守弘; 中川 和彦; 山添 譲
    日本乳癌学会総会プログラム抄録集 21回 293 - 293 (一社)日本乳癌学会 2013年06月
  • エリブリンと各種乳癌治療薬との交叉耐性の検討
    鶴谷 純司; 松岡 弘道; 岡本 邦男; 清水 俊雄; 倉田 宝保; 中川 和彦; 藤島 成; 安積 達也; 橋本 幸彦; 菰池 佳史
    日本乳癌学会総会プログラム抄録集 21回 352 - 352 (一社)日本乳癌学会 2013年06月
  • Alice T. Shaw; Dong-Wan Kim; Kazuhiko Nakagawa; Takashi Seto; Lucio Crino; Myung-Ju Ahn; Tommaso De Pas; Benjamin Besse; Benjamin J. Solomon; Fiona Blackhall; Yi-Long Wu; Michael Thomas; Kenneth J. O'Byrne; Denis Moro-Sibilot; D. Ross Camidge; Tony Mok; Vera Hirsh; Gregory J. Riely; Shrividya Iyer; Vanessa Tassell; Anna Polli; Keith D. Wilner; Pasi A. Jaenne
    NEW ENGLAND JOURNAL OF MEDICINE 368 25 2385 - 2394 2013年06月 [査読有り]
     
    Background In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. Methods We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. Results The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P = 0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. Conclusions Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement.
  • Takashi Seto; Katsuyuki Kiura; Makoto Nishio; Kazuhiko Nakagawa; Makoto Maemondo; Akira Inoue; Toyoaki Hida; Nobuyuki Yamamoto; Hiroshige Yoshioka; Masao Harada; Yuichiro Ohe; Naoyuki Nogami; Kengo Takeuchi; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    LANCET ONCOLOGY 14 7 590 - 598 2013年06月 [査読有り]
     
    Background Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. Methods In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC.
  • Yoshikazu Hasegawa; Isamu Okamoto; Ken Takezawa; Masaaki Miyazaki; Junji Tsurutani; Kimio Yonesaka; Ryotaroh Morinaga; Asuka Tsuya; Masaaki Terashima; Toshihiro Kudoh; Koichi Azuma; Takayasu Kurata; Tatsuyuki Nishikawa; Masahiro Fukuoka; Yasumasa Nishimura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 3 599 - 604 2013年06月 [査読有り]
     
    Background A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (a parts per thousand yen70 years of age) patients with locally advanced non-small cell lung cancer. Methods S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m(-2) day(-1). TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n = 6) or 80 (n = 6) mg m(-2) day(-1). Results All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n = 2), infection (n = 1), and stomatitis (n = 1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m(-2) day(-1). No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. Conclusions Administration of S-1 at 80 mg m(-2) day(-1) on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.
  • Hiroaki Akamatsu; Akira Inoue; Tetsuya Mitsudomi; Kunihiko Kobayashi; Kazuhiko Nakagawa; Keita Mori; Toshihiro Nukiwa; Yoichi Nakanishi; Nobuyuki Yamamoto
    Japanese journal of clinical oncology 43 6 664 - 8 2013年06月 [査読有り]
     
    OBJECTIVE: Interstitial lung disease associated with gefitinib is a critical adverse reaction. When geftinib was administered to EGFR-unknown patients, the interstitial lung disease incidence rate was approximately 3-4% in Japan, and usually occurs during the first 4 weeks of treatment. However, it has not been fully investigated in EGFR-mutated patients. METHODS: We collected clinical records of participants of two Phase III trials (WJTOG 3405 and NEJ 002), which compared gefitinib with platinum doublet chemotherapy. All patients were EGFR mutated, chemo-naïve and had good performance status. RESULTS: A total of 402 patients were enrolled in this study. In the gefitinib arm, 10 (5.0%) of 201 patients developed interstitial lung disease, of whom five (2.5%) were Grade 3 or greater, with two deaths (1.0%). In contrast, only one patient developed interstitial lung disease (Grade 1) in the chemotherapy arm. With regard to gefitinib, smoking history was significantly associated with developing interstitial lung disease (odds ratio 0.18; 95% confidence interval: 0.05-0.74; P = 0.01). The cumulative incidence rate of interstitial lung disease was similar in the 0-4, 5-8 and 9-12 week time periods. However, between smokers and never-smokers, cumulative incidence rates in the first 4 weeks were significantly different (4.7% versus 0%, P = 0.03). Three of 10 patients developed interstitial lung disease after 8 weeks of gefitinib administration (days 135, 171 and 190, respectively). CONCLUSIONS: Among EGFR-mutated patients, the incidence of interstitial lung disease associated with gefitinib was not different from that in previous reports. Smoking history was associated with developing interstitial lung disease, and smokers had a higher incidence rate of interstitial lung disease in the first 4 weeks.
  • Yoshiko Urata; Isamu Okamoto; Masayuki Takeda; Yoshihiro Hattori; Keiko Okuno; Temiko Shimada; Takayasu Kurata; Hiroyasu Kaneda; Masaki Miyazaki; Masaaki Terashima; Kaoru Tanaka; Satoshi Morita; Kazuhiko Nakagawa; Shunichi Negoro; Miyako Satouchi
    CANCER 119 12 2275 - 2281 2013年06月 [査読有り]
     
    BACKGROUND A previous phase 3 trial demonstrated noninferiority in terms of overall survival for combined S-1 (an oral fluoropyrimidine) and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). In the current study, the authors evaluated the efficacy and safety of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC. METHODS Patients received carboplatin (area under the concentration-time curve, 5 mg mL-1 per minute) and bevacizumab (15mg/kg) on day 1 plus oral S-1 (80 mg/m2 per day) on days 1 through 14 every 21 days for up to 6 cycles. For patients without disease progression, S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed. RESULTS Forty-eight patients were enrolled in the phase 2 study; of these, 35 patients (72.9%) completed at least 4 cycles. Most toxicities of grade 3 were hematologic, and no increase in relative incidence associated with maintenance with S-1 and bevacizumab was observed. The objective response rate was 54.2% (95% confidence interval, 39.2%-68.6%), and the median progression-free survival was 6.8 months (95% confidence interval, 4.3-8.2 months). CONCLUSIONS The regimen of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC. Cancer 2013;119:2275-2281. (c) 2013 American Cancer Society.
  • Yoshihito Kogure; Masahiko Ando; Hideo Saka; Yasutaka Chiba; Nobuyuki Yamamoto; Kazuhiro Asami; Tomonori Hirashima; Takashi Seto; Seisuke Nagase; Kojiro Otsuka; Kazuhiro Yanagihara; Koji Takeda; Isamu Okamoto; Takuya Aoki; Koichi Takayama; Masahiro Yamasaki; Shinzo Kudoh; Nobuyuki Katakami; Mikinori Miyazaki; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 8 6 753 - 758 2013年06月 [査読有り]
     
    Introduction: Smoking status is one of the prognostic factors in advanced non-small-cell lung cancer (NSCLC). Currently, adenocarcinoma (Ad) histology is considered a predictive factor in advanced NSCLC. We investigated the correlation between histology or smoking status and survival of NSCLC patients receiving chemotherapy. Methods: We retrospectively reviewed clinical data from stage IIIB or IV NSCLC patients who started first-line chemotherapy at affiliated institutions of West Japan Oncology Group from 2004 to 2005. We also collected information on pack-years of cigarette smoking and years since cessation. Overall survival was compared using log-rank test, and Cox regression analysis was used to identify independent prognostic factors. Results: In total, 2542 consecutive patients were enrolled at 40 institutions. Of those, 71 were excluded because of unknown smoking history. The median overall survival of nonsmoking Ad patients (593 days) was longer than that of smoking Ad, nonsmoking non-Ad, and smoking non-Ad patients (384, 374, and 319 days, respectively; p < 0.001). In Cox regression with sex, age, stage, performance, and treatment as covariates, we found significant interaction (p = 0.039) between histology (Ad/non-Ad) and smoking status (smoker/non-smoker); smoking conferred a hazard ratio of 1.34 (95% confidence interval, 1.15-1.55) in Ad, but only 0.99 (0.75-1.31) in non-Ad. Higher pack-years and shorter period since cessation were significantly associated with poorer survival in Ad (p < 0.001), but not in non-Ad (p >= 0.434). Conclusion: Ad histology is associated with better prognosis, and only smoking status had a prognostic impact in Ad.
  • Yoshikazu Hasegawa; Isamu Okamoto; Ken Takezawa; Masaaki Miyazaki; Junji Tsurutani; Kimio Yonesaka; Ryotaroh Morinaga; Asuka Tsuya; Masaaki Terashima; Toshihiro Kudoh; Koichi Azuma; Takayasu Kurata; Tatsuyuki Nishikawa; Masahiro Fukuoka; Yasumasa Nishimura; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 31 3 599 - 604 2013年06月 [査読有り]
     
    Background A phase I study was performed to evaluate dose-limiting toxicity and the recommended dose for the oral fluoropyrimidine S-1 administered concurrently with thoracic radiotherapy (TRT) in elderly (a parts per thousand yen70 years of age) patients with locally advanced non-small cell lung cancer. Methods S-1 was administered on days 1 to 14 and 22 to 35 at oral doses of 65 or 80 mg m(-2) day(-1). TRT was administered in 2-Gy fractions five times weekly for a total dose of 60 Gy. Twelve previously untreated patients were treated with S-1 at 65 (n = 6) or 80 (n = 6) mg m(-2) day(-1). Results All patients completed the planned 60 Gy of TRT. Dose-limiting toxicity included pneumonitis (n = 2), infection (n = 1), and stomatitis (n = 1), each of grade 3, but each event was reversible. The recommended dose for S-1 was determined to be 80 mg m(-2) day(-1). No patient experienced toxicity of grade 4. The dose intensity of S-1 was well maintained and the combination of S-1 plus TRT was well tolerated overall. The overall response rate was 83.3 %, with a median survival time of 34.0 months. Conclusions Administration of S-1 at 80 mg m(-2) day(-1) on days 1 to 14 and 22 to 35 can be safely combined with concurrent TRT in elderly patients with locally advanced non-small cell lung cancer.
  • Yoshiko Urata; Isamu Okamoto; Masayuki Takeda; Yoshihiro Hattori; Keiko Okuno; Temiko Shimada; Takayasu Kurata; Hiroyasu Kaneda; Masaki Miyazaki; Masaaki Terashima; Kaoru Tanaka; Satoshi Morita; Kazuhiko Nakagawa; Shunichi Negoro; Miyako Satouchi
    CANCER 119 12 2275 - 2281 2013年06月 [査読有り]
     
    BACKGROUND A previous phase 3 trial demonstrated noninferiority in terms of overall survival for combined S-1 (an oral fluoropyrimidine) and carboplatin compared with combined paclitaxel and carboplatin as first-line treatment for advanced non-small cell lung cancer (NSCLC). In the current study, the authors evaluated the efficacy and safety of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab in chemotherapy-naive patients with advanced nonsquamous NSCLC. METHODS Patients received carboplatin (area under the concentration-time curve, 5 mg mL-1 per minute) and bevacizumab (15mg/kg) on day 1 plus oral S-1 (80 mg/m2 per day) on days 1 through 14 every 21 days for up to 6 cycles. For patients without disease progression, S-1 and bevacizumab were continued until disease progression or unacceptable toxicity developed. RESULTS Forty-eight patients were enrolled in the phase 2 study; of these, 35 patients (72.9%) completed at least 4 cycles. Most toxicities of grade 3 were hematologic, and no increase in relative incidence associated with maintenance with S-1 and bevacizumab was observed. The objective response rate was 54.2% (95% confidence interval, 39.2%-68.6%), and the median progression-free survival was 6.8 months (95% confidence interval, 4.3-8.2 months). CONCLUSIONS The regimen of combined S-1, carboplatin, and bevacizumab followed by maintenance with S-1 and bevacizumab was active and feasible as first-line treatment for advanced nonsquamous NSCLC. Cancer 2013;119:2275-2281. (c) 2013 American Cancer Society.
  • Yoshihito Kogure; Masahiko Ando; Hideo Saka; Yasutaka Chiba; Nobuyuki Yamamoto; Kazuhiro Asami; Tomonori Hirashima; Takashi Seto; Seisuke Nagase; Kojiro Otsuka; Kazuhiro Yanagihara; Koji Takeda; Isamu Okamoto; Takuya Aoki; Koichi Takayama; Masahiro Yamasaki; Shinzo Kudoh; Nobuyuki Katakami; Mikinori Miyazaki; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 8 6 753 - 758 2013年06月 [査読有り]
     
    Introduction: Smoking status is one of the prognostic factors in advanced non-small-cell lung cancer (NSCLC). Currently, adenocarcinoma (Ad) histology is considered a predictive factor in advanced NSCLC. We investigated the correlation between histology or smoking status and survival of NSCLC patients receiving chemotherapy. Methods: We retrospectively reviewed clinical data from stage IIIB or IV NSCLC patients who started first-line chemotherapy at affiliated institutions of West Japan Oncology Group from 2004 to 2005. We also collected information on pack-years of cigarette smoking and years since cessation. Overall survival was compared using log-rank test, and Cox regression analysis was used to identify independent prognostic factors. Results: In total, 2542 consecutive patients were enrolled at 40 institutions. Of those, 71 were excluded because of unknown smoking history. The median overall survival of nonsmoking Ad patients (593 days) was longer than that of smoking Ad, nonsmoking non-Ad, and smoking non-Ad patients (384, 374, and 319 days, respectively; p < 0.001). In Cox regression with sex, age, stage, performance, and treatment as covariates, we found significant interaction (p = 0.039) between histology (Ad/non-Ad) and smoking status (smoker/non-smoker); smoking conferred a hazard ratio of 1.34 (95% confidence interval, 1.15-1.55) in Ad, but only 0.99 (0.75-1.31) in non-Ad. Higher pack-years and shorter period since cessation were significantly associated with poorer survival in Ad (p < 0.001), but not in non-Ad (p >= 0.434). Conclusion: Ad histology is associated with better prognosis, and only smoking status had a prognostic impact in Ad.
  • Hiroaki Akamatsu; Akira Inoue; Tetsuya Mitsudomi; Kunihiko Kobayashi; Kazuhiko Nakagawa; Keita Mori; Toshihiro Nukiwa; Yoichi Nakanishi; Nobuyuki Yamamoto
    Japanese journal of clinical oncology 43 6 664 - 8 2013年06月 [査読有り]
     
    OBJECTIVE: Interstitial lung disease associated with gefitinib is a critical adverse reaction. When geftinib was administered to EGFR-unknown patients, the interstitial lung disease incidence rate was approximately 3-4% in Japan, and usually occurs during the first 4 weeks of treatment. However, it has not been fully investigated in EGFR-mutated patients. METHODS: We collected clinical records of participants of two Phase III trials (WJTOG 3405 and NEJ 002), which compared gefitinib with platinum doublet chemotherapy. All patients were EGFR mutated, chemo-naïve and had good performance status. RESULTS: A total of 402 patients were enrolled in this study. In the gefitinib arm, 10 (5.0%) of 201 patients developed interstitial lung disease, of whom five (2.5%) were Grade 3 or greater, with two deaths (1.0%). In contrast, only one patient developed interstitial lung disease (Grade 1) in the chemotherapy arm. With regard to gefitinib, smoking history was significantly associated with developing interstitial lung disease (odds ratio 0.18; 95% confidence interval: 0.05-0.74; P = 0.01). The cumulative incidence rate of interstitial lung disease was similar in the 0-4, 5-8 and 9-12 week time periods. However, between smokers and never-smokers, cumulative incidence rates in the first 4 weeks were significantly different (4.7% versus 0%, P = 0.03). Three of 10 patients developed interstitial lung disease after 8 weeks of gefitinib administration (days 135, 171 and 190, respectively). CONCLUSIONS: Among EGFR-mutated patients, the incidence of interstitial lung disease associated with gefitinib was not different from that in previous reports. Smoking history was associated with developing interstitial lung disease, and smokers had a higher incidence rate of interstitial lung disease in the first 4 weeks.
  • Takashi Seto; Katsuyuki Kiura; Makoto Nishio; Kazuhiko Nakagawa; Makoto Maemondo; Akira Inoue; Toyoaki Hida; Nobuyuki Yamamoto; Hiroshige Yoshioka; Masao Harada; Yuichiro Ohe; Naoyuki Nogami; Kengo Takeuchi; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    LANCET ONCOLOGY 14 7 590 - 598 2013年06月 [査読有り]
     
    Background Currently, crizotinib is the only drug that has been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). We aimed to study the activity and safety of CH5424802, a potent, selective, and orally available ALK inhibitor. Methods In this multicentre, single-arm, open-label, phase 1-2 study of CH5424802, we recruited ALK inhibitor-naive patients with ALK-rearranged advanced NSCLC from 13 hospitals in Japan. In the phase 1 portion of the study, patients received CH5424802 orally twice daily by dose escalation. The primary endpoints of the phase 1 were dose limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetic parameters. In the phase 2 portion of the study, patients received CH5424802 at the recommended dose identified in the phase 1 portion of the study orally twice a day. The primary endpoint of the phase 2 was the proportion of patients who had an objective response. Treatment was continued in 21-day cycles until disease progression, intolerable adverse events, or withdrawal of consent. The analysis was done by intent to treat. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-101264. Findings Patients were enrolled between Sept 10, 2010, and April 18, 2012. The data cutoff date was July 31, 2012. In the phase 1 portion, 24 patients were treated at doses of 20-300 mg twice daily. No DLTs or adverse events of grade 4 were noted up to the highest dose; thus 300 mg twice daily was the recommended phase 2 dose. In the phase 2 portion of the study, 46 patients were treated with the recommended dose, of whom 43 achieved an objective response (93.5%, 95% CI 82.1-98.6) including two complete responses (4.3%, 0.5-14.8) and 41 partial responses (89.1%, 76.4-96.4). Treatment-related adverse events of grade 3 were recorded in 12 (26%) of 46 patients, including two patients each experiencing decreased neutrophil count and increased blood creatine phosphokinase. Serious adverse events occurred in five patients (11%). No grade 4 adverse events or deaths were reported. The study is still ongoing, since 40 of the 46 patients in the phase 2 portion remain on treatment. Interpretation CH5424802 is well tolerated and highly active in patients with advanced ALK-rearranged NSCLC.
  • Alice T. Shaw; Dong-Wan Kim; Kazuhiko Nakagawa; Takashi Seto; Lucio Crino; Myung-Ju Ahn; Tommaso De Pas; Benjamin Besse; Benjamin J. Solomon; Fiona Blackhall; Yi-Long Wu; Michael Thomas; Kenneth J. O'Byrne; Denis Moro-Sibilot; D. Ross Camidge; Tony Mok; Vera Hirsh; Gregory J. Riely; Shrividya Iyer; Vanessa Tassell; Anna Polli; Keith D. Wilner; Pasi A. Jaenne
    NEW ENGLAND JOURNAL OF MEDICINE 368 25 2385 - 2394 2013年06月 [査読有り]
     
    Background In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. Methods We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. Results The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P = 0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. Conclusions Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement.
  • 仁科慎一; 上田眞也; 中川和彦
    消化器内科 56 6 618 - 623 科学評論社 2013年06月 [査読有り]
  • Yasuhito Fujisaka; Takayasu Kurata; Junji Tsurutani; Wataru Okamoto; Hidetoshi Hayashi; Hisato Kawakami; Eisei Shin; Nobuya Hayashi; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 31 15 2013年05月 [査読有り]
  • Takayasu Kurata; Junji Furuse; Isamu Okamoto; Akiyoshi Kasuga; Yasuhito Fujisaka; Hiroshi Kitamura; Toshio Shimizu; Atsuko Takasu; Wataru Okamoto; Daisuke Naruge; Fumio Nagashima; Koichi Katsura; Akihira Mukaiyama; Hideki Matsushita; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 31 15 2013年05月 [査読有り]
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 8 5 654 - 657 2013年05月 [査読有り]
     
    INTRODUCTION: Although crizotinib manifests marked antitumor activity in individuals with non-small-cell lung cancer positive for ALK abnormalities, all treated patients ultimately develop resistance to this drug. The central nervous system (CNS) is a frequent site of disease progression in such patients, with palliative radiotherapy usually being administered for the CNS metastasis. However, subsequent chemotherapy has not been optimized in these patients. METHODS: We retrospectively evaluated the continuation of crizotinib treatment after radiotherapy for isolated CNS progression in ALK-rearrangement-positive non-small-cell lung cancer patients. RESULTS: Among 21 ALK-rearrangement- positive patients treated with crizotinib, seven individuals resumed daily crizotinib administration after the completion of radiotherapy for isolated CNS failure. All these patients continued to receive crizotinib for at least 4 months after radiotherapy without disease progression. One patient experienced a recurrent isolated CNS failure during the second period of crizotinib administration but subsequently resumed crizotinib treatment again for at least 8.5 months after another application of radiotherapy. CONCLUSIONS: Development of isolated CNS metastasis is emerging as a clinical concern for patients treated with crizotinib. Our data suggest that continued administration of crizotinib after radiotherapy for isolated CNS progression is a potential treatment option for such patients. Copyright © 2013 by the International Association for the Study of Lung Cancer.
  • Sayaka Ogi; Hideaki Fujita; Masaki Kashihara; Chizuko Yamamoto; Kahori Sonoda; Isamu Okamoto; Kazuhiko Nakagawa; Shigehiro Ohdo; Yoshitaka Tanaka; Michihiko Kuwano; Mayumi Ono
    CANCER SCIENCE 104 5 573 - 583 2013年05月 [査読有り]
     
    The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. SNX1 and SNX2 are components of the mammalian retromer complex and they also play critical roles in the membrane trafficking of growth factor receptors including epidermal growth factor receptor (EGFR) and c-Met. The human lung cancer cell lines, which harbor activating mutations in the kinase domain of EGFR gene, are sensitive to EGFR-targeted drugs gefitinib or erlotinib. However, a lung cancer cell line harboring gene amplification of c-Met is sensitive to the c-Met-targeted drug SU11274 but not to EGFR-targeted drugs. C-Met overexpression is identified as one of the bypass mechanisms for acquired resistance to EGFR-targeted drugs. Here we show that the siRNA-mediated knockdown of SNX2 decreases the cell-surface localization of c-Met, but not that of EGFR, resulting in lysosomal degradation of the c-Met protein. SNX2 specifically interacts with c-Met and treatment with lysosomal inhibitors almost completely annihilates downregulation of c-Met protein by SNX2 knockdown. Therefore, silencing of SNX2 markedly alters sensitivity to anticancer drugs targeted to c-Met (SU11274) and EGFR (gefitinib and erlotinib) through promotion of compensatory activation of the EGFR pathway in lung cancer cells. These findings suggest that development of drugs targeting SNX2 could be useful in overcoming drug resistance to EGFR-targeted drugs in lung cancer cells harboring c-Met gene amplification.
  • Hidetoshi Hayashi; Isamu Okamoto; Masataka Taguri; Satoshi Morita; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 14 3 261 - 266 2013年05月 [査読有り]
     
    The effect of subsequent chemotherapy on overall survival (OS) has the potential to result in underestimation of the efficacy of an experimental treatment in clinical trials for advanced non-small-cell lung cancer (NSCLC). In this study, we investigated postprogression survival (PPS), defined as overall survival (OS) minus progression-free survival (PFS), in the second-line setting. PPS was highly associated with OS, and the induction rate for subsequent chemotherapy was associated with the duration of PPS. Our findings indicate that a beneficial effect of treatment on OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Background: The increased availability of active agents has improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). We previously showed that postprogression survival (PPS) is highly associated with OS in the first-line setting, but little is known about PPS in the salvage setting. In this study, we analyzed PPS in phase III trials in the second-line or third-line setting. Patients and Methods: A literature search identified 18 trials for previously treated patients with advanced NSCLC. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the association between OS and either PFS or PPS. Correlation analysis to examine whether a treatment benefit for PFS carried over to OS was performed by calculation of incremental gains in OS and PFS at the trial level. Results: The average median PPS was longer than the average median PFS (5.4 and 2.6 months, respectively). The induction rate for subsequent chemotherapy after second-line or third-line treatment was related to the duration of PPS in linear regression analysis (r(2) = 0.4813). Median OS was highly associated with median PPS but not with PFS (r = 0.94 and 0.51, respectively), and only a weak association between the treatment benefits for PFS and OS was detected (r = 0.29). Conclusions: Treatment benefit for OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Whether PFS or OS is the more appropriate endpoint for trials in the salvage setting should be considered. Clinical Lung Cancer, Vol. 14, No. 3, 261-6 (C) 2013 Elsevier Inc. All rights reserved.
  • Sayaka Ogi; Hideaki Fujita; Masaki Kashihara; Chizuko Yamamoto; Kahori Sonoda; Isamu Okamoto; Kazuhiko Nakagawa; Shigehiro Ohdo; Yoshitaka Tanaka; Michihiko Kuwano; Mayumi Ono
    CANCER SCIENCE 104 5 573 - 583 2013年05月 [査読有り]
     
    The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. SNX1 and SNX2 are components of the mammalian retromer complex and they also play critical roles in the membrane trafficking of growth factor receptors including epidermal growth factor receptor (EGFR) and c-Met. The human lung cancer cell lines, which harbor activating mutations in the kinase domain of EGFR gene, are sensitive to EGFR-targeted drugs gefitinib or erlotinib. However, a lung cancer cell line harboring gene amplification of c-Met is sensitive to the c-Met-targeted drug SU11274 but not to EGFR-targeted drugs. C-Met overexpression is identified as one of the bypass mechanisms for acquired resistance to EGFR-targeted drugs. Here we show that the siRNA-mediated knockdown of SNX2 decreases the cell-surface localization of c-Met, but not that of EGFR, resulting in lysosomal degradation of the c-Met protein. SNX2 specifically interacts with c-Met and treatment with lysosomal inhibitors almost completely annihilates downregulation of c-Met protein by SNX2 knockdown. Therefore, silencing of SNX2 markedly alters sensitivity to anticancer drugs targeted to c-Met (SU11274) and EGFR (gefitinib and erlotinib) through promotion of compensatory activation of the EGFR pathway in lung cancer cells. These findings suggest that development of drugs targeting SNX2 could be useful in overcoming drug resistance to EGFR-targeted drugs in lung cancer cells harboring c-Met gene amplification.
  • Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 8 5 654 - 657 2013年05月 [査読有り]
     
    INTRODUCTION: Although crizotinib manifests marked antitumor activity in individuals with non-small-cell lung cancer positive for ALK abnormalities, all treated patients ultimately develop resistance to this drug. The central nervous system (CNS) is a frequent site of disease progression in such patients, with palliative radiotherapy usually being administered for the CNS metastasis. However, subsequent chemotherapy has not been optimized in these patients. METHODS: We retrospectively evaluated the continuation of crizotinib treatment after radiotherapy for isolated CNS progression in ALK-rearrangement-positive non-small-cell lung cancer patients. RESULTS: Among 21 ALK-rearrangement- positive patients treated with crizotinib, seven individuals resumed daily crizotinib administration after the completion of radiotherapy for isolated CNS failure. All these patients continued to receive crizotinib for at least 4 months after radiotherapy without disease progression. One patient experienced a recurrent isolated CNS failure during the second period of crizotinib administration but subsequently resumed crizotinib treatment again for at least 8.5 months after another application of radiotherapy. CONCLUSIONS: Development of isolated CNS metastasis is emerging as a clinical concern for patients treated with crizotinib. Our data suggest that continued administration of crizotinib after radiotherapy for isolated CNS progression is a potential treatment option for such patients. Copyright © 2013 by the International Association for the Study of Lung Cancer.
  • Issei Kurahashi; Yoshihiko Fujita; Tokuzo Arao; Takayasu Kurata; Yasuhiro Koh; Kazuko Sakai; Koji Matsumoto; Maki Tanioka; Koji Takeda; Yuichi Takiguchi; Nobuyuki Yamamoto; Asuka Tsuya; Nobuaki Matsubara; Hirofumi Mukai; Hironobu Minami; Naoko Chayahara; Yasuhiro Yamanaka; Keisuke Miwa; Shin Takahashi; Shunji Takahashi; Kazuhiko Nakagawa; Kazuto Nishio
    PLOS ONE 8 5 e63249  2013年05月 [査読有り]
     
    Background: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. Methods: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). Results: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2-p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. Conclusions: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP.
  • H. Yoshioka; I. Okamoto; S. Morita; M. Ando; K. Takeda; T. Seto; N. Yamamoto; H. Saka; S. Atagi; T. Hirashima; S. Kudoh; M. Satouchi; N. Ikeda; Y. Iwamoto; T. Sawa; Y. Nakanishi; K. Nakagawa
    ANNALS OF ONCOLOGY 24 5 1326 - 1331 2013年05月 [査読有り]
     
    Background: A phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Patients and methods: A total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1-14 or carboplatin-paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented. Results: The updated analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793-1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm (HR 0.713; 95% CI 0.476-1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859-1.308) for those with non-SCC. Conclusions: These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology.
  • Hiroaki Iwasa; Sainawaer Maimaiti; Hidehito Kuroyanagi; Shodai Kawano; Kazutoshi Inami; Shikshya Timalsina; Mitsunobu Ikeda; Kentaro Nakagawa; Yutaka Hata
    Experimental Cell Research 319 7 931 - 945 2013年04月 [査読有り]
     
    The mammalian Hippo pathway comprises mammalian Ste20-like kinases (MST1/2) and large tumor suppressor kinases (LATS1/2). LATS1/2, which are activated by MST1/2, phosphorylate a transcriptional co-activator, yes-associated protein (YAP), and induce the recruitment of YAP by 14-3-3 to cytoplasm, so that the TEAD-dependent gene transcriptions are turned off. Although the core components of the Hippo pathway are well conserved in metazoans, it has been discussed that Caenorhabditis elegans lacks YAP ortholog, we found that F13E6.4 gene encodes a protein that shows sequence similarities to YAP in the N-terminal TEAD-binding domain and in the WW domain. We designated this gene as yap-1. YAP-1 is widely expressed in various cells such as epithelial cells, muscles, hypodermal cells, gonadal sheath cells, spermatheca, and hypodermal cells. YAP-1 is distributed in cytoplasm and nuclei. wts-1 (LATS ortholog) and ftt-2 (14-3-3 ortholog) knockdowns cause nuclear accumulation of YAP-1, supporting that the subcellular localization of YAP-1 is regulated in a similar way as that of YAP. Heat shock also causes the nuclear accumulation of YAP-1 but after heat shock, YAP-1 translocates to cytoplasm. Knockdowns of DAF-21 (HSP90 ortholog) and HSF-1block the nuclear export of YAP-1 during this recovery. YAP-1 overexpression is beneficial for thermotolerance, whereas YAP-1 hyperactivity induced by wts-1 and ftt-2 knockdowns is deleterious on thermal response and yap-1 deficiency promotes health aging. In short, YAP-1 partially shares basal characters with mammalian YAP and plays a role in thermal stress response and healthy aging. © 2013 Elsevier Inc.
  • Tanizaki Junko; Okamoto Isamu; Okabe Takafumi; Sakai Kazuko; Tanaka Kaoru; Hayashi Hidetoshi; Kaneda Hiroyasu; Takezawa Ken; Nishio Kazuto; Nakagawa Kazuhiko
    CANCER RESEARCH 73 8 2013年04月 [査読有り]
  • Tomohiro Maniwa; Mitsuhiro Isaka; Kazuo Nakagawa; Yasuhisa Ohde; Takehiro Okumura; Masahiro Endo; Haruhiko Kondo
    Surgery Today 43 4 408 - 411 2013年04月 [査読有り]
     
    Purpose: Interstitial lung disease (ILD) is associated with primary lung cancer and an increased risk of postoperative acute exacerbation (AE). Although the preoperative factors associated with AE of ILD are well described, there is little information about the postoperative factors. Thus, the present study focuses on the postoperative management of chest-tube drainage associated with AE of ILD. Methods: We conducted a retrospective chart study of 1,309 patients with lung cancer, who underwent pulmonary resection at Shizuoka Cancer Center between September 2002 and January 2011. ILD was diagnosed by chest computed tomography (CT) findings in 95 patients. After the exclusion of 6 patients with a history of pneumonectomy, the subjects of this study were 8 patients who suffered AE after surgery (AE group) and 81 patients (non-AE group) who did not. We investigated the clinicopathological findings and postoperative management of chest-tube drainage in the two groups. Results: The clinicopathological findings of the two groups did not differ significantly. The chest tubes could not be removed before postoperative day 5 because of pleural effusion in 5 patients (62.5 %) from the AE group and 12 patients (14.8 %) from the non-AE group (P = 0.0040). Conclusions: The postoperative volume draining from the chest-tube is an important sign of AE of ILD. © 2012 Springer Japan.
  • 非小細胞肺癌術後アジュバント治療におけるTS1 vs.CDDP+TS1の無作為化第II相臨床試験 WJOG4107
    吉野 一郎; 岩本 康男; 光冨 徹哉; 多田 弘人; 吉村 雅裕; 太田 三徳; 杉尾 賢二; 岡田 守人; 中山 竹春; 中川 和彦; 中西 洋一
    日本呼吸器外科学会雑誌 27 3 376 - 376 (一社)日本呼吸器外科学会 2013年04月
  • Hiroyasu Kaneda; Isamu Okamoto; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 8 4 e32 - e33 2013年04月 [査読有り]
  • Hidemi Kiyota; Isamu Okamoto; Masayuki Takeda; Haruko Daga; Tateaki Naito; Masaki Miyazaki; Hideaki Okada; Hidetoshi Hayashi; Kaoru Tanaka; Masaaki Terashima; Koichi Azuma; Haruyasu Murakami; Koji Takeda; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 71 4 859 - 865 2013年04月 [査読有り]
     
    A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m(2) (level 1) and escalating to 80 mg/m(2) (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib. Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected. The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.
  • Hidetoshi Hayashi; Junji Tsurutani; Taro Satoh; Norikazu Masuda; Wataru Okamoto; Ryotaro Morinaga; Masaaki Terashima; Masaki Miyazaki; Isamu Okamoto; Yukihiro Nishida; Shusei Tominaga; Yukihiko Tokunaga; Masahide Yamaguchi; Junichi Sakamoto; Takahiro Nakayama; Kazuhiko Nakagawa
    BREAST CANCER 20 2 131 - 136 2013年04月 [査読有り]
     
    A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy. Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m(2) on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol. Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1-16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred. This study demonstrated that biweekly administration of 150 mg/m(2) irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.
  • Hidetoshi Hayashi; Junji Tsurutani; Taro Satoh; Norikazu Masuda; Wataru Okamoto; Ryotaro Morinaga; Masaaki Terashima; Masaki Miyazaki; Isamu Okamoto; Yukihiro Nishida; Shusei Tominaga; Yukihiko Tokunaga; Masahide Yamaguchi; Junichi Sakamoto; Takahiro Nakayama; Kazuhiko Nakagawa
    BREAST CANCER 20 2 131 - 136 2013年04月 [査読有り]
     
    A trial was conducted to evaluate the feasibility, efficacy, and safety of biweekly administration of irinotecan, a novel topoisomerase I inhibitor, for patients with metastatic breast cancer (MBC) previously treated with either anthracycline-based or taxane-based chemotherapy. Eligible patients were HER2-negative, had a performance status of 0 to 2, and had been treated previously with either anthracyclines or taxanes for MBC. Patients received irinotecan intravenously at 150 mg/m(2) on days 1 and 15 every 4 weeks. The primary end-point was feasibility, and the treatment was considered feasible if a patient was able to receive three administrations of irinotecan within the first 8 weeks, as pre-specified in the protocol. Eighteen patients (median age 60 years) were enrolled. Fifteen patients received irinotecan more than 3 times within the first 8 weeks, with resulting feasibility of 83.3%. The median number of treatment cycles was 2 (range 1-16) during this period, and the relative dose intensity was 91.2%. Partial response was observed for one patient, so overall response rate was 5.6%. Nine patients (50.0%) had stable disease, and overall disease control was 50.0%. Median progression-free survival and overall survival periods were 3.2 and 9.6 months, respectively. The only grade 3/4 hematological toxicity was neutropenia (22.2%). Grade 3/4 non-hematological toxicities were anorexia (11.2%), diarrhea (11.2%), and fatigue (5.6%). No treatment-related death occurred. This study demonstrated that biweekly administration of 150 mg/m(2) irinotecan was feasible for patients with MBC treated previously with anthracyclines or taxanes.
  • Hidemi Kiyota; Isamu Okamoto; Masayuki Takeda; Haruko Daga; Tateaki Naito; Masaki Miyazaki; Hideaki Okada; Hidetoshi Hayashi; Kaoru Tanaka; Masaaki Terashima; Koichi Azuma; Haruyasu Murakami; Koji Takeda; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 71 4 859 - 865 2013年04月 [査読有り]
     
    A phase I dose-escalation study was performed to investigate the safety and pharmacokinetics of the combination of S-1 and gefitinib in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. Patients received gefitinib at a fixed daily oral dose of 250 mg, and S-1 was administered on days 1-14 every 21 days at doses starting at 60 mg/m(2) (level 1) and escalating to 80 mg/m(2) (level 2). The primary end point of the study was determination of the recommended dose for S-1 given in combination with a fixed dose of gefitinib. Twenty patients were enrolled in the study. Two of the first six patients at dose level 2 experienced a dose-limiting toxicity (elevation of alkaline phosphatase of grade 3 in one patient; elevations of aspartate and alanine aminotransferases of grade 3 in the other). The recommended dose was thus determined as level 2, and an additional 11 patients were assigned to this level. All observed adverse events were well managed. The response rate was 50 % (10 of 20 patients), and the median progression-free survival (PFS) and overall survival times were 10.5 and 21.2 months, respectively. In EGFR mutation-positive patients (n = 9), seven patients achieved an objective response and the median PFS was 12.4 months, whereas none with wild-type EGFR (n = 6) responded. No pharmacokinetic interaction between S-1 and gefitinib was detected. The combination of S-1 and gefitinib is well tolerated and appears to possess activity against EGFR mutation-positive NSCLC.
  • Hiroyasu Kaneda; Isamu Okamoto; Kazuhiko Nakagawa
    Journal of Thoracic Oncology 8 4 e32 - e33 2013年04月 [査読有り]
  • Takashi Satoh; Hiroyasu Kidoya; Hisamichi Naito; Masahiro Yamamoto; Naoki Takemura; Katsuhiro Nakagawa; Yoshichika Yoshioka; Eiichi Morii; Nobuyuki Takakura; Osamu Takeuchi; Shizuo Akira
    Nature 495 7442 524 - 528 2013年03月 [査読有り]
     
    Macrophages consist of at least two subgroups, M1 and M2 (refs 1, 2, 3). Whereas M1 macrophages are proinflammatory and have a central role in host defence against bacterial and viral infections, M2 macrophages are associated with responses to anti-inflammatory reactions, helminth infection, tissue remodelling, fibrosis and tumour progression. Trib1 is an adaptor protein involved in protein degradation by interacting with COP1 ubiquitin ligase. Genome-wide association studies in humans have implicated TRIB1 in lipid metabolism. Here we show that Trib1 is critical for the differentiation of F4/80 + MR + tissue-resident macrophages-that share characteristics with M2 macrophages (which we term M2-like macrophages)-and eosinophils but not for the differentiation of M1 myeloid cells. Trib1 deficiency results in a severe reduction of M2-like macrophages in various organs, including bone marrow, spleen, lung and adipose tissues. Aberrant expression of C/EBPα in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation. Unexpectedly, mice lacking Trib1 in haematopoietic cells show diminished adipose tissue mass accompanied by evidence of increased lipolysis, even when fed a normal diet. Supplementation of M2-like macrophages rescues the pathophysiology, indicating that a lack of these macrophages is the cause of lipolysis. In response to a high-fat diet, mice lacking Trib1 in haematopoietic cells develop hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine gene induction. Collectively, these results demonstrate that Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages. © 2013 Macmillan Publishers Limited. All rights reserved.
  • 長谷川喜一; 川口知哉; 久保昭仁; 安藤昌彦; 伊佐俊一; 白石順二; 辻泰佑; 辻野和之; 高田實; 中川和彦
    日本呼吸器学会誌 2 141  2013年03月
  • 石本 修; 光冨 徹哉; 吉岡 弘鎮; 岩本 康男; 多田 弘人; 吉村 雅裕; 中川 和彦; 吉野 一郎; 菅原 俊一; 山中 竹春; 中西 洋一
    日本呼吸器学会誌 2 増刊 135 - 135 (一社)日本呼吸器学会 2013年03月
  • Hiroaki Iwasa; Hidehito Kuroyanagi; Sainawaer Maimaiti; Mitsunobu Ikeda; Kentaro Nakagawa; Yutaka Hata
    EXPERIMENTAL CELL RESEARCH 319 3 1 - 11 2013年02月 [査読有り]
     
    Mammals have 10 RASSF proteins, which are characterized by the Ras-association (RA) domain. Among them, RASSF1 to RASSF6 have the Salvador/RASSF/Hippo (SARAH) domain and form the subclass C-terminal RASSF proteins. Drosophila genome has a single C-terminal RASSF, dRASSF. All these RASSF proteins are related to the tumor suppressive Hippo pathway, and are considered to function as tumor suppressors. Caenorhabditis elegans T24F1.3 encodes a protein with the RA and the SARAH domains. The amino acid sequences are 40% and 55% similar to those of RASSF1 in the RA and the SARAH domains, respectively. We have characterized T24F1.3 gene product and named it RSF-1 as RASSF1 homolog. RSF-1 is widely expressed in epithelial cells. About 14% rsf-1 mutants exhibit defects in embryonal morphogenesis and the actin disorganization. The combinatorial synthetic lethal analysis demonstrates that the lethality is enhanced to more than 80% in rsf-1 mutants with the WASP-family verprolin homologous protein complex-related gene depletions and corroborates the implication of RSF-1 in the regulation of actin cytoskeleton. In rsf-1 mutants, the structures of muscle actin are preserved, but the swimming ability is impaired. Although we could not detect the direct physical interaction of LET-60 with RSF-1, rsf-1 mutants suppress the multivulva phenotype of the active let-60 mutants, suggesting that rsf-1 genetically interacts with the Ras signaling. (c) 2012 Elsevier Inc. All rights reserved.
  • 転移性乳がん患者におけるエリブリンの臨床効果と安全性プロファイル
    崎山 勉; 鶴谷 純司; 谷崎 潤子; 松岡 弘道; 岡本 邦男; 清田 秀美; 倉田 宝保; 中川 和彦
    日本内科学会雑誌 102 Suppl. 195 - 195 (一社)日本内科学会 2013年02月
  • 西村 恭昌
    Jpn J Clin Oncol 43 12 1233 - 1237 2013年 [査読有り]
  • Masato Taki; Shinya Inada; Ryo Ariyasu; Yoshinobu Konishi; Natsumi Okamoto; Masanori Yoshida; Hiroaki Nagano; Kenji Hanaoka; Kazuhiko Nakagawa; Yasukiyo Nakamura; Chie Yoshimura; Toshiaki Wakayama; Yasuo Nishizaka; Tomoko Wakasa; Mitsuru Tsudo; Ryoichi Amitani
    INTERNAL MEDICINE 52 23 2645 - 2651 2013年 [査読有り]
     
    Fibrosing mediastinitis is rare. One type of this disease is idiopathic fibrosing mediastinitis. It is necessary to rule out malignancy in order to accurately diagnose fibrosing mediastinitis. We herein report a case of anaplastic large cell lymphoma diagnosed three months after a preliminary diagnosis of fibrosing mediastinitis. Glucocorticoid therapy was not successful in controlling disease progression. Immediately after initiating chemotherapy for lymphoma, the patient's symptoms improved dramatically and the mediastinal lesion decreased in size. Although few similar cases have been reported, hidden malignancy may present as fibrosing mediastinitis. Therefore, physicians should consider the probability of malignancy in patients with fibrosing mediastinitis because treatments may vary accordingly.
  • Hisato Kawakami; Isamu Okamoto; Kyoichi Terao; Kazuko Sakai; Minoru Suzuki; Shinya Ueda; Kaoru Tanaka; Kiyoko Kuwata; Yume Morita; Koji Ono; Kazuto Nishio; Yasumasa Nishimura; Katsumi Doi; Kazuhiko Nakagawa
    Cancer Medicine 2 6 933 - 941 2013年 [査読有り]
     
    Human papillomavirus (HPV) is a major etiologic factor for oropharyngeal squamous cell carcinoma (OPSCC). However, little is known about HPV-related OPSCC in Japan. During the study, formalin-fixed, paraffin-embedded OPSCC specimens from Japanese patients were analyzed for HPV DNA by the polymerase chain reaction (PCR) and for the surrogate marker p16 by immuno-histochemistry. For HPV DNA-positive, p16-negative specimens, the methylation status of the p16 gene promoter was examined by methylation-specific PCR. Overall survival was calculated in relation to HPV DNA and p16 status and was subjected to multivariate analysis. OPSCC cell lines were examined for sensitivity to radiation or cisplatin in vitro. The study results showed that tumor specimens from 40 (38%) of the 104 study patients contained HPV DNA, with such positivity being associated with tumors of the tonsils, lymph node metastasis, and nonsmoking. Overall survival was better for OPSCC patients with HPV DNA than for those without it (hazard ratio, 0.214 95% confidence interval, 0.074-0.614 P = 0.002). Multivariate analysis revealed HPV DNA to be an independent prognostic factor for overall survival (P = 0.015). Expression of p16 was associated with HPV DNA positivity. However, 20% of HPV DNA-positive tumors were negative for p16, with most of these tumors manifesting DNA methylation at the p16 gene promoter. Radiation or cisplatin sensitivity did not differ between OPSCC cell lines positive or negative for HPV DNA. Thus, positivity for HPV DNA identifies a distinct clinical subset of OPSCC with a more favorable outcome in Japanese. © 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
  • Regression of brain metastases from breast cancer with eribulin: a case report.
    Matsuoka H; Tsurutani J; Tanizaki J; Iwasa T; Komoike Y; Koyama A; Nakagawa K
    BMC Res Notes. 65 412  2013年 [査読有り]
  • Hisato Kawakami; Isamu Okamoto; Tokuzo Arao; Wataru Okamoto; Kazuko Matsumoto; Hirokazu Taniguchi; Kiyoko Kuwata; Haruka Yamaguchi; Kazuto Nishio; Kazuhiko Nakagawa; Yasuhide Yamada
    ONCOTARGET 4 1 9 - 17 2013年01月 [査読有り]
     
    Our aim was to investigate both the prevalence of MET amplification in gastric cancer as well as the potential of this genetic alteration to serve as a therapeutic target in gastric cancer. MET amplification was assessed by initial screening with a PCR-based copy number assay followed by confirmatory FISH analysis in formalin-fixed, paraffin-embedded specimens of gastric cancer obtained at surgery. The effects of MET tyrosine kinase inhibitors (MET-TKIs) in gastric cancer cells with or without MET amplification were also examined. The median MET copy number in 266 cases of gastric cancer was 1.7, with a range of 0.41 to 21.3. We performed FISH analysis for the 15 cases with the highest MET copy numbers. MET amplification was confirmed in the four assessable cases with a MET copy number of at least 4, whereas MET amplification was not detected in those with a gene copy number of <4. The prevalence of MET amplification was thus 1.5% (4 out of 266 cases). Inhibition of MET by MET-TKIs resulted in the induction of apoptosis accompanied by attenuation of downstream MET signaling in gastric cancer cell lines with MET amplification but not in those without this genetic change. MET amplification identifies a small but clinically important subgroup of gastric cancer patients who are likely to respond to MET-TKIs. Furthermore, screening with a PCR-based copy number assay is an efficient way to reduce the number of patients requiring confirmation of MET amplification by FISH analysis.
  • Hidetoshi Hayashi; Isamu Okamoto; Masataka Taguri; Satoshi Morita; Kazuhiko Nakagawa
    Clinical Lung Cancer 14 3 261 - 266 2013年 [査読有り]
     
    The effect of subsequent chemotherapy on overall survival (OS) has the potential to result in underestimation of the efficacy of an experimental treatment in clinical trials for advanced non-small-cell lung cancer (NSCLC). In this study, we investigated postprogression survival (PPS), defined as overall survival (OS) minus progression-free survival (PFS), in the second-line setting. PPS was highly associated with OS, and the induction rate for subsequent chemotherapy was associated with the duration of PPS. Our findings indicate that a beneficial effect of treatment on OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Background: The increased availability of active agents has improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). We previously showed that postprogression survival (PPS) is highly associated with OS in the first-line setting, but little is known about PPS in the salvage setting. In this study, we analyzed PPS in phase III trials in the second-line or third-line setting. Patients and Methods: A literature search identified 18 trials for previously treated patients with advanced NSCLC. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the association between OS and either PFS or PPS. Correlation analysis to examine whether a treatment benefit for PFS carried over to OS was performed by calculation of incremental gains in OS and PFS at the trial level. Results: The average median PPS was longer than the average median PFS (5.4 and 2.6 months, respectively). The induction rate for subsequent chemotherapy after second-line or third-line treatment was related to the duration of PPS in linear regression analysis (r2 = 0.4813). Median OS was highly associated with median PPS but not with PFS (r = 0.94 and 0.51, respectively), and only a weak association between the treatment benefits for PFS and OS was detected (r = 0.29). Conclusions: Treatment benefit for OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Whether PFS or OS is the more appropriate endpoint for trials in the salvage setting should be considered. © 2013 Elsevier Inc. All rights reserved.
  • Hidetoshi Hayashi; Takayasu Kurata; Yasuhito Fujisaka; Hisato Kawakami; Kaoru Tanaka; Takafumi Okabe; Masayuki Takeda; Taroh Satoh; Koji Yoshida; Takuya Tsunoda; Tokuzo Arao; Kazuto Nishio; Kazuhiko Nakagawa
    Cancer science 104 1 98 - 104 2013年01月 [査読有り]
     
    OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.0, 2.0, or 3.0 mg of OTS11101 subcutaneously, once a week in a 28-day cycle. Three patients experienced grade 1 injection site reactions, which were the most frequent adverse events. Grade 2 proteinuria and hypertension each occurred in one patient. As other toxicities were generally mild, the maximum tolerated dose was not reached. Furthermore, we explored the induction of specific activated CTLs, and biomarkers related to angiogenesis. A pharmacodynamics study revealed that induction of specific CTLs was observed for a dose of 2.0 and 3.0 mg. The serum concentrations of soluble VEGF receptor 1 and 2 after vaccination increased significantly compared with baseline. A microarray was performed to give a comprehensive analysis of gene expression, suggesting that OTS11101 vaccination resulted in T cell activation in a clinical setting. In conclusion, OTS11101 was well tolerated in patients up to 3.0 mg once weekly and our biomarker analysis suggested that this anti-angiogenesis vaccine is biologically active.
  • Akihiro Tamiya; Isamu Okamoto; Masaki Miyazaki; Shigeki Shimizu; Masanori Kitaichi; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 31 1 E15 - E17 2013年01月 [査読有り]
  • Hisato Kawakami; Isamu Okamoto; Tokuzo Arao; Wataru Okamoto; Kazuko Matsumoto; Hirokazu Taniguchi; Kiyoko Kuwata; Haruka Yamaguchi; Kazuto Nishio; Kazuhiko Nakagawa; Yasuhide Yamada
    ONCOTARGET 4 1 9 - 17 2013年01月 [査読有り]
     
    Our aim was to investigate both the prevalence of MET amplification in gastric cancer as well as the potential of this genetic alteration to serve as a therapeutic target in gastric cancer. MET amplification was assessed by initial screening with a PCR-based copy number assay followed by confirmatory FISH analysis in formalin-fixed, paraffin-embedded specimens of gastric cancer obtained at surgery. The effects of MET tyrosine kinase inhibitors (MET-TKIs) in gastric cancer cells with or without MET amplification were also examined. The median MET copy number in 266 cases of gastric cancer was 1.7, with a range of 0.41 to 21.3. We performed FISH analysis for the 15 cases with the highest MET copy numbers. MET amplification was confirmed in the four assessable cases with a MET copy number of at least 4, whereas MET amplification was not detected in those with a gene copy number of <4. The prevalence of MET amplification was thus 1.5% (4 out of 266 cases). Inhibition of MET by MET-TKIs resulted in the induction of apoptosis accompanied by attenuation of downstream MET signaling in gastric cancer cell lines with MET amplification but not in those without this genetic change. MET amplification identifies a small but clinically important subgroup of gastric cancer patients who are likely to respond to MET-TKIs. Furthermore, screening with a PCR-based copy number assay is an efficient way to reduce the number of patients requiring confirmation of MET amplification by FISH analysis.
  • A Randomized Phase III Study of Single-Agent Amrubicin Vs. Carboplatin/Etoposide in Elderly Patients With Extensive-Disease Small-Cell Lung Cancer.
    Sekine I; Okamoto H; Horai T; Nakagawa K; Ohmatsu H; Yokoyama A; Katakami N; Shibuya M; Saijo N; Fukuoka M
    Clin Lung Cancer. S1525-7304 13 232 - 235 2013年 [査読有り]
  • Epidermal growth factor receptor mutation analysis in previously unanalyzed histology samples and cytology samples from the phase III Iressa Pan-ASia Study (IPASS).
    Yang JC; Wu YL; Chan V; Kurnianda J; Nakagawa K; Saijo N; Fukuoka M; McWalter G; McCormack R; Mok TS
    Lung Cancer. S0169-5002 13 535 - 537 2013年 [査読有り]
  • Practical Use of Gemcitabine and Cisplatin Combination Therapy as First-Line Treatment for Japanese Patients with Advanced Biliary Tract Cancer
    Kawakami H; Okamoto I; Okamoto W; Takeda M; Ueda S; Kudo T; Nishina S; Fujisaka Y; Miyazaki M; Tsurutani J; Kurata T; Nakagawa K
    Journal of Cancer Therapy 4 1068 - 1073 2013年 [査読有り]
  • Nishina S; Yoshida K; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 70 12 2093 - 2097 2012年12月 [査読有り]
  • Isamu Okamoto; Tokuzo Arao; Masaki Miyazaki; Taroh Satoh; Kunio Okamoto; Takuya Tsunoda; Kazuto Nishio; Kazuhiko Nakagawa
    Cancer Science 103 12 2135 - 2138 2012年12月 [査読有り]
     
    Targeting of tumor angiogenesis with vaccines is a potentially valuable approach to cancer treatment. Elpamotide is an immunogenic peptide derived from vascular endothelial growth factor receptor 2, which is expressed at a high level in vascular endothelial cells. We have now carried out a phase I study to evaluate safety, the maximum tolerated dose, and potential pharmacodynamic biomarkers for this vaccine. Ten HLA-A*24:02-positive patients with advanced refractory solid tumors received elpamotide s.c. at dose levels of 0.5, 1.0, or 2.0 mg once a week on a 28-day cycle. Five patients experienced an injection site reaction of grade 1 and 2, which was the most frequent adverse event. In the 1.0 mg cohort, one patient experienced proteinuria of grade 1 and another patient developed both hypertension and proteinuria of grade 1. No adverse events of grade 3 or higher were observed, and the maximum tolerated dose was therefore not achieved. The serum concentration of soluble vascular endothelial growth factor receptor 2 decreased significantly after elpamotide vaccination. Microarray analysis of gene expression in PBMCs indicated that several pathways related to T cell function and angiogenesis were affected by elpamotide vaccination, supporting the notion that this peptide induces an immune response that targets angiogenesis in the clinical setting. In conclusion, elpamotide is well tolerated and our biomarker analysis indicates that this anti-angiogenic vaccine is biologically active. Clinical trial registration no. UMIN000008336. © 2012 Japanese Cancer Association.
  • M. Takeda; I. Okamoto; K. Sakai; H. Kawakami; K. Nishio; K. Nakagawa
    ANNALS OF ONCOLOGY 23 11 2931 - 2936 2012年11月 [査読有り]
     
    The EML4-ALK fusion oncogene represents a recently identified molecular target in a subset of patients with non-small-cell lung cancer (NSCLC). Limited data have been available, however, on the outcome of first-line platinum-based chemotherapy in patients with EML4-ALK-positive advanced NSCLC who have not been treated with an ALK kinase inhibitor. The efficacy of platinum-based chemotherapy was compared between patients with advanced nonsquamous NSCLC who harbor EML4-ALK and those who harbor EGFR mutations and those with neither molecular abnormality. Among 200 patients with advanced nonsquamous NSCLC, 18 (9.0%) were positive for EML4-ALK, 31 (15.5%) harbored EGFR mutations, and 151 (75.5%) were wild type for both abnormalities. Platinum-based combination chemotherapy showed similar efficacies in the EML4-ALK, EGFR mutation, and wild-type cohorts in terms of response rate and progression-free survival, and overall survival in the EML4-ALK cohort closely resembled that in the wild-type cohort. Within the EML4-ALK cohort, patients with variants 1 or 3 of the fusion gene were predominant and did not appear to differ in their sensitivity to the platinum-based regimens. Patients with EML4-ALK-positive advanced NSCLC manifest an aggressive clinical course similar to that of those with wild-type tumors if the effective targeted therapy is not instituted.
  • Hiromichi Matsuoka; Atsuko Koyama; Chihiro Makimura; Otsuka Masatomo; Kiyohiro Sakai; Ryo Sakamoto; Minoru Niki; Kazuhiko Nakagawa
    ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY 8 289 - 289 2012年11月 [査読有り]
  • Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 1 - 4 2012年11月 [査読有り]
  • Junko Tanizaki; Isamu Okamoto; Takafumi Okabe; Kazuko Sakai; Kaoru Tanaka; Hidetoshi Hayashi; Hiroyasu Kaneda; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Erina Hatashita; Kazuto Nishio; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 18 22 6219 - 6226 2012年11月 [査読有り]
     
    Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. Clin Cancer Res; 18(22); 6219-26. (C)2012 AACR.
  • Junko Tanizaki; Isamu Okamoto; Takafumi Okabe; Kazuko Sakai; Kaoru Tanaka; Hidetoshi Hayashi; Hiroyasu Kaneda; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Erina Hatashita; Kazuto Nishio; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 18 22 6219 - 6226 2012年11月 [査読有り]
     
    Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. Clin Cancer Res; 18(22); 6219-26. (C)2012 AACR.
  • Nakagawa T; Takeuchi S; Yamada T; Nanjo S; Ishikawa D; Sano T; Kita K; Nakamura T; Matsumoto K; Suda K; Mitsudomi T; Sekido Y; Uenaka T; Yano S
    Molecular cancer therapeutics 11 10 2149 - 57 2012年10月 [査読有り]
     
    Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted.
  • 既治療非小細胞肺癌症例におけるS-1+経口ロイコボリン併用療法の臨床第二相試験
    内藤 立暁; 瀬戸 貴司; 武田 晃司; 後藤 功一; 中川 和彦; 大場 太郎; 村上 晴泰; 高橋 利明; 山中 竹春; 山本 信之
    日本癌治療学会誌 47 3 1023 - 1023 (一社)日本癌治療学会 2012年10月
  • 前門戸 任; 西尾 誠人; 木浦 勝行; 中川 和彦; 瀬戸 貴司; 井上 彰; 樋田 豊明; 大江 裕一郎; 野上 尚之; 田村 友秀
    肺癌 52 5 511 - 511 (NPO)日本肺癌学会 2012年10月
  • 武田 真幸; 岡本 勇; 鶴谷 純司; 大磯 直毅; 川田 暁; 中川 和彦
    肺癌 52 5 624 - 624 (NPO)日本肺癌学会 2012年10月
  • 高齢者総合機能評価(CGA)の有用性 JCOG0207、JCOG0803/WJOG4307L統合解析
    片山 宏; 武田 晃司; 福田 治彦; 中村 慎一郎; 中村 健一; 水澤 純基; 西條 長宏; 横山 晶; 大江 裕一郎; 中川 和彦; 阿部 徹哉; 光岡 茂樹; 安藤 昌彦; 田村 友秀
    日本癌治療学会誌 47 3 920 - 920 (一社)日本癌治療学会 2012年10月
  • 谷口 博之; 安藤 昌彦; 大江 裕一郎; 中川 和彦; 荒川 浩明; 井上 義一; 海老名 雅仁; 楠本 昌彦; 桑野 和善; 弦間 昭彦; 酒井 文和; 上甲 剛; 福田 悠; 山崎 直也; 清原 祥夫; 関 顕洋; 工藤 翔二; 福岡 正博; エルロチニブ適正使用検討委員会
    肺癌 52 5 661 - 661 (NPO)日本肺癌学会 2012年10月
  • EGFR遺伝子変異肺癌における1st EGFR-TKIによる有害事象後の2nd EGFR-TKIの意義
    武田 真幸; 岡本 勇; 鶴谷 純司; 大磯 直毅; 川田 暁; 中川 和彦
    日本癌治療学会誌 47 3 2126 - 2126 (一社)日本癌治療学会 2012年10月
  • Hidetoshi Hayashi; Isamu Okamoto; Hideharu Kimura; Kazuko Sakai; Yasumasa Nishimura; Kazuto Nishio; Kazuhiko Nakagawa
    ANTICANCER RESEARCH 32 10 4533 - 4537 2012年10月 [査読有り]
     
    Background: Little is known about the occurrence and consequences of epidermal growth factor receptor gene (EGFR) mutations and the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes in locally advanced non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively examined 37 patients with locally advanced NSCLC treated with definitive thoracic radiotherapy (TRT). Characteristics were compared among patients classified positive for EGFR mutations, EML4-ALK rearrangement, or patients who were double-negative for these changes. Results: We identified 11 (29.7%) patients with EGFR mutations and 3 (8.1%) with an EML4-ALK rearrangement. Progression-free survival of patients with EGFR mutation-positive NSCLC was similar to the one of those with double-negative disease (13.1 and 18.6 months). The incidence of local recurrence was higher in EGFR mutation positive patients with NSCLC than in double-negative NSCLC. Conclusion: EGFR mutations and the EML4-ALK rearrangements were detected in substantial proportions of patients with locally advanced NSCLC. The efficacy of TRT was limited in patients with EGFR mutations.
  • K. Tanaka; T. Arao; D. Tamura; K. Aomatsu; K. Furuta; K. Matsumoto; H. Kaneda; K. Kudo; Y. Fujita; H. Kimura; K. Yanagihara; Y. Yamada; I. Okamoto; K. Nakagawa; K. Nishio
    ANNALS OF ONCOLOGY 23 1 132 - 132 2012年10月 [査読有り]
  • Hidetoshi Hayashi; Isamu Okamoto; Hideharu Kimura; Kazuko Sakai; Yasumasa Nishimura; Kazuto Nishio; Kazuhiko Nakagawa
    Anticancer Research 32 10 4533 - 4538 2012年10月 [査読有り]
     
    Background: Little is known about the occurrence and consequences of epidermal growth factor receptor gene (EGFR) mutations and the fusion of the echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) genes in locally advanced non-small cell lung cancer (NSCLC). Patients and Methods: We retrospectively examined 37 patients with locally advanced NSCLC treated with definitive thoracic radiotherapy (TRT). Characteristics were compared among patients classified positive for EGFR mutations, EML4-ALK rearrangement, or patients who were double-negative for these changes. Results: We identified 11 (29.7%) patients with EGFR mutations and 3 (8.1%) with an EML4-ALK rearrangement. Progression-free survival of patients with EGFR mutation-positive NSCLC was similar to the one of those with double-negative disease (13.1 and 18.6 months). The incidence of local recurrence was higher in EGFR mutation-positive patients with NSCLC than in double-negative NSCLC. Conclusion: EGFR mutations and the EML4-ALK rearrangements were detected in substantial proportions of patients with locally advanced NSCLC. The efficacy of TRT was limited in patients with EGFR mutations.
  • M. Takeda; I. Okamoto; K. Sakai; H. Kawakami; K. Nishio; K. Nakagawa
    ANNALS OF ONCOLOGY 23 11 44 - 44 2012年10月 [査読有り]
  • Kyoichi Kaira; Yasuhisa Ohde; Kazuo Nakagawa; Takehiro Okumura; Haruyasu Murakami; Toshiaki Takahashi; Haruhiko Kondo; Takashi Nakajima; Masahiro Endo; Nobuyuki Yamamoto
    MEDICAL ONCOLOGY 29 3 1663 - 1672 2012年09月 [査読有り]
     
    The aim of this study is to elucidate the prognostic significance of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD) in completely resected non-small cell lung cancer (NSCLC). One hundred and sixty patients with NSCLC were included in this study. Tumor sections were stained by immunohistochemistry for TS, OPRT, DPD, glucose transporter 1 (Glut1), hypoxia inducible factor-1 alpha (HIF-1 alpha), vascular endothelial growth factor (VEGF), microvessel density (MVD) determinated by CD34, epidermal growth factor receptor (EGFR), phosph-Akt, phosph-mammalian target of rapamycin (mTOR) and p53. TS, OPRT and DPD were positively expressed in 46, 71 and 54%, respectively. The expression of TS and OPRT was significantly higher in patients with non-adenocarcinoma (non-AC) (n = 53) than adenocarcinoma (AC) (n = 107), and DPD expression was higher in adenocarcinoma as compared with non-adenocarcinoma. A positive TS expression was an independent prognostic factor for predicting a poor outcome in patients with AC, but not in those with non-AC. In AC patients, TS expression was significantly associated with advanced stage, lymph node metastases, vascular invasion, Glut1, HIF-1 alpha, angiogenesis, EGFR signaling pathway and p53. In patients with non-AC, TS expression was not closely correlated with outcome and these biomarkers. A positive TS expression was a powerful prognostic factor to predict a poor outcome in completely resected AC patients.
  • Kyoichi Kaira; Masato Abe; Kazuo Nakagawa; Yasuhisa Ohde; Takehiro Okumura; Toshiaki Takahashi; Haruyasu Murakami; Takehito Shukuya; Hirotsugu Kenmotsu; Tateaki Naito; Isamu Hayashi; Noboru Oriuchi; Masahiro Endo; Haruhiko Kondo; Takashi Nakajima; Nobuyuki Yamamoto
    EUROPEAN JOURNAL OF RADIOLOGY 81 9 2423 - 2429 2012年09月 [査読有り]
     
    Background: The usefulness of 2-[F-18]-fluoro-2-deoxy-D-glucose (F-18-FDG) positron emission tomography (PET) has been investigated in thymic epithelial tumors. However, little is known about PET imaging of F-18-FDG in primary non-thymic mediastinal neoplasms. The aim of this study is to explore the clinicopathological significance of F-18-FDG PET in primary mediastinal (non-thymic) neoplasms. Methods: Twenty-one patients with mediastinal neoplasms who underwent F-18-FDG PET before treatment were included in this study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (Glut1); glucose transporter 3 (Glut3); hypoxia-inducible factor-1 alpha (HIF-1 alpha); hexokinase I; vascular endothelial growth factor (VEGF); microvessels (CD34); epidermal growth factor receptor (EGFR); Akt/mTOR signaling pathway (p-Akt and p-mTOR); cell cycle control (p53). Results: Seventeen of 21 patients were imaged on PET system using F-18-FDG, but 4 patients with a histology of cyst showed nothing abnormal in PET scans. The histology of the resected tumors was as follows: 6 schwannoma, 3 teratoma, 4 cyst, 3 sarcoma, 1 undifferentiated carcinoma, 1 seminoma, 1 mediastinal goiter, 1 ganglioneuroma, and 1 Hodgkin lymphoma. F-18-FDG uptake was significantly correlated with Glut1, HIF-1 alpha, EGFR, p-Akt and p-S6K. These biomarkers were highly expressed in schwannoma, teratoma and high grade malignancies, whereas all patients with cyst and ganglioneuroma had no positive expression of these biomarkers. High uptake of F-18-FDG was significant associated with Glut1, VEGF, EGFR, p-Akt, p-S6K and tumor maximal size. Conclusion: The amount of F-18-FDG uptake in primary mediastinal non-thymic neoplasms is determined by the presence of glucose metabolism (Glut1), hypoxia (HIF-1 alpha) and upstream components of HIF-1 alpha (EGFR, p-Akt and p-S6K). (c) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Yumiko Aoyama; Tetsuya Nishimura; Taiji Sawamoto; Taroh Satoh; Masataka Katashima; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 70 3 373 - 380 2012年09月 [査読有り]
     
    The purpose of this analysis was to investigate the pharmacokinetics (PK) of sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of sepantronium. Sepantronium was administered as a continuous intravenous infusion of 1.8-10.6 mg/m(2)/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. The PK of sepantronium was dose proportional in the dose range of 1.8-10.6 mg/m(2)/day. Age and sex did not significantly affect the PK of sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. While age and sex did not significantly affect the PK of sepantronium, moderate renal impairment increased exposure of sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
  • Hiroyasu Kaneda; Isamu Okamoto; Kazuko Sakai; Junko Tanizaki; Masayuki Takeda; Kazuto Nishio; Kazuhiko Nakagawa
    ACTA ONCOLOGICA 51 7 942 - U150 2012年09月 [査読有り]
  • Yumiko Aoyama; Tetsuya Nishimura; Taiji Sawamoto; Taroh Satoh; Masataka Katashima; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 70 3 373 - 380 2012年09月 [査読有り]
     
    The purpose of this analysis was to investigate the pharmacokinetics (PK) of sepantronium (YM155), a small-molecule suppressor of the expression of the antiapoptosis protein survivin, in Japanese patients with advanced solid tumors and to evaluate the effect of renal impairment on the PK profile of sepantronium. Sepantronium was administered as a continuous intravenous infusion of 1.8-10.6 mg/m(2)/day for 168 h (7 days) to 33 patients. PK parameters were estimated via non-compartmental method. Renal function was categorized for the analysis based on the chronic kidney disease guidance using eGFR values at pre-dose. The PK of sepantronium was dose proportional in the dose range of 1.8-10.6 mg/m(2)/day. Age and sex did not significantly affect the PK of sepantronium. Results suggested that total clearance and renal clearance in patients with moderate renal impairment were 0.7-fold lower than those in patients with normal renal function, resulting in 1.3-fold higher steady-state concentration and area under the curve values. The PK parameters of sepantronium in patients with mild renal impairment were comparable to those in the patients with normal renal function. While age and sex did not significantly affect the PK of sepantronium, moderate renal impairment increased exposure of sepantronium by about 30 %. The results suggest that no dose adjustment is required for patients with mild renal impairment.
  • 清田 秀美; 岡本 勇; 田中 薫; 林 秀敏; 寺嶋 応顕; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 倉田 宝保; 中川 和彦
    近畿大学医学雑誌 = Medical journal of Kinki University 37 3 139 - 147 近畿大学医学会 2012年09月 [査読有り]
     
    [抄録] 我々はヒト非小細胞肺癌細胞株を用いたin vitro及び動物実験モデルによるin vivoの系において，EGFR 遺伝子変異の有無に関わらずGefitinibとS-1併用によって腫瘍増殖抑制効果の相乗効果が認められる事を報告してきた．しかし本併用療法に関して至摘投与量の検討はされていない．本試験では進行肺腺癌に対するGefitinibとS-1併用療法の推奨投与量の決定を主目的とし，併用による両薬剤の体内動態に及ぼす影響も併せて検討した．対象は1レジメンまたは2レジメンの化学療法を受けている進行肺腺癌症例とした．投与方法は最初の14日間は導入コースとしてGefitinib単独1日1錠（250mg）連日内服，Gefitinib内服開始15日目からS-1（Level 1：60mg/m^2/day，Level 2：80mg/m^2/day）1日2回内服を併用開始し，以降Gefitinib連日内服，S-1は2週間内服1週間休薬をもって1コース（21日間隔）とした．用量制限毒性はLevel 1の3例で認めず，Level 2では6例中2例（ALP高値，AST・ALT高値）に認められたが2例とも休薬により改善した為，推奨投与量をLevel 2と決定した．本試験に付随する血中薬物動態試験によりGefitinibとS-1には薬物相互作用がないことが示唆された．
  • 金田裕靖; 宮崎昌樹; 清田秀美; 田中 薫; 林 秀敏; 鶴谷純司; 倉田宝保; 岡本 勇; 中川 和彦
    気管支学 34 5 423 - 427 (NPO)日本呼吸器内視鏡学会 2012年09月 [査読有り]
     
    背景.超音波気管支鏡下針生検(EBUS-TBNA)は気管支鏡分野における新しい検査法で、縦隔や肺門リンパ節腫大の評価において有用性があり安全性の高い手技である。目的.当科で施行したEBUS-TBNA症例について病理学的診断における有用性を検討した。方法.2009年4月から2011年3月までの2年間に診断目的でEBUS-TBNAを施行した肺門・縦隔リンパ節腫大を有する51症例を対象とした。結果.51症例(延べ58症例)にEBUS-TBNAを施行した。診断率は86.3%(44/51)で46症例に確定診断が得られた。32症例が悪性腫瘍、14症例が良性疾患であった。EBUS-TBNAで確定診断に至らなかった5症例はCTガイド下肺生検と縦隔鏡で病理診断を得た。穿刺部位別診断率は、#4Rが75%、#7が89%、#11が80%、右上葉結節が0%で、その他の部位はすべて100%であった。また、リンパ節のサイズ別(短径)診断率は、10〜15mmが60%、16〜20mmが68%、21〜25mmが83%で、26mm以上はすべて100%であった。検査中・検査後において重篤な合併症は認めなかった。結語.当科で施行したEBUS-TBNAの診断率はこれまでのsystematic reviewと同等であった。EBUS-TBNAは肺門または縦隔リンパ節腫大を評価する方法として低侵襲かつ高い診断率が得られる手技である。(著者抄録)
  • EGFR遺伝子変異陽性非小細胞肺癌患者におけるEGFR遺伝子特異抗体により検出されるEGFR遺伝子変異蛋白の発現と治療との関係
    東 公一; 山田 一彦; 山下 文恵; 吉田 つかさ; 内藤 佳子; 岡山 雄亮; 財前 圭晃; 岡本 勇; 中川 和彦
    肺癌 52 4 439 - 439 (NPO)日本肺癌学会 2012年08月
  • Masayuki Takeda; Isamu Okamoto; Takeharu Yamanaka; Kazuhiko Nakagawa; Yoichi Nakanishi
    BMC CANCER 12 1 327  2012年08月 [査読有り]
     
    Background: Bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF), shows clinical activity against human cancer, with its addition to standard chemotherapy having been found to improve outcome in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). However, there have been no evidence-based studies to support the continued use of bevacizumab beyond disease progression in such patients treated with the drug in first-line therapy. We have now designed a randomized phase II trial to examine the clinical benefit and safety of continued bevacizumab treatment in patients with advanced nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Methods/Design: WJOG 5910L was designed as a multicenter, open-label, randomized, phase II trial by the West Japan Oncology Group of docetaxel (arm A) versus docetaxel plus bevacizumab (arm B) in patients with recurrent or metatstatic nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Patients in arm A will receive docetaxel at 60 mg/m(2) and those in arm B will receive docetaxel at 60 mg/m(2) plus bevacizumab at 15 mg/kg, with each drug administered on day 1 every 21 days until progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival, with secondary endpoints including response rate, overall survival, and safety, for patients treated in either arm.
  • Takayasu Kurata; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 8 663 - 669 2012年08月 [査読有り]
     
    Bone metastases are known to be caused by all types of cancer. Cancer metastasis to bone has been said to considerably compromise patients quality of life and adversely affect lifetime prognosis. Although progress in cancer treatment has prolonged survival significantly, this may make increased numbers of patients suffer from bone metastases. Until now, as for the treatment of bone metastases, local therapies, including radiation therapy and surgery, were performed mainly as palliative therapies. However, bisphosphonate-based therapies have recently become available and are frequently administered to delay or prevent skeletal-related events, which include pathologic bone fracture, spinal cord compression, radiologic treatment for bone lesions, surgical procedures for bone lesions and hypercalcemia. Moreover, denosumab, the first fully human monoclonal antibody to receptor activator of nuclear factor -B ligand, was approved in the USA because of its evidence-supported clinical effects. Denosumab was effective for prolonging the time to skeletal-related events and inhibiting the onset of pain via the suppression of osteoclast activation. Denosumab has been shown to have a greater effect compared with zoledronic acid, most notably in patients with breast or prostate cancer. In this article, the efficacy and safety of denosumab for the treatment of bone metastases in patients with various advanced cancers are discussed.
  • Kazuhiko Nakagawa; Shoji Kudoh; Yuichiro Ohe; Takeshi Johkoh; Masahiko Ando; Naoya Yamazaki; Akihiro Seki; Shinya Takemoto; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 7 8 1296 - 1303 2012年08月 [査読有り]
     
    Introduction: Interstitial lung disease (ILD) is an adverse drug reaction (ADR) of concern in Japanese patients with non-small-cell lung cancer (NSCLC) receiving erlotinib. To investigate erlotinib safety and efficacy in Japanese patients, a large-scale surveillance study was implemented. Methods: All patients with recurrent/advanced NSCLC receiving erlotinib in Japan were enrolled (December 2007-October 2009). During the 12-month observation period, adverse-event data were collected; any adverse event where erlotinib could not be excluded as a causative factor was termed an ADR. An independent review committee assessed ILD-like events. Overall survival and progression-free survival were also assessed. Interim data were analyzed for patients registered before June 30, 2008. Results: In total, 10,708 patients were enrolled, 3743 by June 30, 2008, with data available for 3488 patients. Overall ADR incidence was 81.8% (mostly grade 1/2); skin disorders (68.5%) including rash (63.0%) were most common. However, 81.8% of patients who experienced rash recovered or improved. ILD-like events, diagnosed by local physicians, were reported in 189 patients. The independent review committee confirmed ILD (all grades) in 158 patients (4.5% of interim population) with a mortality rate of 1.6% (55 patients). Significant ILD risk factors included concomitant or previous ILD, smoking history, concomitant or previous lung infection, and Eastern Cooperative Oncology Group performance status 2 to 4. Median overall survival and progression-free survival were 260 and 64 days, respectively. Conclusions: These interim data support the clinical benefits of erlotinib in Japanese NSCLC patients with no new safety signals. The risk/benefit balance for erlotinib in recurrent/advanced NSCLC remains favorable.
  • Isamu Okamoto; Kazuhiko Nakagawa
    CANCER SCIENCE 103 8 1391 - 1396 2012年08月 [査読有り]
     
    The identification of oncogenic genomic alterations is expected to facilitate the development of new molecularly targeted therapies for cancer. EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer (NSCLC). A small-molecule tyrosine kinase inhibitor of ALK, crizotinib, shows pronounced clinical activity in the treatment of patients with NSCLC positive for EML4-ALK, and it has rapidly entered into daily clinical practice. This review focuses on the biology and clinical features of, as well as diagnostic testing for, EML4-ALK-positive NSCLC. Current data on the efficacy and toxicity of crizotinib are also examined, and future directions for the treatment of NSCLC positive for ALK rearrangement are addressed. (Cancer Sci 2012; 103: 13911396)
  • Hiroyasu Kaneda; Isamu Okamoto; Taroh Satoh; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 4 1766 - 1767 2012年08月 [査読有り]
     
    Reversible posterior leukoencephalopathy syndrome (RPLS) is a serious condition that manifests as headache, convulsions, visual disturbance, and a characteristic magnetic resonance image (MRI) of the brain. We now describe a case of RPLS that was likely attributable to trastuzumab, a monoclonal antibody against human epidermal growth factor receptor-2 (HER2). Accumulating evidence has shown that molecular targeted agents, especially those with antiangiogenic activity cause significant hypertension which can lead to development of RPLS. Trastuzumab is also shown to inhibit tumor angiogenesis by decreasing the production of VEGF and activating antiangiogenic factors. In a clinical trial of trastuzumab, adverse effects of trastuzumab include hypertension, even though it is low incidence (similar to 10%). Although RPLS is potently reversible, it may result in an irreversible brain damage without prompt appropriate treatment. Given the increasing use of trastuzumab in patients with breast cancer, gastric cancer, or other solid tumors, physicians should be aware of this syndrome associated with acute hypertension during trastuzumab treatment.
  • Hiroyasu Kaneda; Isamu Okamoto; Taroh Satoh; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 4 1766 - 1767 2012年08月 [査読有り]
     
    Reversible posterior leukoencephalopathy syndrome (RPLS) is a serious condition that manifests as headache, convulsions, visual disturbance, and a characteristic magnetic resonance image (MRI) of the brain. We now describe a case of RPLS that was likely attributable to trastuzumab, a monoclonal antibody against human epidermal growth factor receptor-2 (HER2). Accumulating evidence has shown that molecular targeted agents, especially those with antiangiogenic activity cause significant hypertension which can lead to development of RPLS. Trastuzumab is also shown to inhibit tumor angiogenesis by decreasing the production of VEGF and activating antiangiogenic factors. In a clinical trial of trastuzumab, adverse effects of trastuzumab include hypertension, even though it is low incidence (similar to 10%). Although RPLS is potently reversible, it may result in an irreversible brain damage without prompt appropriate treatment. Given the increasing use of trastuzumab in patients with breast cancer, gastric cancer, or other solid tumors, physicians should be aware of this syndrome associated with acute hypertension during trastuzumab treatment.
  • Isamu Okamoto; Kazuhiko Nakagawa
    CANCER SCIENCE 103 8 1391 - 1396 2012年08月 [査読有り]
     
    The identification of oncogenic genomic alterations is expected to facilitate the development of new molecularly targeted therapies for cancer. EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer (NSCLC). A small-molecule tyrosine kinase inhibitor of ALK, crizotinib, shows pronounced clinical activity in the treatment of patients with NSCLC positive for EML4-ALK, and it has rapidly entered into daily clinical practice. This review focuses on the biology and clinical features of, as well as diagnostic testing for, EML4-ALK-positive NSCLC. Current data on the efficacy and toxicity of crizotinib are also examined, and future directions for the treatment of NSCLC positive for ALK rearrangement are addressed. (Cancer Sci 2012; 103: 13911396)
  • Kazuhiko Nakagawa; Shoji Kudoh; Yuichiro Ohe; Takeshi Johkoh; Masahiko Ando; Naoya Yamazaki; Akihiro Seki; Shinya Takemoto; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 7 8 1296 - 1303 2012年08月 [査読有り]
     
    Introduction: Interstitial lung disease (ILD) is an adverse drug reaction (ADR) of concern in Japanese patients with non-small-cell lung cancer (NSCLC) receiving erlotinib. To investigate erlotinib safety and efficacy in Japanese patients, a large-scale surveillance study was implemented. Methods: All patients with recurrent/advanced NSCLC receiving erlotinib in Japan were enrolled (December 2007-October 2009). During the 12-month observation period, adverse-event data were collected; any adverse event where erlotinib could not be excluded as a causative factor was termed an ADR. An independent review committee assessed ILD-like events. Overall survival and progression-free survival were also assessed. Interim data were analyzed for patients registered before June 30, 2008. Results: In total, 10,708 patients were enrolled, 3743 by June 30, 2008, with data available for 3488 patients. Overall ADR incidence was 81.8% (mostly grade 1/2); skin disorders (68.5%) including rash (63.0%) were most common. However, 81.8% of patients who experienced rash recovered or improved. ILD-like events, diagnosed by local physicians, were reported in 189 patients. The independent review committee confirmed ILD (all grades) in 158 patients (4.5% of interim population) with a mortality rate of 1.6% (55 patients). Significant ILD risk factors included concomitant or previous ILD, smoking history, concomitant or previous lung infection, and Eastern Cooperative Oncology Group performance status 2 to 4. Median overall survival and progression-free survival were 260 and 64 days, respectively. Conclusions: These interim data support the clinical benefits of erlotinib in Japanese NSCLC patients with no new safety signals. The risk/benefit balance for erlotinib in recurrent/advanced NSCLC remains favorable.
  • Takayasu Kurata; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 8 663 - 669 2012年08月 [査読有り]
     
    Bone metastases are known to be caused by all types of cancer. Cancer metastasis to bone has been said to considerably compromise patients quality of life and adversely affect lifetime prognosis. Although progress in cancer treatment has prolonged survival significantly, this may make increased numbers of patients suffer from bone metastases. Until now, as for the treatment of bone metastases, local therapies, including radiation therapy and surgery, were performed mainly as palliative therapies. However, bisphosphonate-based therapies have recently become available and are frequently administered to delay or prevent skeletal-related events, which include pathologic bone fracture, spinal cord compression, radiologic treatment for bone lesions, surgical procedures for bone lesions and hypercalcemia. Moreover, denosumab, the first fully human monoclonal antibody to receptor activator of nuclear factor -B ligand, was approved in the USA because of its evidence-supported clinical effects. Denosumab was effective for prolonging the time to skeletal-related events and inhibiting the onset of pain via the suppression of osteoclast activation. Denosumab has been shown to have a greater effect compared with zoledronic acid, most notably in patients with breast or prostate cancer. In this article, the efficacy and safety of denosumab for the treatment of bone metastases in patients with various advanced cancers are discussed.
  • Masayuki Takeda; Isamu Okamoto; Takeharu Yamanaka; Kazuhiko Nakagawa; Yoichi Nakanishi
    BMC CANCER 12 327  2012年08月 [査読有り]
     
    Background: Bevacizumab, a humanized antibody to vascular endothelial growth factor (VEGF), shows clinical activity against human cancer, with its addition to standard chemotherapy having been found to improve outcome in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). However, there have been no evidence-based studies to support the continued use of bevacizumab beyond disease progression in such patients treated with the drug in first-line therapy. We have now designed a randomized phase II trial to examine the clinical benefit and safety of continued bevacizumab treatment in patients with advanced nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Methods/Design: WJOG 5910L was designed as a multicenter, open-label, randomized, phase II trial by the West Japan Oncology Group of docetaxel (arm A) versus docetaxel plus bevacizumab (arm B) in patients with recurrent or metatstatic nonsquamous NSCLC whose disease has progressed after first-line treatment with bevacizumab plus a platinum-based doublet. Patients in arm A will receive docetaxel at 60 mg/m(2) and those in arm B will receive docetaxel at 60 mg/m(2) plus bevacizumab at 15 mg/kg, with each drug administered on day 1 every 21 days until progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival, with secondary endpoints including response rate, overall survival, and safety, for patients treated in either arm.
  • Yano S; Takeuchi S; Nakagawa T; Yamada T
    Cancer science 103 7 1189 - 94 2012年07月 [査読有り]
     
    Recent advances in molecular biology have led to the identification of new molecular targets, such as epidermal growth factor receptor ( EGFR ) mutations and echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene, in lung cancer. Dramatic response has been achieved with EGFR inhibitors (gefitinib and erlotinib) and an ALK inhibitor (crizotinib) in lung cancer expressing corresponding targets. However, cancer cells acquire resistance to these drugs and cause recurrence. Known major mechanisms for resistance to molecular targeted drugs include gatekeeper mutations in the target gene and activation of bypass survival signal via receptors other than the target receptors. The latter mechanism can involve receptor gene amplification and ligand-triggered receptor activation as well. For example, hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells. Moreover, EGFR ligands activate EGFR and downstream pathways and trigger resistance to crizotinib in EML4-ALK lung cancer cells. These observations indicate that signals from oncogenic drivers (EGFR signaling in EGFR -mutant lung cancer and ALK signaling in EML4-ALK lung cancer) and ligand-triggered bypass signals (HGF-Met and EGFR ligands-EGFR, respectively) must be simultaneously blocked to avoid the resistance. This review focuses specifically on receptor activation by ligand stimulation and discusses novel therapeutic strategies that are under development for overcoming resistance to molecular targeted drugs in lung cancer.
  • Koizumi H; Yamada T; Takeuchi S; Nakagawa T; Kita K; Nakamura T; Matsumoto K; Suda K; Mitsudomi T; Yano S
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7 7 1078 - 85 2012年07月 [査読有り]
     
    INTRODUCTION: The three major clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90 kDa molecular chaperone for proteins that include EGFR, Met, and echinoderm microtubule-associated proetin-like-4-the anaplastic lymphoma kinase. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer cells. METHODS: The effects of the Hsp90 inhibitor 17-demethoxygeldanamycin (17-DMAG) on the growth of lung cancer cells resistant to the EGFR-TKI were examined in the presence and absence of HGF, and in cells transfected with the HGF gene in vitro and in vivo. RESULTS: EGFR-TKI erlotinib did not inhibit the growth of HGF-gene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, containing the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells, with deletions in EGFR exon19, in the presence of HGF. However, 17-DMAG induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met in tumor cells. An in vivo model of HGF-triggered erlotinib-resistance, which used Ma-1/HGF cells, showed that 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis. CONCLUSIONS: Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and may result in more successful treatment of patients with EGFR-mutant lung cancers.
  • Kanchanamala Withanage; Kentaro Nakagawa; Mitsunobu Ikeda; Hidetake Kurihara; Takumi Kudo; Zeyu Yang; Ayuko Sakane; Takuya Sasaki; Yutaka Hata
    JOURNAL OF BIOCHEMISTRY 152 1 111 - 119 2012年07月 [査読有り]
     
    RASSF6, a member of RASSF tumour suppressor proteins, binds to mammalian Ste20-like kinases (MST1/2), core kinases of the proapoptotic Hippo pathway and cooperates with the Hippo pathway to induce apoptosis. We originally identified RASSF6 as a putative interactor of membrane-associated guanylate kinase inverted (MAGI)-1 by the yeast two-hybrid screening. We used human kidney cDNA library for the screening. MAGI-1 is abundantly expressed in kidney and is a core component of the slit diaphragm. These findings suggest that RASSF6 is expressed in kidney. However, the function of RASSF6 in kidney is not yet studied. We performed this study to confirm the interaction of RASSF6 with MAGI-1, to analyse the expression of RASSF6 in kidney and to gain insight into the function of RASSF6 in kidney. RASSF6 binds to PDZ domains of MAGI-1 through its C-terminal PDZ-binding motif and is coimmunoprecipitated with MAGI-1 from rat liver. RASSF6 is localized in normal kidney glomerulus but disappears when the slit diaphragm is disrupted in nephrotic kidney. RASSF6 is also localized on apical membranes in renal proximal tubular epithelial cells. We demonstrated that RASSF6 as well as the Hippo pathway are involved in the sorbitol-induced apoptosis in immortalized human proximal renal tubular epithelial HK-2 cells.
  • Wataru Okamoto; Isamu Okamoto; Tokuzo Arao; Kiyoko Kuwata; Erina Hatashita; Haruka Yamaguchi; Kazuko Sakai; Kazuyoshi Yanagihara; Kazuto Nishio; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 11 7 1557 - 1564 2012年07月 [査読有り]
     
    Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference-mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification-positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification. Mol Cancer Ther; 11(7); 1557-64. (C)2012 AACR.
  • Takayasu Kurata; Tomonori Hirashima; Yasuo Iwamoto; Tomoya Kawaguchi; Norihiko Ikeda; Masahiro Tsuboi; Toshiyuki Sawa; Takashi Ishiguro; Takuya Aoki; Yoshikazu Kotani; Kazuhiko Nakagawa; Masahiro Fukuoka
    LUNG CANCER 77 1 110 - 115 2012年07月 [査読有り]
     
    Introduction: Monotherapy with a third generation anticancer agent has been regarded as the standard therapy for elderly patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether elderly patients with a good performance status can tolerate platinum-doublet chemotherapy like younger patients. Methods: A combination phase I/II study was conducted in chemo-naive elderly patients with NSCLC to establish the toxicity and maximum tolerated dose (MTD) and to investigate the antitumor activity of carboplatin (CBDCA) plus gemcitabine (GEM). GEM was infused on days 1 and 8, and CBDCA on day 1 every 3 weeks. Results: Seventy-five patients were enrolled. The most frequent toxicities were hematological, especially thrombocytopenia. Three of three patients experienced a dose-limiting toxicity at dose level 3: 1000 mg/m(2) GEM with AUC 5 CBDCA (MTD), and one of seven patients at level 2a: 1000 mg/m(2) GEM with AUC 4 CBDCA (recommended dose). In the phase II study, the overall response rate was 22.2% and the median overall survival time was 14.2 months. Conclusions: Although the recommended dosage is restricted to a lower level compared to younger patients, combination therapy using CBDCA with GEM is tolerable and promising for elderly patients with advanced NSCLC. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
  • Takayasu Kurata; Tomonori Hirashima; Yasuo Iwamoto; Tomoya Kawaguchi; Norihiko Ikeda; Masahiro Tsuboi; Toshiyuki Sawa; Takashi Ishiguro; Takuya Aoki; Yoshikazu Kotani; Kazuhiko Nakagawa; Masahiro Fukuoka
    LUNG CANCER 77 1 110 - 115 2012年07月 [査読有り]
     
    Introduction: Monotherapy with a third generation anticancer agent has been regarded as the standard therapy for elderly patients with advanced non-small-cell lung cancer (NSCLC). However, it is unclear whether elderly patients with a good performance status can tolerate platinum-doublet chemotherapy like younger patients. Methods: A combination phase I/II study was conducted in chemo-naive elderly patients with NSCLC to establish the toxicity and maximum tolerated dose (MTD) and to investigate the antitumor activity of carboplatin (CBDCA) plus gemcitabine (GEM). GEM was infused on days 1 and 8, and CBDCA on day 1 every 3 weeks. Results: Seventy-five patients were enrolled. The most frequent toxicities were hematological, especially thrombocytopenia. Three of three patients experienced a dose-limiting toxicity at dose level 3: 1000 mg/m(2) GEM with AUC 5 CBDCA (MTD), and one of seven patients at level 2a: 1000 mg/m(2) GEM with AUC 4 CBDCA (recommended dose). In the phase II study, the overall response rate was 22.2% and the median overall survival time was 14.2 months. Conclusions: Although the recommended dosage is restricted to a lower level compared to younger patients, combination therapy using CBDCA with GEM is tolerable and promising for elderly patients with advanced NSCLC. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
  • Wataru Okamoto; Isamu Okamoto; Tokuzo Arao; Kiyoko Kuwata; Erina Hatashita; Haruka Yamaguchi; Kazuko Sakai; Kazuyoshi Yanagihara; Kazuto Nishio; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 11 7 1557 - 1564 2012年07月 [査読有り]
     
    Therapeutic strategies that target the tyrosine kinase MET hold promise for gastric cancer, but the mechanism underlying the antitumor activity of such strategies remains unclear. We examined the antitumor action of the MET tyrosine kinase inhibitor crizotinib (PF-02341066) in gastric cancer cells positive or negative for MET amplification. Inhibition of MET signaling by crizotinib or RNA interference-mediated MET depletion resulted in induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in gastric cancer cells with MET amplification but not in those without it, suggesting that MET signaling is essential for the survival of MET amplification-positive cells. Crizotinib upregulated the expression of BIM, a proapoptotic member of the Bcl-2 family, as well as downregulated that of survivin, X-linked inhibitor of apoptosis protein (XIAP), and c-IAP1, members of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM inhibited crizotinib-induced apoptosis, suggesting that upregulation of BIM contributes to the proapoptotic effect of crizotinib. Crizotinib also exhibited a marked antitumor effect in gastric cancer xenografts positive for MET amplification, whereas it had little effect on those negative for this genetic change. Crizotinib thus shows a marked antitumor action both in vitro and in vivo specifically in gastric cancer cells positive for MET amplification. Mol Cancer Ther; 11(7); 1557-64. (C)2012 AACR.
  • Kyoichi Kaira; Kazuo Nakagawa; Yasuhisa Ohde; Takehiro Okumura; Toshiaki Takahashi; Haruyasu Murakami; Masahiro Endo; Haruhiko Kondo; Takashi Nakajima; Nobuyuki Yamamoto
    INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY 20 3 223 - 232 2012年06月 [査読有り]
     
    MUC1 is transmembrane mucin aberrantly overexpressed in various cancers. However, little is known about how MUC1 expression is associated with hypoxia, glucose metabolism, and epidermal growth factor receptor (EGFR) pathway, which are related to cancer progression. The aim of this study is to evaluate the relationship between MUC1 expression and these molecular markers in lung cancer. Of all 126 patients, high-grade polarized expression (HP), low-grade polarized expression (LP), and depolarized expression (DP) group were 50 (39.7%), 35 (27.8%), and 41 (32.5%), respectively. Depolarized MUC1 expression was significantly associated with poor outcome and was closely correlated with glucose metabolism (Glut1), hypoxia (HIF-1 alpha), angiogenesis (vascular endothelial growth factor and microvessel density), amino acid metabolism (LAT1), and EGFR expression. High-grade polarized MUC1 expression was associated with favorable prognosis and adenocarcinoma. Depolarized MUC1 expression was significantly associated with poor outcome. Glucose metabolism, hypoxia, angiogenesis, amino acid metabolism, and EGFR pathway may play an important role in the development of depolarized MUC1 expression.
  • がん性疼痛患者に対するオピオイド鎮痛緩和と心理尺度変化
    牧村 ちひろ; 松岡 弘道; 鶴谷 純司; 大塚 正友; 小山 敦子; 中川 和彦
    日本緩和医療学会学術大会プログラム・抄録集 17回 435 - 435 (NPO)日本緩和医療学会 2012年06月
  • Hiroyasu Kaneda; Shinya Ueda; Chihiro Makimura; Hidemi Kiyota; Hisato Kawakami; Isamu Okamoto; Kaoru Tanaka; Shinichi Nishina; Toshihiro Kudo; Junji Turutani; Masaki Miyazaki; Yasuhito Fujisaka; Wataru Okamoto; Takayasu Kurata; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 23 65 - 65 2012年06月 [査読有り]
  • Shinya Ueda; Hisato Kawakami; Wataru Okamoto; Shinichi Nishina; Toshihiro Kudo; Chihiro Makimura; Hidemi Kiyota; Kaoru Tanaka; Hiroyasu Kaneda; Yasuhito Fujisaka; Masaki Miyazaki; Junji Turutani; Isamu Okamoto; Takayasu Kurata; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 23 65 - 65 2012年06月 [査読有り]
  • Kudo T; Ikeda M; Nishikawa M; Yang Z; Ohno K; Nakagawa K; Hata Y
    Cancer research 72 11 2901 - 2911 2012年06月 [査読有り]
  • Seiji Niho; Hideo Kunitoh; Hiroshi Nokihara; Takeshi Horai; Yukito Ichinose; Toyoaki Hida; Nobuyuki Yamamoto; Masaaki Kawahara; Tetsu Shinkai; Kazuhiko Nakagawa; Kaoru Matsui; Shunichi Negoro; Akira Yokoyama; Shinzoh Kudoh; Katsuyuki Kiura; Kiyoshi Mori; Hiroaki Okamoto; Hiroshi Sakai; Koji Takeda; Soichiro Yokota; Nagahiro Saijo; Masahiro Fukuoka
    LUNG CANCER 76 3 362 - 367 2012年06月 [査読有り]
     
    Purpose: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Chemonaive patients with stage IIIB. IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed >= 3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p = 0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p = 0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p = 0.9526). No new safety signals were detected. Conclusion: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338). (c) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Isamu Okamoto; Nobuyuki Yamamoto; Kaoru Kubota; Yuichiro Ohe; Naoyuki Nogami; Haruyasu Murakami; Hidetoshi Yamaya; Katsuhiro Ono; Kazuhiko Nakagawa
    Investigational new drugs 30 3 1132 - 7 2012年06月 [査読有り]
     
    BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a Cremophor EL-free formulation of paclitaxel newly designed to avoid solvent-related toxicities. We have evaluated the safety, tolerability, pharmacokinetics, and tumor response profile of weekly nab-paclitaxel (100 mg/m(2)) infusion together with administration of carboplatin at an area under the curve (AUC) of 6 every 3 weeks in Japanese patients with advanced non-small cell lung cancer (NSCLC). METHODS: Nab-paclitaxel (100 mg/m(2)) was administered without steroid or antihistamine premedication as a 30-min intravenous infusion once a week in combination with carboplatin at an AUC of 6 on day 1 of repeated 21-day cycles. The pharmacokinetics of both drugs were analyzed, and both adverse events and treatment response were monitored. RESULTS: Eighteen patients were enrolled in the study. The most frequent treatment-related toxicities of grade 3 or 4 were neutropenia (67%), leukopenia (50%), and anemia (22%). No severe hypersensitivity reactions were observed despite the lack of premedication, and no unexpected or new toxicities were detected. Pharmacokinetics analysis did not reveal any substantial drug-drug interactions. Seven partial responses were observed among the 18 evaluable patients, yielding a treatment response rate of 38.9%. CONCLUSIONS: The combination of nab-paclitaxel (100 mg/m(2)) administered weekly and carboplatin at an AUC of 6 every 3 weeks was well tolerated in Japanese patients with advanced NSCLC. This combination therapy also showed promising antitumor activity and was not associated with relevant pharmacokinetic interactions.
  • Isamu Okamoto; Nobuyuki Yamamoto; Kaoru Kubota; Yuichiro Ohe; Naoyuki Nogami; Haruyasu Murakami; Hidetoshi Yamaya; Katsuhiro Ono; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 3 1132 - 1137 2012年06月 [査読有り]
     
    Background Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a Cremophor EL-free formulation of paclitaxel newly designed to avoid solvent-related toxicities. We have evaluated the safety, tolerability, pharmacokinetics, and tumor response profile of weekly nab-paclitaxel (100 mg/m(2)) infusion together with administration of carboplatin at an area under the curve (AUC) of 6 every 3 weeks in Japanese patients with advanced non-small cell lung cancer (NSCLC). Methods Nab-paclitaxel (100 mg/m(2)) was administered without steroid or antihistamine premedication as a 30-min intravenous infusion once a week in combination with carboplatin at an AUC of 6 on day 1 of repeated 21-day cycles. The pharmacokinetics of both drugs were analyzed, and both adverse events and treatment response were monitored. Results Eighteen patients were enrolled in the study. The most frequent treatment-related toxicities of grade 3 or 4 were neutropenia (67%), leukopenia (50%), and anemia (22%). No severe hypersensitivity reactions were observed despite the lack of premedication, and no unexpected or new toxicities were detected. Pharmacokinetics analysis did not reveal any substantial drug-drug interactions. Seven partial responses were observed among the 18 evaluable patients, yielding a treatment response rate of 38.9%. Conclusions The combination of nab-paclitaxel (100 mg/m(2)) administered weekly and carboplatin at an AUC of 6 every 3 weeks was well tolerated in Japanese patients with advanced NSCLC. This combination therapy also showed promising antitumor activity and was not associated with relevant pharmacokinetic interactions.
  • Seiji Niho; Hideo Kunitoh; Hiroshi Nokihara; Takeshi Horai; Yukito Ichinose; Toyoaki Hida; Nobuyuki Yamamoto; Masaaki Kawahara; Tetsu Shinkai; Kazuhiko Nakagawa; Kaoru Matsui; Shunichi Negoro; Akira Yokoyama; Shinzoh Kudoh; Katsuyuki Kiura; Kiyoshi Mori; Hiroaki Okamoto; Hiroshi Sakai; Koji Takeda; Soichiro Yokota; Nagahiro Saijo; Masahiro Fukuoka
    LUNG CANCER 76 3 362 - 367 2012年06月 [査読有り]
     
    Purpose: This multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Methods: Chemonaive patients with stage IIIB. IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed >= 3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results: After confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p = 0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p = 0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p = 0.9526). No new safety signals were detected. Conclusion: Study JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338). (c) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Isamu Okamoto; Junji Tsurutani; Naoki Oiso; Akira Kawada; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 6 528 - 533 2012年06月 [査読有り]
     
    Somatic mutations in the epidermal growth factor receptor gene are associated with a therapeutic response to epidermal growth factor receptor tyrosine kinase inhibitors such as gefitinib and erlotinib in patients with non-small cell lung cancer. Although the safety profile of these drugs is favorable, a small proportion of patients with EGFR mutation-positive non-small cell lung cancer must discontinue treatment because of adverse events such as interstitial lung disease and hepatotoxicity. Subsequent chemotherapy has not been optimized in such patients. We performed a retrospective analysis of EGFR mutation-positive non-small cell lung cancer patients who received both gefitinib and erlotinib at our institution. Patients received the second epidermal growth factor receptor-tyrosine kinase inhibitor after experiencing an adverse event or progressive disease on the first epidermal growth factor receptor-tyrosine kinase inhibitor. We identified 14 patients who received both gefitinib and erlotinib in the course of their treatment. Three patients initially treated with gefitinib and two with erlotinib discontinued epidermal growth factor receptor-tyrosine kinase inhibitor therapy because of severe non-hematologic toxicity (one because of gefitinib-induced interstitial lung disease, one because of erlotinib-induced lupus erythematosus-like eruption and three because of hepatotoxicity). All five of these patients were able successfully to continue therapy with the second epidermal growth factor receptor-tyrosine kinase inhibitor with no evidence of a recurrent adverse event. Progression-free survival was significantly longer in these five patients than in the nine patients who discontinued treatment with the first epidermal growth factor receptor-tyrosine kinase inhibitor because of disease progression. EGFR mutation-positive non-small cell lung cancer patients who discontinue treatment with a first epidermal growth factor receptor-tyrosine kinase inhibitor because of an adverse event benefit substantially from switching to a second epidermal growth factor receptor-tyrosine kinase inhibitor before the development of drug resistance.
  • H. Hayashi; I. Okamoto; S. Morita; M. Taguri; K. Nakagawa
    ANNALS OF ONCOLOGY 23 6 1537 - 1541 2012年06月 [査読有り]
     
    Background: Given the growing number of drugs available for non-small-cell lung cancer (NSCLC), an effect of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. We examined the relation between postprogression survival (PPS) and OS in phase III trials of first-line chemotherapy for advanced NSCLC. Patients and methods: A literature search identified 69 trials that were published during the past decade. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the relation between OS and either PFS or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment. Results: The average PPS was longer in recent trials than in older trials (6.5 versus 4.4 months, P < 0.0001). For all trials, PPS was strongly associated with OS (r = 0.82), whereas PFS was moderately associated with OS (r = 0.43). The correlation between OS and PPS in recent trials was stronger than that in older trials (r = 0.89 and 0.66). Conclusions: Our findings indicate that, especially for recent trials, PPS is highly associated with OS in first-line chemotherapy for advanced NSCLC, whereas PFS is only moderately associated with OS.
  • 東 公一; 岡本 勇; 山田 一彦; 山下 文恵; 吉田 つかさ; 内藤 佳子; 岡山 雄亮; 財前 圭晃; 中川 和彦
    気管支学 34 3 281 - 281 (NPO)日本呼吸器内視鏡学会 2012年05月
  • 心身両面からの全人的病態理解が治療に役立った術後乳がんの2症例
    松岡 弘道; 鶴谷 純司; 牧村 ちひろ; 小山 敦子; 中川 和彦
    日本乳癌学会総会プログラム抄録集 20回 271 - 271 (一社)日本乳癌学会 2012年05月
  • エリブリン療法における用量調節の重要性について
    鶴谷 純司; 牧村 ちひろ; 松岡 弘道; 中川 和彦
    日本乳癌学会総会プログラム抄録集 20回 480 - 480 (一社)日本乳癌学会 2012年05月
  • Hiroyasu Kaneda; Yoshiko Urata; Isamu Okamoto; Yoshihiro Hattori; Keiko Okuno; Temiko Shimada; Masayuki Takeda; Takayasu Kurata; Masaki Miyazaki; Masaaki Terashima; Kaoru Tanaka; Hidemi Kiyota; Hidetoshi Hayashi; Toshihiro Kudo; Takafumi Okabe; Koichi Azuma; Satoshi Morita; Kazuhiko Nakagawa; Shunichi Negoro; Miyako Satouchi
    JOURNAL OF CLINICAL ONCOLOGY 30 15 2012年05月 [査読有り]
  • Koichi Azuma; Akihiko Kawahara; Satoshi Hattori; Tomoki Taira; Junji Tsurutani; Kosuke Watari; Tomohiro Shibata; Yuichi Murakami; Shinzo Takamori; Mayumi Ono; Hiroto Izumi; Masayoshi Kage; Takashi Yanagawa; Kazuhiko Nakagawa; Tomoaki Hoshino; Michihiko Kuwano
    JOURNAL OF THORACIC ONCOLOGY 7 5 779 - 789 2012年05月 [査読有り]
     
    Objective: Expression of N-myc downstream-regulated gene 1 (NDRG1)/Cap43 is a prognostic indicator of human malignancies according to the tumor type in which it occurs. We investigated how NDRG1/Cap43 could affect tumor growth and angiogenesis in non-small-cell lung cancer (NSCLC) in vivo using an animal experimental model, and also how it could affect tumor angiogenesis and prognosis in NSCLC patients. Methods and Results: Knockdown of NDRG1/Cap43 in lung cancer cells using a specific small interfering RNA resulted in growth rates in culture that were similar to those of counterpart control cells, but decreased tumor growth rates in vivo markedly. Stable NDRG1/Cap43 knockdown did not induce consistent changes in the expression of Epidermal growth factor receptor (EGFR) family proteins and c-Met in two human lung cancer cell lines in vitro. However, cell lines with NDRG1/Cap43 knockdown showed markedly decreased production of the potent angiogenic factors vascular endothelial growth factor-A and interleukin-8. Cells with knockdown of NDRG1/Cap43 showed marked reduction of tumor-induced angiogenesis. Using immunohistochemistry, we examined 182 surgically resected specimens of NSCLC for expression of NDRG1/Cap43 and tumor angiogenesis. High microvessel density in the tumor was significantly associated with nuclear positivity for NDRG1/Cap43 in both adenocarcinoma (p = 0.003) and squamous cell carcinoma (p=0.041). For both adenocarcinoma (p = 0.031) and squamous cell carcinoma (p=0.034), the survival curve of patients negative for nuclear NDRG1/Cap43 expression differed significantly from that of patients who were positive. Conclusion: Therefore, the expression of NDRG1/Cap43 may be predictive of tumor angiogenesis and poor prognosis in NSCLC.
  • Takuhito Tada; Yasutaka Chiba; Kayoko Tsujino; Haruyuki Fukuda; Yasumasa Nishimura; Masaki Kokubo; Shunichi Negoro; Shinzoh Kudoh; Masahiro Fukuoka; Kazuhiko Nakagawa; Yoichi Nakanishi
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 83 1 327 - 331 2012年05月 [査読有り]
     
    Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m(2)) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m(2)). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade >= 4 esophagitis and neutropenic fever and Grade >= 3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient. (C) 2012 Elsevier Inc.
  • Kazuko Sakai; Isamu Okamoto; Ken Takezawa; Tomonori Hirashima; Hiroyasu Kaneda; Masayuki Takeda; Kazuko Matsumoto; Hideharu Kimura; Yoshihiko Fujita; Kazuhiko Nakagawa; Tokuzo Arao; Kazuto Nishio
    JOURNAL OF THORACIC ONCOLOGY 7 5 913 - 918 2012年05月 [査読有り]
     
    Introduction: The presence of the transforming fusion gene echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC) is a predictive marker for the efficacy of anaplastic lymphoma kinase inhibitors. However, the currently available assays for the detection of the different variants of EML4-ALK have limitations. Methods: We developed an assay system for the detection of EML4-ALK variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, or 7 transcripts in total RNA obtained from formalin-fixed, paraffin-embedded (FFPE) specimens of NSCLC tissue. The assay is based on region-specific polymerase chain reaction amplification of EML4-ALK complementary DNA followed by specific single-base primer extension and analysis of the extension products by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The assay was validated by fluorescence in situ hybridization and the results confirmed by subcloning and sequencing of polymerase chain reaction products. Results: Evaluation of the analytic sensitivity of the assay with serial dilutions of plasmids containing EML4-ALK complementary DNA sequences revealed it to be capable of the reliable detection of one copy of each plasmid per reaction. The assay also detected EML4-ALK variants 1 or 3 in three FFPE samples of surgically resected NSCLC shown to be positive for anaplastic lymphoma kinase rearrangement by fluorescence in situ hybridization. Furthermore, the assay identified variant 1 of EML4-ALK in 3 of 20 FFPE biopsy samples from patients with advanced NSCLC. All positive samples were confirmed by subcloning and sequencing. Conclusions: Our novel assay is highly sensitive and effective for the detection of EML4-ALK in FFPE specimens.
  • Hiromichi Matsuoka; Tokuzo Arao; Chihiro Makimura; Masayuki Takeda; Hidemi Kiyota; Junji Tsurutani; Yoshihiko Fujita; Kazuko Matsumoto; Hideharu Kimura; Masatomo Otsuka; Atsuko Koyama; Chiyo K. Imamura; Yusuke Tanigawara; Takeharu Yamanaka; Kyoko Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOLOGY REPORTS 27 5 1393 - 1399 2012年05月 [査読有り]
     
    Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naive cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRMI, 118A -> G) and catechol-O-methyltransferase (COMT, 472G -> A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the m RNA expression levels of arrestin beta 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRMI and morphine treatrnent; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G -> A genotype may be a predictive biomarker of the response to morphine treatment.
  • Takuhito Tada; Yasutaka Chiba; Kayoko Tsujino; Haruyuki Fukuda; Yasumasa Nishimura; Masaki Kokubo; Shunichi Negoro; Shinzoh Kudoh; Masahiro Fukuoka; Kazuhiko Nakagawa; Yoichi Nakanishi
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 83 1 327 - 331 2012年05月 [査読有り]
     
    Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m(2)) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m(2)). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade >= 4 esophagitis and neutropenic fever and Grade >= 3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient. (C) 2012 Elsevier Inc.
  • Hiromichi Matsuoka; Tokuzo Arao; Chihiro Makimura; Masayuki Takeda; Hidemi Kiyota; Junji Tsurutani; Yoshihiko Fujita; Kazuko Matsumoto; Hideharu Kimura; Masatomo Otsuka; Atsuko Koyama; Chiyo K. Imamura; Yusuke Tanigawara; Takeharu Yamanaka; Kyoko Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    ONCOLOGY REPORTS 27 5 1393 - 1399 2012年05月 [査読有り]
     
    Genetic differences in individuals with regard to opioid-receptor signaling create clinical difficulties for opioid treatment; consequently, useful pharmacodynamic and predictive biomarkers are needed. In this prospective study, we studied gene expression changes in peripheral blood leukocytes using a microarray and real-time RT-PCR analysis to identify pharmacodynamic biomarkers for monitoring the effect of morphine in a cohort of opioid-treatment-naive cancer patients. We also examined genetic variations in opioid receptor mu 1 (OPRMI, 118A -> G) and catechol-O-methyltransferase (COMT, 472G -> A) to evaluate predictive biomarkers of the treatment outcome of morphine. The plasma concentration of morphine was measured using a liquid chromatography-tandem mass spectrometry method. Microarray analysis revealed that the m RNA expression levels of arrestin beta 1 (ARRB1) were significantly down-regulated by morphine treatment. Real-time RT-PCR analysis against independent samples confirmed the results (P=0.003) and changes during treatment were negatively correlated with the plasma morphine concentration (R=-0.42). No correlation was observed between the genotype of OPRMI and morphine treatrnent; however, the plasma concentration of morphine and the required dose of morphine were significantly lower for the A/A genotype of COMT (vs. A/G+G/G, P=0.008 and 0.03). We found that changes in the expression of ARRB1 may be a novel pharmacodynamic biomarker and the COMT 472G -> A genotype may be a predictive biomarker of the response to morphine treatment.
  • Koichi Azuma; Akihiko Kawahara; Satoshi Hattori; Tomoki Taira; Junji Tsurutani; Kosuke Watari; Tomohiro Shibata; Yuichi Murakami; Shinzo Takamori; Mayumi Ono; Hiroto Izumi; Masayoshi Kage; Takashi Yanagawa; Kazuhiko Nakagawa; Tomoaki Hoshino; Michihiko Kuwano
    JOURNAL OF THORACIC ONCOLOGY 7 5 779 - 789 2012年05月 [査読有り]
     
    Objective: Expression of N-myc downstream-regulated gene 1 (NDRG1)/Cap43 is a prognostic indicator of human malignancies according to the tumor type in which it occurs. We investigated how NDRG1/Cap43 could affect tumor growth and angiogenesis in non-small-cell lung cancer (NSCLC) in vivo using an animal experimental model, and also how it could affect tumor angiogenesis and prognosis in NSCLC patients. Methods and Results: Knockdown of NDRG1/Cap43 in lung cancer cells using a specific small interfering RNA resulted in growth rates in culture that were similar to those of counterpart control cells, but decreased tumor growth rates in vivo markedly. Stable NDRG1/Cap43 knockdown did not induce consistent changes in the expression of Epidermal growth factor receptor (EGFR) family proteins and c-Met in two human lung cancer cell lines in vitro. However, cell lines with NDRG1/Cap43 knockdown showed markedly decreased production of the potent angiogenic factors vascular endothelial growth factor-A and interleukin-8. Cells with knockdown of NDRG1/Cap43 showed marked reduction of tumor-induced angiogenesis. Using immunohistochemistry, we examined 182 surgically resected specimens of NSCLC for expression of NDRG1/Cap43 and tumor angiogenesis. High microvessel density in the tumor was significantly associated with nuclear positivity for NDRG1/Cap43 in both adenocarcinoma (p = 0.003) and squamous cell carcinoma (p=0.041). For both adenocarcinoma (p = 0.031) and squamous cell carcinoma (p=0.034), the survival curve of patients negative for nuclear NDRG1/Cap43 expression differed significantly from that of patients who were positive. Conclusion: Therefore, the expression of NDRG1/Cap43 may be predictive of tumor angiogenesis and poor prognosis in NSCLC.
  • Hiromichi Matsuoka; Chihiro Makimura; Atsuko Koyama; Masatomo Otsuka; Wataru Okamoto; Yasuhito Fujisaka; Hiroyasu Kaneda; Junji Tsurutani; Kazuhiko Nakagawa
    ANTICANCER RESEARCH 32 5 1805 - 1809 2012年05月 [査読有り]
     
    Background: Neuropathic pain frequently occurs in cancer patients, but no drug therapy has been established for this type of disorder. The purpose of this study was to investigate the effect of dulasetine in cancer patients suffering from neuropathic pain. Patients and Methods: The subjects of the study were 15 cancer patients with neuropathic pain who visited the Kinki University Faculty of Medicine Hospital and met the International Association for the Study of Pain diagnostic criteria for neuropathic pain. Duloxetine was administered to patients in whom pregabalin could not be administered. The influence of duloxetine was investigated retrospectively with the use of a numerical rating scale. Results: Pain was reduced in 7 out of the 15 patients. Sleepiness and the light-headed feeling were improved in four patients, in whom, however, the pain was not reduced. Thus, duloxetine was judged to be effective in 11 patients. The maintenance dose of duloxetine was 20-40 mg/day. Conclusion: Duloxetine administration may be effective for neuropathic pain in cancer patients who cannot tolerate pregabalin administration.
  • Kazuko Sakai; Isamu Okamoto; Ken Takezawa; Tomonori Hirashima; Hiroyasu Kaneda; Masayuki Takeda; Kazuko Matsumoto; Hideharu Kimura; Yoshihiko Fujita; Kazuhiko Nakagawa; Tokuzo Arao; Kazuto Nishio
    JOURNAL OF THORACIC ONCOLOGY 7 5 913 - 918 2012年05月 [査読有り]
     
    Introduction: The presence of the transforming fusion gene echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer (NSCLC) is a predictive marker for the efficacy of anaplastic lymphoma kinase inhibitors. However, the currently available assays for the detection of the different variants of EML4-ALK have limitations. Methods: We developed an assay system for the detection of EML4-ALK variants 1, 2, 3a, 3b, 4, 5a, 5b, 6, or 7 transcripts in total RNA obtained from formalin-fixed, paraffin-embedded (FFPE) specimens of NSCLC tissue. The assay is based on region-specific polymerase chain reaction amplification of EML4-ALK complementary DNA followed by specific single-base primer extension and analysis of the extension products by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. The assay was validated by fluorescence in situ hybridization and the results confirmed by subcloning and sequencing of polymerase chain reaction products. Results: Evaluation of the analytic sensitivity of the assay with serial dilutions of plasmids containing EML4-ALK complementary DNA sequences revealed it to be capable of the reliable detection of one copy of each plasmid per reaction. The assay also detected EML4-ALK variants 1 or 3 in three FFPE samples of surgically resected NSCLC shown to be positive for anaplastic lymphoma kinase rearrangement by fluorescence in situ hybridization. Furthermore, the assay identified variant 1 of EML4-ALK in 3 of 20 FFPE biopsy samples from patients with advanced NSCLC. All positive samples were confirmed by subcloning and sequencing. Conclusions: Our novel assay is highly sensitive and effective for the detection of EML4-ALK in FFPE specimens.
  • Kawakami H; Nishina S; Ueda S; Kudo T; Okamoto W; Kurata T; Okamoto I; Nakagawa K
    Gastrointestinal cancer research : GCR 5 3 103 - 105 2012年05月 [査読有り]
  • Mitsuhiro Isaka; Kazuo Nakagawa; Yasuhisa Ohde; Takehiro Okumura; Reiko Watanabe; Ichiro Ito; Takashi Nakajima; Haruhiko Kondo
    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 41 4 841 - 846 2012年04月 [査読有り]
     
    Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine carcinoma (LCNEC) are categorized as high-grade neuroendocrine tumours because of their poor prognosis compared with those of other neuroendocrine tumours of the lung. There have been no clinicopathological studies focusing on small-sized high-grade neuroendocrine tumours. We analysed clinicopathological features of peripheral, small-sized high-grade neuroendocrine tumours of the lung retrospectively. A total of 28 patients with peripheral, small-sized tumours (maximum diameter of 3.0 cm) of SCLC and LCNEC underwent surgical resection in our hospital and were enrolled in this study. Of 28 tumours, 18 were SCLC and 10 were LCNEC. In terms of serum tumour marker levels, carcinoembryonic antigen was elevated in 50% of both types of tumour, and progastrin-releasing peptide was elevated in 28% of SCLC and 10% of LCNEC. With regard to preoperative diagnosis, only seven SCLC cases were correctly diagnosed as SCLC, but no LCNEC case was correctly diagnosed before surgery. Lymphatic involvement was significantly more frequent in SCLC than in LCNEC (P = 0.013). Although adjuvant chemotherapy was carried out more frequently in the patients with SCLC than LCNEC, the recurrence rate after the standard surgery was significantly higher in the patients with SCLC than LCNEC (P = 0.0037). There was a significant difference between SCLC and LCNEC in terms of overall survival in clinical-stage IA small-sized tumours (P = 0.029). In peripheral, small-sized high-grade neuroendocrine tumours, there are several clinicopathological differences between SCLC and LCNEC. This study suggested that the prognosis of patients with LCNEC tended to be better than for those with SCLC in small-sized tumours.
  • Kyoichi Kaira; Takehiro Okumura; Kazuo Nakagawa; Yasuhisa Ohde; Toshiaki Takahashi; Haruyasu Murakami; Tateaki Naito; Masahiro Endo; Haruhiko Kondo; Takashi Nakajima; Nobuyuki Yamamoto
    PATHOLOGY & ONCOLOGY RESEARCH 18 2 439 - 447 2012年04月 [査読有り]
     
    MUC1 expression has been described as a predictor for tumor progression and worsening of prognosis in various human neoplasms. However, little is known about the role of MUC1 expression in pulmonary metastatic tumors. The aim of this study is to examine the clinicopathological significance of MUC1 expression in pulmonary metastatic tumors (PMT). One hundred forty-seven patients with PMT who underwent F-18-FDG PET before metastasectomy were included in this study. Tumor sections were stained by immunohistochemistry for MUC1, glucose transporter 1 (Glut1), hypoxia-inducible-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). F-18-FDG uptake and the expression of these biomarkers were correlated in primary lung cancer. MUC1 expression pattern was classified into high-grade polarized expression (HP), low-grade polarized expression (LP), or depolarized expression (DP) group. Of 147 patients, HP, LP and DP group were 9 (6%), 114 (78%) and 24 (16%), respectively. The expression of Glut1, HIF-1 alpha and VEGF, and F-18-FDG uptake were significantly higher in DP group than HP or LP groups. MUC1 expression with HP and DP pattern was significantly higher in primary lung cancer than in PMT, whereas, MUC1 expression with LP pattern yielded a significantly high positive rate in PMT. LP group was recognized in the majority of patients with pulmonary metastatic adenocarcinoma, especially colon cancer, whereas, HP group was significantly low in pulmonary metastatic adenocarcinoma as compared with primary adenocarcinoma. Polarized MUC1 has a different expression pattern between primary and metastatic tumors with adenocarcinoma, and depolarized MUC1 is closely associated with glucose metabolism and hypoxia.
  • Hidetoshi Hayashi; Isamu Okamoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 2 808 - 809 2012年04月 [査読有り]
     
    We now describe the first example of a patient who developed perirenal hematoma during the course of bevacizumab-containing chemotherapy. A 59-years-old woman with metastatic rectal cancer treated with bevacizumab, who developed low back pain after 11 cycles of chemotherapy. CT-scan was consistent with perirenal hematoma and discontinuation of bevacizumab resulted in symptomatic improvement. Nontraumatic perirenal hematoma is a rare condition that can cause shock in severe cases. Given that several types of bleeding complication are known to be associated with bevacizumab treatment, we concluded that bevacizumab likely contributed to the perirenal hematoma in this case. Although the appropriate modification of bevacizumab treatment in the setting of perirenal hematoma is still unclear, physicians should be aware of this potential bevacizumab-associated bleeding complication.
  • Isamu Okamoto; Toshio Shimizu; Masaki Miyazaki; Junji Tsurutani; Yasuko Ichikawa; Masaki Terashima; Masayuki Takeda; Soichi Fumita; Emiko Ohki; Nobuyuki Kimura; Junichi Hashimoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 2 639 - 646 2012年04月 [査読有り]
     
    Background Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. Methods Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m(2) on day 1 of repeated 21-day cycles. Results Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug-drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. Conclusions Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m(2)) was well tolerated in previously treated patients with advanced solid tumors.
  • Hidetoshi Hayashi; Isamu Okamoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 2 808 - 809 2012年04月 [査読有り]
     
    We now describe the first example of a patient who developed perirenal hematoma during the course of bevacizumab-containing chemotherapy. A 59-years-old woman with metastatic rectal cancer treated with bevacizumab, who developed low back pain after 11 cycles of chemotherapy. CT-scan was consistent with perirenal hematoma and discontinuation of bevacizumab resulted in symptomatic improvement. Nontraumatic perirenal hematoma is a rare condition that can cause shock in severe cases. Given that several types of bleeding complication are known to be associated with bevacizumab treatment, we concluded that bevacizumab likely contributed to the perirenal hematoma in this case. Although the appropriate modification of bevacizumab treatment in the setting of perirenal hematoma is still unclear, physicians should be aware of this potential bevacizumab-associated bleeding complication.
  • Isamu Okamoto; Toshio Shimizu; Masaki Miyazaki; Junji Tsurutani; Yasuko Ichikawa; Masaki Terashima; Masayuki Takeda; Soichi Fumita; Emiko Ohki; Nobuyuki Kimura; Junichi Hashimoto; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 30 2 639 - 646 2012年04月 [査読有り]
     
    Background Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. Methods Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m(2) on day 1 of repeated 21-day cycles. Results Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug-drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. Conclusions Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m(2)) was well tolerated in previously treated patients with advanced solid tumors.
  • Wang W; Li Q; Takeuchi S; Yamada T; Koizumi H; Nakamura T; Matsumoto K; Mukaida N; Nishioka Y; Sone S; Nakagawa T; Uenaka T; Yano S
    Clinical cancer research : an official journal of the American Association for Cancer Research 18 6 1663 - 71 2012年03月 [査読有り]
     
    PURPOSE: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We assayed whether a new Met kinase inhibitor, E7050, which is currently being evaluated in clinical trials, could overcome these three mechanisms of resistance to EGFR-TKIs. EXPERIMENTAL DESIGN: The effects of E7050 on HGF-induced resistance to reversible (gefitinib), irreversible (BIBW2992), and mutant-selective (WZ4002) EGFR-TKIs were determined using the EGFR mutant human lung cancer cell lines PC-9 and HCC827 with an exon 19 deletion and H1975 with an T790M secondary mutation. PC-9 cells were mixed with HGF-producing fibroblasts, MRC-5 cells, and subcutaneously inoculated into severe combined immunodeficient mice, and the therapeutic effects of E7050 plus gefitinib were assayed. RESULTS: E7050 circumvented resistance to all of the reversible, irreversible, and mutant-selective EGFR-TKIs induced by exogenous and/or endogenous HGF in EGFR mutant lung cancer cell lines, by blocking the Met/Gab1/PI3K/Akt pathway in vitro. E7050 also prevented the emergence of gefitinib-resistant HCC827 cells induced by continuous exposure to HGF. In the in vivo model, E7050 plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. CONCLUSIONS: A new Met kinase inhibitor, E7050, reverses the three HGF-induced mechanisms of gefitinib resistance, suggesting that E7050 may overcome HGF-induced resistance to gefitinib and next-generation EGFR-TKIs.
  • Igaki H; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 70 3 475 - 478 2012年03月 [査読有り]
     
    Medical radiation exposures are increasing world-wide and especially in Japan, because of the progress in medical care. In order to keep the patients safe from medical exposure, we should know not only possible radiation injuries through the radiological interventions provided to the patients, but also the factors which increase or decrease medical exposure. In addition, we have to keep aware of the radiation dose level exposed to the patients, every time we use medical radiation to our patients. Continuing educations and guidelines on medical exposure and consciousness of the dose level are helpful in decreasing the patients' medical exposures, and in consequences, also in protecting ourselves from occupational exposures.
  • Hiroyasu Kaneda; Isamu Okamoto; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 7 3 621 - 622 2012年03月 [査読有り]
  • Masayuki Takeda; Isamu Okamoto; Kazuko Sakai; Kaoru Tanaka; Masaaki Terashima; Kazuto Nishio; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 13 2 157 - 158 2012年03月 [査読有り]
  • Masayuki Takeda; Isamu Okamoto; Kazuko Sakai; Kaoru Tanaka; Masaaki Terashima; Kazuto Nishio; Kazuhiko Nakagawa
    CLINICAL LUNG CANCER 13 2 157 - 158 2012年03月 [査読有り]
  • Hiroyasu Kaneda; Isamu Okamoto; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 7 3 621 - 622 2012年03月 [査読有り]
  • 文田壮一; 岡本 勇; 岡本邦男; 岡本 渉; 中川和彦
    近畿大学医学雑誌 37 1-2 21 - 29 近畿大学医学会 2012年03月 [査読有り]
     
    [抄録] ゲフィチニブは選択的EGFRチロシンキナーゼ阻害剤（EGFR-TKI）であり, 非小細胞肺癌においてEGFR遺伝子変異を有する症例では非常に高い奏効率を示すと報告されている．しかし, EGFR-TKIの耐性化が問題となっており, この耐性機序としてEGFR遺伝子の二次変異（T790M）やc-METの増幅, HGF刺激など, 細胞質内シグナルの賦活化によるものが報告されている．一方, 非小細胞肺癌細胞株において, 間葉型を示す細胞は上皮型のものに比べEGFR-TKI感受性が低いことが報告され, EGFR-TKI感受性と上皮間葉移行（EMT）の関連が示唆されている．本研究では, EGFR遺伝子変異陽性の非小細胞肺癌細胞株でゲフィチニブ感受性であるHCC827と, c-METの遺伝子増幅によりゲフィチニブ耐性となったHCC827GR5, HCC827GR6とHGF産生によりゲフィチニブ耐性となったHCC827HGF1, CC827HGF2を比較し, 細胞形態を検討した．この結果, HCC827とHCC827GR5, HCC827GR6では上皮型の細胞形態を示したのに対し, HCC827HGF1及びHCC827HGF2では間葉型の細胞形態を示した．次に, HCC827HGF1及びHCC827HGF2はHCC827及びHCC827GR5, HCC827GR6と比較し, E-cadherinの低発現とvimentinの高発現を認めた．さらに, EMT PCR arrayでHCC827HGF1はHCC827と比べZEB1, ZEB2のmRNAレベルの高発現を認めた．加えて, がん浸潤アッセイでHCC827HGF1はHCC827及びHCC827GR5と比較し, 遊走能及び浸潤能ともに機能亢進を認めた．この結果から, EGFR-TKIに対しHGF産生によりゲフィチニブ耐性となったHCC827HGF株はEMTを起こしていることが示された．このことから, 耐性獲得におけるc-METの遺伝子増幅とHGF産生ではEMT変化に違いがあることが示唆された．
  • XP療法が有効であった黄疸を伴う高度肝障害を有する進行胃癌の1症例
    川上 尚人; 仁科 慎一; 上田 眞也; 工藤 敏啓; 岡本 渉; 鶴谷 純司; 倉田 宝保; 岡本 勇; 中川 和彦
    日本胃癌学会総会記事 84回 339 - 339 (一社)日本胃癌学会 2012年02月
  • Morio Yamamoto; Kengo Takeuchi; Masaki Shimoji; Tomohiro Maniwa; Mitsuhiro Isaka; Kazuo Nakagawa; Yasuhisa Ohde; Haruhiko Kondo; Takashi Nakajima
    CANCER SCIENCE 103 2 390 - 392 2012年02月 [査読有り]
     
    Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4ALK) and kinesin family member 5B (KIF5B)ALK are newly identified transforming fusion oncogenes causing non-small-cell lung cancers. These molecular abnormalities have become detectable using not only molecular biological methods, but also highly sensitive immunohistochemistry. During the immunohistochemical study of ALK expression in adenocarcinoma of the lung, we unexpectedly discovered that a small bronchioloalveolar carcinoma (BAC) showed strong ALK immunoreactivity. However, FISH studies failed to reveal EML4ALK and KIF5BALK fusion genes in this BAC. These findings suggest the possibility that a novel or unknown ALK fusion gene plays a crucial role in BAC development. (Cancer Sci 2012; 103: 390392)
  • Isamu Okamoto; Hiroshige Yoshioka; Koji Takeda; Miyako Satouchi; Nobuyuki Yamamoto; Takashi Seto; Kazuo Kasahara; Masaki Miyazaki; Ryuichi Kitamura; Akio Ohyama; Noriko Hokoda; Hiroshi Nakayama; Eiji Yoshihara; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 7 2 427 - 433 2012年02月 [査読有り]
     
    Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer. Methods: Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6mg . min/mL) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days. Results: Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9-57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6-7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs. Conclusions: TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.
  • Hiroshi Saito; Kazuhiko Nakagawa; Koji Takeda; Yasuo Iwamoto; Masahiko Ando; Masao Maeda; Nobuyuki Katakami; Takashi Nakano; Takayasu Kurata; Masahiro Fukuoka
    AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS 35 1 58 - 63 2012年02月 [査読有り]
     
    Objectives: The aim of the present study was to evaluate the efficacy and safety of carboplatin plus paclitaxel versus gemcitabine plus vinorelbine in patients with advanced nonsmall cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group performance status (PS) of 2. Methods: Chemotherapy-naive patients with NSCLC of stage IIIB or IV and a PS of 2 were eligible. The patients received 3-week cycles of carboplatin (area under the curve of 6) plus paclitaxel (200 mg/m(2)) on day 1 (CP) or gemcitabine (1000 mg/m2) plus vinorelbine (25 mg/m(2)) on days 1 and 8 (GV). The primary end point was 1-year survival rate for selection of the better treatment arm for further study. Results: Of the 89 patients enrolled, 84 were assessable (41 in the CP arm, 43 in the GV arm). The overall response rate, median survival time, and 1-year survival rate were 29.3%, 5.9 months, and 22.0%, respectively, for the CP arm and 20.9%, 6.0 months, and 27.9% for the GV arm. Common toxicities of grade 3 or 4 included neutropenia (67.5% for the CP arm vs. 65.1% for the GV arm), febrile neutropenia (20% vs. 14%), and infection (25.0% vs. 23.2%). The frequency of nausea of grade 3 was greater for the CP arm (17.5% vs. 2.3%), whereas that of anemia of grade 3 or 4 (30.2% vs. 12.5%) or treatment-related death (7.0% vs. 2.4%) was greater for the GV arm. Conclusions: The 1-year survival rate did not exceed 30% for either doublet chemotherapy. Furthermore, each treatment was associated with a substantial degree of toxicity.
  • Isamu Okamoto; Hiroshige Yoshioka; Koji Takeda; Miyako Satouchi; Nobuyuki Yamamoto; Takashi Seto; Kazuo Kasahara; Masaki Miyazaki; Ryuichi Kitamura; Akio Ohyama; Noriko Hokoda; Hiroshi Nakayama; Eiji Yoshihara; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 7 2 427 - 433 2012年02月 [査読有り]
     
    Introduction: TSU-68 is an oral small-molecule inhibitor that targets vascular endothelial growth factor receptor 2, platelet-derived growth factor receptor beta, and fibroblast growth factor receptor 1. An open-label, single-arm, phase I study was performed to evaluate escalating doses of TSU-68 in combination with standard chemotherapy in patients with advanced non-small cell lung cancer. Methods: Eligible patients received TSU-68 at 200 or 400 mg twice daily and continuously in combination with carboplatin (area under the curve, 6mg . min/mL) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days. Results: Thirty-seven patients were enrolled at the two dose levels of TSU-68. No dose-limiting toxicities were observed with TSU-68 at the 200 mg twice a day dose level. At 400 mg twice a day, one of six patients experienced a dose-limiting toxicity (anorexia of grade 3) during the first cycle. The 400 mg twice a day dose level was determined to be the recommended dose, and a total of 34 patients were treated at this dose. Overall, adverse events were mild to moderate in severity, with the most frequently observed such events being myelosuppression, neuropathy, and gastrointestinal disorders. No drug-related bleeding was observed. The objective response rate was 39.4% (95% confidence interval, 22.9-57.9%), and median progression-free survival was 5.6 months (95% confidence interval, 3.6-7.2 months). Coadministration of TSU-68, carboplatin, and paclitaxel had no substantial impact on the pharmacokinetics of these drugs. Conclusions: TSU-68 can be safely combined with standard doses of carboplatin-paclitaxel, with the combination manifesting promising antitumor activity.
  • J. Tanizaki; I. Okamoto; K. Takezawa; K. Sakai; K. Azuma; K. Kuwata; H. Yamaguchi; E. Hatashita; K. Nishio; P. A. Janne; K. Nakagawa
    BRITISH JOURNAL OF CANCER 106 4 763 - 767 2012年02月 [査読有り]
     
    BACKGROUND: Although most non-small-cell lung cancer (NSCLC) patients with the echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene - benefit from ALK tyrosine kinase inhibitors (ALK-TKIs), the efficacy of these drugs varies greatly among individuals. METHODS: The antitumour action of ALK-TKIs in EML4-ALK-positive NSCLC cell lines was evaluated from their effects on cell proliferation, signal transduction, and apoptosis. RESULTS: The ALK-TKI TAE684 inhibited cell proliferation and induced apoptosis, in association with inhibition of STAT3 and ERK phosphorylation, in EML4-ALK-positive H3122 cells. TAE684 inhibited STAT3 phosphorylation, but not ERK phosphorylation, and it showed little effect on cell proliferation or apoptosis, in EML4-ALK-positive H2228 cells. The combination of TAE684 and a MEK inhibitor-induced marked apoptosis accompanied by inhibition of STAT3 and ERK pathways in H2228 cells. Such dual interruption of STAT3 and ERK pathways induced downregulation of the antiapoptotic protein survivin and upregulation of the proapoptotic protein BIM. CONCLUSION: Our results indicate that interruption of both STAT3-survivin and ERK-BIM pathways is required for induction of apoptosis in NSCLC harbouring EML4-ALK, providing a rationale for combination therapy with ALK and MEK inhibitors in EML4-ALK-positive NSCLC patients for whom ALK inhibitors alone are ineffective.
  • Kaira, K.; Ohde, Y.; Okumura, T.; Nakagawa, K.; Takahashi, T.; Murakami, H.; Naito, T.; Tsuya, A.; Nakamura, Y.; Oriuchi, N.; Endo, M.; Kondo, H.; Nakajima, T.; Yamamoto, N.
    Annals of Nuclear Medicine 26 3 288 - 288 2012年
  • Mun M; Okumura S; Sakao Y; Uehara H; Nakada T; Gorai A; Nakagawa K
    Kyobu geka. The Japanese journal of thoracic surgery 65 1 35 - 39 南江堂 2012年01月 [査読有り]
  • 藤井 慎嗣; 澤 祥幸; 江口 研二; 岩本 康男; 千場 博; 瀬戸 貴司; 山本 英彦; 中川 和彦; 中西 洋一
    気管支学 34 3 281 - 281 特定非営利活動法人 日本呼吸器内視鏡学会 2012年
  • 池田 昌人; 米阪 仁雄; 佃 博; 福岡 正博; 宮崎 昌樹; 中川 和彦
    気管支学 34 S225  特定非営利活動法人 日本呼吸器内視鏡学会 2012年
  • 藤田 悦生; 江川 亜早子; 阪中 啓一郎; 河合 純; 石垣 貴彦; 大星 隆司; 岡本 邦男; 中川 和彦; 西川 裕作; 宮嶋 宏之; 久米 裕昭; 東田 有智; 山本 勝廣
    気管支学 34 1 95 - 95 特定非営利活動法人 日本呼吸器内視鏡学会 2012年
  • Kaoru Tanaka; Tokuzo Arao; Daisuke Tamura; Keiichi Aomatsu; Kazuyuki Furuta; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideharu Kimura; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    PLOS ONE 7 1 2012年01月 [査読有り]
     
    SRPX2 (Sushi repeat-containing protein, X-linked 2) has recently emerged as a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion. Here, we analyzed this protein biochemically. SRPX2 protein was secreted with a highly posttranslational modification. Chondroitinase ABC treatment completely decreased the molecular mass of purified SRPX2 protein to its predicted size, whereas heparitinase, keratanase and hyaluroinidase did not. Secreted SRPX2 protein was also detected using an anti-chondroitin sulfate antibody. These results indicate that SRPX2 is a novel chondroitin sulfate proteoglycan (CSPG). Furthermore, a binding assay revealed that hepatocyte growth factor dose-dependently binds to SRPX2 protein, and a ligand-glycosaminoglycans interaction was speculated to be likely in proteoglycans. Regarding its molecular architecture, SRPX2 has sushi repeat modules similar to four other CSPGs/lecticans; however, the molecular architecture of SRPX2 seems to be quite different from that of the lecticans. Taken together, we found that SRPX2 is a novel CSPG that is overexpressed in gastrointestinal cancer cells. Our findings provide key glycobiological insight into SRPX2 in cancer cells and demonstrate that SRPX2 is a new member of the cancer-related proteoglycan family.
  • Severe Acute Interstitial Lung Disease After Crizotinib Therapy in a Patient With EML4-ALK-Positive Non-Small-Cell Lung Cancer.
    Tamiya A; Okamoto I; Miyazaki M; Shimizu S; Kitaichi M; Nakagawa K
    J Clin Oncol. 31 1 e15 - e17 2012年 [査読有り]
  • Phase I trial of OTS11101, an anti-angiogenic vaccine targeting Vascular Endothelial Growth Factor Receptor 1 in solid tumor.
    Hayashi H; Kurata T; Fujisaka Y; Kawakami H; Tanaka K; Okabe T; Takeda M; Satoh T; Yoshida K; Tsunoda T; Arao T; Nishio K; Nakagawa K
    Cancer Science 104 1 98 - 104 2012年 [査読有り]
  • Clinical Phase I Study of Elpamotide, a Peptide Vaccine for VEGFR 2, in Patients with Advanced Solid Tumors.
    Okamoto I; Arao T; Miyazaki M; Satoh T; Okamoto K; Tsunoda T; Nishio K; Nakagawa K
    Cancer Science 103 12 2135 - 2138 2012年 [査読有り]
  • Kawakami H; Nishina S; Ueda S; Kudo T; Okamoto W; Kurata T; Okamoto I; Nakagawa K
    Gastrointest Cancer Res. 5 3 103 - 105 2012年 [査読有り]
  • Pilot study of duloxetine for cancer patients with neuropathic pain non-responsive to pregabalin.
    Matsuoka H; Makimura C; Koyama A; Otsuka M; Okamoto W; Fujisaka Y; Kaneda H; Tsurutani J; Nakagawa K
    Anticancer Res. 32 5 1805 - 1809 2012年 [査読有り]
  • Takeda M; Okamoto I; Tsurutani J; Oiso N; Kawada A; Nakagawa K
    Jpn J Clin Oncol. 42 6 528 - 533 2012年 [査読有り]
     
    Gefitinibおよびerlotinibの投与を受けた上皮細胞増殖因子受容体(EGFR)変異陽性非小細胞肺癌(NSCLC)患者について後向きに検討した。一次選択EGFR-チロシンキナーゼ阻害剤(TKI)で有害事象の発現や疾患進行をきたした後に、二次EGFR-TKI療法を受けた。治療コースの中でgefitinibとerlotinibの両方を投与された患者14名を特定した。最初にgefitinibを投与された3名と最初にerlotinibを投与された2名は、重度の非血液学的毒性により(1名はgefitinibによる間質性肺疾患、1名はerlotinibによるエリテマトーデス様発疹、3名は肝毒性)、EGFR-TKIを中止した。これら5名の患者では、いずれも二次EGFR-TKI療法を、有害事象の再発の徴候を認めずに順調に継続できた。これら5名の患者における無増悪生存率は、疾患進行により一次選択EGFR-TKIの投与を中止した患者9名と比べて有意に長かった。一次EGFR-TKI療法を有害事象のため中止したEGFR陽性NSCLC患者は、薬剤抵抗性が発現する前に二次選択のEGFR-TKIに切り替えることにより、多大な利点が得られた。
  • Marked response to both S-1 and pemetrexed in a patient with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-positive lung adenocarcinoma.
    Kaneda H; Okamoto I; Sakai K; Tanizaki J; Takeda M; Nishio K; Nakagawa K
    Acta Oncol. 51 7 942 - 944 2012年 [査読有り]
  • Kunio Okamoto; Isamu Okamoto; Erina Hatashita; Kiyoko Kuwata; Haruka Yamaguchi; Aya Kita; Kentaro Yamanaka; Mayumi Ono; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 11 1 204 - 213 2012年01月 [査読有り]
     
    Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutation-positive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC. Mol Cancer Ther; 11(1); 204-13. (C) 2011 AACR.
  • Koichi Azuma; Isamu Okamoto; Akihiko Kawahara; Tomoki Taira; Kazutaka Nakashima; Satoshi Hattori; Takashi Kinoshita; Masayuki Takeda; Kazuhiko Nakagawa; Shinzo Takamori; Michihiko Kuwano; Mayumi Ono; Masayoshi Kage
    JOURNAL OF THORACIC ONCOLOGY 7 1 122 - 127 2012年01月 [査読有り]
     
    Introduction: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with an increased response to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib in patients with non-small cell lung cancer (NSCLC). Although most NSCLC patients with EGFR mutations benefit from EGFR-TKI treatment, the efficacy of such treatment varies among individuals. Molecular markers for prediction of EGFR-TKI treatment efficacy in EGFR mutation-positive NSCLC have not been well defined. Methods: The expression of mutant EGFR proteins was quantitated by immunohistochemical analysis with mutation-specific antibodies in tumor specimens from 47 NSCLC patients with postoperative recurrent disease who harbored activating EGFR mutations. The expression score was determined from both the staining intensity and the proportion of tumor tissue expressing the mutant EGFR. Results: The median progression-free survival after the start of gefitinib treatment was significantly longer in patients with a high score for mutant EGFR expression than in those with a low score (12.2 versus 3.4 months, p < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (24.9 versus 17.7 months, respectively, p = 0.144). This association between the expression score for mutant EGFR and progression-free survival was apparent both in patients with deletions in exon 19 of EGFR and in those with the L858R mutation in exon 21. Conclusions: Quantitative analysis of mutant EGFR expression by immunohistochemical analysis with mutation-specific antibodies may predict the efficacy of gefitinib treatment for EGFR mutation-positive NSCLC.
  • Koichi Azuma; Isamu Okamoto; Akihiko Kawahara; Tomoki Taira; Kazutaka Nakashima; Satoshi Hattori; Takashi Kinoshita; Masayuki Takeda; Kazuhiko Nakagawa; Shinzo Takamori; Michihiko Kuwano; Mayumi Ono; Masayoshi Kage
    JOURNAL OF THORACIC ONCOLOGY 7 1 122 - 127 2012年01月 [査読有り]
     
    Introduction: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with an increased response to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib in patients with non-small cell lung cancer (NSCLC). Although most NSCLC patients with EGFR mutations benefit from EGFR-TKI treatment, the efficacy of such treatment varies among individuals. Molecular markers for prediction of EGFR-TKI treatment efficacy in EGFR mutation-positive NSCLC have not been well defined. Methods: The expression of mutant EGFR proteins was quantitated by immunohistochemical analysis with mutation-specific antibodies in tumor specimens from 47 NSCLC patients with postoperative recurrent disease who harbored activating EGFR mutations. The expression score was determined from both the staining intensity and the proportion of tumor tissue expressing the mutant EGFR. Results: The median progression-free survival after the start of gefitinib treatment was significantly longer in patients with a high score for mutant EGFR expression than in those with a low score (12.2 versus 3.4 months, p < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (24.9 versus 17.7 months, respectively, p = 0.144). This association between the expression score for mutant EGFR and progression-free survival was apparent both in patients with deletions in exon 19 of EGFR and in those with the L858R mutation in exon 21. Conclusions: Quantitative analysis of mutant EGFR expression by immunohistochemical analysis with mutation-specific antibodies may predict the efficacy of gefitinib treatment for EGFR mutation-positive NSCLC.
  • Kunio Okamoto; Isamu Okamoto; Erina Hatashita; Kiyoko Kuwata; Haruka Yamaguchi; Aya Kita; Kentaro Yamanaka; Mayumi Ono; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 11 1 204 - 213 2012年01月 [査読有り]
     
    Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutation-positive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC. Mol Cancer Ther; 11(1); 204-13. (C) 2011 AACR.
  • Kazuhiko Nakagawa; Junji Tsurutani
    Chinese Clinical Oncology 1 2 17  2012年 [査読有り]
  • S-1 plus cisplatin with concurrent radiotherapy for locally advanced non-small cell lung cancer: a multi-institutional phase II trial (West Japan Thoracic Oncology Group 3706).
    Ichinose Y; Seto T; Sasaki T; Yamanaka T; Okamoto I; Takeda K; Tanaka M; Katakami N; Sawa T; Kudoh S; Saka H; Nishimura Y; Nakagawa K; Fukuoka M
    J Thorac Oncol. 6 12 2069 - 2075 2012年 [査読有り]
  • Masaki Shimoji; Takashi Nakajima; Chihiro Yamatani; Morio Yamamoto; Shinsuke Saishou; Mitsuhiro Isaka; Tomohiro Maniwa; Yasuhisa Ode; Kazuo Nakagawa; Takehiro Okumura; Reiko Watanabe; Ichiro Ito; Toru Kameya; Masahiro Endo; Haruhiko Kondo
    PATHOLOGY INTERNATIONAL 61 12 717 - 722 2011年12月 [査読有り]
     
    Since the World Health Organization histological criteria were published in 1999, several studies have focused on adenosquamous carcinoma of the lung. Therefore, we aimed to clinicopathologically re-evaluate this tumor using immunohistochemical methods. In our hospital, there have been 21 surgically resected adenosquamous carcinomas. The frequency of adenosquamous carcinoma was 1.9% and the clinical data including the patient prognosis data obtained in this study were similar to those reported previously. A fluorodeoxyglucose positron emission tomography study first revealed that the median maximum standardized uptake value of adenosquamous carcinoma was 9.3 and ranged from 2.0 to 24.5. According to the results of immunohistochemical staining for thyroid transcription factor-1 (TTF-1) and p63, adenosquamous carcinomas were divided into four subgroups: group 1, TTF-1+ and p63+ (10 cases); group 2, TTF-1- and p63+ (six cases); group 3, TTF-1+ and p63- (three cases); and group 4, TTF-1- and p63- (two cases). Of the six group 2 tumors, three were composed of unique solid nests with mucin-filled cysts and showed characteristic p63 expression, which might suggest a special type of adenosquamous carcinoma. Immunohistochemical analysis of TTF-1 and p63 expression shows that adenosquamous carcinoma is composed of diverse tumor groups, for which the biological and histogenetic nature further needs to be clarified.
  • Kudo K; Ohyanagi F; Horiike A; Miyauchi E; Yanagitani N; Hoshi R; Satoh Y; Motoi N; Hamanaka W; Ishikawa Y; Mun M; Sakao Y; Okumura S; Nakagawa K; Horai T; Nishio M
    Lung cancer (Amsterdam, Netherlands) 74 3 401 - 404 2011年12月 [査読有り]
  • Kaira K; Serizawa M; Koh Y; Miura S; Kaira R; Abe M; Nakagawa K; Ohde Y; Okumura T; Murakami H; Tsuya A; Nakamura Y; Naito T; Takahashi T; Kondo H; Nakajima T; Endo M; Yamamoto N
    Lung cancer (Amsterdam, Netherlands) 74 3 419 - 425 2011年12月 [査読有り]
  • Chihiro Makimura; Tokuzo Arao; Hiromichi Matsuoka; Masayuki Takeda; Hidemi Kiyota; Junji Tsurutani; Yoshihiko Fujita; Kazuko Matsumoto; Hideharu Kimura; Masatomo Otsuka; Atsuko Koyama; Chiyo K. Imamura; Takeharu Yamanaka; Kyoko Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    ANTICANCER RESEARCH 31 12 4561 - 4568 2011年12月 [査読有り]
     
    Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naive cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GMCSF), interferon alpha 2 (IFN-alpha 2), IFN-gamma, interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 beta, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1 alpha significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1 alpha and MIP-1 beta were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.
  • Yukito Ichinose; Takashi Seto; Tomonari Sasaki; Takeharu Yamanaka; Isamu Okamoto; Koji Takeda; Masahiro Tanaka; Nobuyuki Katakami; Toshiyuki Sawa; Shinzoh Kudoh; Hideo Saka; Yasumasa Nishimura; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 6 12 2069 - 2075 2011年12月 [査読有り]
     
    Purpose: To evaluate the combination chemotherapy using oral antimetabolite S-1 plus cisplatin (SP) with concurrent thoracic radiotherapy (RT) followed by the consolidation SP for locally advanced non-small cell lung cancer. Patients and Methods: Patients with stage III non-small cell lung cancer, 20 to 74 years of age, and Eastern Cooperative Oncology Group performance status 0 to 1 were eligible. The concurrent phase consisted of full dose S-1 (orally at 40 mg/m(2)/dose twice daily, on days 1-14) and cisplatin (60 mg/m(2) on day 1) repeated every 4 weeks for two cycles with RT delivered beginning on day 1 (60 Gy/30 fractions over 6 weeks). After SP-RT, patients received an additional two cycles of SP as the consolidation phase. Results: Fifty-five patients were registered between November 2006 and December 2007. Of the 50 patients for efficacy analysis, the median age was 64 years; male/female 40/10; Eastern Cooperative Oncology Group performance status 0/1, 21/29; clinical stage IIIA/IIIB 18/32; and adenocarcinoma/others 20/30. There were 42 clinical responses including one complete response with an objective response rate of 84% (95% confidence interval [CI], 71-93%). The 1- and 2-year overall survival rates were 88% (95% CI, 75-94%) and 70% (95% CI, 55-81%), respectively. The median progression-free survival was 20 months. Of the 54 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 neutropenia (26%), thrombocytopenia (9%), and grade 3 esophagitis (9%) and febrile neutropenia (9%). In one patient, grade 3 pneumonitis was observed in the consolidation phase. There were two treatment-related deaths caused by infection in the concurrent phase. Conclusions: SP-RT showed a promising efficacy against locally advanced NCSLC with acceptable toxicity.
  • Chihiro Makimura; Tokuzo Arao; Hiromichi Matsuoka; Masayuki Takeda; Hidemi Kiyota; Junji Tsurutani; Yoshihiko Fujita; Kazuko Matsumoto; Hideharu Kimura; Masatomo Otsuka; Atsuko Koyama; Chiyo K. Imamura; Takeharu Yamanaka; Kyoko Tanaka; Kazuto Nishio; Kazuhiko Nakagawa
    ANTICANCER RESEARCH 31 12 4561 - 4568 2011年12月 [査読有り]
     
    Cytokine signaling is involved in pain and opioid-receptor signaling. In this prospective study, we studied the plasma cytokine levels in order to identify candidate biomarkers for predicting resistance to morphine treatment in a cohort of opioid-treatment-naive cancer patients. We analyzed pain rating and the plasma concentrations of 26 cytokines at baseline and after morphine treatment using a multiplex immunoassay system for the following cytokines: eotaxin, colony stimulating factor, granulocyte (G-CSF), colony stimulating factor granulocyte-macrophage (GMCSF), interferon alpha 2 (IFN-alpha 2), IFN-gamma, interleukin 1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 beta, tumor necrosis factor-alpha (TNF-alpha) and TNF-beta. No correlation was observed between the clinical characteristics and the numerical rating scale for pain at baseline or among patients who developed resistance to morphine treatment. Interestingly, the plasma concentration of MIP-1 alpha significantly decreased during morphine treatment (day 8 vs. baseline, p=0.03). Regarding the baseline plasma cytokine concentrations, none of the cytokine levels were correlated with the numerical rating scale for pain at baseline; however, the baseline plasma concentrations of eotaxin, IL-8, IL-12 (p40), IL-12 (p70), MIP-1 alpha and MIP-1 beta were significantly lower in patients who required a high dose of morphine or who developed resistance to morphine treatment. In conclusion, this is the first report revealing that the plasma concentrations of several cytokines were significantly modulated during treatment and were correlated with treatment outcome of morphine. Our results suggest that plasma cytokine levels may be promising biomarkers for morphine treatment and that they warrant further study.
  • Shunji Takahashi; Masaki Miyazaki; Isamu Okamoto; Yoshinori Ito; Kyoji Ueda; Taku Seriu; Kazuhiko Nakagawa; Kiyohiko Hatake
    CANCER SCIENCE 102 11 2058 - 2064 2011年11月 [査読有り]
     
    Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200 mg/day. Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients) and 200 mg (four patients). The most frequent adverse events (AE; >= 50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade >= 3 (>= 10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200 mg. Therefore, 150 mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6 months. In this study population, the safety profile of dasatinib was generally acceptable and 150 mg of dasatinib administered once daily was determined to be the MTD. (Cancer Sci 2011; 102: 2058-2064)
  • Yoshikazu Hasegawa; Tomoya Kawaguchi; Akihito Kubo; Masahiko Ando; Junji Shiraishi; Shun-ichi Isa; Taisuke Tsuji; Kazuyuki Tsujino; Sai-Hong I. Ou; Kazuhiko Nakagawa; Minoru Takada
    JOURNAL OF THORACIC ONCOLOGY 6 11 1881 - 1888 2011年11月 [査読有り]
     
    Introduction: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied. Methods: We performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian. We chose three treatment regimens used for NSCLC globally: cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV), and carboplatin plus paclitaxel (CP). We applied sensitivity analysis to examine unreported ethnic differences in hematological toxicities by changing the percentage of Asian patients from 0 to 18% in trials reported from the United States and Europe. Results: We identified 12 phase II trials and 38 phase III trials of NSCLC with a total of 11,271 patients. Among these, 14 trials had reported ethnic origins. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, odds ratio of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian, when treated with CG (OR = 1.55-3.45, p < 0.001), CV (OR = 2.99-4.43, p < 0.001), and CP (OR = 4.79-6.22, p < 0.001). Grade 3/4 anemia was also significantly higher in Asians with CG (OR = 3.10-3.27, p < 0.001), CV (OR = 1.99-2.43, p < 0.001), and CP (OR = 1.34-1.52, p < 0.001-0.004). However, no significant difference was observed in thrombocytopenia with CG (OR = 0.66-2.04, p < 0.001-1.000), CV (OR = 0.42-0.57, p < 0.097-0.323), or CP (OR = 1.21-1.39, p < 0.114-0.152). Conclusions: Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly whites) in the treatment of chemotherapy for NSCLC.
  • Shunji Takahashi; Masaki Miyazaki; Isamu Okamoto; Yoshinori Ito; Kyoji Ueda; Taku Seriu; Kazuhiko Nakagawa; Kiyohiko Hatake
    CANCER SCIENCE 102 11 2058 - 2064 2011年11月 [査読有り]
     
    Dasatinib is a potent oral inhibitor of tyrosine kinases including the SRC family kinases, which are activated in tumors, and implicated in invasion and bone metastasis. This phase I dose-escalation study assessed safety, tolerability, maximum tolerated dose (MTD), antitumor activity, pharmacokinetics and pharmacodynamics in Japanese patients with refractory, advanced solid tumors. Dasatinib was administered once daily at 100, 150 and 200 mg/day. Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients) and 200 mg (four patients). The most frequent adverse events (AE; >= 50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting and increased aspartate aminotransferase (AST). The most frequent AE of grade >= 3 (>= 10%) were anemia, decreased lymphocyte count, fatigue and increased blood magnesium. Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level. In addition, grade 2 pleural effusion was observed in all four patients treated with 200 mg. Therefore, 150 mg was determined to be the MTD. The pharmacokinetic parameters were comparable among the dose levels. As a pharmacodynamic study, markers of bone metabolism were assessed. Bone resorption markers, NTx and TRACP-5b, showed a decrease of 46.3% and 22.2%, respectively. No objective responses were observed, but three patients had stable disease that lasted for over 6 months. In this study population, the safety profile of dasatinib was generally acceptable and 150 mg of dasatinib administered once daily was determined to be the MTD. (Cancer Sci 2011; 102: 2058-2064)
  • Yoshikazu Hasegawa; Tomoya Kawaguchi; Akihito Kubo; Masahiko Ando; Junji Shiraishi; Shun-ichi Isa; Taisuke Tsuji; Kazuyuki Tsujino; Sai-Hong I. Ou; Kazuhiko Nakagawa; Minoru Takada
    JOURNAL OF THORACIC ONCOLOGY 6 11 1881 - 1888 2011年11月 [査読有り]
     
    Introduction: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been adequately studied. Methods: We performed a systematic search in PubMed for randomized phase II and III trials of NSCLC from January 2000 to December 2009, examining ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian. We chose three treatment regimens used for NSCLC globally: cisplatin plus gemcitabine (CG), cisplatin plus vinorelbine (CV), and carboplatin plus paclitaxel (CP). We applied sensitivity analysis to examine unreported ethnic differences in hematological toxicities by changing the percentage of Asian patients from 0 to 18% in trials reported from the United States and Europe. Results: We identified 12 phase II trials and 38 phase III trials of NSCLC with a total of 11,271 patients. Among these, 14 trials had reported ethnic origins. Grade 3/4 toxicities were more frequently observed in the Asian studies. On the basis of sensitivity analysis, odds ratio of grade 3/4 neutropenia was significantly higher in Asian patients than non-Asian, when treated with CG (OR = 1.55-3.45, p < 0.001), CV (OR = 2.99-4.43, p < 0.001), and CP (OR = 4.79-6.22, p < 0.001). Grade 3/4 anemia was also significantly higher in Asians with CG (OR = 3.10-3.27, p < 0.001), CV (OR = 1.99-2.43, p < 0.001), and CP (OR = 1.34-1.52, p < 0.001-0.004). However, no significant difference was observed in thrombocytopenia with CG (OR = 0.66-2.04, p < 0.001-1.000), CV (OR = 0.42-0.57, p < 0.097-0.323), or CP (OR = 1.21-1.39, p < 0.114-0.152). Conclusions: Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly whites) in the treatment of chemotherapy for NSCLC.
  • 横井 香平; 多田 弘人; 光冨 徹哉; 一瀬 幸人; 片上 信之; 小田 誠; 根来 俊一; 松隈 治久; 中川 和彦; 中西 洋一
    肺癌 51 5 346 - 346 (NPO)日本肺癌学会 2011年10月
  • 内藤 立暁; 岡本 勇; 吉岡 弘鎮; 武田 晃司; 里内 美弥子; 瀬戸 貴司; 笠原 寿郎; 中川 和彦
    肺癌 51 5 437 - 437 (NPO)日本肺癌学会 2011年10月
  • 上甲 剛; 酒井 文和; 荒川 浩明; 楠本 昌彦; 福岡 正博; 工藤 翔二; 安藤 昌彦; 井上 義一; 大江 裕一郎; 中川 和彦; 海老名 雅仁; 桑野 和善; 弦間 昭彦; 谷口 博之; 福田 悠; 山崎 直也; 清原 祥夫; 田中 慎一
    肺癌 51 5 432 - 432 (NPO)日本肺癌学会 2011年10月
  • Kyoichi Kaira; Yasuhisa Ohde; Masahiro Endo; Kazuo Nakagawa; Takehiro Okumura; Toshiaki Takahashi; Haruyasu Murakami; Asuka Tsuya; Yukiko Nakamura; Tateaki Naito; Haruhiko Kondo; Takashi Nakajima; Nobuyuki Yamamoto
    ONCOLOGY REPORTS 26 4 931 - 937 2011年10月 [査読有り]
     
    4F2hc (CD98) has been associated with tumor growth, and is highly expressed in various tumors. The aim of this study was to evaluate the clinicopathological significance of 4F2hc expression in pulmonary neuroendocrine (NE) tumors. Surgically-resected patient tumors including 16 large cell neuroendocrine carcinoma (LCNEC), 12 small cell lung cancer (SCLC), 1 atypical carcinoid (AC) and 5 typical carcinoid (TC) samples were included in this study. Tumor sections were immunohistochemically stained for 4F2hc (CD98), glucose transporter 1 (Glut1) and 3 (Glut3), hypoxia-inducible factor-1 alpha (HIF-1 alpha), hexokinase 1, vascular endothelial growth factor (VEGF), microvessel density (CD34), epidermal growth factor receptor (EGFR), Akt/mammalian target of rapamycin (mTOR) signaling pathway (p-Akt, p-mTOR and p-S6K) and for a cell cycle regulator (p53). 4F2hc was overexpressed in 0% of the pulmonary carcinoids (TCs and ACs), 62.5% of the LCNECs and 50.0% of the SCLCs. A positive 4F2hc expression was significantly associated with age, histology and Glut1 expression. Moreover, a significant correlation was found between 4F2hc expression, and Glut I, HIF-1 alpha, p-Akt, p-mTOR and p-S6K. The expression of 4F2hc was also significantly associated with poor overall survival. The expression of 4F2hc expression tended to increase from low-grade to high-grade pulmonary NE tumors. Our results suggest that 4F2hc may play a significant role in tumor progression, hypoxic conditions and poor outcome in patients with pulmonary NE tumors.
  • K. Yonesaka; K. Zejnullahu; I. Okamoto; T. Satoh; F. Cappuzzo; J. Souglakos; J. Engelman; M. Varella-Garcia; K. Nakagawa; P. Jaenne
    EUROPEAN JOURNAL OF CANCER 47 99 S10 - S10 2011年10月 [査読有り]
  • Junko Tanizaki; Isamu Okamoto; Kunio Okamoto; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 6 10 1624 - 1631 2011年10月 [査読有り]
     
    Introduction: Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. Methods: The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. Results: Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. Conclusions: Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.
  • Junko Tanizaki; Isamu Okamoto; Kunio Okamoto; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 6 10 1624 - 1631 2011年10月 [査読有り]
     
    Introduction: Tyrosine kinase inhibitors (TKIs) targeted to MET are undergoing clinical trials in patients with solid tumors, but the precise mechanism of the antitumor activity of these drugs remains unclear. We examined the antitumor action of the MET-TKI crizotinib (PF-02341066) in lung cancer cells that are positive or negative for MET amplification or mutation. Methods: The antitumor action of crizotinib was evaluated on the basis of signal transduction, cell proliferation, apoptosis, and progression of tumor xenografts. Results: Inhibition of MET signaling by crizotinib or by RNA interference-mediated MET depletion resulted in the induction of apoptosis accompanied by inhibition of AKT and extracellular signal-regulated kinase phosphorylation in lung cancer cells with MET amplification but not in cells with a MET mutation or in those without amplification or mutation of MET. These results suggest that MET signaling is essential for the survival of cells with MET amplification but not for that of cells without this genetic change, including those with a MET mutation. Crizotinib up-regulated the expression of BIM, a proapoptotic member of the Bcl-2 family, and down-regulated that of survivin, a member of the inhibitor of apoptosis protein family, in cells with MET amplification. Forced depletion of BIM and expression of survivin each inhibited crizotinib-induced apoptosis, suggesting that both up-regulation of BIM and down-regulation of survivin contribute to the proapoptotic effect of crizotinib. Conclusions: Crizotinib shows a marked antitumor action in MET amplification-positive lung cancer cells but not in cells without MET amplification, including those with a MET mutation.
  • H. Kaneda; T. Arao; K. Matsumoto; M. A. De Velasco; D. Tamura; K. Aomatsu; K. Kudo; K. Sakai; T. Nagai; Y. Fujita; K. Tanaka; K. Yanagihara; Y. Yamada; I. Okamoto; K. Nakagawa; K. Nishio
    BRITISH JOURNAL OF CANCER 105 8 1210 - 1217 2011年10月 [査読有り]
     
    BACKGROUND: Activin A is a multi-functional cytokine belonging to the transforming growth factor-beta (TGF-beta) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin beta A subunit (INHBA) mRNA is overexpressed in gastric cancer (GC) specimens and investigated the effect of activin A, a homodimer of INHBA, on angiogenesis in GC. METHODS: Anti-angiogenic effects of activin A via p21 induction were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro and a stable INHBA-introduced GC cell line in vivo. RESULTS: Compared with TGF-beta, activin A potently inhibited the cellular proliferation and tube formation of HUVECs with induction of p21. A promoter assay and a chromatin immunoprecipitation assay revealed that activin A directly regulates p21 transcriptional activity through Smads. Stable p21-knockdown significantly enhanced the cellular proliferation of HUVECs. Notably, stable p21-knockdown exhibited a resistance to activin-mediated growth inhibition in HUVECs, indicating that p21 induction has a key role on activin A-mediated growth inhibition in vascular endothelial cells. Finally, a stable INHBA-introduced GC cell line exhibited a decrease in tumour growth and angiogenesis in vivo. CONCLUSION: Our findings highlight the suppressive role of activin A, unlike TGF-beta, on tumour growth and angiogenesis in GC. British Journal of Cancer (2011) 105, 1210-1217. doi:10.1038/bjc.2011.348 www.bjcancer.com Published online 6 September 2011 (C) 2011 Cancer Research UK
  • Tomohiro Maniwa; Kazuo Nakagawa; Mitsuhiro Isaka; Yasuhisa Ohde; Takehiro Okumura; Haruhiko Kondo
    INTERACTIVE CARDIOVASCULAR AND THORACIC SURGERY 13 3 257 - 261 2011年09月 [査読有り]
     
    Pneumothorax associated with treatment for pulmonary malignancy (PATPM) is a rare complication. Its clinicopathological features have not yet been clearly defined. Forty-one patients with PATPM from September 2002 to March 2009 were included. We evaluated the clinicopathological findings and treatment outcome of these patients. Of the 41 patients, 21 had primary lung cancer and 20 had metastatic lung tumours. Twenty-four patients (58.5%) required chest tube drainage for more than six days. Ten patients (24%) finally, received surgical treatment. Regarding the surgical procedure, conversion to open thoracotomy was required in seven (70%) of these 10 patients because of dense adhesions or anatomical changes in the thoracic cavity caused by treatment or the progression of the tumours. Two patients had severe complications after surgery. One of these two patients and another patient died of primary disease within 30 days after surgery. The median survival time in the 10 patients with surgery was 223 days (range 22-1059 days). PATPM tends to require chest tube drainage for a long period, and sometimes needs surgical treatment, which may be difficult. We should carefully identify patients who would derive considerable benefit from surgical treatment. (c) 2011 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
  • 非小細胞肺癌治癒切除症例に対する術後補助化学療法の第III相試験(WJTOG0101)
    一瀬 幸人; 多田 弘人; 光冨 徹哉; 横井 香平; 片上 信之; 小田 誠; 根来 俊一; 千葉 康敬; 中川 和彦; 中西 洋一
    日本癌治療学会誌 46 2 403 - 403 (一社)日本癌治療学会 2011年09月
  • J. Tanizaki; I. Okamoto; S. Fumita; W. Okamoto; K. Nishio; K. Nakagawa
    ONCOGENE 30 39 4097 - 4106 2011年09月 [査読有り]
     
    Lapatinib, a dual tyrosine kinase inhibitor of the epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), is clinically active in patients with breast cancer positive for HER2 amplification. The mechanism of this anti-tumor action has remained unclear, however. We have now investigated the effects of lapatinib in HER2 amplification-positive breast cancer cells with or without an activating PIK3CA mutation. Lapatinib induced apoptosis in association with upregulation of the pro-apoptotic protein Bcl-2 interacting mediator of cell death (BIM) through inhibition of the MEK-ERK signaling pathway in breast cancer cells with HER2 amplification. RNA interference (RNAi)-mediated depletion of BIM inhibited lapatinib-induced apoptosis, implicating BIM induction in this process. The proapoptotic effect of lapatinib was less pronounced in cells with a PIK3CA mutation than in those without one. Lapatinib failed to inhibit AKT phosphorylation in PIK3CA mutant cells, likely because of hyperactivation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway by the mutation. Depletion of PIK3CA (a catalytic subunit of PI3K) revealed that survivin expression is regulated by the PI3K pathway in these cells, suggesting that insufficient inhibition of PI3K-survivin signaling is responsible for the limited pro-apoptotic effect of lapatinib in HER2 amplification-positive cells with a PIK3CA mutation. Consistent with this notion, depletion of survivin by RNAi or treatment with a PI3K inhibitor markedly increased the level of apoptosis in PIK3CA mutant cells treated with lapatinib. Our results thus suggest that inhibition of both PI3K-survivin and MEK-ERK-BIM pathways is required for effective induction of apoptosis in breast cancer cells with HER2 amplification. Oncogene (2011) 30, 4097-4106; doi:10.1038/onc.2011.111; published online 18 April 2011
  • Kimio Yonesaka; Kreshnik Zejnullahu; Isamu Okamoto; Taroh Satoh; Federico Cappuzzo; John Souglakos; Dalia Ercan; Andrew Rogers; Massimo Roncalli; Masayuki Takeda; Yasuhito Fujisaka; Juliet Philips; Toshio Shimizu; Osamu Maenishi; Yonggon Cho; Jason Sun; Annarita Destro; Koichi Taira; Koji Takeda; Takafumi Okabe; Jeffrey Swanson; Hiroyuki Itoh; Minoru Takada; Eugene Lifshits; Kiyotaka Okuno; Jeffrey A. Engelman; Ramesh A. Shivdasani; Kazuto Nishio; Masahiro Fukuoka; Marileila Varella-Garcia; Kazuhiko Nakagawa; Pasi A. Jaenne
    SCIENCE TRANSLATIONAL MEDICINE 3 99 99ra86  2011年09月 [査読有り]
     
    Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.
  • J. Tanizaki; I. Okamoto; K. Sakai; K. Nakagawa
    BRITISH JOURNAL OF CANCER 105 6 807 - 813 2011年09月 [査読有り]
     
    BACKGROUND: MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification. METHODS: With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays. RESULTS: We identified epidermal growth factor receptor (EGFR), human EGFR (HER) 2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling. CONCLUSION: Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with MET amplification. British Journal of Cancer (2011) 105, 807-813. doi: 10.1038/bjc.2011.322 www.bjcancer.com Published online 16 August 2011 (C) 2011 Cancer Research UK
  • Mitsuhiro Isaka; Kazuo Nakagawa; Tomohiro Maniwa; Shinsuke Saisho; Yasuhisa Ohde; Takehiro Okumura; Haruhiko Kondo; Takashi Nakajima
    General Thoracic and Cardiovascular Surgery 59 8 579 - 582 2011年08月 [査読有り]
     
    Calcifying tumor of the pleura is a rare benign tumor, similar to the calcifying fibrous pseudotumor originally described in the subcutaneous and deep soft tissues of the extremities, trunk, and neck. Calcifying tumors of the pleura have also been reported infrequently as disseminated lesions. Here we report a case of disseminated calcifying tumor of the pleura, with some new findings obtained in this study, and review the literature of disseminated calcifying tumor of the pleura. © 2011 The Japanese Association for Thoracic Surgery.
  • Yijun Bao; Kentaro Nakagawa; Zeyu Yang; Mitsunobu Ikeda; Kanchanamala Withanage; Mari Ishigami-Yuasa; Yukiko Okuno; Shoji Hata; Hiroshi Nishina; Yutaka Hata
    JOURNAL OF BIOCHEMISTRY 150 2 199 - 208 2011年08月 [査読有り]
     
    The mammalian Hippo pathway is composed of mammalian Ste20-like (MST) kinases and large tumour suppressor (LATS) kinases. Upon the activation of the pathway, MST kinases phosphorylate and activate LATS kinases, which in turn phosphorylate transcriptional co-activators, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), recruit them to the cytosol from the nucleus and turn off cell cycle-promoting and anti-apoptotic gene transcriptions. Thus, the pathway restricts cell overgrowth and prevents tumourigenesis. Although a high cell density and stress signallings are known to activate the pathway, no specific stimulators are so far reported. As the dysfunction of the pathway is frequent in human cancers and correlates with poor prognosis, it is important to find out reagents that stimulate the pathway for not only basic research but also clinical medicine. We here developed a cell-based method of screening reagents that induce the recruitment of YAP to the cytosol. Using this method, we found that dobutamine inhibits the YAP-dependent gene transcription. Contrary to our expectations, the effect of dobutamine is independent of the Hippo pathway but our method opens the possibility to discover Hippo pathway stimulators or Hippo-independent YAP inhibitors.
  • Hisato Kawakami; Koji Sugioka; Kimio Yonesaka; Taroh Satoh; Yoshikazu Shimomura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 29 23 E678 - E679 2011年08月 [査読有り]
  • Primo N. Lara; Jean-Yves Douillard; Kazuhiko Nakagawa; Joachim von Pawel; Mark J. McKeage; Istvan Albert; Gyoergy Losonczy; Martin Reck; Dae-Seog Heo; Xiaolin Fan; Abderrahim Fandi; Giorgio Scagliotti
    JOURNAL OF CLINICAL ONCOLOGY 29 22 2965 - 2971 2011年08月 [査読有り]
     
    Purpose This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone. Patients and Methods Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm. Conclusion The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.
  • Masashi Kobayashi; Kaoru Matsui; Nobuyuki Katakami; Koji Takeda; Adusa Moriyama; Yasuo Iwamoto; Minoru Takada; Hiroshige Yoshioka; Naoko Sueoka-Aragane; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 8 948 - 952 2011年08月 [査読有り]
     
    Objective: Elderly patients prefer to receive less-toxic therapy. Monotherapy using drugs such as vinorelbine, gemcitabine or docetaxel is a preferable chemotherapy in elderly patients with advanced non-small-cell lung cancer. Gefitinib shows remarkable efficacy in patients with advanced non-small-cell lung cancer, who have activating epidermal growth factor receptor mutations. Adenocarcinoma histology is related to these mutations. Therefore, we conducted a phase II study of gefitinib as a first-line therapy in elderly patients with pulmonary adenocarcinoma. Methods: Eligible patients were 70 years or older, had pulmonary adenocarcinoma, stage IIIB or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ functions. Patients were treated with oral gefitinib 250 mg daily until disease progression or unacceptable toxicity. Results: Thirty-one patients were enrolled, of whom 30 were eligible. The median age was 78.5 years. The response rate was 20%, the disease control rate was 47%, the median progression-free survival was 2.7 months and the median overall survival was 11.9 months. Narrowing it down to those who had never smoked, the response rate increased to 43%, the disease control rate increased to 57%, the median progression-free survival prolonged to 7.1 months and the median overall survival prolonged to 13.0 months. The most frequent toxicity was rash. Other major toxicities were diarrhea, anorexia, liver dysfunction and anemia. These toxicities were mild and easily managed. Conclusions: Gefitinib as a first-line therapy is active and well tolerated in elderly patients with pulmonary adenocarcinoma, especially in those who have never smoked.
  • Hisato Kawakami; Koji Sugioka; Kimio Yonesaka; Taroh Satoh; Yoshikazu Shimomura; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 29 23 E678 - E679 2011年08月 [査読有り]
  • Primo N. Lara; Jean-Yves Douillard; Kazuhiko Nakagawa; Joachim von Pawel; Mark J. McKeage; Istvan Albert; Gyoergy Losonczy; Martin Reck; Dae-Seog Heo; Xiaolin Fan; Abderrahim Fandi; Giorgio Scagliotti
    JOURNAL OF CLINICAL ONCOLOGY 29 22 2965 - 2971 2011年08月 [査読有り]
     
    Purpose This phase III trial was conducted to test whether the novel vascular disrupting agent ASA404 (vadimezan), when combined with first-line platinum-based chemotherapy, improves survival in patients with advanced non-small-cell lung cancer (NSCLC) versus chemotherapy alone. Patients and Methods Patients with advanced stage IIIB or IV NSCLC, stratified by sex and tumor histology, were randomly assigned 1:1 to paclitaxel (200 mg/m(2)) and carboplatin (area under the curve, 6.0) with or without ASA404 (1,800 mg m(2)), given intravenously once every 3 weeks for six cycles followed by maintenance ASA404 or placebo. Primary end point was overall survival (OS); secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results One thousand two hundred ninety-nine patients were randomly assigned. The trial was stopped for futility at interim analysis. At final analysis, there was no difference in OS seen between ASA404 (n = 649) and placebo (n = 650) arms: median OS was 13.4 and 12.7 months respectively (hazard ratio [HR], 1.01; 95% CI, 0.85 to 1.19; P = .535). Similarly, no OS difference was seen in the histologic (squamous or nonsquamous) and sex (male or female) strata. Median PFS was 5.5 months in both arms (HR, 1.04; P = .727), while ORR was 25% in both arms (P = 1.0). Overall rate of adverse events (AEs) was comparable between the ASA404 and placebo arms. Grade 4 neutropenia (27% v 19%) and infusion site pain (10% v 0.5%) were reported more frequently in the ASA404 arm. Conclusion The addition of ASA404 to carboplatin and paclitaxel, although generally well tolerated, failed to improve frontline efficacy in advanced NSCLC.
  • Masashi Kobayashi; Kaoru Matsui; Nobuyuki Katakami; Koji Takeda; Adusa Moriyama; Yasuo Iwamoto; Minoru Takada; Hiroshige Yoshioka; Naoko Sueoka-Aragane; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 8 948 - 952 2011年08月 [査読有り]
     
    Objective: Elderly patients prefer to receive less-toxic therapy. Monotherapy using drugs such as vinorelbine, gemcitabine or docetaxel is a preferable chemotherapy in elderly patients with advanced non-small-cell lung cancer. Gefitinib shows remarkable efficacy in patients with advanced non-small-cell lung cancer, who have activating epidermal growth factor receptor mutations. Adenocarcinoma histology is related to these mutations. Therefore, we conducted a phase II study of gefitinib as a first-line therapy in elderly patients with pulmonary adenocarcinoma. Methods: Eligible patients were 70 years or older, had pulmonary adenocarcinoma, stage IIIB or IV disease, an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ functions. Patients were treated with oral gefitinib 250 mg daily until disease progression or unacceptable toxicity. Results: Thirty-one patients were enrolled, of whom 30 were eligible. The median age was 78.5 years. The response rate was 20%, the disease control rate was 47%, the median progression-free survival was 2.7 months and the median overall survival was 11.9 months. Narrowing it down to those who had never smoked, the response rate increased to 43%, the disease control rate increased to 57%, the median progression-free survival prolonged to 7.1 months and the median overall survival prolonged to 13.0 months. The most frequent toxicity was rash. Other major toxicities were diarrhea, anorexia, liver dysfunction and anemia. These toxicities were mild and easily managed. Conclusions: Gefitinib as a first-line therapy is active and well tolerated in elderly patients with pulmonary adenocarcinoma, especially in those who have never smoked.
  • Masahiro Fukuoka; Yi-Long Wu; Sumitra Thongprasert; Patrapim Sunpaweravong; Swan-Swan Leong; Virote Sriuranpong; Tsu-Yi Chao; Kazuhiko Nakagawa; Da-Tong Chu; Nagahiro Saijo; Emma L. Duffield; Yuri Rukazenkov; Georgina Speake; Haiyi Jiang; Alison A. Armour; Ka-Fai To; James Chih-Hsin Yang; Tony S. K. Mok
    JOURNAL OF CLINICAL ONCOLOGY 29 21 2866 - 2874 2011年07月 [査読有り]
     
    Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment. J Clin Oncol 29:2866-2874. (C) 2011 by American Society of Clinical Oncology
  • Masayuki Takeda; Isamu Okamoto; Naoko Hirabayashi; Mami Kitano; Kazuhiko Nakagawa
    LUNG CANCER 73 1 103 - 109 2011年07月 [査読有り]
     
    S-1 is an oral fluoropyrimidine derivative that is active against non-small cell lung cancer (NSCLC). Development of S-1 combination chemotherapy for advanced NSCLC is under way. Given the importance of designing therapeutic strategies based on specific tumor biology, we have evaluated the relation between immunohistochemical expression levels of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT), or dihydropyrimidine dehydrogenase (DPD) and the response to treatment with S-1 plus carboplatin in patients with advanced NSCLC. Chemotherapy-naive patients with advanced (stage IIIB or IV) NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and archival tumor tissue were assigned to receive S-1-carboplatin (n = 22). The predictive or prognostic relevance of the molecular markers was also examined by their evaluation in patients treated with paclitaxel plus carboplatin (n 25). Expression levels of TS, OPRT, or DPD in tumor specimens did not differ significantly between patients treated with S-1-carboplatin and those treated with paclitaxel-carboplatin. A low expression level of TS or of DPD was associated with a better response and longer survival in patients treated with S-1-carboplatin but not in those treated with paclitaxel-carboplatin. Tumor expression levels of TS and DPD are predictive of response to S-1-carboplatin chemotherapy in patients with advanced NSCLC. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Masayuki Takeda; Isamu Okamoto; Naoko Hirabayashi; Mami Kitano; Kazuhiko Nakagawa
    LUNG CANCER 73 1 103 - 109 2011年07月 [査読有り]
     
    S-1 is an oral fluoropyrimidine derivative that is active against non-small cell lung cancer (NSCLC). Development of S-1 combination chemotherapy for advanced NSCLC is under way. Given the importance of designing therapeutic strategies based on specific tumor biology, we have evaluated the relation between immunohistochemical expression levels of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT), or dihydropyrimidine dehydrogenase (DPD) and the response to treatment with S-1 plus carboplatin in patients with advanced NSCLC. Chemotherapy-naive patients with advanced (stage IIIB or IV) NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and archival tumor tissue were assigned to receive S-1-carboplatin (n = 22). The predictive or prognostic relevance of the molecular markers was also examined by their evaluation in patients treated with paclitaxel plus carboplatin (n 25). Expression levels of TS, OPRT, or DPD in tumor specimens did not differ significantly between patients treated with S-1-carboplatin and those treated with paclitaxel-carboplatin. A low expression level of TS or of DPD was associated with a better response and longer survival in patients treated with S-1-carboplatin but not in those treated with paclitaxel-carboplatin. Tumor expression levels of TS and DPD are predictive of response to S-1-carboplatin chemotherapy in patients with advanced NSCLC. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Masahiro Fukuoka; Yi-Long Wu; Sumitra Thongprasert; Patrapim Sunpaweravong; Swan-Swan Leong; Virote Sriuranpong; Tsu-Yi Chao; Kazuhiko Nakagawa; Da-Tong Chu; Nagahiro Saijo; Emma L. Duffield; Yuri Rukazenkov; Georgina Speake; Haiyi Jiang; Alison A. Armour; Ka-Fai To; James Chih-Hsin Yang; Tony S. K. Mok
    JOURNAL OF CLINICAL ONCOLOGY 29 21 2866 - 2874 2011年07月 [査読有り]
     
    Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation-positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation-negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation-positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation-positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment. J Clin Oncol 29:2866-2874. (C) 2011 by American Society of Clinical Oncology
  • W. Okamoto; I. Okamoto; T. Arao; K. Yanagihara; K. Nishio; K. Nakagawa
    BRITISH JOURNAL OF CANCER 105 3 407 - 412 2011年07月 [査読有り]
     
    BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated in response to growth factors and cytokines, and which contributes to the regulation of cell proliferation, apoptosis, and motility in many human tumour types. METHODS: We investigated the mechanisms of STAT3 activation and the function of STAT3 depending on its mechanism of activation in gastric cancer cells. RESULTS: The MET-tyrosine kinase inhibitor (TKI) and cell transfection with a small interfering RNA (siRNA) specific for MET mRNA inhibited STAT3 phosphorylation in MET-activated cells, indicating that STAT3 activation is linked to MET signalling. Forced expression of a constitutively active form of STAT3 also attenuated MET-TKI-induced apoptosis, suggesting that inhibition of STAT3 activity contributes to MET-TKI-induced apoptosis. MKN1 and MKN7 cells, both of which are negative for MET activation, produced interleukin-6 (IL-6) that activated STAT3 through the Janus kinase pathway. Depletion of STAT3 by siRNA inhibited migration and invasion of these cells, suggesting that STAT3 activated by IL-6 contributes to regulation of cell motility. CONCLUSION: Our data thus show that activated STAT3 contributes to either cell survival or motility in gastric cancer cells, and that these actions are related to different mechanisms of STAT3 activation. British Journal of Cancer (2011) 105, 407-412. doi:10.1038/bjc.2011.246 www.bjcancer.com Published online 5 July 2011 (C) 2011 Cancer Research UK
  • Yuichi Saito; Hironori Ninomiya; Kentaro Inamura; Noriko Motoi; Hirofuimi Uehara; Mingyon Mun; Yukinori Sakao; Sakae Okumura; Ken Nakagawa; Genta Nagae; Teruyuki Satoh; Atsushi Kaneda; Hiroyuki Aburatani; Yukitoshi Satoh; Yuichi Ishikawa
    JOURNAL OF THORACIC ONCOLOGY 6 6 S1055 - S1055 2011年06月 [査読有り]
  • Toshiyuki Sawa; Takayasu Kurata; Takashi Ishiguro; Tomonori Hirashima; Yasuo Iwamoto; Kazuhiro Asami; Norihiko Ikeda; Masahiro Tsuboi; Takuya Aoki; Yoshikazu Kotani; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 6 6 S1190 - S1191 2011年06月 [査読有り]
  • Yasuhiro Kidera; Taroh Satoh; Shinya Ueda; Wataru Okamoto; Isamu Okamoto; Soichi Fumita; Kimio Yonesaka; Hidetoshi Hayashi; Chihiro Makimura; Kunio Okamoto; Hidemi Kiyota; Junji Tsurutani; Masaki Miyazaki; Masahiro Yoshinaga; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Masanobu Tsubaki; Yasutaka Chiba; Shozo Nishida; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 3 244 - 249 2011年06月 [査読有り]
     
    Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective. A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8 mg and granisetron 3 mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50 mg orally, followed by dexamethasone 20 mg, granisetron 3 mg, and famotidine 20 mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts. A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P = 0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2. Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.
  • Yasuhiro Kidera; Taroh Satoh; Shinya Ueda; Wataru Okamoto; Isamu Okamoto; Soichi Fumita; Kimio Yonesaka; Hidetoshi Hayashi; Chihiro Makimura; Kunio Okamoto; Hidemi Kiyota; Junji Tsurutani; Masaki Miyazaki; Masahiro Yoshinaga; Kimiko Fujiwara; Yuzuru Yamazoe; Kenzo Moriyama; Masanobu Tsubaki; Yasutaka Chiba; Shozo Nishida; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 16 3 244 - 249 2011年06月 [査読有り]
     
    Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective. A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8 mg and granisetron 3 mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50 mg orally, followed by dexamethasone 20 mg, granisetron 3 mg, and famotidine 20 mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts. A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P = 0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2. Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned.
  • Fumiyoshi Ohyanagi; Takeshi Horai; Ikuo Sekine; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Makoto Nishio; Stefanie Senger; Nassim Morsli; Tomohide Tamura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 5 718 - 722 2011年05月 [査読有り]
     
    Preliminary safety findings are presented from the open-label Phase I part of a combined Phase I/II study of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable Stage III non-small-cell lung cancer after primary chemoradiotherapy. Six patients received four or more once-weekly vaccinations with L-BLP25 1000 mu g subcutaneously prior to a preliminary safety evaluation. Treatment continued with once-weekly vaccinations with L-BLP25 1000 mg subcutaneously until week 8, then maintenance vaccinations every 6 weeks until progressive disease. Cyclophosphamide (300 mg/m(2) i.v. single dose) was given 3 days before first vaccination. Median age was 63.5 years and performance status was 0-1. No serious adverse events occurred; none necessitated discontinuation. L-BLP25-related adverse events (Grade 1) were myalgia, arthralgia and nausea; cyclophosphamide-related adverse events comprised dysgeusia, anorexia and nausea. The first evaluation of L-BLP25 in Japanese patients shows that it is well tolerated, and the safety profile is consistent with that seen in previous studies of Caucasian patients.
  • Isamu Okamoto; Toshiaki Takahashi; Hiroaki Okamoto; Kazuhiko Nakagawa; Koshiro Watanabe; Kiyoshi Nakamatsu; Yasumasa Nishimura; Masahiro Fukuoka; Nobuyuki Yamamoto
    LUNG CANCER 72 2 199 - 204 2011年05月 [査読有り]
     
    Introduction: A feasibility study was performed to examine the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive thoracic radiation therapy (TRT) in patients with unresectable non-small cell lung cancer (NSCLC) of stage III. Methods: Patients received a 14-day induction therapy with gefitinib at 250 mg daily. TRT was initiated on day 15 in 2-Gy fractions administered five times weekly to a total dose of 60 Gy. The primary end point of the study was the rate of treatment completion. Mutation status of the epidermal growth factor receptor gene (EGFR) was evaluated for patients with available tumor specimens. Results: Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of > 5 years. Conclusions: Our results do not support further trials of gefitinib and TRT for unselected NSCLC patients. This therapeutic strategy may hold promise, however, for locally advanced NSCLC in patients with sensitizing EGFR mutations. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Isamu Okamoto; Toshiaki Takahashi; Hiroaki Okamoto; Kazuhiko Nakagawa; Koshiro Watanabe; Kiyoshi Nakamatsu; Yasumasa Nishimura; Masahiro Fukuoka; Nobuyuki Yamamoto
    LUNG CANCER 72 2 199 - 204 2011年05月 [査読有り]
     
    Introduction: A feasibility study was performed to examine the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive thoracic radiation therapy (TRT) in patients with unresectable non-small cell lung cancer (NSCLC) of stage III. Methods: Patients received a 14-day induction therapy with gefitinib at 250 mg daily. TRT was initiated on day 15 in 2-Gy fractions administered five times weekly to a total dose of 60 Gy. The primary end point of the study was the rate of treatment completion. Mutation status of the epidermal growth factor receptor gene (EGFR) was evaluated for patients with available tumor specimens. Results: Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of > 5 years. Conclusions: Our results do not support further trials of gefitinib and TRT for unselected NSCLC patients. This therapeutic strategy may hold promise, however, for locally advanced NSCLC in patients with sensitizing EGFR mutations. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Fumiyoshi Ohyanagi; Takeshi Horai; Ikuo Sekine; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Makoto Nishio; Stefanie Senger; Nassim Morsli; Tomohide Tamura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 5 718 - 722 2011年05月 [査読有り]
     
    Preliminary safety findings are presented from the open-label Phase I part of a combined Phase I/II study of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable Stage III non-small-cell lung cancer after primary chemoradiotherapy. Six patients received four or more once-weekly vaccinations with L-BLP25 1000 mu g subcutaneously prior to a preliminary safety evaluation. Treatment continued with once-weekly vaccinations with L-BLP25 1000 mg subcutaneously until week 8, then maintenance vaccinations every 6 weeks until progressive disease. Cyclophosphamide (300 mg/m(2) i.v. single dose) was given 3 days before first vaccination. Median age was 63.5 years and performance status was 0-1. No serious adverse events occurred; none necessitated discontinuation. L-BLP25-related adverse events (Grade 1) were myalgia, arthralgia and nausea; cyclophosphamide-related adverse events comprised dysgeusia, anorexia and nausea. The first evaluation of L-BLP25 in Japanese patients shows that it is well tolerated, and the safety profile is consistent with that seen in previous studies of Caucasian patients.
  • K. Takezawa; I. Okamoto; W. Okamoto; M. Takeda; K. Sakai; S. Tsukioka; K. Kuwata; H. Yamaguchi; K. Nishio; K. Nakagawa
    BRITISH JOURNAL OF CANCER 104 10 1594 - 1601 2011年05月 [査読有り]
     
    BACKGROUND: Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in non-small cell lung cancer (NSCLC). We have now investigated the effect of TS overexpression on pemetrexed sensitivity in NSCLC cells. METHODS: We established NSCLC cell lines that stably overexpress TS and examined the effects of such overexpression on the cytotoxicity of pemetrexed both in vitro and in xenograft models. We further examined the relation between TS expression in tumour specimens from NSCLC patients and the tumour response to pemetrexed by immunohistochemical analysis. RESULTS: The sensitivity of NSCLC cells overexpressing TS to the antiproliferative effect of pemetrexed was markedly reduced compared with that of control cells. The inhibition of DNA synthesis and induction of apoptosis by pemetrexed were also greatly attenuated by forced expression of TS. Furthermore, tumours formed by TS-overexpressing NSCLC cells in nude mice were resistant to the growth-inhibitory effect of pemetrexed observed with control tumours. Finally, the level of TS expression in tumours of non-responding patients was significantly higher than that in those of responders, suggestive of an inverse correlation between TS expression and tumour response to pemetrexed. CONCLUSION: A high level of TS expression confers a reduced sensitivity to pemetrexed. TS expression is thus a potential predictive marker for response to pemetrexed-based chemotherapy in NSCLC patients. British Journal of Cancer (2011) 104, 1594-1601. doi: 10.1038/bjc.2011.129 www.bjcancer.com Published online 12 April 2011 (C) 2011 Cancer Research UK
  • Kawakami H; Satoh T; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 3 439 - 445 2011年04月 [査読有り]
  • Ken Takezawa; Isamu Okamoto; Kazuto Nishio; Pasi A. Jaenne; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 17 8 2140 - 2148 2011年04月 [査読有り]
     
    Purpose: EML4-ALK (echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer. The purpose of the present study was to characterize the mechanism of malignant transformation by EML4-ALK. Experimental Design: We established NIH 3T3 cells that stably express variant 1 or 3 of EML4-ALK and examined the signaling molecules that function downstream of EML4-ALK. Results: Forced expression of EML4-ALK induced marked activation of extracellular signal-regulated kinase (ERK) and STAT3, but not that of AKT. Inhibition of ERK or STAT3 signaling resulted in substantial attenuation of the proliferation of cells expressing either variant of EML4-ALK, suggesting that these signaling pathways function downstream of EML4-ALK in lung cancer cells. The specific ALK inhibitor TAE684 induced apoptosis that was accompanied both by upregulation of BIM, a proapoptotic member of the Bcl-2 family, and by downregulation of survivin, a member of the inhibitor of apoptosis protein (IAP) family, in EML4-ALK-expressing NIH 3T3 cells as well as in H3122 human lung cancer cells harboring endogenous EML4-ALK. Depletion of BIM and overexpression of survivin each inhibited TAE684-induced apoptosis, suggesting that both upregulation of BIM and downregulation of survivin contribute to TAE684-induced apoptosis in EML4-ALK-positive lung cancer cells. Furthermore, BIM and survivin expression was found to be independently regulated by ERK and STAT3 signaling pathways, respectively. Conclusions: ALK inhibitor-induced apoptosis is mediated both by BIM upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells. Clin Cancer Res; 17(8); 2140-8. (C) 2011 AACR.
  • Koichi Azuma; Junji Tsurutani; Kazuko Sakai; Hiroyasu Kaneda; Yasuhito Fujisaka; Masayuki Takeda; Masahiro Watatani; Tokuzo Arao; Taroh Satoh; Isamu Okamoto; Takayasu Kurata; Kazuto Nishio; Kazuhiko Nakagawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 407 1 219 - 224 2011年04月 [査読有り]
     
    Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGER2 and reduced expression of HER2, and a cell proliferation assay showed that the IC50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that EGER-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer. (C) 2011 Elsevier Inc. All rights reserved.
  • Koichi Azuma; Junji Tsurutani; Kazuko Sakai; Hiroyasu Kaneda; Yasuhito Fujisaka; Masayuki Takeda; Masahiro Watatani; Tokuzo Arao; Taroh Satoh; Isamu Okamoto; Takayasu Kurata; Kazuto Nishio; Kazuhiko Nakagawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 407 1 219 - 224 2011年04月 [査読有り]
     
    Agents that target HER2 have improved the prognosis of patients with HER2-amplified breast cancers. However, patients who initially respond to such targeted therapy eventually develop resistance to the treatment. We have established a line of lapatinib-resistant breast cancer cells (UACC812/LR) by chronic exposure of HER2-amplified and lapatinib-sensitive UACC812 cells to the drug. The mechanism by which UACC812/LR acquired resistance to lapatinib was explored using comprehensive gene hybridization. The FGFR2 gene in UACC812/LR was highly amplified, accompanied by overexpression of FGER2 and reduced expression of HER2, and a cell proliferation assay showed that the IC50 of PD173074, a small-molecule inhibitor of FGFR tyrosine kinase, was 10,000 times lower in UACC812/LR than in the parent cells. PD173074 decreased the phosphorylation of FGFR2 and substantially induced apoptosis in UACC812/LR, but not in the parent cells. FGFR2 appeared to be a pivotal molecule for the survival of UACC812/LR as they became independent of the HER2 pathway, suggesting that a switch of addiction from the HER2 to the FGFR2 pathway enabled cancer cells to become resistant to HER2-targeted therapy. The present study is the first to implicate FGFR in the development of resistance to lapatinib in cancer, and suggests that EGER-targeted therapy might become a promising salvage strategy after lapatinib failure in patients with HER2-positive breast cancer. (C) 2011 Elsevier Inc. All rights reserved.
  • Ken Takezawa; Isamu Okamoto; Kazuto Nishio; Pasi A. Jaenne; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 17 8 2140 - 2148 2011年04月 [査読有り]
     
    Purpose: EML4-ALK (echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase) was recently identified as a transforming fusion gene in non-small cell lung cancer. The purpose of the present study was to characterize the mechanism of malignant transformation by EML4-ALK. Experimental Design: We established NIH 3T3 cells that stably express variant 1 or 3 of EML4-ALK and examined the signaling molecules that function downstream of EML4-ALK. Results: Forced expression of EML4-ALK induced marked activation of extracellular signal-regulated kinase (ERK) and STAT3, but not that of AKT. Inhibition of ERK or STAT3 signaling resulted in substantial attenuation of the proliferation of cells expressing either variant of EML4-ALK, suggesting that these signaling pathways function downstream of EML4-ALK in lung cancer cells. The specific ALK inhibitor TAE684 induced apoptosis that was accompanied both by upregulation of BIM, a proapoptotic member of the Bcl-2 family, and by downregulation of survivin, a member of the inhibitor of apoptosis protein (IAP) family, in EML4-ALK-expressing NIH 3T3 cells as well as in H3122 human lung cancer cells harboring endogenous EML4-ALK. Depletion of BIM and overexpression of survivin each inhibited TAE684-induced apoptosis, suggesting that both upregulation of BIM and downregulation of survivin contribute to TAE684-induced apoptosis in EML4-ALK-positive lung cancer cells. Furthermore, BIM and survivin expression was found to be independently regulated by ERK and STAT3 signaling pathways, respectively. Conclusions: ALK inhibitor-induced apoptosis is mediated both by BIM upregulation resulting from inhibition of ERK signaling as well as by survivin downregulation resulting from inhibition of STAT3 signaling in EML4-ALK-positive lung cancer cells. Clin Cancer Res; 17(8); 2140-8. (C) 2011 AACR.
  • Junko Tanizaki; Isamu Okamoto; Soichi Fumita; Wataru Okamoto; Kazuhiko Nakagawa
    CANCER RESEARCH 71 39 4097 - 4106 2011年04月 [査読有り]
  • 久保 昭仁; 洪 泰浩; 堀 隆; 伊佐 俊一; 福岡 順也; 川口 知哉; 安藤 昌彦; 岡本 勇; 北市 正則; 安宅 信二; 河原 正明; 楠 洋子; 山口 悦郎; 中川 和彦; 高田 實
    日本呼吸器学会雑誌 49 増刊 264 - 264 (一社)日本呼吸器学会 2011年03月
  • Paclitaxel療法後Docetaxel療法を行った進行再発胃癌14例の検討
    工藤 敏啓; 佐藤 太郎; 川上 尚人; 上田 眞也; 宮崎 昌樹; 藤阪 保人; 鶴谷 純司; 倉田 宝保; 岡本 勇; 中川 和彦
    日本胃癌学会総会記事 83回 188 - 188 (一社)日本胃癌学会 2011年03月
  • Kaira K; Serizawa M; Koh Y; Miura S; Kaira R; Abe M; Nakagawa K; Ohde Y; Okumura T; Naito T; Murakami H; Takahashi T; Kondo H; Nakajima T; Endo M; Yamamoto N
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 6 3 606 - 613 2011年03月 [査読有り]
  • Noriyuki Masuda; Shunichi Negoro; Frederick Hausheer; Kazuhiko Nakagawa; Kaoru Matsui; Shinzoh Kudoh; Koji Takeda; Nobuyuki Yamamoto; Naruo Yoshimura; Yasuo Ohashi; Masahiro Fukuoka
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 67 3 533 - 542 2011年03月 [査読有り]
     
    We conducted a phase I trial of BNP7787 (disodium 2,2'-dithio-bis-ethane sulfonate, Tavocept (TM)), a novel chemoprotective and antitumor enhancing agent administered in combination with paclitaxel and cisplatin. The primary aim was to determine a safe and potentially efficacious BNP7787 dose for preventing and mitigating paclitaxel- and cisplatin-induced toxicities and to evaluate for preliminary evidence of efficacy of treatment. Twenty-two patients with stage IIIB/IV non-small cell lung cancer (NSCLC) received BNP7787 alone 1 week before co-administration of BNP7787 with paclitaxel followed by cisplatin. Twenty-one patients were treated with BNP7787 in escalating doses of 4.1-41.0 g/m(2) concurrently with paclitaxel 175 mg/m(2) and cisplatin 75 mg/m(2) every 3 weeks. The appropriate dose was determined to be 18.4 g/m(2) of BNP7787 although no dose-limiting toxicity was observed up to 41.0 g/m(2). Mild intravenous site discomfort, thirst, and nausea were the most common toxicities. One patient developed grade 2 skin rash, which was severe enough to preclude further study treatment. The AUC(0-inf) of the metabolite mesna was approximately 6.3% of the AUC(0-inf) of BNP7787. Co-administration of paclitaxel and cisplatin did not appear to influence the pharmacokinetics of BNP7787 and mesna. The overall response rate was encouraging; 43% including 11 patients with prior chemotherapy. The recommended dose for phase II/III studies is 18.4 mg/m(2) of BNP7787 in combination with paclitaxel and cisplatin. Further studies are warranted to assess whether BNP7787 prevents and mitigates common and serious paclitaxel- and cisplatin-related side effects and enhances the efficacy of paclitaxel and cisplatin in advanced NSCLC patients.
  • Kaira K; Endo M; Abe M; Nakagawa K; Ohde Y; Okumura T; Takahashi T; Murakami H; Tsuya A; Nakamura Y; Naito T; Hayashi I; Kondo H; Nakajima T; Yamamoto N
    Lung cancer (Amsterdam, Netherlands) 71 2 144 - 150 2011年02月 [査読有り]
  • Takuji Okusaka; Junji Furuse; Akihiro Funakoshi; Tatsuya Ioka; Kenji Yamao; Shinichi Ohkawa; Narikazu Boku; Yoshito Komatsu; Shoji Nakamori; Haruo Iguchi; Tetsuhide Ito; Kazuhiko Nakagawa; Kohei Nakachi
    CANCER SCIENCE 102 2 425 - 431 2011年02月 [査読有り]
     
    Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m(2) (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425-431)
  • Takuji Okusaka; Junji Furuse; Akihiro Funakoshi; Tatsuya Ioka; Kenji Yamao; Shinichi Ohkawa; Narikazu Boku; Yoshito Komatsu; Shoji Nakamori; Haruo Iguchi; Tetsuhide Ito; Kazuhiko Nakagawa; Kohei Nakachi
    CANCER SCIENCE 102 2 425 - 431 2011年02月 [査読有り]
     
    Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m(2) (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients. (Cancer Sci 2011; 102: 425-431)
  • 西田 升三; 田中 京子; 倉田 宝保; 中川 和彦
    腫瘍内科 7 1 43 - 48 (有)科学評論社 2011年01月
  • Akihito Kubo; Yasuhiro Koh; Tomoya Kawaguchi; Shun-Ichi Isa; Isamu Okamoto; Junya Fukuoka; Yoko Kusunoki; Masanori Kitaichi; Minoru Takada; Kazuhiko Nakagawa
    INTERNAL MEDICINE 50 7 745 - 748 2011年 [査読有り]
     
    Small molecule inhibitors targeting epidermal growth factor receptor (EGFR) are known to be active against non-small cell lung cancer (NSCLC) although the pharmacodynamics of these agents on malignant pleural effusion (MPE) remains unclear. Here we describe a case of lung adenocarcinoma with massive MPE treated successfully by gefitinib and chest drainage. Using sequential MPE samples before and during gefitinib therapy, the morphological changes and apoptosis of cancer cells were analyzed. Apoptosis of cancer cells was detected as early as 4 hours on, but not before, gefitinib therapy, suggesting that the pharmacodynamic assessment of such molecular targeting agents might be feasible for MPE.
  • Randomized Phase II Study of Carboplatin-Paclitaxel or Gemcitabine-Vinorelbine in Patients With Advanced Nonsmall Cell Lung Cancer and a Performance Status of 2: West Japan Thoracic Oncology Group 0004.
    Saito H; Nakagawa K; Takeda K; Iwamoto Y; Ando M; Maeda M; Katakami N; Nakano T; Kurata T; Fukuoka M
    Am J Clin Oncol. 35 1 58 - 63 2011年 [査読有り]
  • Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-na?ve patients with advanced non-small-cell lung cancer: results of a west Japan oncology group study.
    Okamoto I; Yoshioka H; Morita S; Ando M; Takeda K; Seto T; Yamamoto N; Saka H; Asami K; Hirashima T; Kudoh S; Satouchi M; Ikeda N; Iwamoto Y; Sawa T; Miyazaki M; Tamura K; Kurata T; Fukuoka M; Nakagawa K
    Journal of Clinical Oncology 28 36 5240 - 5246 2011年 [査読有り]
  • Ayaka Hirao; Naoki Oiso; Junji Tsurutani; Masatomo Kimura; Masahiro Watatani; Kazuhiko Nakagawa; Akira Kawada
    Case Reports in Dermatology 3 1 42 - 48 2011年01月 [査読有り]
     
    Recent chemotherapies for skin metastases from breast cancer have shown to be effective for regression, disappearance, and favorable quality of life. We describe the case of a 76-year-old male showing transient effectiveness with an oral 5-fluorouracil derivative, S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate), for epirubicin, cyclophosphamide and paclitaxel refractory skin metastases from possible occult breast cancer. The male patient was initially diagnosed as having lymph node metastases in the left axilla as possible occult breast cancer. The skin metastases developed after chemotherapy with a combination of epirubicin and cyclophosphamide, subsequent chemotherapy with paclitaxel, and radiotherapy. Chemotherapy with paclitaxel was resumed for skin metastases, but it was not effective. Alternative chemotherapy with the oral agent S-1 was administered. The skin metastases completely disappeared after the second course, but recurred at the end of the third course. This case suggests that S-1 may be a candidate for chemotherapy for skin metastases from occult breast cancer in males. Copyright © 2011 S. Karger AG, Basel.
  • Phase I and pharmacologic study of BNP7787, a novel chemoprotector in patients with advanced non-small cell lung cancer.
    Masuda N; Negoro S; Hausheer F; Nakagawa K; Matsui K; Kudoh S; Takeda K; Yamamoto N; Yoshimura N; Ohashi Y; Fukuoka M
    Cancer Chemother Pharmacol 67 3 533 - 542 2011年 [査読有り]
  • Koji Takeda; Shunichi Negoro; Masahiro Tanaka; Haruhiko Fukuda; Kazuhiko Nakagawa; Masaaki Kawahara; Hiroshi Semba; Shinzoh Kudoh; Toshiyuki Sawa; Nagahiro Saijo; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 1 25 - 31 2011年01月 [査読有り]
     
    It is important to identify optimal regimens of cisplatin-based, third-generation chemotherapy and thoracic radiotherapy for patients with unresectable, Stage III, non-small cell lung cancer. Patients with unresectable, Stage III non-small cell lung cancer were treated with the following regimen: cisplatin 80 mg/m(2) on days 1 and 29, with irinotecan 60 mg/m(2) on days 1, 8, 15, 29, 36, and 43 and 30 mg/m(2) on days 57, 64, 71, 78, 85 and 92. Thoracic radiotherapy was started on day 57 at 2 Gy/day (total 60 Gy). From February 1998 to January 1999, 68 patients were enrolled. Grade 3/4 toxicities during induction chemotherapy primarily included neutropenia (73.5%) and diarrhea (20.6%), while Grade 3/4 toxicities during concomitant thoracic radiotherapy with irinotecan consisted of neutropenia (18.4%), esophagitis (4.1%) and hypoxia (6.5%). There was one treatment-related death due to radiation pneumonitis. The response rate was 64.7% (95% confidence interval, 52.2-75.9%). The median survival time was 16.5 (95% confidence interval, 12.6-19.8) months. The 1- and 2 year survival rates were 65.8% (95% confidence interval, 54.4-77.1%) and 32.9% (95% confidence interval, 21.6-44.1%), respectively. Overall, only 36 (56%) completed both the scheduled chemotherapy and thoracic radiotherapy. Induction chemotherapy with cisplatin plus irinotecan followed by low-dose irinotecan and concomitant thoracic radiotherapy was feasible according to the prespecified decision criteria in this study for patients with unresectable Stage III non-small cell lung cancer. We did not decide to select this regimen for further investigations because approximately half of the patients completed the scheduled treatment.
  • Koji Takeda; Shunichi Negoro; Masahiro Tanaka; Haruhiko Fukuda; Kazuhiko Nakagawa; Masaaki Kawahara; Hiroshi Semba; Shinzoh Kudoh; Toshiyuki Sawa; Nagahiro Saijo; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 1 25 - 31 2011年01月 [査読有り]
     
    It is important to identify optimal regimens of cisplatin-based, third-generation chemotherapy and thoracic radiotherapy for patients with unresectable, Stage III, non-small cell lung cancer. Patients with unresectable, Stage III non-small cell lung cancer were treated with the following regimen: cisplatin 80 mg/m(2) on days 1 and 29, with irinotecan 60 mg/m(2) on days 1, 8, 15, 29, 36, and 43 and 30 mg/m(2) on days 57, 64, 71, 78, 85 and 92. Thoracic radiotherapy was started on day 57 at 2 Gy/day (total 60 Gy). From February 1998 to January 1999, 68 patients were enrolled. Grade 3/4 toxicities during induction chemotherapy primarily included neutropenia (73.5%) and diarrhea (20.6%), while Grade 3/4 toxicities during concomitant thoracic radiotherapy with irinotecan consisted of neutropenia (18.4%), esophagitis (4.1%) and hypoxia (6.5%). There was one treatment-related death due to radiation pneumonitis. The response rate was 64.7% (95% confidence interval, 52.2-75.9%). The median survival time was 16.5 (95% confidence interval, 12.6-19.8) months. The 1- and 2 year survival rates were 65.8% (95% confidence interval, 54.4-77.1%) and 32.9% (95% confidence interval, 21.6-44.1%), respectively. Overall, only 36 (56%) completed both the scheduled chemotherapy and thoracic radiotherapy. Induction chemotherapy with cisplatin plus irinotecan followed by low-dose irinotecan and concomitant thoracic radiotherapy was feasible according to the prespecified decision criteria in this study for patients with unresectable Stage III non-small cell lung cancer. We did not decide to select this regimen for further investigations because approximately half of the patients completed the scheduled treatment.
  • Ayaka Hirao; Naoki Oiso; Junji Tsurutani; Masatomo Kimura; Masahiro Watatani; Kazuhiko Nakagawa; Akira Kawada
    Case Reports in Dermatology 3 1 42 - 48 2011年01月 [査読有り]
     
    Recent chemotherapies for skin metastases from breast cancer have shown to be effective for regression, disappearance, and favorable quality of life. We describe the case of a 76-year-old male showing transient effectiveness with an oral 5-fluorouracil derivative, S-1 (tegafur, 5-chloro-2,4-dihydroxypyridine and potassium oxonate), for epirubicin, cyclophosphamide and paclitaxel refractory skin metastases from possible occult breast cancer. The male patient was initially diagnosed as having lymph node metastases in the left axilla as possible occult breast cancer. The skin metastases developed after chemotherapy with a combination of epirubicin and cyclophosphamide, subsequent chemotherapy with paclitaxel, and radiotherapy. Chemotherapy with paclitaxel was resumed for skin metastases, but it was not effective. Alternative chemotherapy with the oral agent S-1 was administered. The skin metastases completely disappeared after the second course, but recurred at the end of the third course. This case suggests that S-1 may be a candidate for chemotherapy for skin metastases from occult breast cancer in males. Copyright © 2011 S. Karger AG, Basel.
  • Hidetoshi Hayashi; Takayasu Kurata; Kazuhiko Nakagawa
    Clinical Medicine Insights: Oncology 5 177 - 184 2011年 [査読有り]
     
    Lung cancer is the leading cause of cancer-related death in many countries. Approximately half of the patients with non-small cell lung cancer have advanced disease and systemic chemotherapy, especially platinum-based doublets, is currently the standard treatment. Several trials have recently indicated the importance of histological subtype for treatment with molecular target chemotherapy and pemetrexed. Over the last decade, gemcitabine, a pyrimidine nucleoside antimetabolite, has been one of the most effective agents for patients with advanced non-small cell lung cancer. It is unknown whether histological type is a predictor of the outcome of treatment with this agent. This is a review of the past trials and reviews of first-line treatment for advanced NSCLC, focusing on efficacy and safety of treatment with gemcitabine according to histological subtype. © the author(s), publisher and licensee Libertas Academica Ltd.
  • Takeda M; Okamoto I; Nishimura Y; Nakagawa K
    Lung Cancer (Auckland, N.Z.) 2 59 - 67 2011年 [査読有り]
  • Kunio Okamoto; Isamu Okamoto; Wataru Okamoto; Kaoru Tanaka; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Kazuto Nishio; Kazuhiko Nakagawa
    CANCER RESEARCH 70 24 10402 - 10410 2010年12月 [査読有り]
     
    The molecular mechanism by which epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non-small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation-positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI-induced apoptotic death in these cells. Cancer Res; 70(24); 10402-10. (C)2010 AACR.
  • Isamu Okamoto; Hiroshige Yoshioka; Satoshi Morita; Masahiko Ando; Koji Takeda; Takashi Seto; Nobuyuki Yamamoto; Hideo Saka; Kazuhiro Asami; Tomonori Hirashima; Shinzoh Kudoh; Miyako Satouchi; Norihiko Ikeda; Yasuo Iwamoto; Toshiyuki Sawa; Masaki Miyazaki; Kenji Tamura; Takayasu Kurata; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 28 36 5240 - 5246 2010年12月 [査読有り]
     
    Purpose The primary goal of this open-label, multicenter, randomized phase III trial was to determine whether treatment with carboplatin plus the oral fluoropyrimidine derivative S-1 was noninferior versus that with carboplatin plus paclitaxel with regard to overall survival (OS) in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods A total of 564 patients were randomly assigned to receive either carboplatin (area under the curve, 5) on day 1 plus oral S-1 (40 mg/m(2) twice per day) on days 1 to 14 or carboplatin (area under the curve, 6) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days. Results At the planned interim analysis, with a total of 268 death events available, the study passed the O'Brien-Fleming boundary of 0.0080 for a positive result and noninferiority of carboplatin and S-1 compared with carboplatin and paclitaxel was confirmed for OS (hazard ratio, 0.928; 99.2% CI, 0.671 to 1.283). Median OS was 15.2 months in the carboplatin and S-1 arm and 13.3 months in the carboplatin and paclitaxel arm, with 1-year survival rates of 57.3% and 55.5%, respectively. Rates of leukopenia or neutropenia of grade 3/4, febrile neutropenia, alopecia, and neuropathy were more frequent in the carboplatin and paclitaxel arm, whereas thrombocytopenia, nausea, vomiting, and diarrhea were more common in the carboplatin and S-1 arm. The carboplatin and S-1 arm had significantly more dose delays than the carboplatin and paclitaxel arm. Conclusion Oral S-1 with carboplatin was noninferior in terms of OS compared with carboplatin and paclitaxel in patients with advanced NSCLC, and is thus a valid treatment option.
  • Isamu Okamoto; Masaki Miyazaki; Ryotaro Morinaga; Hiroyasu Kaneda; Shinya Ueda; Yoshikazu Hasegawa; Taroh Satoh; Akira Kawada; Masahiro Fukuoka; Koichi Fukino; Takahiko Tanigawa; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 28 6 844 - 853 2010年12月 [査読有り]
     
    Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m(2)) and carboplatin (area under the curve [AUC]of 6 mg min mL(-1)) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL(-1) and paclitaxel 200 mg/m(2) is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.
  • Isamu Okamoto; Masaki Miyazaki; Ryotaro Morinaga; Hiroyasu Kaneda; Shinya Ueda; Yoshikazu Hasegawa; Taroh Satoh; Akira Kawada; Masahiro Fukuoka; Koichi Fukino; Takahiko Tanigawa; Kazuhiko Nakagawa
    INVESTIGATIONAL NEW DRUGS 28 6 844 - 853 2010年12月 [査読有り]
     
    Objectives Unsatisfactory efficacy of current treatments for advanced lung cancer has prompted the search for new therapies, with sorafenib, a multikinase inhibitor, being one candidate drug. This phase I trial was conducted to evaluate drug safety and pharmacokinetics as well as tumor response of sorafenib in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods Eligible patients received paclitaxel (200 mg/m(2)) and carboplatin (area under the curve [AUC]of 6 mg min mL(-1)) on day 1 and sorafenib (400 mg, twice daily) on days 2 through 19 of a 21-day cycle. Results Four of the initial six patients (cohort 1) experienced dose-limiting toxicities (DLTs), resulting in amendment of the treatment protocol. An additional seven patients (cohort 2) were enrolled, two of whom developed DLTs. DLTs included erythema multiforme, hand-foot skin reaction, and elevated plasma alanine aminotransferase in cohort 1 as well as gastrointestinal perforation at a site of metastasis and pneumonia in cohort 2. Most adverse events were manageable. One complete and six partial responses were observed among the 12 evaluable patients. Coadministration of the three drugs had no impact on their respective pharmacokinetics. Conclusion The present study confirmed that sorafenib at 400 mg once daily in combination with carboplatin AUC 5 mg min mL(-1) and paclitaxel 200 mg/m(2) is feasible in Japanese patients with advanced NSCLC. The results of this study also showed that this combination therapy had encouraging antitumor activity and was not associated with relevant pharmacokinetic interaction in Japanese NSCLC patients.
  • Isamu Okamoto; Hiroshige Yoshioka; Satoshi Morita; Masahiko Ando; Koji Takeda; Takashi Seto; Nobuyuki Yamamoto; Hideo Saka; Kazuhiro Asami; Tomonori Hirashima; Shinzoh Kudoh; Miyako Satouchi; Norihiko Ikeda; Yasuo Iwamoto; Toshiyuki Sawa; Masaki Miyazaki; Kenji Tamura; Takayasu Kurata; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 28 36 5240 - 5246 2010年12月 [査読有り]
     
    Purpose The primary goal of this open-label, multicenter, randomized phase III trial was to determine whether treatment with carboplatin plus the oral fluoropyrimidine derivative S-1 was noninferior versus that with carboplatin plus paclitaxel with regard to overall survival (OS) in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods A total of 564 patients were randomly assigned to receive either carboplatin (area under the curve, 5) on day 1 plus oral S-1 (40 mg/m(2) twice per day) on days 1 to 14 or carboplatin (area under the curve, 6) plus paclitaxel (200 mg/m(2)) on day 1 every 21 days. Results At the planned interim analysis, with a total of 268 death events available, the study passed the O'Brien-Fleming boundary of 0.0080 for a positive result and noninferiority of carboplatin and S-1 compared with carboplatin and paclitaxel was confirmed for OS (hazard ratio, 0.928; 99.2% CI, 0.671 to 1.283). Median OS was 15.2 months in the carboplatin and S-1 arm and 13.3 months in the carboplatin and paclitaxel arm, with 1-year survival rates of 57.3% and 55.5%, respectively. Rates of leukopenia or neutropenia of grade 3/4, febrile neutropenia, alopecia, and neuropathy were more frequent in the carboplatin and paclitaxel arm, whereas thrombocytopenia, nausea, vomiting, and diarrhea were more common in the carboplatin and S-1 arm. The carboplatin and S-1 arm had significantly more dose delays than the carboplatin and paclitaxel arm. Conclusion Oral S-1 with carboplatin was noninferior in terms of OS compared with carboplatin and paclitaxel in patients with advanced NSCLC, and is thus a valid treatment option.
  • Kunio Okamoto; Isamu Okamoto; Wataru Okamoto; Kaoru Tanaka; Ken Takezawa; Kiyoko Kuwata; Haruka Yamaguchi; Kazuto Nishio; Kazuhiko Nakagawa
    CANCER RESEARCH 70 24 10402 - 10410 2010年12月 [査読有り]
     
    The molecular mechanism by which epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) induce apoptosis in non-small cell-lung cancer (NSCLC) cells that are positive for activating mutations of the EGFR remains unclear. In this study, we report the effects of the EGFR-TKI gefitinib on expression of the antiapoptotic protein survivin that have functional consequences in EGFR mutation-positive NSCLC cells. Immunoblot analysis revealed that gefitinib downregulated survivin expression, likely through inhibition of the PI3K-AKT signaling pathway, in NSCLC cells positive for EGFR mutation. Stable overexpression of survivin attenuated gefitinib-induced apoptosis and also inhibited the antitumor effect of gefitinib in human tumor xenografts. Furthermore, the combination of survivin overexpression with inhibition of the gefitinib-induced upregulation of the proapoptotic protein BIM attenuated gefitinib-induced apoptosis to a greater extent than either approach alone. Our results indicate that downregulation of survivin plays a pivotal role in gefitinib-induced apoptosis in EGFR mutation-positive NSCLC cells. Furthermore, they suggest that simultaneous interruption of the PI3K-AKT-survivin and MEK-ERK-BIM signaling pathways is responsible for EGFR-TKI-induced apoptotic death in these cells. Cancer Res; 70(24); 10402-10. (C)2010 AACR.
  • Tsurutani Junji; Okamoto Kunio; Makimura Chihior; Azuma Koichi; Takeda Masayuki; Takezawa Ken; Okamoto Wataru; Kiyota Hidemi; Hayashi Hidetoshi; Tanaka Kaoru; Tanizaki Junko; Okamoto Isamu; Saijoh Nagahiro; Fukuoka Masahiro; Nakagawa Kazuhiko
    ANNALS OF ONCOLOGY 21 38 - 39 2010年11月 [査読有り]
  • Ken Takezawa; Isamu Okamoto; Kaoru Tanaka; Hidetoshi Hayashi; Kunio Okamoto; Kimio Yonesaka; Masahiro Fukuoka; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 20 - 20 2010年11月 [査読有り]
  • Kunio Okamoto; Isamu Okamoto; Ken Takezawa; Kaoru Tanaka; Junko Tanizaki; Chihiro Makimura; Hidetoshi Hayashi; Izumi Tachibana; Yasumasa Nishimura; Masahiro Fukuoka; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 27 - 27 2010年11月 [査読有り]
  • Hidetoshi Hayashi; Isamu Okamoto; Masaki Miyazaki; Yasuko Ichikawa; Hiroshige Yoshioka; Kei Kunimasa; Kaoru Tanaka; Kunio Okamoto; Chihiro Makimura; Masahiro Iwasaku; Akihiro Nisiyama; Yohhei Korogi; Kazuhiko Nakagawa
    ANNALS OF ONCOLOGY 21 26 - 26 2010年11月 [査読有り]
  • Isamu Okamoto; Koji Takeda; Haruko Daga; Masaki Miyazaki; Kimio Yonesaka; Hidemi Kiyota; Junji Tsurutani; Shinya Ueda; Yasuko Ichikawa; Masayuki Takeda; Risa Sekiguchi; Kiyomi Tominaga; Sotaro Enatsu; Yoshihiro Nambu; Kazuhiko Nakagawa
    LUNG CANCER 70 2 168 - 173 2010年11月 [査読有り]
     
    Introduction: The primary objectives of this study were to determine the recommended dose of pemetrexed and carboplatin in patients with chemo-naive advanced non-small cell lung cancer (NSCLC). Methods: Patients received escalated doses of carboplatin area under the concentration-time curve (AUC) of 5 (cohort 1) or 6 (cohort 2) and pemetrexed 500 mg/m(2) every 3 weeks for six cycles. For patients with objective response and stable disease, pemetrexed were continued until disease progression or unacceptable toxicity. Results: In cohort 1, a dose-limiting toxicity (DLT) was observed in one of the six patients: grade 4 thrombocytopenia. No DLTs were seen in the first 6 patients of cohort 2, and thus the combination of pemetrexed 500 mg/m2 plus carboplatin at AUC 6 was determined as the recommended dose. Among a total of 20 patients, 8 patients received a median of four cycles of pemetrexed monotherapy in a maintenance setting without unexpected or cumulative toxicities. No complete responses and 12 partial responses were observed, giving an overall response rate of 60.0% [95% confidence interval (CI), 36.1-80.9%]. Median progression-free survival time for all patients was 7.6 months (95% CI: 4.8-8.0 months). Conclusions: Pemetrexed 500 mg/m(2) plus carboplatin AUC 6 combination therapy followed by pemetrexed maintenance therapy, is generally tolerable, and shows encouraging antitumor activity in chemotherapy-naive patients with advanced NSCLC. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • Isamu Okamoto; Koji Takeda; Haruko Daga; Masaki Miyazaki; Kimio Yonesaka; Hidemi Kiyota; Junji Tsurutani; Shinya Ueda; Yasuko Ichikawa; Masayuki Takeda; Risa Sekiguchi; Kiyomi Tominaga; Sotaro Enatsu; Yoshihiro Nambu; Kazuhiko Nakagawa
    LUNG CANCER 70 2 168 - 173 2010年11月 [査読有り]
     
    Introduction: The primary objectives of this study were to determine the recommended dose of pemetrexed and carboplatin in patients with chemo-naive advanced non-small cell lung cancer (NSCLC). Methods: Patients received escalated doses of carboplatin area under the concentration-time curve (AUC) of 5 (cohort 1) or 6 (cohort 2) and pemetrexed 500 mg/m(2) every 3 weeks for six cycles. For patients with objective response and stable disease, pemetrexed were continued until disease progression or unacceptable toxicity. Results: In cohort 1, a dose-limiting toxicity (DLT) was observed in one of the six patients: grade 4 thrombocytopenia. No DLTs were seen in the first 6 patients of cohort 2, and thus the combination of pemetrexed 500 mg/m2 plus carboplatin at AUC 6 was determined as the recommended dose. Among a total of 20 patients, 8 patients received a median of four cycles of pemetrexed monotherapy in a maintenance setting without unexpected or cumulative toxicities. No complete responses and 12 partial responses were observed, giving an overall response rate of 60.0% [95% confidence interval (CI), 36.1-80.9%]. Median progression-free survival time for all patients was 7.6 months (95% CI: 4.8-8.0 months). Conclusions: Pemetrexed 500 mg/m(2) plus carboplatin AUC 6 combination therapy followed by pemetrexed maintenance therapy, is generally tolerable, and shows encouraging antitumor activity in chemotherapy-naive patients with advanced NSCLC. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
  • 乳がんに対する化学療法の著効例
    寺嶋応顕; 鶴谷純司; 中川和彦
    臨床腫瘍プラクティス 6 4 465 - 468 2010年11月 [査読有り]
  • 久保 昭仁; 洪 泰浩; 堀 隆; 安藤 昌彦; 伊佐 俊一; 福岡 順也; 川口 知哉; 安宅 信二; 岡本 勇; 北市 正則; 河原 正明; 楠 洋子; 山口 悦郎; 中川 和彦; 高田 實
    肺癌 50 5 510 - 510 (NPO)日本肺癌学会 2010年10月
  • 井上 義一; 福岡 正博; 工藤 翔二; 安藤 昌彦; 大江 裕一郎; 中川 和彦; 荒川 浩明; 海老名 雅仁; 清原 祥夫; 楠本 昌彦; 桑野 和善; 弦間 昭彦; 酒井 文和; 上甲 剛; 谷口 博之; 福田 悠; 山崎 直也; 竹本 信也; 秋山 晋一郎
    肺癌 50 5 541 - 541 (NPO)日本肺癌学会 2010年10月
  • Kyoichi Kaira; Toshiaki Takahashi; Masato Abe; Hiroaki Akamatsu; Kazuo Nakagawa; Yasuhisa Ohde; Takehiro Okumura; Haruyasu Murakami; Asuka Tsuya; Yukiko Nakamura; Tateaki Naito; Haruhiko Kondo; Takashi Nakajima; Masahiro Endo; Nobuyuki Yamamoto
    ONCOLOGY REPORTS 24 4 861 - 867 2010年10月 [査読有り]
     
    CD98 has been associated with tumor growth and is highly expressed in human neoplasms. The aim of this study was to evaluate the clinicopathological significance of CD98 expression in thymic epithelial tumors. Forty-nine patients with thymic epithelial tumors were included in this study. Tumor sections were stained by immunohistochemistry for CD98; vascular endothelial growth factor (VEGF); microvessels (CD31 and CD34); cell cycle control marker (p53); and apoptosis marker (Bcl-2). CD98 expression for low-risk thymomas, high-risk thymomas, and thymic carcinomas were 1 (4%) of 27, 9 (82%) of 11, and 11 (100%) of 11, respectively. There was positive correlation between CD98 and VEGF (p<0.001), microvessel density (CD31 and CD34) (p<0.001) and p53 (p<0.001). However, Bcl-2 showed no positive correlation with CD98 expression. The expression of CD98 were also significantly associated with the grade of malignancy in thymic epithelial tumors. Multivariate analysis revealed that overexpression of CD98 was a significant independent factor predicting a poor outcome in thymic epithelial tumors. CD98 expression was associated with the grade of malignancy in thymic epithelial tumors. Moreover, CD98 expression was closely correlated with angiogenesis and cell cycle control, and was useful for predicting poor outcome.
  • Azuma K; Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 68 10 1848 - 1853 2010年10月 [査読有り]
  • Isamu Okamoto; Hiroyasu Kaneda; Taroh Satoh; Wataru Okamoto; Masaki Miyazaki; Ryotaro Morinaga; Shinya Ueda; Masaaki Terashima; Asuka Tsuya; Akiko Sarashina; Koichi Konishi; Tokuzo Arao; Kazuto Nishio; Rolf Kaiser; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 10 2825 - 2833 2010年10月 [査読有り]
     
    BIBF 1120 is an oral multitargeted tyrosine kinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) and other growth factor receptors. We have done a phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamic biomarkers of BIBF 1120. Patients with advanced refractory solid tumors were treated with BIBF 1120 at oral doses of 150 to 250 mg twice daily. Drug safety and pharmacokinetics were evaluated, as were baseline and post-treatment levels of circulating CD117-positive bone marrow-derived progenitor cells and plasma soluble VEGF receptor 2 as potential biomarkers for BIBF 1120. Twenty-one patients were treated at BIBF 1120 doses of 150 (n = 3), 200 (n = 12), or 250 mg twice daily (n = 6). Dose-limiting toxicities of reversible grade 3 or 4 elevations of liver enzymes occurred in 3 of 12 patients at 200 mg twice daily and 3 of 6 patients at 250 mg twice daily. Stable disease was achieved in 16 (76.2%) patients, and median progression-free survival was 113 days (95% confidence interval, 77-119 d). Pharmacokinetic analysis indicated that the maximum plasma concentration and area under the curve for BIBF 1120 increased with the dose within the dose range tested. Levels of CD117-positive bone marrow-derived progenitors and soluble VEGF receptor 2 decreased significantly during treatment over all BIBF 1120 dose cohorts. In conclusion, the maximum tolerated dose of BIBF 1120 in the current study was determined to be 200 mg twice daily, and our biomarker analysis indicated that this angiokinase inhibitor is biologically active. Mol Cancer Ther; 9(10); 2825-33. (C) 2010 AACR.
  • Wataru Okamoto; Isamu Okamoto; Kaoru Tanaka; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Haruka Yamaguchi; Tokuzo Arao; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Jaenne; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 10 2785 - 2792 2010年10月 [査読有り]
     
    Most non-small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKI) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827-HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827-HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, extracellular signal-regulated kinase, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK-701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation. Mol Cancer Ther; 9(10); 2785-92. (C) 2010 AACR.
  • Takayasu Kurata; Nobuyuki Yamamoto; Takefumi Komiya; Junji Tsurutani; Masaki Miyazaki; Kenji Tamura; Koji Takeda; Kazuhiko Nakagawa; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 10 992 - 994 2010年10月 [査読有り]
     
    A combination Phase I study of gemcitabine and irinotecan in patients with previously untreated advanced non-small-cell lung cancer was conducted. Patients received gemcitabine and irinotecan on Days 1 and 8 every 3 weeks. A total of 11 patients were enrolled. Three of six patients who received the starting dose (gemcitabine, 800 mg/m(2); irinotecan, 80 mg/m(2)) experienced dose-limiting toxicities (Grade 4 neutropenia, Grade 3 elevation of transaminase and Grade 5 interstitial pneumonia). At the reduced dose level (gemcitabine, 800 mg/m(2); irinotecan, 60 mg/m(2)), all two assessable patients could not meet the administration criteria of Day 8 (one, Grade 2 elevation of transaminase; the other, Grade 1 diarrhea). No objective response was observed in eight evaluable patients. We could not determine the recommended dose of this combination because of intolerable toxicities and no efficacy. Therefore, it is difficult to forward this combination chemotherapy toward further studies.
  • Hidetoshi Hayashi; Isamu Okamoto; Yasuko Ichikawa; Masaki Miyazaki; Hiroshige Yoshioka; Kei Kunimasa; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 15 5 497 - 499 2010年10月 [査読有り]
     
    Combination chemotherapy with cisplatin and pemetrexed is the most active first-line regimen for malignant pleural mesothelioma (MPM). However, no drugs have been approved for second-line treatment of MPM, with effective regimens remaining to be identified for patients in relapse. We have now evaluated the combination of cisplatin and pemetrexed for retreatment of patients with recurrent MPM. Four men with MPM, all of whom received initial treatment with cisplatin and pemetrexed, underwent retreatment with this drug combination. Two of the patients achieved an objective response to the first-line chemotherapy with no evidence of disease progression for 6.4 or 11.4 months, respectively. The other two patients had stable disease with a duration of 7.8 or 5.0 months, respectively. The two patients who showed an objective response to first-line chemotherapy showed a partial response to retreatment, with a time to progression of 5.0 or 8.2 months, whereas the other two patients had progressive disease with a time to progression of 1.0 or 1.4 months, respectively. Retreatment with cisplatin plus pemetrexed was generally well tolerated. Retreatment with cisplatin and pemetrexed is a potential therapeutic option for certain patients with recurrent epithelioid MPM, possibly including those who show tumor regression with a time to progression of 6 months or more after the initial chemotherapy. Further studies are warranted to evaluate the efficacy of such retreatment and to clarify the criteria for patient selection.
  • Takayasu Kurata; Nobuyuki Yamamoto; Takefumi Komiya; Junji Tsurutani; Masaki Miyazaki; Kenji Tamura; Koji Takeda; Kazuhiko Nakagawa; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 10 992 - 994 2010年10月 [査読有り]
     
    A combination Phase I study of gemcitabine and irinotecan in patients with previously untreated advanced non-small-cell lung cancer was conducted. Patients received gemcitabine and irinotecan on Days 1 and 8 every 3 weeks. A total of 11 patients were enrolled. Three of six patients who received the starting dose (gemcitabine, 800 mg/m(2); irinotecan, 80 mg/m(2)) experienced dose-limiting toxicities (Grade 4 neutropenia, Grade 3 elevation of transaminase and Grade 5 interstitial pneumonia). At the reduced dose level (gemcitabine, 800 mg/m(2); irinotecan, 60 mg/m(2)), all two assessable patients could not meet the administration criteria of Day 8 (one, Grade 2 elevation of transaminase; the other, Grade 1 diarrhea). No objective response was observed in eight evaluable patients. We could not determine the recommended dose of this combination because of intolerable toxicities and no efficacy. Therefore, it is difficult to forward this combination chemotherapy toward further studies.
  • Isamu Okamoto; Hiroyasu Kaneda; Taroh Satoh; Wataru Okamoto; Masaki Miyazaki; Ryotaro Morinaga; Shinya Ueda; Masaaki Terashima; Asuka Tsuya; Akiko Sarashina; Koichi Konishi; Tokuzo Arao; Kazuto Nishio; Rolf Kaiser; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 10 2825 - 2833 2010年10月 [査読有り]
     
    BIBF 1120 is an oral multitargeted tyrosine kinase inhibitor that blocks the activity of vascular endothelial growth factor (VEGF) and other growth factor receptors. We have done a phase I study to evaluate the safety, pharmacokinetics, and pharmacodynamic biomarkers of BIBF 1120. Patients with advanced refractory solid tumors were treated with BIBF 1120 at oral doses of 150 to 250 mg twice daily. Drug safety and pharmacokinetics were evaluated, as were baseline and post-treatment levels of circulating CD117-positive bone marrow-derived progenitor cells and plasma soluble VEGF receptor 2 as potential biomarkers for BIBF 1120. Twenty-one patients were treated at BIBF 1120 doses of 150 (n = 3), 200 (n = 12), or 250 mg twice daily (n = 6). Dose-limiting toxicities of reversible grade 3 or 4 elevations of liver enzymes occurred in 3 of 12 patients at 200 mg twice daily and 3 of 6 patients at 250 mg twice daily. Stable disease was achieved in 16 (76.2%) patients, and median progression-free survival was 113 days (95% confidence interval, 77-119 d). Pharmacokinetic analysis indicated that the maximum plasma concentration and area under the curve for BIBF 1120 increased with the dose within the dose range tested. Levels of CD117-positive bone marrow-derived progenitors and soluble VEGF receptor 2 decreased significantly during treatment over all BIBF 1120 dose cohorts. In conclusion, the maximum tolerated dose of BIBF 1120 in the current study was determined to be 200 mg twice daily, and our biomarker analysis indicated that this angiokinase inhibitor is biologically active. Mol Cancer Ther; 9(10); 2825-33. (C) 2010 AACR.
  • Wataru Okamoto; Isamu Okamoto; Kaoru Tanaka; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Haruka Yamaguchi; Tokuzo Arao; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Jaenne; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 10 2785 - 2792 2010年10月 [査読有り]
     
    Most non-small cell lung cancer (NSCLC) tumors with an activating mutation of the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (TKI) such as gefitinib but ultimately develop resistance to these drugs. Hepatocyte growth factor (HGF) induces EGFR-TKI resistance in NSCLC cells with such a mutation. We investigated strategies to overcome gefitinib resistance induced by HGF. Human NSCLC cells with an activating EGFR mutation (HCC827 cells) were engineered to stably express HGF (HCC827-HGF cells). HCC827-HGF cells secreted large amounts of HGF and exhibited resistance to gefitinib in vitro to an extent similar to that of HCC827 GR cells, in which the gene for the HGF receptor MET is amplified. A MET-TKI reversed gefitinib resistance in HCC827-HGF cells as well as in HCC827 GR cells, suggesting that MET activation induces gefitinib resistance in both cell lines. TAK-701, a humanized monoclonal antibody to HGF, in combination with gefitinib inhibited the phosphorylation of MET, EGFR, extracellular signal-regulated kinase, and AKT in HCC827-HGF cells, resulting in suppression of cell growth and indicating that autocrine HGF-MET signaling contributes to gefitinib resistance in these cells. Combination therapy with TAK-701 and gefitinib also markedly inhibited the growth of HCC827-HGF tumors in vivo. The addition of TAK-701 to gefitinib is a promising strategy to overcome EGFR-TKI resistance induced by HGF in NSCLC with an activating EGFR mutation. Mol Cancer Ther; 9(10); 2785-92. (C) 2010 AACR.
  • Takehito Shukuya; Toshiaki Takahashi; Akihiro Tamiya; Akira Ono; Satoshi Igawa; Yukiko Nakamura; Asuka Tsuya; Haruyasu Murakami; Masahiro Endo; Yasuhisa Ohde; Kazuo Nakagawa; Takehiro Okumura; Haruhiko Kondo; Nobuyuki Yamamoto
    MEDICAL ONCOLOGY 27 3 932 - 937 2010年09月 [査読有り]
     
    Adjuvant chemotherapy improves the prognosis of patients with non-small-cell lung cancer (NSCLC) treated by complete resection. At Shizuoka Cancer Center, thoracic surgeons evaluate the indications for adjuvant chemotherapy, and once a patient is judged as suitable for adjuvant chemotherapy, uracil-tegafur (UFT) is prescribed by them mainly in cases of stage TB, or the patient is referred to a medical oncologist for parenteral chemotherapy mainly in cases of stages IIA to IIIA. However, both the medical oncologists and the surgeons at our institute often encounter differences in attitudes toward adjuvant chemotherapy among them. One hundred and nine patients with NSCLC, of pathological stages IB to IIIA, who underwent complete resection at our institute, between April 2005 and June 2007, were recruited for this study. By reviewing medical charts of the patients and interviewing medical oncologists and surgeons at our institute, we mainly analyzed the differences in the judgment of the patients' suitability for adjuvant chemotherapy among surgeons and the differences in the proportion of patients who agreed to the adjuvant chemotherapy recommended by the medical oncologists. The proportion of patients judged as unsuitable for adjuvant chemotherapy by one surgeon was higher when compared with that by the other three surgeons. While all patients who were referred to two medical oncologists agreed to the adjuvant chemotherapy, few patients referred to the other medical oncologists agreed. This study revealed that there were considerable differences in whether patients consented to adjuvant chemotherapy depending on the medical oncologists that they were referred to, and suggested possible differences in the judgment of the patients' suitability for adjuvant chemotherapy among surgeons.
  • Mutsumi Fujii; Kazuhiko Nakagawa; Hiroki Tomita; Osamu Tone; Masashi Tamaki; Yoshiaki Takada; Mitsuhiko Hokari; Tadashi Nariai; Kikuo Ohno
    JOURNAL OF CLINICAL NEUROSCIENCE 17 9 1136 - 1139 2010年09月 [査読有り]
     
    Whether the intentional antihypertensive therapy recommended by the American Heart Association/American Stroke Association (AHA/ASA) guidelines has clinical benefit for patients who have acute spontaneous intracerebral hemorrhage (ICH) has yet to be proven. We retrospectively reviewed the clinical charts of 175 patients with putaminal or thalamic ICH with acute hypertension to examine the correlation between the efficacy of antihypertensive therapy within 3 hours of onset, hematoma expansion (HE) after hospitalization and clinical outcome. The aim of the antihypertensive therapy was to achieve and maintain a systolic blood pressure of 120 mm Hg to 160 mm Hg until the second CT scan. The mean arterial pressure (MAP) after admission was the average MAP values measured every hour for the first 3 hours of hospitalization or until the second CT scan, if this was performed within the same timeframe. Thirtytwo (18.3%) patients were found to have HE. Prior to the second CT scan, antihypertensive medications were administered to all patients without any major complications. A multiple logistic regression analysis revealed that a MAP of >110 mm Hg after admission was the only variable independently associated with HE (odds ratio [OR] = 3.455; 95% confidence interval [CI] = 1.510-8.412; p = 0.004). Modified Rankin Scale scores of <= 3 on day 30 were significantly more common in those patients without HE (p = 0.002). Our findings suggest that there are clinical benefits, by the prevention of subsequent HE, in maintaining a MAP level lower than that recommended by the AHA/ASA (110 mm Hg) after hospitalization for patients who have ICH. (C) 2010 Elsevier Ltd. All rights reserved.
  • Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yasumasa Nishimura; Kayoko Tsujino; Miyako Satouchi; Shinzoh Kudo; Toyoaki Hida; Masaaki Kawahara; Koji Takeda; Nobuyuki Katakami; Toshiyuki Sawa; Soichiro Yokota; Takashi Seto; Fumio Imamura; Hideo Saka; Yasuo Iwamoto; Hiroshi Semba; Yasutaka Chiba; Hisao Uejima; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 28 23 3739 - 3745 2010年08月 [査読有り]
     
    Purpose This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). Patients and Methods Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m2 on day1)/carboplatin (AUC 5 on day 1). Results The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. Conclusion Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC. J Clin Oncol 28: 3739-3745. (C) 2010 by American Society of Clinical Oncology
  • 抗癌剤治療における血液毒性の人種差 非小細胞肺癌抗がん剤治療の系統的レビュー
    長谷川 喜一; 高田 實; 川口 知哉; 伊佐 俊一; 辻 泰佑; 久保 昭仁; 安藤 昌彦; 白石 順二; 辻野 和之; 中川 和彦
    肺癌 50 4 398 - 398 (NPO)日本肺癌学会 2010年08月
  • 分子標的治療 肺癌癌性胸膜炎におけるゲフィチニブの薬物動態・薬力学・臨床第II相試験(Molecular target therapy Pharmacokinetics, pharmacodynamics (PK/PD) and phase II study of gefitinib on malignant pleural effusion of lung)
    久保 昭仁; 洪 泰浩; 福岡 順也; 安藤 昌彦; 川口 知哉; 岡本 勇; 北市 正則; 安宅 信二; 河原 正明; 楠 洋子; 山口 悦郎; 高田 實; 中川 和彦
    日本癌学会総会記事 69回 274 - 274 2010年08月
  • 男性潜在性乳癌の皮膚転移と考えられた1例
    平尾 文香; 大磯 直毅; 川原 繁; 川田 暁; 鶴谷 純司; 中川 和彦; 綿谷 正弘
    皮膚の科学 9 4 401 - 401 日本皮膚科学会-大阪地方会・京滋地方会 2010年08月
  • Kaira K; Endo M; Abe M; Nakagawa K; Ohde Y; Okumura T; Takahashi T; Murakami H; Tsuya A; Nakamura Y; Naito T; Hayashi I; Serizawa M; Koh Y; Hanaoka H; Tominaga H; Oriuchi N; Kondo H; Nakajima T; Yamamoto N
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 28 23 3746 - 3753 2010年08月 [査読有り]
  • Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yasumasa Nishimura; Kayoko Tsujino; Miyako Satouchi; Shinzoh Kudo; Toyoaki Hida; Masaaki Kawahara; Koji Takeda; Nobuyuki Katakami; Toshiyuki Sawa; Soichiro Yokota; Takashi Seto; Fumio Imamura; Hideo Saka; Yasuo Iwamoto; Hiroshi Semba; Yasutaka Chiba; Hisao Uejima; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 28 23 3739 - 3745 2010年08月 [査読有り]
     
    Purpose This phase III trial of concurrent thoracic radiotherapy (TRT) was conducted to compare third-generation chemotherapy with second-generation chemotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). Patients and Methods Eligible patients received the following treatments: A (control), four cycles of mitomycin (8 mg/m(2) on day 1)/vindesine (3 mg/m(2) on days 1, 8)/cisplatin (80 mg/m(2) on day 1) plus TRT 60 Gy (treatment break for 1 week); B, weekly irinotecan (20 mg/m(2))/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200 mg/m2 on day1)/carboplatin (AUC 5 on day 1). Results The median survival time and 5-year survival rates were 20.5, 19.8, and 22.0 months and 17.5%, 17.8%, and 19.8% in arms A, B, and C, respectively. Although no significant differences in overall survival were apparent among the treatment arms, noninferiority of the experimental arms was not achieved. The incidences of grade 3 to 4 neutropenia, febrile neutropenia, and gastrointestinal disorder were significantly higher in arm A than in arm B or C (P < .001). Chemotherapy interruptions were more common in arm B than in arm A or C. Conclusion Arm C was equally efficacious and exhibited a more favorable toxicity profile among three arms. Arm C should be considered a standard regimen in the management of locally advanced unresectable NSCLC. J Clin Oncol 28: 3739-3745. (C) 2010 by American Society of Clinical Oncology
  • 中川 和彦; 清田 秀美
    日本内科学会雑誌 99 7 1605 - 1610 The Japanese Society of Internal Medicine 2010年07月 
    血管新生は癌の悪性化に大きな役割を果たすことが知られており，近年様々な血管新生阻害剤の開発が進んでいる．ベバシズマブは血管内皮増殖因子（vascular endothelial growth factor：VEGF）に対する中和抗体で，非小細胞肺癌に対して2つの第III相比較試験で化学療法との上乗せ効果を示した唯一の薬剤である．進行・再発結腸直腸癌に続いて2009年11月に本邦で承認を受けた．すでに海外のガイドラインで推奨されており新たな標準治療となる薬剤として注目されている．
  • Masashi Kobayashi; Kaoru Matsui; Yasuo Iwamoto; Noriyuki Ebi; Satoshi Oizumi; Koji Takeda; Toshiyuki Sawa; Kazuhiko Shibata; Hideo Saka; Fumio Imamura; Nobuhiko Seki; Hiroshi Saito; Isao Goto; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 7 1075 - 1080 2010年07月 [査読有り]
     
    Introduction: Combination chemotherapy of irinotecan, a topoisomerase I inhibitor, and cisplatin is a standard treatment in patients with extensive-stage small cell lung cancer (SCLC). Amrubicin, a novel 9-aminoanthracycline, inhibits topoisomerase II. We investigated a sequential triplet chemotherapy consisting of irinotecan and cisplatin followed by amrubicin in patients with extensive-stage SCLC. Methods: Eligible patients were aged 20 to 70 years and had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable lesions, and adequate organ functions. Chemotherapy consisted of irinotecan 60 mg/m(2) on days 1 and 8 plus cisplatin 60 mg/m(2) on day 1 every 3 weeks for three cycles and then amrubicin 40 mg/m(2) alone on days 1 to 3 every 3 weeks for three cycles. Results: From September 2004 to September 2006, 45 patients were enrolled, 43 were evaluable for response and survival, and 44 were evaluable for toxicity. Twenty-eight patients (64%) completed the full planned chemotherapy. One patient achieved complete response and 33 had partial response for an overall response rate of 79%. Median progression-free survival was 6.5 months. Median overall survival was 15.4 months. Major toxicity was myelosuppression. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia occurred in 57%, 7%, 0%, and 7% of patients during irinotecan/cisplatin cycles and in 91%, 27%, 9%, and 15% of patients during amrubicin cycles, respectively. Conclusions: The sequential triplet chemotherapy, irinotecan and cisplatin followed by amrubicin, is an effective and well-tolerated treatment in patients with extensive-stage SCLC. Further investigation of this treatment is warranted.
  • Noriyuki Masuda; Kaoru Matsui; Shunichi Negoro; Koji Takeda; Shinzoh Kudoh; Kazuhiko Nakagawa; Akihira Mukaiyama; Hiroaki Arase; Pascal Yoshida; Toshiyuki Ijima; Minoru Takada; Masahiro Fukuoka
    CLINICAL LUNG CANCER 11 4 271 - 279 2010年07月 [査読有り]
     
    Purpose: We conducted a phase I trial of the topoisomerase I inhibitor topotecan for the purpose of determining the maximum tolerated dose (MID) and the dose-limiting toxicities (DLTs) of topotecan when administered weekly to patients with advanced non small-cell lung cancer Patients and Methods: Twelve patients with stage IIIB or IV disease were treated with topotecan by 30-minute intravenous infusion on days 1, 8, and 15 every 4 weeks The dose was escalated in 2-mg/m(2) increments from the starting dose of 4 mg/m(2) until the MID was reached After the MID had been reached in previously treated patients, chemotherapy-naive patients were enrolled for treatment at that dose, and the dose was escalated to estimate the MID in the treatment-naive group Results: The MTD of topotecan was determined to be 6 mg/m(2) in the previously treated group and 8 mg/m(2) in the chemotherapy-naive group. All 3 previously treated patients experienced DLT at the 6-mg/m(2) dose level. Although only 1 of the 3 previously treated patients experienced DLT (grade 4 neutropenia for >= 3 days) at the 8-mg/m(2) dose level, skipping the topotecan dose on day 15 because of neutropenia was reported in 2 patients. Anorexia and general fatigue were the common nonhematologic toxicities. Conclusion: The recommended dose of topotecan for phase II studies in previously untreated patients is 6 mg/m(2) on days 1, 8, and 15, every 28 days, and 4 mg/m(2) appears to be a suitable dose for use in previously treated patients with this schedule
  • Masayuki Takeda; Isamu Okamoto; Chihiro Makimura; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 7 1103 - 1104 2010年07月 [査読有り]
  • Masashi Kobayashi; Kaoru Matsui; Yasuo Iwamoto; Noriyuki Ebi; Satoshi Oizumi; Koji Takeda; Toshiyuki Sawa; Kazuhiko Shibata; Hideo Saka; Fumio Imamura; Nobuhiko Seki; Hiroshi Saito; Isao Goto; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 7 1075 - 1080 2010年07月 [査読有り]
     
    Introduction: Combination chemotherapy of irinotecan, a topoisomerase I inhibitor, and cisplatin is a standard treatment in patients with extensive-stage small cell lung cancer (SCLC). Amrubicin, a novel 9-aminoanthracycline, inhibits topoisomerase II. We investigated a sequential triplet chemotherapy consisting of irinotecan and cisplatin followed by amrubicin in patients with extensive-stage SCLC. Methods: Eligible patients were aged 20 to 70 years and had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable lesions, and adequate organ functions. Chemotherapy consisted of irinotecan 60 mg/m(2) on days 1 and 8 plus cisplatin 60 mg/m(2) on day 1 every 3 weeks for three cycles and then amrubicin 40 mg/m(2) alone on days 1 to 3 every 3 weeks for three cycles. Results: From September 2004 to September 2006, 45 patients were enrolled, 43 were evaluable for response and survival, and 44 were evaluable for toxicity. Twenty-eight patients (64%) completed the full planned chemotherapy. One patient achieved complete response and 33 had partial response for an overall response rate of 79%. Median progression-free survival was 6.5 months. Median overall survival was 15.4 months. Major toxicity was myelosuppression. Grade 3 or 4 neutropenia, anemia, thrombocytopenia, and febrile neutropenia occurred in 57%, 7%, 0%, and 7% of patients during irinotecan/cisplatin cycles and in 91%, 27%, 9%, and 15% of patients during amrubicin cycles, respectively. Conclusions: The sequential triplet chemotherapy, irinotecan and cisplatin followed by amrubicin, is an effective and well-tolerated treatment in patients with extensive-stage SCLC. Further investigation of this treatment is warranted.
  • Masayuki Takeda; Isamu Okamoto; Chihiro Makimura; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 7 1103 - 1104 2010年07月 [査読有り]
  • Noriyuki Masuda; Kaoru Matsui; Shunichi Negoro; Koji Takeda; Shinzoh Kudoh; Kazuhiko Nakagawa; Akihira Mukaiyama; Hiroaki Arase; Pascal Yoshida; Toshiyuki Ijima; Minoru Takada; Masahiro Fukuoka
    CLINICAL LUNG CANCER 11 4 271 - 279 2010年07月 [査読有り]
     
    Purpose: We conducted a phase I trial of the topoisomerase I inhibitor topotecan for the purpose of determining the maximum tolerated dose (MID) and the dose-limiting toxicities (DLTs) of topotecan when administered weekly to patients with advanced non small-cell lung cancer Patients and Methods: Twelve patients with stage IIIB or IV disease were treated with topotecan by 30-minute intravenous infusion on days 1, 8, and 15 every 4 weeks The dose was escalated in 2-mg/m(2) increments from the starting dose of 4 mg/m(2) until the MID was reached After the MID had been reached in previously treated patients, chemotherapy-naive patients were enrolled for treatment at that dose, and the dose was escalated to estimate the MID in the treatment-naive group Results: The MTD of topotecan was determined to be 6 mg/m(2) in the previously treated group and 8 mg/m(2) in the chemotherapy-naive group. All 3 previously treated patients experienced DLT at the 6-mg/m(2) dose level. Although only 1 of the 3 previously treated patients experienced DLT (grade 4 neutropenia for >= 3 days) at the 8-mg/m(2) dose level, skipping the topotecan dose on day 15 because of neutropenia was reported in 2 patients. Anorexia and general fatigue were the common nonhematologic toxicities. Conclusion: The recommended dose of topotecan for phase II studies in previously untreated patients is 6 mg/m(2) on days 1, 8, and 15, every 28 days, and 4 mg/m(2) appears to be a suitable dose for use in previously treated patients with this schedule
  • K. Takezawa; I. Okamoto; S. Tsukioka; J. Uchida; M. Kiniwa; M. Fukuoka; K. Nakagawa
    BRITISH JOURNAL OF CANCER 103 3 354 - 361 2010年07月 [査読有り]
     
    BACKGROUND: Thymidylate synthase (TS), a key enzyme in the de novo synthesis of thymidine, is an important chemotherapeutic target for malignant tumours including lung cancer. Although inhibition of TS has an antiproliferative effect in cancer cells, the precise mechanism of this effect has remained unclear. METHODS: We examined the effects of TS inhibition with an RNA interference-based approach. The effect of TS depletion on the growth of lung cancer cells was examined using colorimetric assay and flow cytometry. RESULTS: Measurement of the enzymatic activity of TS in 30 human lung cancer cell lines revealed that such activity differs among tumour histotypes. Almost complete elimination of TS activity by RNA interference resulted in inhibition of cell proliferation in all tested cell lines, suggestive of a pivotal role for TS in cell proliferation independent of the original level of enzyme activity. The antiproliferative effect of TS depletion was accompanied by arrest of cells in S phase of the cell cycle and the induction of caspase-dependent apoptosis as well as by changes in the expression levels of cyclin E and c-Myc. Moreover, TS depletion induced downregulation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP), and it seemed to activate the mitochondrial pathway of apoptosis. CONCLUSION: Our data provide insight into the biological relevance of TS as well as a basis for clinical development of TS-targeted therapy for lung cancer. British Journal of Cancer (2010) 103, 354-361. doi:10.1038/sj.bjc.6605793 www.bjcancer.com Published online 13 July 2010 (C) 2010 Cancer Research UK
  • Ken Takezawa; Isamu Okamoto; Junko Tanizaki; Kiyoko Kuwata; Haruka Yamaguchi; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 6 1647 - 1656 2010年06月 [査読有り]
     
    Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647-56. (C)2010 AACR.
  • Masayuki Takeda; Isamu Okamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 28 17 E273 - E274 2010年06月 [査読有り]
  • Masayuki Takeda; Isamu Okamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF CLINICAL ONCOLOGY 28 17 E273 - E274 2010年06月 [査読有り]
  • Ken Takezawa; Isamu Okamoto; Junko Tanizaki; Kiyoko Kuwata; Haruka Yamaguchi; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 6 1647 - 1656 2010年06月 [査読有り]
     
    Most non-small cell lung cancer (NSCLC) tumors with activating mutations of the epidermal growth factor receptor (EGFR) are initially responsive to first-generation, reversible EGFR tyrosine kinase inhibitors (TKI) such as gefitinib, but they subsequently develop resistance to these drugs through either acquisition of an additional T790M mutation of EGFR or amplification of the proto-oncogene MET. We have now investigated the effects of combination treatment with thymidylate synthase (TS)-targeting drugs and the second-generation, irreversible EGFR-TKI BIBW2992 on the growth of NSCLC cells with the T790M mutation. The effects of BIBW2992 on EGFR signaling and TS expression in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of BIBW2992 and the TS-targeting agents S-1 (or 5-fluorouracil) or pemetrexed on the growth of gefitinib-resistant NSCLC cells were examined both in vitro and in vivo. The combination of BIBW2992 with 5-fluorouracil or pemetrexed synergistically inhibited the proliferation of NSCLC cells with the T790M mutation in vitro, whereas an antagonistic interaction was apparent in this regard between gefitinib and either of these TS-targeting agents. BIBW2992 induced downregulation of TS in the gefitinib-resistant NSCLC cells, implicating depletion of TS in the enhanced antitumor effect of the combination therapy. The combination of BIBW2992 and either the oral fluoropyrimidine S-1 or pemetrexed also inhibited the growth of NSCLC xenografts with the T790M mutation to an extent greater than that apparent with either agent alone. The addition of TS-targeting drugs to BIBW2992 is a promising strategy to overcome EGFR-TKI resistance in NSCLC with the T790M mutation of EGFR. Mol Cancer Ther; 9(6); 1647-56. (C)2010 AACR.
  • T. Iwasa; I. Okamoto; K. Takezawa; K. Yamanaka; T. Nakahara; A. Kita; H. Koutoku; M. Sasamata; E. Hatashita; Y. Yamada; K. Kuwata; M. Fukuoka; K. Nakagawa
    BRITISH JOURNAL OF CANCER 103 1 36 - 42 2010年06月 [査読有り]
     
    BACKGROUND: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effects of the combination of YM155, a novel small-molecule inhibitor of survivin expression, and platinum compounds (cisplatin and carboplatin) on human non-small cell lung cancer (NSCLC) cell lines. METHODS: The anti-cancer efficacy of YM155 in combination with platinum compounds was evaluated on the basis of cell death and progression of tumour xenografts. Platinum compound-induced DNA damage was evaluated by immunofluorescence analysis of histone gamma-H2AX. RESULTS: Immunofluorescence analysis of histone g-H2AX showed that YM155 delayed the repair of double-strand breaks induced in nuclear DNA by platinum compounds. The combination of YM155 and platinum compounds also induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Finally, combination therapy with YM155 and platinum compounds delayed the growth of NSCLC tumour xenografts in nude mice to an extent greater than that apparent with either treatment modality alone. CONCLUSION: These results suggest that YM155 sensitises tumour cells to platinum compounds both in vitro and in vivo, and that this effect is likely attributable to the inhibition of DNA repair and consequent enhancement of apoptosis. British Journal of Cancer (2010) 103, 36-42. doi:10.1038/sj.bjc.6605713 www.bjcancer.com Published online 1 June 2010 (C) 2010 Cancer Research UK
  • H. Kunitoh; T. Tamura; T. Shibata; K. Takeda; N. Katakami; K. Nakagawa; A. Yokoyama; Y. Nishiwaki; K. Noda; K. Watanabe; N. Saijo
    BRITISH JOURNAL OF CANCER 103 1 6 - 11 2010年06月 [査読有り]
     
    BACKGROUND: This study aimed to evaluate the safety and efficacy of dose-dense weekly chemotherapy, followed by resection and/or thoracic radiotherapy. METHODS: Patients with histologically documented thymoma with unresectable stage III disease received 9 weeks of chemotherapy: cisplatin 25 mgm(-2) on weeks 1-9; vincristine 1 mgm(-2) on weeks 1, 2, 4, 6 and 8; and doxorubicin 40 mgm(-2) and etoposide 80 mgm(-2) on days 1-3 of weeks 1, 3, 5, 7 and 9. Patients went on to surgery and post-operative radiotherapy of 48 Gy; those with unresectable disease received 60 Gy radiotherapy. RESULTS: A total of 23 patients were entered. The main toxicities of the chemotherapy regimen were neutropenia and anaemia, and 57% of patients completed the planned 9 weeks of therapy. There were no toxic deaths. Of the 21 eligible patients, 13 (62%) achieved a partial response (95% confidence interval: 38-82%). Thirteen patients underwent a thoracotomy and nine (39%) underwent complete resection. Progression-free survival at 2 and 5 years was 80 and 43%, respectively. Overall survival at 5 and 8 years was 85 and 69%, respectively. Survival did not seem to be affected by resection. CONCLUSION: In thymoma patients, weekly dose-dense chemotherapy has activity similar to that of conventional regimens. Although some patients could achieve complete resection, the role of surgery remains unclear. British Journal of Cancer (2010) 103, 6-11. doi:10.1038/sj.bjc.6605731 www.bjcancer.com Published online 15 June 2010 (C) 2010 Cancer Research UK
  • Wataru Okamoto; Isamu Okamoto; Takeshi Yoshida; Kunio Okamoto; Ken Takezawa; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Tokuzo Arao; Kazuyoshi Yanagihara; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 5 1188 - 1197 2010年05月 [査読有り]
     
    Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188-97. (C) 2010 AACR.
  • Junko Tanizaki; Isamu Okamoto; Ken Takezawa; Sayaka Tsukioka; Junji Uchida; Mamoru Kiniwa; Masahiro Fukuoka; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 5 1198 - 1207 2010年05月 [査読有り]
     
    Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 20% to 30% of gastric cancers and is associated with a poor outcome. Combination therapies with HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for gastric cancer with HER2 amplification. We have now investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the HER2-targeting agents lapatinib or trastuzumab in gastric cancer cells with or without HER2 amplification. We used 5-fluorouracil (5FU) instead of S-1 for in vitro experiments, given that tegafur, a component of S-1, is metabolized to 5FU in the liver. The combination of 5FU and HER2-targeting agents synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in gastric cancer cells with HER2 amplification, but not in those without it. Lapatinib or trastuzumab also induced downregulation of thymidylate synthase (TS) expression and activity only in cells with HER2 amplification. The combination of 5FU and TS depletion by RNA interference also exhibited an enhanced proapoptotic effect in cells with HER2 amplification. These observations thus suggest that lapatinib-induced or trastuzumab-induced downregulation of TS is responsible, at least in part, for the synergistic antitumor effect of combined treatment with 5FU and HER2-targeting agents. The antitumor effect of the combination of S-1 and HER2-targeting agents in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and HER2-targeting agents is a promising treatment option for gastric cancer with HER2 amplification. Mol Cancer Ther; 9(5); 1198-207. (C) 2010 AACR.
  • Kaoru Kubota; Hiroshi Sakai; Nobuyuki Yamamoto; Hideo Kunitoh; Kazuhiko Nakagawa; Koji Takeda; Yukito Ichinose; Nagahiro Saijo; Yutaka Ariyoshi; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 5 5 702 - 706 2010年05月 [査読有り]
     
    Introduction: To determine the dose-limiting toxicity and recommended dose (RD) of cisplatin (CDDP) combined with S-1 (tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate) for patients with non-small cell lung cancer and to evaluate efficacy and toxicity of this regimen at RD. Methods: Patients with stages III and IV non-small cell lung cancer received 3-week cycles of treatment, each consisting of oral administration of S-1 at 80 mg/m(2) in 2 divided doses per day for 14 consecutive days, intravenous administration of CDDP (60 mg/m(2), 70 mg/m(2), or 80 mg/m(2)) on the first day, and no medication during the subsequent 7 days. The primary objective of phase I study was to estimate the maximum tolerable dose and the RD, and the primary end point of phase II study was response. Results: RD of CDDP in the analysis of 18 eligible patients was 60 mg/m(2). Evaluation of efficacy and toxicity at RD in 55 eligible patients showed that partial response was observed in 18 patients (32.7%, 95% confidence interval: 20.7-46.7%). The median survival time was 18.1 months, and the time to disease progression was 3.8 months. Grade 3 or severer adverse events were observed in 27 patients (49.1%). Conclusions: CDDP combined with S-1 showed a satisfactory overall survival time and acceptable toxicity profile. However, the response as the primary end point did not reach the predetermined threshold level.
  • Kaoru Kubota; Hiroshi Sakai; Nobuyuki Yamamoto; Hideo Kunitoh; Kazuhiko Nakagawa; Koji Takeda; Yukito Ichinose; Nagahiro Saijo; Yutaka Ariyoshi; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 5 5 702 - 706 2010年05月 [査読有り]
     
    Introduction: To determine the dose-limiting toxicity and recommended dose (RD) of cisplatin (CDDP) combined with S-1 (tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate) for patients with non-small cell lung cancer and to evaluate efficacy and toxicity of this regimen at RD. Methods: Patients with stages III and IV non-small cell lung cancer received 3-week cycles of treatment, each consisting of oral administration of S-1 at 80 mg/m(2) in 2 divided doses per day for 14 consecutive days, intravenous administration of CDDP (60 mg/m(2), 70 mg/m(2), or 80 mg/m(2)) on the first day, and no medication during the subsequent 7 days. The primary objective of phase I study was to estimate the maximum tolerable dose and the RD, and the primary end point of phase II study was response. Results: RD of CDDP in the analysis of 18 eligible patients was 60 mg/m(2). Evaluation of efficacy and toxicity at RD in 55 eligible patients showed that partial response was observed in 18 patients (32.7%, 95% confidence interval: 20.7-46.7%). The median survival time was 18.1 months, and the time to disease progression was 3.8 months. Grade 3 or severer adverse events were observed in 27 patients (49.1%). Conclusions: CDDP combined with S-1 showed a satisfactory overall survival time and acceptable toxicity profile. However, the response as the primary end point did not reach the predetermined threshold level.
  • Wataru Okamoto; Isamu Okamoto; Takeshi Yoshida; Kunio Okamoto; Ken Takezawa; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Tokuzo Arao; Kazuyoshi Yanagihara; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 5 1188 - 1197 2010年05月 [査読有り]
     
    Therapeutic strategies that target c-Src hold promise for a wide variety of cancers. We have now investigated both the effects of dasatinib, which inhibits the activity of c-Src and several other kinases, on cell growth as well as the mechanism of dasatinib resistance in human gastric cancer cell lines. Immunoblot analysis revealed the activation of c-Src at various levels in most gastric cancer cell lines examined. Dasatinib inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) and induced G(1) arrest, as revealed by flow cytometry, in a subset of responsive cell lines. In other responsive cell lines, dasatinib inhibited both ERK and AKT phosphorylation and induced apoptosis, as revealed by an increase in caspase-3 activity and cleavage of poly(ADP-ribose) polymerase. Depletion of c-Src by RNA interference also induced G(1) arrest or apoptosis in dasatinib-responsive cell lines, indicating that the antiproliferative effect of dasatinib is attributable to c-Src inhibition. Gastric cancer cell lines positive for the activation of MET were resistant to dasatinib. Dasatinib had no effect on ERK or AKT signaling, whereas the MET inhibitor PHA-665752 induced apoptosis in these cells. The subsets of gastric cancer cells defined by a response to c-Src or MET inhibitors were distinct and nonoverlapping. Our results suggest that c-Src is a promising target for the treatment of gastric cancer and that analysis of MET amplification might optimize patient selection for treatment with c-Src inhibitors. Mol Cancer Ther; 9(5); 1188-97. (C) 2010 AACR.
  • Junko Tanizaki; Isamu Okamoto; Ken Takezawa; Sayaka Tsukioka; Junji Uchida; Mamoru Kiniwa; Masahiro Fukuoka; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 9 5 1198 - 1207 2010年05月 [査読有り]
     
    Amplification of human epidermal growth factor receptor 2 (HER2) has been detected in 20% to 30% of gastric cancers and is associated with a poor outcome. Combination therapies with HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for gastric cancer with HER2 amplification. We have now investigated the effects of combination treatment with the oral fluoropyrimidine S-1 and the HER2-targeting agents lapatinib or trastuzumab in gastric cancer cells with or without HER2 amplification. We used 5-fluorouracil (5FU) instead of S-1 for in vitro experiments, given that tegafur, a component of S-1, is metabolized to 5FU in the liver. The combination of 5FU and HER2-targeting agents synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect in gastric cancer cells with HER2 amplification, but not in those without it. Lapatinib or trastuzumab also induced downregulation of thymidylate synthase (TS) expression and activity only in cells with HER2 amplification. The combination of 5FU and TS depletion by RNA interference also exhibited an enhanced proapoptotic effect in cells with HER2 amplification. These observations thus suggest that lapatinib-induced or trastuzumab-induced downregulation of TS is responsible, at least in part, for the synergistic antitumor effect of combined treatment with 5FU and HER2-targeting agents. The antitumor effect of the combination of S-1 and HER2-targeting agents in vivo was also greater than that of either drug alone. Our preclinical findings thus indicate that the combination of S-1 and HER2-targeting agents is a promising treatment option for gastric cancer with HER2 amplification. Mol Cancer Ther; 9(5); 1198-207. (C) 2010 AACR.
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Kazuko Sakai; Marco Antonio De Velasco; Kazuko Matsumoto; Fujita Yoshihiko; Yasuhide Yamada; Junji Tsurutani; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio; Tomoyuki Nagai; Kazuyuki Furuta
    CANCER RESEARCH 70 2010年04月 [査読有り]
  • Michiko Furugaito; Motohiro Imano; Tomoyo Kinboshi; Keisuke Yonemoto; Yumiko Takaie; Terumi Shimokawa; Mayumi Imoto; Yoshiyuki Morishima; Syouchi Naitou; Toshinori Kamisako; Megumi Nikake; Megumi Shichijyou; Kiyoko Matsubayashi; Masami Kado; Satoshi Hara; Kazuhiko Nakagawa; Yasumasa Nishimura; Kiyotaka Okuno; Hitoshi Shiozaki
    Japanese Journal of Cancer and Chemotherapy 37 3 555 - 558 2010年03月 [査読有り]
     
    As interprofessional work in cancer treatment becomes increasingly important, medical technologists are required to play active roles as part of the team. The cancer center of our hospital organized a lecture meeting, "The 6th Lecture Meeting: Living Together," for cancer patients and their families, and a medical technologist presented a lecture entitled: "Cancer treatment and clinical examinations." According to the results of a questionnaire survey conducted following the meeting, most participants were able to understand the lecture and were satisfied with it. Based on the opinions expressed by meeting participants and the questionnaire results, medical technologists initiate the following services and activities: Circled digit one They explain the results of white blood cell and neutrophil counts of patients on chemotherapy and/or radiation therapy and Circled digit two provide medical examinations and consultation at outpatient chemotherapy centers. We believe that these efforts will help improve cancer treatment and further contribute to interprofessional health care.
  • 平島 智徳; 光冨 徹哉; 浅見 和弘; 齋藤 博; 菓子井 達彦; 横山 彰仁; 森永 亮太郎; 山口 悦郎; 小谷 義一; 阿部 直; 伊達 洋至; 木村 弘; 中川 和彦
    日本呼吸器学会雑誌 48 増刊 112 - 112 (一社)日本呼吸器学会 2010年03月
  • 木村 達郎; 多田 弘人; 田中 正博; 片上 信之; 西村 恭昌; 光冨 徹哉; 里内 美弥子; 千場 博; 新海 哲; 坂 英雄; 中川 和彦
    日本呼吸器学会雑誌 48 増刊 129 - 129 (一社)日本呼吸器学会 2010年03月
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Kazuko Sakai; Marco A. De Velasco; Kazuko Matsumoto; Yoshihiko Fujita; Yasuhide Yamada; Junji Tsurutani; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 70 5 2053 - 2063 2010年03月 [査読有り]
     
    Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21(CIP1/WAF1) expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [ enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 +/- 301 versus 1735 +/- 769 mm(3), P < 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053-63. (C) 2010 AACR.
  • Isamu Okamoto; Masaki Munakata; Masaki Miyazaki; Taroh Satoh; Takenori Takahata; Yasushi Takamatsu; Osamu Muto; Kazuhiko Koike; Kunihiko Ishitani; Taketo Mukaiyama; Yuh Sakata; Kazuhiko Nakagawa; Kazuo Tamura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 3 222 - 226 2010年03月 [査読有り]
     
    Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH-IGF-1 axis in cancer patients. We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0-1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH-IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis. The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T-3 and T-4) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated. The present study suggests that the GH-IGF-1 axis is disturbed in patients with cancer.
  • Masayuki Takeda; Isamu Okamoto; Yoshihiko Fujita; Tokuzo Arao; Hiroyuki Ito; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 3 399 - 400 2010年03月 [査読有り]
     
    Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to treatment with EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, mechanisms of de novo resistance to these drugs in patients harboring EGFR mutations have remained unclear. We examined whether the mutational status of KRAS might be associated with primary resistance to EGFR-TKIs in EGFR mutation-positive patients with NSCLC. Methods: Forty patients with NSCLC with EGFR mutations who were treated with gefitinib or erlotinib and had archival tissue specimens available were enrolled in the study. KRAS mutations were analyzed by direct sequencing. Results: Three (7.5%) of the 40 patients had progressive disease, and two (67%) of these three individuals had both KRAS and EGFR mutations. Conclusions: Our results suggest that KRAS mutation is a negative predictor of response to EGFR-TKIs in EGFR mutation-positive patients with NSCLC.
  • Isamu Okamoto; Masaki Munakata; Masaki Miyazaki; Taroh Satoh; Takenori Takahata; Yasushi Takamatsu; Osamu Muto; Kazuhiko Koike; Kunihiko Ishitani; Taketo Mukaiyama; Yuh Sakata; Kazuhiko Nakagawa; Kazuo Tamura
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 3 222 - 226 2010年03月 [査読有り]
     
    Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH-IGF-1 axis in cancer patients. We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0-1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH-IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis. The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T-3 and T-4) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated. The present study suggests that the GH-IGF-1 axis is disturbed in patients with cancer.
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Kazuko Sakai; Marco A. De Velasco; Kazuko Matsumoto; Yoshihiko Fujita; Yasuhide Yamada; Junji Tsurutani; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 70 5 2053 - 2063 2010年03月 [査読有り]
     
    Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family, and it has recently been proposed to participate in gastric acid secretion and mucin gene expression in mice. However, the role of FOXQ1 in humans and especially in cancer cells remains unknown. We found that FOXQ1 mRNA is overexpressed in clinical specimens of colorectal cancer (CRC; 28-fold/colonic mucosa). A microarray analysis revealed that the knockdown of FOXQ1 using small interfering RNA resulted in a decrease in p21(CIP1/WAF1) expression, and a reporter assay and a chromatin immunoprecipitation assay showed that p21 was one of the target genes of FOXQ1. Stable FOXQ1-overexpressing cells (H1299/FOXQ1) exhibited elevated levels of p21 expression and inhibition of apoptosis induced by doxorubicin or camptothecin. Although cellular proliferation was decreased in H1299/FOXQ1 cells in vitro, H1299/FOXQ1 cells significantly increased tumorigenicity [ enhanced green fluorescent protein (EGFP): 2/15, FOXQ1: 7/15] and enhanced tumor growth (437 +/- 301 versus 1735 +/- 769 mm(3), P < 0.001) in vivo. Meanwhile, stable p21 knockdown of H1299/FOXQ1 cells increased tumor growth, suggesting that FOXQ1 promotes tumor growth independent of p21. Microarray analysis of H1299/EGFP and H1299/FOXQ1 revealed that FOXQ1 overexpression upregulated several genes that have positive roles for tumor growth, including VEGFA, WNT3A, RSPO2, and BCL11A. CD31 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining of the tumor specimens showed that FOXQ1 overexpression mediated the angiogenic and antiapoptotic effect in vivo. In conclusion, FOXQ1 is overexpressed in CRC and enhances tumorigenicity and tumor growth presumably through its angiogenic and antiapoptotic effects. Our findings show that FOXQ1 is a new member of the cancer-related FOX family. Cancer Res; 70(5); 2053-63. (C) 2010 AACR.
  • Masayuki Takeda; Isamu Okamoto; Yoshihiko Fujita; Tokuzo Arao; Hiroyuki Ito; Masahiro Fukuoka; Kazuto Nishio; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 3 399 - 400 2010年03月 [査読有り]
     
    Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to treatment with EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, mechanisms of de novo resistance to these drugs in patients harboring EGFR mutations have remained unclear. We examined whether the mutational status of KRAS might be associated with primary resistance to EGFR-TKIs in EGFR mutation-positive patients with NSCLC. Methods: Forty patients with NSCLC with EGFR mutations who were treated with gefitinib or erlotinib and had archival tissue specimens available were enrolled in the study. KRAS mutations were analyzed by direct sequencing. Results: Three (7.5%) of the 40 patients had progressive disease, and two (67%) of these three individuals had both KRAS and EGFR mutations. Conclusions: Our results suggest that KRAS mutation is a negative predictor of response to EGFR-TKIs in EGFR mutation-positive patients with NSCLC.
  • Tetsuya Mitsudomi; Satoshi Morita; Yasushi Yatabe; Shunichi Negoro; Isamu Okamoto; Junji Tsurutani; Takashi Seto; Miyako Satouchi; Hirohito Tada; Tomonori Hirashima; Kazuhiro Asami; Nobuyuki Katakami; Minoru Takada; Hiroshige Yoshioka; Kazuhiko Shibata; Shinzoh Kudoh; Eiji Shimizu; Hiroshi Saito; Shinichi Toyooka; Kazuhiko Nakagawa; Masahiro Fukuoka
    LANCET ONCOLOGY 11 2 121 - 128 2010年02月 [査読有り]
     
    Background Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain. Methods We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m(2), intravenously) plus docetaxel (60 mg/m(2), intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. Findings Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9.2 months (95% CI 8.0-13.9) versus 6.3 months (5.8-7.8; HR 0.489, 95% CI 0.336-0.710, log-rank p<0.0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2.3%), one of whom died. Interpretation Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel.
  • Koji Takeda; Toyoaki Hida; Tosiya Sato; Masahiko Ando; Takashi Seto; Miyako Satouchi; Yukito Ichinose; Nobuyuki Katakami; Nobuyuki Yamamoto; Shinzoh Kudoh; Jiichiro Sasaki; Kaoru Matsui; Koichi Takayama; Tatsuhiko Kashii; Yasuo Iwamoto; Toshiyuki Sawa; Isamu Okamoto; Takayasu Kurata; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 28 5 753 - 760 2010年02月 [査読有り]
     
    Purpose Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naive patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life. Results Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P = .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). Conclusion This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.
  • Tetsuya Mitsudomi; Satoshi Morita; Yasushi Yatabe; Shunichi Negoro; Isamu Okamoto; Junji Tsurutani; Takashi Seto; Miyako Satouchi; Hirohito Tada; Tomonori Hirashima; Kazuhiro Asami; Nobuyuki Katakami; Minoru Takada; Hiroshige Yoshioka; Kazuhiko Shibata; Shinzoh Kudoh; Eiji Shimizu; Hiroshi Saito; Shinichi Toyooka; Kazuhiko Nakagawa; Masahiro Fukuoka
    LANCET ONCOLOGY 11 2 121 - 128 2010年02月 [査読有り]
     
    Background Patients with non-small-cell lung cancer harbouring mutations in the epidermal growth factor receptor (EGFR) gene respond well to the EGFR-specific tyrosine kinase inhibitor gefitinib. However, whether gefitinib is better than standard platinum doublet chemotherapy in patients selected by EGFR mutation is uncertain. Methods We did an open label, phase 3 study (WJTOG3405) with recruitment between March 31, 2006, and June 22, 2009, at 36 centres in Japan. 177 chemotherapy-naive patients aged 75 years or younger and diagnosed with stage IIIB/IV non-small-cell lung cancer or postoperative recurrence harbouring EGFR mutations (either the exon 19 deletion or L858R point mutation) were randomly assigned, using a minimisation technique, to receive either gefitinib (250 mg/day orally; n=88) or cisplatin (80 mg/m(2), intravenously) plus docetaxel (60 mg/m(2), intravenously; n=89), administered every 21 days for three to six cycles. The primary endpoint was progression-free survival. Survival analysis was done with the modified intention-to-treat population. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539. Findings Five patients were excluded (two patients were found to have thyroid and colon cancer after randomisation, one patient had an exon 18 mutation, one patient had insufficient consent, and one patient showed acute allergic reaction to docetaxel). Thus, 172 patients (86 in each group) were included in the survival analyses. The gefitinib group had significantly longer progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival compared with the cisplatin plus docetaxel goup, with a median progression-free survival time of 9.2 months (95% CI 8.0-13.9) versus 6.3 months (5.8-7.8; HR 0.489, 95% CI 0.336-0.710, log-rank p<0.0001). Myelosuppression, alopecia, and fatigue were more frequent in the cisplatin plus docetaxel group, but skin toxicity, liver dysfunction, and diarrhoea were more frequent in the gefitinib group. Two patients in the gefitinib group developed interstitial lung disease (incidence 2.3%), one of whom died. Interpretation Patients with lung cancer who are selected by EGFR mutations have longer progression-free survival if they are treated with gefitinib than if they are treated with cisplatin plus docetaxel.
  • Koji Takeda; Toyoaki Hida; Tosiya Sato; Masahiko Ando; Takashi Seto; Miyako Satouchi; Yukito Ichinose; Nobuyuki Katakami; Nobuyuki Yamamoto; Shinzoh Kudoh; Jiichiro Sasaki; Kaoru Matsui; Koichi Takayama; Tatsuhiko Kashii; Yasuo Iwamoto; Toshiyuki Sawa; Isamu Okamoto; Takayasu Kurata; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 28 5 753 - 760 2010年02月 [査読有り]
     
    Purpose Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase. We conducted a phase III trial to evaluate whether gefitinib improves survival as sequential therapy after platinum-doublet chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Patients and Methods Chemotherapy-naive patients with advanced stage (IIIB/IV) NSCLC, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate organ function were randomly assigned to either platinum-doublet chemotherapy up to six cycles (arm A) or platinum-doublet chemotherapy for three cycles followed by gefitinib 250 mg orally once daily, until disease progression (arm B). Patients were stratified by disease stage, sex, histology, and chemotherapy regimens. The primary end point was overall survival; secondary end points included progression-free survival, tumor response, safety, and quality of life. Results Between March 2003 and May 2005, 604 patients were randomly assigned. There was a statistically significant improvement in progression-free survival in arm B (hazard ratio [HR], 0.68; 95% CI, 0.57 to 0.80; P = .001); however, overall survival results did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.03; P = .11). In an exploratory subset analysis of overall survival by histologic group, patients in arm B with adenocarcinoma did significantly better than patients in arm A with adenocarcinoma (n = 467; HR, 0.79; 95% CI, 0.65 to 0.98; P = .03). Conclusion This trial failed to meet the primary end point of OS in patients with NSCLC. The exploratory subset analyses demonstrate a possible survival prolongation for sequential therapy of gefitinib, especially for patients with adenocarcinoma.
  • 肺癌臨床試験デザインとデータ解釈 －肺癌診療のＥＢＭ－
    武田 真幸; 中川 和彦
    Medical Practice Medical Practice 27 7 1121 - 1125 文ｊ光堂 2010年
  • 呼吸器系の症状・徴候と疾患 Ｇ血痰・喀血
    武田 真幸; 中川 和彦
    疾病と治療 Ｉ 43 - 44 南江堂 2010年
  • 池田 昌人; 市橋 秀夫; 山片 重良; 田中 佐也子; 原口 龍太; 早川 正宣; 東田 有智; 中川 和彦
    気管支学 32 S218  特定非営利活動法人 日本呼吸器内視鏡学会 2010年
  • 藤田 悦生; 岩橋 弘樹; 西川 裕作; 宮崎 昌樹; 角井 一之; 河合 純; 阪中 敬一郎; 大星 隆司; 森下 友紀子; 川内 映理; 久米 裕昭; 中川 和彦; 東田 有智; 山本 勝廣
    アレルギー 59 9 1433 - 1433 一般社団法人 日本アレルギー学会 2010年
  • Yohei Funakoshi; Toru Mukohara; Tomoko Kataoka; Hideo Tomioka; Naoko Chayahara; Yutaka Fujiwara; Naomi Kiyota; Tomonori Shirasaka; Takanori Oka; Kenji Okada; Yutaka Okita; Shigeo Hara; Tomoo Itoh; Soichi Fumita; Kazuhiko Nakagawa; Hironobu Minami
    Rare Tumors 2 3 151 - 153 2010年 [査読有り]
     
    Extension of metastatic lung tumors into the left atrium via pulmonary veins is rare. Here, we report the first case of Ewing sarcoma exhibiting such extension. A 31-year-old man with pulmonary metastasis from Ewing sarcoma presented with a mass in the left lung, extending to the left atrium through the left inferior pulmonary vein. As the patient was considered to be at risk of tumor embolism, the mass was excised surgically. ©Copyright Y. Funakoshi et al., 2010.
  • International Journal of Clinical Oncology.
    Hayashi H; Okamoto I; Ichikawa Y; Miyazaki M; Yoshioka H; Kunimasa K; Nakagawa K; Re; lignan; leural mesothelioma with cisplatin; metrexed
    15 5 497 - 499 2010年 [査読有り]
  • The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations.
    Okamoto I; Mitsudomi T; Nakagawa K; Fukuoka M
    Ther Adv Med Oncol. 2 5 301 - 307 2010年 [査読有り]
  • Hiroyasu Kaneda; Isamu Okamoto; Hidetoshi Hayashi; Hiroshige Yoshioka; Masaki Miyazaki; Shinzoh Kudoh; Tatsuo Kimura; Takamune Sugiura; Toshiyuki Sawa; Koji Takeda; Yasuo Iwamoto; Miyako Satouchi; Kenji Akita; Hiroshi Saito; Isao Goto; Kazuhiko Shibata; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 1 105 - 109 2010年01月 [査読有り]
     
    Background: Amrubicin is a synthetic anthracycline drug that is a potent inhibitor of topoisomerase II. We have performed a phase It trial to evaluate the efficacy and safety of amrubicin for patients with previously treated non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC who experienced disease recurrence after one platinum-based chemotherapy regimen were eligible for enrollment in the study. Amrubicin was administered by intravenous injection at a dose of 40 mg/m(2) on 3 consecutive days every 3 weeks. Results: Sixty-one enrolled patients received a total of 192 treatment cycles (median, 2; range, 1-15). Response was as follows: complete response, 0; partial response, seven (11.5%); stable discase, 20 (32.8%); and. progressive disease, 34 (55.7%). Median progression-free survival was 1.8 months, whereas median overall survival was 8.5 months, and the 1-year survival rate was 32%. Hematologic toxicities of grade 3 or 4 included neutropenia (82.0%), leukopenia (73.8%), thrombocytopenia (24.6%), and anemia (27.9%). Febrile neutropenia occurred in 18 patients (29.5%). One treatment-related death due to infection was observed. Nonhematologic toxicities were mild. Conclusions: Amrubicin is a possible alternative for second-line treatment of advanced NSCLC, although a relevant hematological toxicity is significant, especially with a febrile neutropenia.
  • Isamu Okamoto; Toshihiko Doi; Atsushi Ohtsu; Masaki Miyazaki; Asuka Tsuya; Katsutoshi Kurei; Ken Kobayashi; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 1 17 - 23 2010年01月 [査読有り]
     
    To determine the pharmacokinetics and safety of RAD001 (everolimus) in Japanese patients with advanced solid tumors. An open-label, non-randomized, dose-escalation Phase I study of RAD001 administered continuously once daily in a 28-day cycle was performed. The study had a '3 + 3' design, with three patients recruited to each of three successive cohorts treated with RAD001 at 2.5, 5.0 or 10.0 mg/day. The pharmacokinetics of RAD001 in Japanese patients were similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with RAD001 at 10 mg/day showed marked tumor responses. Treatment of Japanese cancer patients with RAD001 may be undertaken with the expectation that previously determined pharmacokinetic and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer.
  • Takeshi Yoshida; Isamu Okamoto; Wataru Okamoto; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Janne; Kazuhiko Nakagawa
    CANCER SCIENCE 101 1 167 - 172 2010年01月 [査読有り]
     
    The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as gefitinib and erlotinib in non-small cell lung cancer (NSCLC) is often limited by the emergence of drug resistance conferred either by a secondary T790M mutation of EGFR or by acquired amplification of the MET gene. We now show that the extent of activation of the tyrosine kinase Src is markedly increased in gefitinib-resistant NSCLC (HCC827 GR) cells with MET amplification compared with that in the gefitinib-sensitive parental (HCC827) cells. In contrast, the extent of Src activation did not differ between gefitinib-resistant NSCLC (PC9/ZD) cells harboring the T790M mutation of EGFR and the corresponding gefitinib-sensitive parental (PC9) cells. This activation of Src in HCC827 GR cells was largely abolished by the MET-TKI PHA-665752 but was only partially inhibited by gefitinib, suggesting that Src activation is more dependent on MET signaling than on EGFR signaling in gefitinib-resistant NSCLC cells with MET amplification. Src inhibitors blocked Akt and Erk signaling pathways, resulting in both suppression of cell growth and induction of apoptosis, in HCC827 GR cells as effectively as did the combination of gefitinib and PHA-665752. Furthermore, Src inhibitor dasatinib inhibited tumor growth in HCC827 GR xenografts to a significantly greater extent than did treatment with gefitinib alone. These results provide a rationale for clinical targeting of Src in gefitinib-resistant NSCLC with MET amplification. (Cancer Sci 2009).
  • Toshio Shimizu; Isamu Okamoto; Kenji Tamura; Taroh Satoh; Masaki Miyazaki; Yusaku Akashi; Tomohiro Ozaki; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 65 2 243 - 250 2010年01月 [査読有り]
     
    d-19575 (glufosfamide: beta-d-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to beta-d-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of d-19575 in Japanese patients with advanced solid tumors Patients were treated with escalating doses of d-19575 administered by a two-step (fast-slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1-11) at d-19575 doses of 3,200, 4,500, or 6,000 mg/m(2). Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of d-19575 was 6,000 mg/m(2), at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for > 5 months, and eight patients achieved disease stabilization. Our results show that d-19575 can be safely administered by infusion over 6 h at 4,500 mg/m(2) every 3 weeks. The safety profile and potential antitumor activity of d-19575 show that phase II studies of this drug are warranted.
  • Toshio Shimizu; Isamu Okamoto; Kenji Tamura; Taroh Satoh; Masaki Miyazaki; Yusaku Akashi; Tomohiro Ozaki; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 65 2 243 - 250 2010年01月 [査読有り]
     
    d-19575 (glufosfamide: beta-d-glucosylisophosphoramide mustard) is an alkylating agent in which isophosphoramide mustard, the cytotoxic metabolite of ifosfamide, is covalently linked to beta-d-glucose. We have performed a phase I study to determine the safety profile, pharmacokinetics, and antitumor activity of d-19575 in Japanese patients with advanced solid tumors Patients were treated with escalating doses of d-19575 administered by a two-step (fast-slow) intravenous infusion over 6 h every 3 weeks. Thirteen patients received 43 treatment cycles (median 3; range 1-11) at d-19575 doses of 3,200, 4,500, or 6,000 mg/m(2). Hematologic toxicities and other side effects were generally mild. The maximum tolerated dose of d-19575 was 6,000 mg/m(2), at which two patients experienced dose-limiting toxicities (hypophosphatemia, hypokalemia, and metabolic acidosis each of grade 3). Pharmacokinetic analysis revealed a linear relation between the area under the concentration-versus-time curve (AUC) and dose. The AUC values for isophosphoramide mustard were substantially greater than those achieved by bolus administration or continuous infusion of ifosfamide in conventional therapy. One patient with gallbladder cancer previously treated with cisplatin and gemcitabine achieved a partial response lasting for > 5 months, and eight patients achieved disease stabilization. Our results show that d-19575 can be safely administered by infusion over 6 h at 4,500 mg/m(2) every 3 weeks. The safety profile and potential antitumor activity of d-19575 show that phase II studies of this drug are warranted.
  • Isamu Okamoto; Toshihiko Doi; Atsushi Ohtsu; Masaki Miyazaki; Asuka Tsuya; Katsutoshi Kurei; Ken Kobayashi; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 1 17 - 23 2010年01月 [査読有り]
     
    To determine the pharmacokinetics and safety of RAD001 (everolimus) in Japanese patients with advanced solid tumors. An open-label, non-randomized, dose-escalation Phase I study of RAD001 administered continuously once daily in a 28-day cycle was performed. The study had a '3 + 3' design, with three patients recruited to each of three successive cohorts treated with RAD001 at 2.5, 5.0 or 10.0 mg/day. The pharmacokinetics of RAD001 in Japanese patients were similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with RAD001 at 10 mg/day showed marked tumor responses. Treatment of Japanese cancer patients with RAD001 may be undertaken with the expectation that previously determined pharmacokinetic and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer.
  • Takeshi Yoshida; Isamu Okamoto; Wataru Okamoto; Erina Hatashita; Yuki Yamada; Kiyoko Kuwata; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Janne; Kazuhiko Nakagawa
    CANCER SCIENCE 101 1 167 - 172 2010年01月 [査読有り]
     
    The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors such as gefitinib and erlotinib in non-small cell lung cancer (NSCLC) is often limited by the emergence of drug resistance conferred either by a secondary T790M mutation of EGFR or by acquired amplification of the MET gene. We now show that the extent of activation of the tyrosine kinase Src is markedly increased in gefitinib-resistant NSCLC (HCC827 GR) cells with MET amplification compared with that in the gefitinib-sensitive parental (HCC827) cells. In contrast, the extent of Src activation did not differ between gefitinib-resistant NSCLC (PC9/ZD) cells harboring the T790M mutation of EGFR and the corresponding gefitinib-sensitive parental (PC9) cells. This activation of Src in HCC827 GR cells was largely abolished by the MET-TKI PHA-665752 but was only partially inhibited by gefitinib, suggesting that Src activation is more dependent on MET signaling than on EGFR signaling in gefitinib-resistant NSCLC cells with MET amplification. Src inhibitors blocked Akt and Erk signaling pathways, resulting in both suppression of cell growth and induction of apoptosis, in HCC827 GR cells as effectively as did the combination of gefitinib and PHA-665752. Furthermore, Src inhibitor dasatinib inhibited tumor growth in HCC827 GR xenografts to a significantly greater extent than did treatment with gefitinib alone. These results provide a rationale for clinical targeting of Src in gefitinib-resistant NSCLC with MET amplification. (Cancer Sci 2009).
  • Kunio Okamoto; Isamu Okamoto; Ken Takezawa; Izumi Tachibana; Masahiro Fukuoka; Yasumasa Nishimura; Kazuhiko Nakagawa
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 1 54 - 59 2010年01月 [査読有り]
     
    The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. The records of elderly (>= 70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19-33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3-18.2) and 24.1 months (95% confidence interval, 11.3-27.2), respectively. Etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients.
  • Hiroyasu Kaneda; Isamu Okamoto; Hidetoshi Hayashi; Hiroshige Yoshioka; Masaki Miyazaki; Shinzoh Kudoh; Tatsuo Kimura; Takamune Sugiura; Toshiyuki Sawa; Koji Takeda; Yasuo Iwamoto; Miyako Satouchi; Kenji Akita; Hiroshi Saito; Isao Goto; Kazuhiko Shibata; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 5 1 105 - 109 2010年01月 [査読有り]
     
    Background: Amrubicin is a synthetic anthracycline drug that is a potent inhibitor of topoisomerase II. We have performed a phase It trial to evaluate the efficacy and safety of amrubicin for patients with previously treated non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC who experienced disease recurrence after one platinum-based chemotherapy regimen were eligible for enrollment in the study. Amrubicin was administered by intravenous injection at a dose of 40 mg/m(2) on 3 consecutive days every 3 weeks. Results: Sixty-one enrolled patients received a total of 192 treatment cycles (median, 2; range, 1-15). Response was as follows: complete response, 0; partial response, seven (11.5%); stable discase, 20 (32.8%); and. progressive disease, 34 (55.7%). Median progression-free survival was 1.8 months, whereas median overall survival was 8.5 months, and the 1-year survival rate was 32%. Hematologic toxicities of grade 3 or 4 included neutropenia (82.0%), leukopenia (73.8%), thrombocytopenia (24.6%), and anemia (27.9%). Febrile neutropenia occurred in 18 patients (29.5%). One treatment-related death due to infection was observed. Nonhematologic toxicities were mild. Conclusions: Amrubicin is a possible alternative for second-line treatment of advanced NSCLC, although a relevant hematological toxicity is significant, especially with a febrile neutropenia.
  • Isamu Okamoto; Tetsuya Mitsudomi; Kazuhiko Nakagawa; Masahiro Fukuoka
    Therapeutic Advances in Medical Oncology 2 5 301 - 307 2010年 [査読有り]
     
    Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC. © 2010, SAGE Publications. All rights reserved.
  • Yijun Bao; Kazutaka Sumita; Takumi Kudo; Kanchanamala Withanage; Kentaro Nakagawa; Mitsunobu Ikeda; Kikuo Ohno; Yunjie Wang; Yutaka Hata
    GENES TO CELLS 14 12 1369 - 1381 2009年12月 [査読有り]
     
    Mammalian nuclear Dbf2-related (NDR) kinases (LATS1, LATS2, NDR1 and NDR2) play a role in cell proliferation, apoptosis and morphological changes. Mammalian sterile 20-like (MST) kinases and Mps one binder (MOB) proteins are important in the activation of NDR kinases. MOB1 is phosphorylated by MST1 and MST2 and this phosphorylation enhances the ability of MOB1 to activate NDR kinases. The phosphorylated MOB1 can be more effective as a scaffold protein to facilitate the MST-dependent phosphorylation of NDR kinases and/or as a direct activator of NDR kinases. We previously reported that Thr74 of MOB1B is phosphorylated by MST2. Thr12 and Thr35 have also been identified as phosphorylation sites. In this study, we quantified the phosphorylation of Thr74 using the phosphorylated Thr74-specific antibody. Thr74 is indeed phosphorylated by MST2, but the efficiency is low, suggesting that MOB1B can activate NDR kinases without the phosphorylation of Thr74. We also showed that the phosphorylated MOB1B activates NDR1 T444D and LATS2 T1041D, in which threonine residues phosphorylated by MST kinases are replaced with phosphorylation-mimicking aspartic acid, more efficiently than the unphosphorylated MOB1B does. This finding supports that the phosphorylation of MOB1B enhances its ability as a direct activator of NDR kinases.
  • 福岡和也; 本村文宏; 國頭英夫; 樋田豊明; 中川和彦; 玄馬顕一; 新海哲; 一瀬幸人; 南部静洋; 中野孝司
    肺癌 49 7 988 - 993 2009年12月 [査読有り]
     
    Objective. To examine safety and efficacy of combination therapy with LY231514 (pemetrexed) plus cisplatin in malignant pleural mesothelioma. Methods. Patients aged between 20 and 75 years who were not candidates for surgery, who were given histological diagnoses of malignant pleural mesothelioma, had received no prior systemic chemotherapy, with a performance status (PS) of 0 or 1, and who had normal major organ function were enrolled. On day 1 of a 21-day cycle, patients received intravenous infusion of 500 mg/m2 pemetrexed, followed by intravenous infusion of 75 mg/m2 cisplatin, concomitantly with vitamin preparations. Results. Ten men and two women with a mean age of 63 years (range 50 to 73) were analyzed. The histological subtype was epithelioid in 8 patients, sarcomatoid in 2 patients, and biphasic in 2 patients. Ten patients had stage III/IV disease. Seven patients had a history of asbestos exposure. Hematological toxicities of grade 3 or more included decreased white blood cell count in 1 patient (8.3%) and decreased neutrophil count in 1 patient (8.3%), decreased lymphocyte count in 2 patients (16.7%) and decreased red blood cell count in 2 patients (16.7%), decreased hemoglobin in 4 patients (33.3%), and decreased platelet count in 2 patients (16.7%). Pneumonia was observed in 1 patient (8.3%). Common non-hematological toxicities included gastrointestinal toxicities, such as nausea, vomiting, and anorexia. The response rate was 25.0%. Conclusion. Safety of this combination therapy was confirmed in patients with malignant pleural mesothelioma. © 2009 The Japan Lung Cancer Society.
  • Kunio Okamoto; Isamu Okamoto; Ken Takezawa; Izumi Tachibana; Masahiro Fukuoka; Yasumasa Nishimura; Kazuhiko Nakagawa
    Japanese Journal of Clinical Oncology 40 1 54 - 59 2009年10月 [査読有り]
     
    Objective: The optimal management of elderly patients with limited-disease small cell lung cancer (LD-SCLC) has not been established. Methods: The records of elderly (≥70 years of age) patients with LD-SCLC who had been treated with etoposide and cisplatin chemotherapy with early concurrent twice-daily thoracic radiotherapy (TRT) were reviewed retrospectively. Results: Of the 25 elderly patients with LD-SCLC identified, 12 (48%) individuals received etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT. The main toxicities of this treatment regimen were hematologic, with neutropenia of Grade 4 being observed in all patients and febrile neutropenia of Grade 3 in eight patients during the first cycle of chemoradiotherapy. The toxicity of TRT was acceptable, with all patients completing the planned radiotherapy within a median of 29 days (range, 19-33). No treatment-related deaths were observed. The median progression-free survival and overall survival times were 14.2 months (95% confidence interval, 4.3-18.2) and 24.1 months (95% confidence interval, 11.3-27.2), respectively. Conclusions: Etoposide-cisplatin chemotherapy with early concurrent twice-daily TRT was highly myelotoxic in elderly patients with LD-SCLC, although no treatment-related deaths were observed in our cohort. Prospective studies are required to establish the optimal schedule and dose of chemotherapy and TRT in such patients. © The Author (2009). Published by Oxford University Press.
  • 駄賀 晴子; 武田 晃司; 清田 秀美; 鶴谷 純司; 宮崎 昌樹; 上田 眞也; 市川 靖子; 武田 真幸; 米阪 仁雄; 関口 理砂; 松島 三千代; 江夏 総太郎; 南部 静洋; 岡本 勇; 中川 和彦
    肺癌 49 5 633 - 633 (NPO)日本肺癌学会 2009年10月
  • 谷口 博之; 福岡 正博; 工藤 翔二; 安藤 昌彦; 大江 裕一郎; 中川 和彦; 荒川 浩明; 井上 義一; 海老名 雅仁; 楠本 昌彦; 桑野 和善; 弦間 昭彦; 酒井 文和; 上甲 剛; 福田 悠; 清原 祥夫; 山崎 直也; 横山 俊二; 秋山 晋一郎
    肺癌 49 5 656 - 656 (NPO)日本肺癌学会 2009年10月
  • H. Kunitoh; T. Tamura; T. Shibata; K. Nakagawa; K. Takeda; Y. Nishiwaki; Y. Osaki; K. Noda; A. Yokoyama; N. Saijo
    BRITISH JOURNAL OF CANCER 101 9 1549 - 1554 2009年10月 [査読有り]
     
    BACKGROUND: To evaluate the safety and efficacy of dose-dense weekly chemotherapy in the treatment of advanced thymoma. METHODS: Subjects comprised patients with histologically documented chemotherapy-naive thymoma with stage-IVa or IVb disease. Thymic carcinoma, carcinoid or lymphoma cases were excluded. Patients received 9 weeks of chemotherapy: cisplatin (25 mg m(-2)) on weeks 1-9; vincristine (1 mg m(-2)) on weeks 1, 2, 4, 6 and 8; and doxorubicin (40 mg m(-2)) and etoposide (80 mg m(-2)) on days 1-3 of weeks 1, 3, 5, 7 and 9. Chemotherapy courses were supported by granulocyte colony-stimulating factor. Post-protocol local therapy was allowed. RESULTS: From July 1997 to March 2004, 30 patients were entered. Three were ineligible due to different histology. Chemotherapy-associated toxicity was mainly haematological and was well tolerated, with no deaths due to toxicity, and 87% of patients completed the planned 9-week regimen. Overall response rate was 59%, with 16 of the 27 eligible patients achieving partial response. Median progression-fee survival (PFS) was 0.79 years (95% confidence interval: 0.52-1.40 years), and PFS at 1 and 2 years was 37 and 15%, respectively. Overall survival rates at 2 and 5 years were 89 and 65%, respectively. CONCLUSION: In stage-IV thymoma patients, weekly dose-dense chemotherapy offers similar activity to conventional regimens. British Journal of Cancer ( 2009) 101, 1549-1554. doi: 10.1038/sj.bjc.6605347 www.bjcancer.com Published online 6 October 2009 (C) 2009 Cancer Research UK
  • Takehiko Ohba; Yukinori Kimura; Yu Nakamura; Wakako Hamanaka; Kentaro Inamura; Noriko Motoi; Ming-yon Mun; Yukinori Sakao; Sakae Okumura; Ken Nakagawa; Kazuyoshi Kawabata; Yuichi Ishikawa
    JOURNAL OF THORACIC ONCOLOGY 4 9 S485 - S486 2009年09月 [査読有り]
  • Wakako Hamanaka; Noriko Motoi; Sakae Okumura; Ken Nakagawa; Makoto Nishio; Takeshi Horai; Yuichi Ishikawa
    JOURNAL OF THORACIC ONCOLOGY 4 9 S466 - S466 2009年09月 [査読有り]
  • Nakagawa K; Ohde Y; Okumura T; Kondo H
    Gan to kagaku ryoho. Cancer & chemotherapy 36 9 1419 - 1422 2009年09月 [査読有り]
  • I. Sekine; Y. Ichinose; Y. Nishiwaki; N. Yamamoto; M. Tsuboi; K. Nakagawa; T. Shinkai; S. Negoro; F. Imamura; K. Eguchi; K. Takeda; Y. Itoh; T. Tamura; N. Saijo; M. Fukuoka
    ANNALS OF ONCOLOGY 20 9 1483 - 1488 2009年09月 [査読有り]
     
    Patients and methods: This open-label, phase III study randomized 490 Japanese patients to gefitinib (250 mg/day) or docetaxel (60 mg/m(2)/3 weeks), with survival as the primary outcome. Preplanned QoL analyses included Functional Assessment of Cancer Therapy-Lung (FACT-L), Trial Outcome Index (TOI) and Lung Cancer Subscale (LCS) improvement rates, and mean change from baseline. Results: Gefitinib showed statistically significant benefits over docetaxel in QoL improvement rates (FACT-L 23% versus 14%, P = 0.023; TOI 21% versus 9%, P = 0.002) and mean change from baseline score [mean treatment difference: FACT-L 3.72 points, 95% confidence interval (CI) 0.55-6.89, P = 0.022; TOI 4.31 points, 95% CI 2.13-6.49, P < 0.001], although differences did not meet the clinically relevant six-point change. There were no significant differences between treatments in LCS improvement rates (23% versus 20%, P = 0.562) or mean change from baseline score (0.63 points, 95% CI -0.07 to 1.34, P = 0.077). Conclusions: Gefitinib improved aspects of QoL over docetaxel, with superior objective response rate and a more favorable tolerability profile and no statistically significant difference in overall survival (although noninferiority was not statistically proven).
  • Nakagawa K
    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 98 8 1923 - 1931 2009年08月 [査読有り]
  • Ken Takezawa; Isamu Okamoto; Kimio Yonesaka; Erina Hatashita; Yuki Yamada; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER RESEARCH 69 16 6515 - 6521 2009年08月 [査読有り]
     
    Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non-small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G(1) arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G(1) arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G(1) arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G, arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant. KRAS, respectively. The G(1) arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [Cancer Res 2009;69(16):6515-21]
  • Kenji Tamura; Isamu Okamoto; Tomohiro Ozaki; Tatsuhiko Kashii; Koji Takeda; Masashi Kobayashi; Kaoru Matsui; Takashi Shibata; Takayasu Kurata; Kazuhiko Nakagawa; Masahiro Fukuoka
    European Journal of Cancer 45 12 2132 - 2137 2009年08月 [査読有り]
     
    The objective of this phase I/II study was to determine the recommended dose (RD) of S-1 and carboplatin (CBDCA), and to evaluate the efficacy and safety of this combination in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 given orally on days 1-14, and CBDCA infused intravenously on day 1, repeated every 3 weeks. RD was AUC5 of CBDCA and 80 mg/m2 of S-1. Nineteen patients were treated at the RD. The overall response was 30.8% (95% confidence interval: 17.1-58.3%). The response rate in the RD was 36.8% (95% CI: 16.3-61.6%). The median overall survival time was 11.1 months (95% CI: 8.1-15.3 months) and the median progression-free survival time was 5.0 months (95% CI: 3.6-6.0 months). Major grades 3-4 toxicities were thrombocytopaenia (47%), anaemia (26%) and infection (16%). This is the first report to show promising activity of this combination in phase II, including survival data and manageable toxicity, especially in outpatients receiving treatment for advanced NSCLC. © 2009 Elsevier Ltd. All rights reserved.
  • Kenji Tamura; Isamu Okamoto; Tomohiro Ozaki; Tatsuhiko Kashii; Koji Takeda; Masashi Kobayashi; Kaoru Matsui; Takashi Shibata; Takayasu Kurata; Kazuhiko Nakagawa; Masahiro Fukuoka
    EUROPEAN JOURNAL OF CANCER 45 12 2132 - 2137 2009年08月 [査読有り]
     
    The objective of this phase I/II study was to determine the recommended dose (RD) of S-1 and carboplatin (CBDCA), and to evaluate the efficacy and safety of this combination in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naive patients were treated with S-1 given orally on days 1-14, and CBDCA infused intravenously on day 1, repeated every 3 weeks. RD was AUC5 of CBDCA and 80 mg/m(2) of S-1. Nineteen patients were treated at the RD. The overall response was 30.8% (95% confidence interval: 17.1-58.3%). The response rate in the RD was 36.8% (95% CL 16.3-61.6%). The median overall survival time was 11.1 months (95% CL 8.1-15.3 months) and the median progression-free survival time was 5.0 months (95% Cl: 3.6-6.0 months). Major grades 3-4 toxicities were thrombocytopaenia (47%), anaemia (26%) and infection (16%). This is the first report to show promising activity of this combination in phase II, including survival data and manageable toxicity, especially in outpatients receiving treatment for advanced NSCLC. (C) 2009 Elsevier Ltd. All rights reserved.
  • Ken Takezawa; Isamu Okamoto; Kimio Yonesaka; Erina Hatashita; Yuki Yamada; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER RESEARCH 69 16 6515 - 6521 2009年08月 [査読有り]
     
    Sorafenib is a multikinase inhibitor whose targets include B-RAF and C-RAF, both of which function in the extracellular signal-regulated kinase (ERK) signaling pathway but which also have distinct downstream targets. The relative effects of sorafenib on B-RAF and C-RAF signaling in tumor cells remain unclear, however. We have now examined the effects of sorafenib as well as of B-RAF or C-RAF depletion by RNA interference on cell growth and ERK signaling in non-small cell lung cancer (NSCLC) cell lines with or without KRAS mutations. Sorafenib inhibited ERK phosphorylation in cells with wild-type KRAS but not in those with mutant KRAS. Despite this difference, sorafenib inhibited cell growth and induced G(1) arrest in both cell types. Depletion of B-RAF, but not that of C-RAF, inhibited ERK phosphorylation as well as suppressed cell growth and induced G(1) arrest in cells with wild-type KRAS. In contrast, depletion of C-RAF inhibited cell growth and induced G(1) arrest, without affecting ERK phosphorylation, in cells with mutant KRAS; depletion of B-RAF did not induce G, arrest in these cells. These data suggest that B-RAF-ERK signaling and C-RAF signaling play the dominant roles in regulation of cell growth in NSCLC cells with wild-type or mutant. KRAS, respectively. The G(1) arrest induced by either C-RAF depletion or sorafenib in cells with mutant KRAS was associated with down-regulation of cyclin E. Our results thus suggest that sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [Cancer Res 2009;69(16):6515-21]
  • Tsutomu Iwasa; Isamu Okamoto; Minoru Suzuki; Erina Hatashita; Yuki Yamada; Masahiro Fukuoka; Koji Ono; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 15 16 5117 - 5125 2009年08月 [査読有り]
     
    Purpose: Therapeutic strategies that target the insulin-like growth factor I receptor (IGF-1R) hold promise for a wide variety of cancers. We have now investigated the effect of CP-751,871, a fully human monoclonal antibody specific for IGF-IR, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to radiation. Experimental Design: The radiosensitizing effect of CP-751,871 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced damage was evaluated by immunofluorescence analysis of the histone gamma-H2AX and Rad51. Results: A clonogenic survival assay revealed that CP-751,871 increased the sensitivity of NSCLC cells to radiation in vitro. CP-751,871 inhibited radiation-induced IGF-IR signaling, and potentiated the radiation-induced increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of the histone gamma-H2AX and Rad51 also showed that CP-751,871 inhibited the repair of radiation-induced DNA double-strand breaks. Finally, combination therapy with CP-751,871 and radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. Conclusions: These results show that CP-751,871 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of CP-751,871 is likely attributable to the inhibition of DNA repair and enhancement of apoptosis that result from attenuation of IGF-IR signaling. Combined treatment with CP-751,871 and radiation thus warrants further investigation in clinical trials as a potential anticancer strategy. (Clin Cancer Res 2009;15(16):5117-25)
  • Nobuyuki Yamamoto; Ikuo Sekine; Kazuhiko Nakagawa; Minoru Takada; Masahiro Fukuoka; Yusuke Tanigawara; Nagahiro Saijo
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 39 7 425 - 430 2009年07月 [査読有り]
     
    The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts < 0.5 x 10(9) cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 mu g/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration-time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.
  • Nobuyuki Yamamoto; Ikuo Sekine; Kazuhiko Nakagawa; Minoru Takada; Masahiro Fukuoka; Yusuke Tanigawara; Nagahiro Saijo
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 39 7 425 - 430 2009年07月 [査読有り]
     
    The aim of this study was to investigate the safety, pharmacokinetic and pharmacodynamic profiles of pegfilgrastim (KRN125), a long-acting granulocyte colony-stimulating factor, in lung cancer patients with chemotherapy-induced neutropenia. Eighteen Japanese lung cancer patients who had experienced severe neutropenia (absolute neutrophil counts < 0.5 x 10(9) cells/l) were enrolled. Six patients were sequentially enrolled in each pegfilgrastim dose cohort (dose levels of 30, 60 or 100 mu g/kg). Patients received the same chemotherapy regimen as in their previous cycle and pegfilgrastim was injected subcutaneously the day after chemotherapy ended in each treatment cycle. Pharmacokinetic, pharmacodynamic and safety analyses were performed. Dose-limiting toxicity and serious adverse events related to pegfilgrastim were not observed in any patients. Pegfilgrastim antibodies were not detected. Maximum serum concentrations and area under the serum concentration-time curves of pegfilgrastim were dependent on the pegfilgrastim dose in a non-linear manner. Of the 18 patients, severe neutropenia occurred in 4 (22.2%), and, of these, 1 patient (5.5%) required rescue treatment by filgrastim. A single dose of pegfilgrastim increases the serum concentration of pegfilgrastim for several days in a dose-dependent manner and is not associated with significant toxicity. Good efficacy of pegfilgrastim for the prevention of severe neutropenia was observed at all dose levels. Based on these data, further studies are warranted to determine the recommended dose of pegfilgrastim for Japanese patients with chemotherapy-induced neutropenia.
  • 鶴谷 純司; 中川 和彦
    日本医師会雑誌 138 特別1 S156 - S160 (公社)日本医師会 2009年06月
  • Taroh Satoh; Isamu Okamoto; Masaki Miyazaki; Ryotaroh Morinaga; Asuka Tsuya; Yoshikazu Hasegawa; Masaaki Terashima; Shinya Ueda; Masahiro Fukuoka; Yutaka Ariyoshi; Toshikazu Saito; Noriyuki Masuda; Hirokazu Watanabe; Tetsuo Taguchi; Toru Kakihara; Yumiko Aoyama; Yohko Hashimoto; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 15 11 3872 - 3880 2009年06月 [査読有り]
     
    Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles. Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine micro-albumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v.. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
  • Taroh Satoh; Isamu Okamoto; Masaki Miyazaki; Ryotaroh Morinaga; Asuka Tsuya; Yoshikazu Hasegawa; Masaaki Terashima; Shinya Ueda; Masahiro Fukuoka; Yutaka Ariyoshi; Toshikazu Saito; Noriyuki Masuda; Hirokazu Watanabe; Tetsuo Taguchi; Toru Kakihara; Yumiko Aoyama; Yohko Hashimoto; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 15 11 3872 - 3880 2009年06月 [査読有り]
     
    Purpose: YM155, a novel molecular targeted agent, suppresses survivin, a member of the inhibitor of apoptosis protein family that is overexpressed in many tumor types. The aim of this study was to determine the maximum tolerated dose (MTD) and to assess the safety, pharmacokinetics, and antitumor activity of YM155 in patients with advanced refractory solid tumors. Experimental Design: Patients with advanced refractory solid tumors were treated with escalating doses of YM155 administered by continuous i.v. infusion for 168 hours in 21-day cycles. Results: Of the 34 patients enrolled, 33 (median age, 59 years) received at least 1 dose of YM155 (range, 1-19 cycles). The dose levels studied were 1.8, 3.6, 4.8, 6.0, 8.0, and 10.6 mg/m(2)/d. The MTD was determined to be 8.0 mg/m(2)/d, based on a dose-limiting toxicity of increased blood creatinine observed in 2 patients receiving 10.6 mg/m(2)/d. The most common adverse reactions judged to be related to YM155 were urine micro-albumin present; fever; injection-site phlebitis; fatigue; and decreased hemoglobin/anemia, blood albumin, and lymphocyte count. The pharmacokinetic profile was almost linear over the dosing range and was similar between cycles 1 and 2. Urinary excretion of YM155 showed no definite difference among doses. Stable disease was achieved in nine patients. Conclusions: YM155 was safely administered to patients with advanced refractory solid tumors by 168-hour continuous i.v.. infusion in 21-day cycles. The MTD was determined to be 8.0 mg/m(2)/d. The safety profile, plasma concentrations achieved, and antitumor activity observed merit further studies with this survivin suppressant, alone and in combination regimens.
  • 海老名 雅仁; 福岡 正博; 工藤 翔二; 安藤 昌彦; 大江 裕一郎; 中川 和彦; 荒川 浩明; 井上 義一; 楠本 昌彦; 桑野 和善; 弦間 昭彦; 酒井 文和; 上甲 剛; 谷口 博之; 福田 悠; 清原 祥夫; 山崎 直也; 横山 俊二; 秋山 晋一郎
    日本呼吸器学会雑誌 47 増刊 131 - 131 (一社)日本呼吸器学会 2009年05月
  • K. Kudo; F. Ohyanagi; A. Horiike; E. Miyauchi; I. Motokawa; T. Horai; M. Mun; Y. Sakao; S. Okumura; K. Nakagawa; M. Nishio
    JOURNAL OF CLINICAL ONCOLOGY 27 15 2009年05月 [査読有り]
  • Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Daisuke Tamura; Keiichi Aomatsu; Kanae Kudo; Hiroyasu Kaneda; Yoshihiko Fujita; Eiko Honda; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Hiroyasu Kaneda; Tokuzo Arao; Kaoru Tanaka; Mari Maegawa; Kazuko Matsumoto; Kanae Kudo; Daisuke Tamura; Keiichi Aomatsu; Yoshihiko Fujita; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    CANCER RESEARCH 69 2009年05月 [査読有り]
  • Takayasu Kurata; Tatsuhiko Kashii; Koji Takeda; Nobuhiko Seki; Masahiro Tsuboi; Masashi Kobayashi; Taroh Satoh; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 4 5 644 - 648 2009年05月 [査読有り]
     
    Introduction: A phase I study on relapsed small cell lung cancer (SCLC) was conducted to establish the toxicity and maximum tolerated dose of carboplatin with topotecan, and to observe the antitumor activity. Methods: Thirty-two SCLC patients who had received one previous line of chemotherapy were enrolled. Topotecan was infused for 30 minutes on days I to 5, and carboplatin for 60 minutes after the topotecan infusion on day 5 every 3 weeks. Granulocyte colony-stimulating factor prophylaxis was administered from day 8 to white blood cell or neutrophil recovery. Results: The most frequent toxicities were neutropenia and thrombocytopenia. Nonhematological toxicities were generally mild. Three of six patients experienced a dose-limiting toxicity, thrombocytopenia, at dose level 6: 0.85 mg/m(2) topotecan with area under curve 5 carboplatin (maximum tolerated dose). Of 29 evaluable patients, 5 (17.2%) had partial responses. Of 21 patients who relapsed more than 90 days after completion of first-line chemotherapy, 5 (23.8%) had partial responses. Median overall survival time and 1-year survival rate were 11.3 months and 50.0%, respectively. Conclusions: The recommended dose for further studies is 0.75 mg/m(2) of topotecan on days 1 to 5 with area under curve 5 of carboplatin on day 5 every 3 weeks. This combination is well tolerated, and is promising for sensitive relapsed SCLC. A comparative study against single-agent topotecan for sensitive relapsed SCLC is warranted.
  • K. Takeda; S. Negoro; T. Tamura; Y. Nishiwaki; S. Kudoh; S. Yokota; K. Matsui; H. Semba; K. Nakagawa; Y. Takada; M. Ando; T. Shibata; N. Saijo
    ANNALS OF ONCOLOGY 20 5 835 - 841 2009年05月 [査読有り]
     
    Background: This trial evaluated whether a combination of docetaxel and gemcitabine provides better survival than docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC). Patients and methods: Eligibility included pathologically or cytologically proven NSCLC, failure of one platinum-based regimen, performance status of zero or one, 20-75 years old, and adequate organ function. Patients received docetaxel 60 mg/m(2) (day 1) or docetaxel 60 mg/m(2) (day 8) and gemcitabine 800 mg/m(2) (days 1 and 8), both administered every 21 days until disease progression. Results: Sixty-five patients participated in each arm. This trial was terminated early due to an unexpected high incidence of interstitial lung disease (ILD) and three treatment-related deaths due to ILD in the combination arm. Docetaxel plus gemcitabine compared with docetaxel-alone patients experienced similar grade and incidence of toxicity, except for ILD. No baseline factor was identified for predicting ILD. Median survival times were 10.3 and 10.1 months (one-sided P = 0.36) for docetaxel plus gemcitabine and docetaxel arms, respectively. Conclusion: Docetaxel alone is still the standard second-line treatment for NSCLC. The incidence of ILD is higher for docetaxel combined with gemcitabine than for docetaxel alone in patients with previously treated NSCLC.
  • Takayasu Kurata; Tatsuhiko Kashii; Koji Takeda; Nobuhiko Seki; Masahiro Tsuboi; Masashi Kobayashi; Taroh Satoh; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 4 5 644 - 648 2009年05月 [査読有り]
     
    Introduction: A phase I study on relapsed small cell lung cancer (SCLC) was conducted to establish the toxicity and maximum tolerated dose of carboplatin with topotecan, and to observe the antitumor activity. Methods: Thirty-two SCLC patients who had received one previous line of chemotherapy were enrolled. Topotecan was infused for 30 minutes on days I to 5, and carboplatin for 60 minutes after the topotecan infusion on day 5 every 3 weeks. Granulocyte colony-stimulating factor prophylaxis was administered from day 8 to white blood cell or neutrophil recovery. Results: The most frequent toxicities were neutropenia and thrombocytopenia. Nonhematological toxicities were generally mild. Three of six patients experienced a dose-limiting toxicity, thrombocytopenia, at dose level 6: 0.85 mg/m(2) topotecan with area under curve 5 carboplatin (maximum tolerated dose). Of 29 evaluable patients, 5 (17.2%) had partial responses. Of 21 patients who relapsed more than 90 days after completion of first-line chemotherapy, 5 (23.8%) had partial responses. Median overall survival time and 1-year survival rate were 11.3 months and 50.0%, respectively. Conclusions: The recommended dose for further studies is 0.75 mg/m(2) of topotecan on days 1 to 5 with area under curve 5 of carboplatin on day 5 every 3 weeks. This combination is well tolerated, and is promising for sensitive relapsed SCLC. A comparative study against single-agent topotecan for sensitive relapsed SCLC is warranted.
  • K. Takeda; S. Negoro; T. Tamura; Y. Nishiwaki; S. Kudoh; S. Yokota; K. Matsui; H. Semba; K. Nakagawa; Y. Takada; M. Ando; T. Shibata; N. Saijo
    ANNALS OF ONCOLOGY 20 5 835 - 841 2009年05月 [査読有り]
     
    Background: This trial evaluated whether a combination of docetaxel and gemcitabine provides better survival than docetaxel alone in patients with previously treated non-small-cell lung cancer (NSCLC). Patients and methods: Eligibility included pathologically or cytologically proven NSCLC, failure of one platinum-based regimen, performance status of zero or one, 20-75 years old, and adequate organ function. Patients received docetaxel 60 mg/m(2) (day 1) or docetaxel 60 mg/m(2) (day 8) and gemcitabine 800 mg/m(2) (days 1 and 8), both administered every 21 days until disease progression. Results: Sixty-five patients participated in each arm. This trial was terminated early due to an unexpected high incidence of interstitial lung disease (ILD) and three treatment-related deaths due to ILD in the combination arm. Docetaxel plus gemcitabine compared with docetaxel-alone patients experienced similar grade and incidence of toxicity, except for ILD. No baseline factor was identified for predicting ILD. Median survival times were 10.3 and 10.1 months (one-sided P = 0.36) for docetaxel plus gemcitabine and docetaxel arms, respectively. Conclusion: Docetaxel alone is still the standard second-line treatment for NSCLC. The incidence of ILD is higher for docetaxel combined with gemcitabine than for docetaxel alone in patients with previously treated NSCLC.
  • Shintani Y; Ohta M; Iwasaki T; Ikeda N; Kanou T; Tomita E; Nakagawa K; Yasumitsu T; Ohno Y
    The Journal of thoracic and cardiovascular surgery 137 4 835 - 839 2009年04月 [査読有り]
     
    OBJECTIVE: Although malignant pleural effusion or dissemination is regarded as T4 per TNM classification of lung cancer, the prognostic significance in staging of pleural lavage cytologic examination remains undetermined. The purpose of this study was to clarify the utility of pleural lavage cytologic staging as a prognostic factor in patients with non-small cell lung cancer. METHODS: In 1271 patients with lung cancer who underwent curative resection, intraoperative pleural lavage cytologic examination was performed at thoracotomy (first cytologic examination), immediately after pulmonary resection and mediastinal lymph node dissection (second cytologic examination), and after last washing of pleural cavity (third cytologic examination). Positive first cytologic result represented cytologic positive result before lung resection; positive second and third cytologic results were regarded as cytologic positive results after lung resection. RESULTS: Eighty-nine patients (7.0%) had positive findings of pleural lavage cytologic examination before or after lung resection. Five-year survivals were 44.1% for patients with positive results before lung resection and 23.4% for patients with positive results after lung resection, both significantly worse than that for patients with negative results. Multivariate analyses revealed that positive lavage result after lung resection was an independent prognostic factor. We found significantly greater pleural recurrence among patients with positive pleural lavage cytologic results after lung resection than among those with negative results. CONCLUSIONS: In addition to TNM classification, results of pleural lavage cytologic examination after lung resection should be considered when staging non-small cell lung cancer. Adjuvant systemic therapy may improve outcome for patients with positive results.
  • K. Okamoto; J. Tsurutani; M. Terashima; I. Okamoto; K. Nakagawa
    ANNALS OF ONCOLOGY 20 4 796 - 797 2009年04月 [査読有り]
  • Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideyuki Yokote; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    INTERNATIONAL JOURNAL OF CANCER 124 5 1072 - 1080 2009年03月 [査読有り]
     
    SRPX2 (Sushi repeat containing protein, X-linked 2) was first identified as a downstream molecule of the E2A-HLF fusion gene in t(17;19)-positive leukemia cells and the biological function of this gene remains unknown. We found that SRPX2 is overexpressed in gastric cancer and the expression and clinical features showed that high mRNA expression levels were observed in patients with unfavorable outcomes using real-time RT-PCR. The cellular distribution of SRPX2 protein showed the secretion of SRPX2 into extracellular regions and its localization in the cytoplasm. The introduction of the SRPX2 gene into HEK293 cells did not modulate the cellular proliferative activity but did enhance the cellular migration activity, as shown using migration and scratch assays. The conditioned-medium obtained from SRPX2-overexpressing cells increased the cellular migration activity of a gastric cancer cell line, SNU-16. In addition, SRPX2 protein remarkably enhanced the cellular adhesion of SNU-16 and HSC-39 and increased the phosphorylation levels of focal adhesion kinase (FAK), as shown using western blotting, suggesting that SRPX2 enhances cellular migration and adhesion through FAK signaling. In conclusion, the overexpression of SRPX2 enhances cellular migration and adhesion in gastric cancer cells. Here, we report that the biological functions of SRPX2 include cellular migration and adhesion to cancer cells. (c) 2008 Wiley-Liss, Inc.
  • Kaoru Tanaka; Tokuzo Arao; Mari Maegawa; Kazuko Matsumoto; Hiroyasu Kaneda; Kanae Kudo; Yoshihiko Fujita; Hideyuki Yokote; Kazuyoshi Yanagihara; Yasuhide Yamada; Isamu Okamoto; Kazuhiko Nakagawa; Kazuto Nishio
    INTERNATIONAL JOURNAL OF CANCER 124 5 1072 - 1080 2009年03月 [査読有り]
     
    SRPX2 (Sushi repeat containing protein, X-linked 2) was first identified as a downstream molecule of the E2A-HLF fusion gene in t(17;19)-positive leukemia cells and the biological function of this gene remains unknown. We found that SRPX2 is overexpressed in gastric cancer and the expression and clinical features showed that high mRNA expression levels were observed in patients with unfavorable outcomes using real-time RT-PCR. The cellular distribution of SRPX2 protein showed the secretion of SRPX2 into extracellular regions and its localization in the cytoplasm. The introduction of the SRPX2 gene into HEK293 cells did not modulate the cellular proliferative activity but did enhance the cellular migration activity, as shown using migration and scratch assays. The conditioned-medium obtained from SRPX2-overexpressing cells increased the cellular migration activity of a gastric cancer cell line, SNU-16. In addition, SRPX2 protein remarkably enhanced the cellular adhesion of SNU-16 and HSC-39 and increased the phosphorylation levels of focal adhesion kinase (FAK), as shown using western blotting, suggesting that SRPX2 enhances cellular migration and adhesion through FAK signaling. In conclusion, the overexpression of SRPX2 enhances cellular migration and adhesion in gastric cancer cells. Here, we report that the biological functions of SRPX2 include cellular migration and adhesion to cancer cells. (c) 2008 Wiley-Liss, Inc.
  • Kazuhiko Nakagawa; Hironobu Minami; Masayuki Kanezaki; Akihira Mukaiyama; Yoshiyuki Minamide; Hisao Uejima; Takayasu Kurata; Toshiji Nogami; Kenji Kawada; Hirofumi Mukai; Yasutsuna Sasaki; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 39 2 116 - 123 2009年02月 [査読有り]
     
    The Phase I dose-escalation study was conducted to evaluate the safety and pharmacokinetics of lapatinib (GW572016), a dual ErbB-1 and -2 inhibitor, in Japanese patients with solid tumors that generally express ErbB-1 and/or overexpress ErbB-2. Patients received oral lapatinib once daily until disease progression or in an event of unacceptable toxicity. Twenty-four patients received lapatinib at dose levels of 900, 1200, 1600 and 1800 mg/day; six subjects enrolled to each dose level. The majority of drug-related adverse events was mild (Grade 1-2); the most common events were diarrhea (16 of 24; 67%), rash (13 of 24; 54%) and dry skin (8 of 24; 33%). No Grade 4 adverse event was observed. There were four Grade 3 drug-related adverse events in three patients (i.e. two events of diarrhea at 1600 and 1800 mg/day each and gamma-glutamyl transpeptidase increase at 1800 mg/day). The maximum tolerated dose was 1800 mg/day. The pharmacokinetic profile of lapatinib in Japanese patients was comparable to that of western subjects. Lapatinib was well tolerated at doses of 900-1600 mg/day in Japanese solid tumor patients. Overall, our findings were similar to those of overseas studies.
  • Takafumi Okabe; Isamu Okamoto; Sayaka Tsukioka; Junji Uchida; Erina Hatashita; Yuki Yamada; Takeshi Yoshida; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Jaenne; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 15 3 907 - 913 2009年02月 [査読有り]
     
    Purpose: Most non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET protooncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines. Experimental Design: The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice. Results: Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-flucrouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, bur. not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification. Conclusions: Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.
  • Kazuhiko Nakagawa; Hironobu Minami; Masayuki Kanezaki; Akihira Mukaiyama; Yoshiyuki Minamide; Hisao Uejima; Takayasu Kurata; Toshiji Nogami; Kenji Kawada; Hirofumi Mukai; Yasutsuna Sasaki; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 39 2 116 - 123 2009年02月 [査読有り]
     
    The Phase I dose-escalation study was conducted to evaluate the safety and pharmacokinetics of lapatinib (GW572016), a dual ErbB-1 and -2 inhibitor, in Japanese patients with solid tumors that generally express ErbB-1 and/or overexpress ErbB-2. Patients received oral lapatinib once daily until disease progression or in an event of unacceptable toxicity. Twenty-four patients received lapatinib at dose levels of 900, 1200, 1600 and 1800 mg/day; six subjects enrolled to each dose level. The majority of drug-related adverse events was mild (Grade 1-2); the most common events were diarrhea (16 of 24; 67%), rash (13 of 24; 54%) and dry skin (8 of 24; 33%). No Grade 4 adverse event was observed. There were four Grade 3 drug-related adverse events in three patients (i.e. two events of diarrhea at 1600 and 1800 mg/day each and gamma-glutamyl transpeptidase increase at 1800 mg/day). The maximum tolerated dose was 1800 mg/day. The pharmacokinetic profile of lapatinib in Japanese patients was comparable to that of western subjects. Lapatinib was well tolerated at doses of 900-1600 mg/day in Japanese solid tumor patients. Overall, our findings were similar to those of overseas studies.
  • Takafumi Okabe; Isamu Okamoto; Sayaka Tsukioka; Junji Uchida; Erina Hatashita; Yuki Yamada; Takeshi Yoshida; Kazuto Nishio; Masahiro Fukuoka; Pasi A. Jaenne; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 15 3 907 - 913 2009年02月 [査読有り]
     
    Purpose: Most non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET protooncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines. Experimental Design: The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice. Results: Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-flucrouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, bur. not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification. Conclusions: Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.
  • 併用化学療法
    武田 真幸; 中川 和彦
    日本臨床 67 1 365 - 368 2009年01月
  • 光冨 徹哉; 片上 信之; 中川 和彦
    がん分子標的治療 7 1 10 - 17 (株)メディカルレビュー社 2009年01月 
    最近の臨床試験によって、進行非小細胞肺がん(NSCLC)のなかでも腺がんでは、EGFR-TKIが予後を大きく延長させることが明らかになってきた。アジア9ヵ国で行われたIPASS試験では、非喫煙/過去軽度喫煙者、腺がんといった臨床背景因子によって選択された進行NSCLC患者において、ファーストラインとしてのゲフィチニブのPFSでの優越性が示された。さらに、サブセット解析で、EGFR遺伝子変異が陽性の患者と陰性の患者では、EGFR-TKIに対する感受性に大きな違いがあることが確認された。また、EGFR遺伝子変異陽性患者を対象とした7つの第II相臨床試験を統合解析したI-CAMP研究でも、IPASS試験の結果と類似したデータが得られている。未治療の進行NSCLCを対象としたWJTOGO203試験でも、腺がんにおけるサブセット解析で、標準化学療法の後にゲフィチニブを逐次投与した群のほうが、化学療法のみの群に比べて生存期間が有意に延長していた。これらの臨床試験の成果から、EGFR遺伝子変異が陽性の患者ではゲフィチニブをはじめとするEGFR-TKIが有効であるが、陰性の患者に対しては、他の分子標的薬などを検討する必要性がみえてきた。また、EGFR-TKIと化学療法との併用療法や患者選別のための分子マーカーも今後の課題となっている。将来、肺がん患者がさらに増加することが予想されており、トランスレーショナルリサーチを充実させるとともに、早急に治療方法を探究していかなくてはならない。(著者抄録)
  • Yasuko Ichikawa; Isamu Okamoto; Kazuhiko Nakagawa
    Japanese Journal of Cancer and Chemotherapy 36 6 907 - 909 2009年 [査読有り]
     
    Cancer of unknown primary site (CUP) is not a rare entity for 3-5% of all malignant neoplasms. CUP is diagnosed with metastatic lesion so they are all in the advanced stage. The diagnosis is made by biopsy. Patients with CUP need to have a physical examination, basic blood examination and appropriate diagnostic imaging. Those are valuable for final diagnosis of primary site determination. Systemic chemotherapy is applied in many cases, but the standard therapeutic strategy has not yet been determined.
  • Inhibition of Insulin‐Like growth factor 1 receptor by CP-751,871 radiosensitizes Non-Small cell lung cancer cells.
    Iwasa,T; Okamoto,I; Suzuki,M; Hatashita,E; Yamada,Y; Fukuoka,M; Ono,K; Nakagawa,K
    Clin Cancer Res 15 16 5117 - 5125 2009年 [査読有り]
  • Jane E. Latz; Karen Lee Schneck; Kazuhiko Nakagawa; Mary Alice Miller; Chris H. Taki Moto
    CLINICAL CANCER RESEARCH 15 1 346 - 354 2009年01月 [査読有り]
     
    Purpose: The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semi mechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. Experimental Design: An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin 1312, and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Results: Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. Conclusions: The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.
  • Kaoru Kubota; Yutaka Nishiwaki; Tomohide Tamura; Kazuhiko Nakagawa; Kaoru Matsui; Koshiro Watanabe; Toyoaki Hida; Masaaki Kawahara; Nobuyuki Katakami; Kohi Takeda; Akira Yokoyama; Kazumasa Noda; Masahiro Fukuoka; Nagahiro Saijo
    JOURNAL OF THORACIC ONCOLOGY 3 12 1439 - 1445 2008年12月 [査読有り]
     
    Introduction: The aim of this study was to evaluate the efficacy and safety of Erlotinib in Japanese patients with previously treated non-small cell lung cancer (NSCLC). Available tumor biopsy samples were analyzed to examine relationships between biomarkers and clinical outcome. Methods: This open-label phase II trial enrolled stage III/IV NSCLC patients who had progressive disease after at least one prior platinum-based chemotherapy regimen. Erlotinib was administered at a close of 150 mg/d orally until disease progression or intolerable toxicity. Analysis of epidermal growth factor receptor gene mutations in exon 18-21 by direct sequencing was performed in tumor tissue specimens obtained at the first diagnosis. Results: Sixty-two patients were enrolled and 60 patients were evaluable for efficacy. Objective response rate and disease control rate were 28.3% and 50.0%; median little to progression and overall Survival were 77 days and 14.7 months, respectively. In logistic regression analysis, only smoking history was proved to be a statistically significant predictive factor for response (odds ratio: 0.06, p < 0.001). Only 7 patients had samples available for mutation analysis. Three patients who had deletion Mutations oil exert 19 (del E746-A750 or del S752-1759) exhibited objective response. Common toxicities were rash (98%), dry skin (81%), and diarrhea (74%). Discontinuation clue to adverse events occurred in 11 patients (18%). Four patients (6%) experienced interstitial king disease-like events, one of whom died. Conclusion: Erlotinib is efficacious in Japanese patients with previously treated NSCLC. The toxicity profile was similar to that in Western patients, except for a somewhat higher incidence of skin disorders and interstitial lung disease. Further Studies arc needed to determine the relationship between epidermal growth factor receptor Mutations and outcomes with Erlotinib in Japanese patients.
  • Takeshi Yoshida; Isamu Okamoto; Tsutomu Iwasa; Masahiro Fukuoka; Kazuhiko Nakagawa
    FEBS LETTERS 582 30 4125 - 4130 2008年12月 [査読有り]
     
    Cisplatin is a key agent in combination chemotherapy for various types of solid tumor. We now show that cisplatin activates signaling by the epidermal growth factor receptor (EGFR) by inducing cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF). Matuzumab, a monoclonal antibody to EGFR, inhibited cisplatin-induced EGFR signaling, likely through competition with the soluble form of HB-EGF for binding to EGFR. Matuzumab enhanced the antitumor effect of cisplatin in nude mice harboring human non-small cell lung cancer xenografts. Our findings shed light on the mechanism by which monoclonal antibodies to EGFR might augment the efficacy of cisplatin. Crown Copyright (c) 2008 Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. All rights reserved.
  • Ryotaro Morinaga; Isamu Okamoto; Yoshihiko Fujita; Tokuzo Arao; Masaru Sekijima; Kazuto Nishio; Hiroyuki Ito; Masahiro Fukuoka; Jun-ichi Kadota; Kazuhiko Nakagawa
    CANCER SCIENCE 99 12 2455 - 2460 2008年12月 [査読有り]
     
    Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC. (Cancer Sci 2008; 99: 2455-2460).
  • Ryotaro Morinaga; Isamu Okamoto; Yoshihiko Fujita; Tokuzo Arao; Masaru Sekijima; Kazuto Nishio; Hiroyuki Ito; Masahiro Fukuoka; Jun-ichi Kadota; Kazuhiko Nakagawa
    CANCER SCIENCE 99 12 2455 - 2460 2008年12月 [査読有り]
     
    Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the response to EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Increased EGFR copy number has also been associated with sensitivity to these drugs. However, given that it is often difficult to obtain sufficient amounts of tumor tissue for genetic analysis from patients with advanced NSCLC, the relationship between these two types of EGFR alterations has remained unclear. We have now evaluated EGFR mutation status both by direct sequencing and with a high-sensitivity assay, the Scorpion-amplification-refractory mutation system, and have determined EGFR copy number by fluorescence in situ hybridization (FISH) analysis in paired tumor specimens obtained from 100 consecutive patients with advanced NSCLC treated with chemotherapy. EGFR mutations or FISH positivity (EGFR amplification or high polysomy) were apparent in 18% (18/100) and 32% (32/100) of patients, respectively. The Scorpion-amplification-refractory mutation system was more sensitive than direct sequencing for the detection of EGFR mutations. Furthermore, EGFR mutations were associated with EGFR amplification (P = 0.009) but not with FISH positivity (P = 0.266). Our results therefore suggest the existence of a significant association between EGFR mutation and EGFR amplification in patients with advanced NSCLC. (Cancer Sci 2008; 99: 2455-2460).
  • Takeshi Yoshida; Isamu Okamoto; Tsutomu Iwasa; Masahiro Fukuoka; Kazuhiko Nakagawa
    FEBS LETTERS 582 30 4125 - 4130 2008年12月 [査読有り]
     
    Cisplatin is a key agent in combination chemotherapy for various types of solid tumor. We now show that cisplatin activates signaling by the epidermal growth factor receptor (EGFR) by inducing cleavage of heparin-binding epidermal growth factor-like growth factor (HB-EGF). Matuzumab, a monoclonal antibody to EGFR, inhibited cisplatin-induced EGFR signaling, likely through competition with the soluble form of HB-EGF for binding to EGFR. Matuzumab enhanced the antitumor effect of cisplatin in nude mice harboring human non-small cell lung cancer xenografts. Our findings shed light on the mechanism by which monoclonal antibodies to EGFR might augment the efficacy of cisplatin. Crown Copyright (c) 2008 Published by Elsevier B. V. on behalf of the Federation of European Biochemical Societies. All rights reserved.
  • Kaoru Kubota; Yutaka Nishiwaki; Tomohide Tamura; Kazuhiko Nakagawa; Kaoru Matsui; Koshiro Watanabe; Toyoaki Hida; Masaaki Kawahara; Nobuyuki Katakami; Kohi Takeda; Akira Yokoyama; Kazumasa Noda; Masahiro Fukuoka; Nagahiro Saijo
    JOURNAL OF THORACIC ONCOLOGY 3 12 1439 - 1445 2008年12月 [査読有り]
     
    Introduction: The aim of this study was to evaluate the efficacy and safety of Erlotinib in Japanese patients with previously treated non-small cell lung cancer (NSCLC). Available tumor biopsy samples were analyzed to examine relationships between biomarkers and clinical outcome. Methods: This open-label phase II trial enrolled stage III/IV NSCLC patients who had progressive disease after at least one prior platinum-based chemotherapy regimen. Erlotinib was administered at a close of 150 mg/d orally until disease progression or intolerable toxicity. Analysis of epidermal growth factor receptor gene mutations in exon 18-21 by direct sequencing was performed in tumor tissue specimens obtained at the first diagnosis. Results: Sixty-two patients were enrolled and 60 patients were evaluable for efficacy. Objective response rate and disease control rate were 28.3% and 50.0%; median little to progression and overall Survival were 77 days and 14.7 months, respectively. In logistic regression analysis, only smoking history was proved to be a statistically significant predictive factor for response (odds ratio: 0.06, p < 0.001). Only 7 patients had samples available for mutation analysis. Three patients who had deletion Mutations oil exert 19 (del E746-A750 or del S752-1759) exhibited objective response. Common toxicities were rash (98%), dry skin (81%), and diarrhea (74%). Discontinuation clue to adverse events occurred in 11 patients (18%). Four patients (6%) experienced interstitial king disease-like events, one of whom died. Conclusion: Erlotinib is efficacious in Japanese patients with previously treated NSCLC. The toxicity profile was similar to that in Western patients, except for a somewhat higher incidence of skin disorders and interstitial lung disease. Further Studies arc needed to determine the relationship between epidermal growth factor receptor Mutations and outcomes with Erlotinib in Japanese patients.
  • 大学病院における外来化学療法センターの運営
    今野 元博; 奥野 清隆; 上嶋 一臣; 岡本 勇; 辰己 陽一; 愼 玉姫; 藤原 季美子; 野村 守; 山添 譲; 渡部 洋; 中川 和彦; 塩崎 均
    日本癌治療学会誌 43 2 513 - 513 (一社)日本癌治療学会 2008年10月
  • Tsutomu Iwasa; Isamu Okamoto; Minoru Suzuki; Takahito Nakahara; Kentaro Yamanaka; Erina Hatashita; Yuki Yamada; Masahiro Fukuoka; Koji Ono; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 14 20 6496 - 6504 2008年10月 [査読有り]
     
    Purpose: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to gamma-radiation. Experimental Design: The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation. Results: YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration-and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to gamma-radiation in vitro. The combination of YM155 and gamma-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunof luorescence analysis of histone gamma-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and gamma-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. Conclusions: These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.
  • Tsutomu Iwasa; Isamu Okamoto; Minoru Suzuki; Takahito Nakahara; Kentaro Yamanaka; Erina Hatashita; Yuki Yamada; Masahiro Fukuoka; Koji Ono; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 14 20 6496 - 6504 2008年10月 [査読有り]
     
    Purpose: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to gamma-radiation. Experimental Design: The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation. Results: YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration-and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to gamma-radiation in vitro. The combination of YM155 and gamma-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunof luorescence analysis of histone gamma-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and gamma-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. Conclusions: These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.
  • Ken Takezawa; Isamu Okamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 3 9 1073 - 1075 2008年09月 [査読有り]
     
    Cancer chemotherapy is not well established for patients on hemodialysis (HD). A 77-year-old man on HD presented with small cell lung cancer. He was treated with the combination of carboplatin and etoposide while the pharmacokinetics of the drugs were monitored. The patient showed a response with manageable toxicity and remained progression free for at least 8 months. The area Under the concentration-time curve for each antitumor agent in the patient was within the therapeutic range achieved in individuals With normal renal function. Carboplatin and etoposide chemotherapy combined with HD thus allowed the drugs to achieve an appropriate area under the concentration-time curve and sufficient efficacy in a small cell lung cancer patient with chronic renal failure.
  • Satomi Yakushiji; Ukihide Tateishi; Shunji Nagai; Yoshihiro Matsuno; Kazuo Nakagawa; Hisao Asamura; Masahiko Kusumoto
    JOURNAL OF COMPUTER ASSISTED TOMOGRAPHY 32 5 799 - 805 2008年09月 [査読有り]
     
    Objective: To determine which computed tomographic findings are associated with high-risk thymic epithelial tumors mid a poor prognosis. Methods: Computed tomographic findings of thymic epithelial neoplasms were retrospectively evaluated in 75 patients diagnosed with thymic tumor between January 1997 and October 2003. We analyzed the correlation of the computed tomographic findings, histological subtype according to the World Health Organization classification, and the prognosis. Results: There were 34 with type A similar to B1 turnor and 41 with type B2 similar to C Minor. On multiple regression analysis, vascular obliteration and a blunt sternum-anterior mediastinum angle were more frequent with thymic carcinoma than with thymoma. On multivariate analysis, pleural effusion and mediastinal fat infiltration on initial computed tomography had a significant impact on survival. Conclusions: Vascular obliteration and a blunt sternum-anterior mediastinum angle were predictive of thymic carcinoma. Pleural effusion and mediastinal fat infiltration were predictive of a poor prognosis.
  • H. Kunitoh; H. Kato; M. Tsuboi; H. Asamura; H. Tada; K. Nagai; T. Mitsudomi; T. Koike; K. Nakagawa; Y. Ichinose; M. Okada; T. Shibata; N. Saijo
    BRITISH JOURNAL OF CANCER 99 6 852 - 857 2008年09月 [査読有り]
     
    Preoperative chemotherapy is a promising strategy in patients with early-stage resectable non-small-cell lung cancer (NSCLC); optimal chemotherapy remains unclear. Clinical (c-) stage IB/II NSCLC patients were randomised to receive either two cycles of docetaxel (D)-cisplatin (P) combination chemotherapy (D 60 mg m(-2) and P 80 mg m(-2) on day 1) every 3-4 weeks or three cycles of D monotherapy (70 mg m(-2)) every 3 weeks. Thoracotomy was performed 4-5 weeks (DP) or 3-4 weeks (D) after chemotherapy. The primary end point was 1-year disease-free survival (DFS). From October 2002 to November 2003, 80 patients were randomised. Chemotherapy toxicities were mainly haematologic and well tolerated. There were two early postoperative deaths with DP (one intraoperative bleeding and one empyema). Pathologic complete response was observed in two DP patients. Docetaxel-cisplatin was superior to D in terms of response rate (45 vs 15%) and complete resection rate (95 vs 87%). Both DFS and overall survival were better in DP. Disease-free survival at 1, 2 and 4 years were 78, 65 and 57% with DP, and were 62, 44 and 36% with D, respectively. Preoperative DP was associated with encouraging resection rate and DFS data, and phase III trials for c-stage IB/II NSCLC are warranted.
  • Endo M; Nakagawa K; Ohde Y; Okumura T; Kondo H; Igawa S; Nakamura Y; Tsuya A; Murakami H; Takahashi T; Yamamoto N; Ito I; Kameya T
    Lung cancer (Amsterdam, Netherlands) 61 3 350 - 355 2008年09月 [査読有り]
  • Ken Takezawa; Isamu Okamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 3 9 1073 - 1075 2008年09月 [査読有り]
     
    Cancer chemotherapy is not well established for patients on hemodialysis (HD). A 77-year-old man on HD presented with small cell lung cancer. He was treated with the combination of carboplatin and etoposide while the pharmacokinetics of the drugs were monitored. The patient showed a response with manageable toxicity and remained progression free for at least 8 months. The area Under the concentration-time curve for each antitumor agent in the patient was within the therapeutic range achieved in individuals With normal renal function. Carboplatin and etoposide chemotherapy combined with HD thus allowed the drugs to achieve an appropriate area under the concentration-time curve and sufficient efficacy in a small cell lung cancer patient with chronic renal failure.
  • Riichiroh Maruyama; Yutaka Nishiwaki; Tomohide Tamura; Nobuyuki Yamamoto; Masahiro Tsuboi; Kazuhiko Nakagawa; Tetsu Shinkai; Shunichi Negoro; Fumio Imamura; Kenji Eguchi; Koji Takeda; Akira Inoue; Keisuke Tomii; Masao Harada; Noriyuki Masuda; Haiyi Jiang; Yohji Itoh; Yukito Ichinose; Nagahiro Saijo; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 26 26 4244 - 4252 2008年09月 [査読有り]
     
    Purpose This phase III study (V-15-32) compared gefitinib (250 mg/d) with docetaxel (60 mg/m(2)) in patients (N = 489) with advanced/metastatic non-small-cell lung cancer (NSCLC) who had failed one or two chemotherapy regimens. Methods The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel. An unadjusted Cox regression model was used for the primary analysis. Results Noninferiority in overall survival was not achieved (hazard ratio [HR], 1.12; 95.24% CI, 0.89 to 1.40) according to the predefined criterion (upper CI limit for HR <= 1.25); however, no significant difference in overall survival (P = .330) was apparent between treatments. Poststudy, 36% of gefitinib-treated patients received subsequent docetaxel, and 53% of docetaxel-treated patients received subsequent gefitinib. Gefitinib significantly improved objective response rate and quality of life versus docetaxel; progression-free survival, disease control rates, and symptom improvement were similar for the two treatments. Grades 3 to 4 adverse events occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of patients. Incidence of interstitial lung disease was 5.7% (gefitinib) and 2.9% (docetaxel). Four deaths occurred due to adverse events in the gefitinib arm (three deaths as a result of interstitial lung disease, judged to be treatment related; one as a result of pneumonia, not treatment related), and none occurred in the docetaxel arm. Conclusion Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria; however, there was no statistically significant difference in overall survival. Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel. Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC.
  • Riichiroh Maruyama; Yutaka Nishiwaki; Tomohide Tamura; Nobuyuki Yamamoto; Masahiro Tsuboi; Kazuhiko Nakagawa; Tetsu Shinkai; Shunichi Negoro; Fumio Imamura; Kenji Eguchi; Koji Takeda; Akira Inoue; Keisuke Tomii; Masao Harada; Noriyuki Masuda; Haiyi Jiang; Yohji Itoh; Yukito Ichinose; Nagahiro Saijo; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 26 26 4244 - 4252 2008年09月 [査読有り]
     
    Purpose This phase III study (V-15-32) compared gefitinib (250 mg/d) with docetaxel (60 mg/m(2)) in patients (N = 489) with advanced/metastatic non-small-cell lung cancer (NSCLC) who had failed one or two chemotherapy regimens. Methods The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel. An unadjusted Cox regression model was used for the primary analysis. Results Noninferiority in overall survival was not achieved (hazard ratio [HR], 1.12; 95.24% CI, 0.89 to 1.40) according to the predefined criterion (upper CI limit for HR <= 1.25); however, no significant difference in overall survival (P = .330) was apparent between treatments. Poststudy, 36% of gefitinib-treated patients received subsequent docetaxel, and 53% of docetaxel-treated patients received subsequent gefitinib. Gefitinib significantly improved objective response rate and quality of life versus docetaxel; progression-free survival, disease control rates, and symptom improvement were similar for the two treatments. Grades 3 to 4 adverse events occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of patients. Incidence of interstitial lung disease was 5.7% (gefitinib) and 2.9% (docetaxel). Four deaths occurred due to adverse events in the gefitinib arm (three deaths as a result of interstitial lung disease, judged to be treatment related; one as a result of pneumonia, not treatment related), and none occurred in the docetaxel arm. Conclusion Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria; however, there was no statistically significant difference in overall survival. Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel. Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC.
  • Isamu Okamoto; Takashi Nishimura; Masaki Miyazaki; Hiroshige Yoshioka; Akihito Kubo; Koji Takeda; Noriyuki Ebi; Shunichi Sugawara; Nobuyuki Katakami; Masahiro Fukuoka; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 14 16 5250 - 5254 2008年08月 [査読有り]
     
    Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC. Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m(2)) on day 1 and with oral S-1 (80 mg/m(2)) on days 1 to 14 every 3 weeks. Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment, Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.
  • Isamu Okamoto; Takashi Nishimura; Masaki Miyazaki; Hiroshige Yoshioka; Akihito Kubo; Koji Takeda; Noriyuki Ebi; Shunichi Sugawara; Nobuyuki Katakami; Masahiro Fukuoka; Kazuhiko Nakagawa
    CLINICAL CANCER RESEARCH 14 16 5250 - 5254 2008年08月 [査読有り]
     
    Purpose: To evaluate the efficacy and toxicity of combination therapy with the oral fluoropyrimidine formulation S-1 and irinotecan for patients with advanced NSCLC. Experimental Design: Chemotherapy-naive patients with advanced NSCLC were treated with i.v. irinotecan (150 mg/m(2)) on day 1 and with oral S-1 (80 mg/m(2)) on days 1 to 14 every 3 weeks. Results: Fifty-six patients (median age, 63 years; range, 40-74 years) received a total of 286 treatment cycles (median, 5; range, 1-15). No complete responses and 16 partial responses were observed, giving an overall response rate of 28.6% [95% confidence interval (95% CI), 17.3-42.2%]. Twenty-four patients (42.9%) had stable disease and 12 patients (21.4%) had progressive disease as the best response. The overall disease control rate (complete response + partial response + stable disease) was thus 71.4% (95% CI, 57.8-82.7%). Median progression-free survival was 4.9 months (95% CI, 4.0-6.4 months), whereas median overall survival was 15 months. Hematologic toxicities of grade 3 or 4 included neutropenia (25%), thrombocytopenia (3.6%), and anemia (3.6%), with febrile neutropenia being observed in four patients (7.1%). The most common nonhematologic toxicities of grade 3 or 4 included anorexia (14.3%), fatigue (8.9%), and diarrhea (8.9%). There were no deaths attributed to treatment, Conclusions: The combination of S-1 and irinotecan is a potential alternative option with a favorable toxicity profile for the treatment of advanced NSCLC. This nonplatinum regimen warrants further evaluation in randomized trials.
  • Masafumi Kawamura; Jun Nakajima; Haruhisa Matsuguma; Hirotoshi Horio; Shinichiro Miyoshi; Ken Nakagawa; Takehiko Fujisawa; Koichi Kobayashi
    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 34 1 196 - 199 2008年07月 [査読有り]
     
    Background: Although favourable prognosis following aggressive treatment of extrahepatic metastases from hepatocellular carcinoma (HCC) has been reported, surgical outcomes for pulmonary metastases are unclear. Methods and materials: Sixty-one patients (2.6%) of 2297 registered with the Metastatic Lung Tumor Study Group of Japan between 1990 and 2006, who underwent surgery for pulmonary metastases from HCC, were retrospectively reviewed from the registry. Results: The overall 5-year survival rate was 32.2%. The prognosis was significantly better for <= 2 lesions than for >= 3 lesions (p = 0.046), for <= 3 lesions than for >= 4 lesions (p = 0.0070), and for <= 4 Lesions than for >= 5 lesions (p = 0.029). No other factors that influence outcomes were identified. A stepwise regression analysis showed three or less pulmonary metastases to be an independent factor for better prognosis (p = 0.048). Conclusion: With careful patient selection, comparatively good outcomes can be expected following surgical resection of pulmonary HCC metastases. Among them, patients with multiple metastases, if number of metastases is small such as four or less, can be expected to survive tong after surgery. (C) 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.
  • Yuichiro Ohe; Yukito Ichinose; Kazuhiko Nakagawa; Tomohicle Tamura; Kaoru Kubota; Nobuyuki Yamamoto; Susumu Adachi; Yoshihiro Nambu; Toshio Fujimoto; Yutaka Nishiwaki; Nagahiro Saijo; Masahiro Fukuoka
    CLINICAL CANCER RESEARCH 14 13 4206 - 4212 2008年07月 [査読有り]
     
    Purpose: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B-12 in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). Experimental Design: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pernetrexed (P1000) on day 1 every 3 weeks. The primary endpoint Was response rate. Results: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pernetrexed dose was not a significant prognostic factor. Drug-related toxicity Was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%),WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. Conclusion: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.
  • Yuichiro Ohe; Yukito Ichinose; Kazuhiko Nakagawa; Tomohicle Tamura; Kaoru Kubota; Nobuyuki Yamamoto; Susumu Adachi; Yoshihiro Nambu; Toshio Fujimoto; Yutaka Nishiwaki; Nagahiro Saijo; Masahiro Fukuoka
    CLINICAL CANCER RESEARCH 14 13 4206 - 4212 2008年07月 [査読有り]
     
    Purpose: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B-12 in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC). Experimental Design: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m(2) pemetrexed (P500) or 1,000 mg/m(2) pernetrexed (P1000) on day 1 every 3 weeks. The primary endpoint Was response rate. Results: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pernetrexed dose was not a significant prognostic factor. Drug-related toxicity Was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%),WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500. Conclusion: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.
  • J. P. Koivunen; J. Kim; J. Lee; A. M. Rogers; J. O. Park; X. Zhao; K. Naoki; I. Okamoto; K. Nakagawa; B. Y. Yeap; M. Meyerson; K-K Wong; W. G. Richards; D. J. Sugarbaker; B. E. Johnson; P. A. Jaenne
    BRITISH JOURNAL OF CANCER 99 2 245 - 252 2008年07月 [査読有り]
     
    Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n = 143) and Korean (n = 167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT-PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P = 0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P = 0.066). LKB1 mutations associated with smoking history (P = 0.007) and KRAS mutations (P = 0.042) were almost mutually exclusive with EGFR mutations (P = 0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations.
  • 【肺癌 診療最前線 がん対策基本法で何が変わった】基礎的話題 肺癌の新薬開発状況
    鶴谷 純司; 中川 和彦
    Modern Physician 28 6 840 - 844 (株)新興医学出版社 2008年06月
  • Shoji Kudoh; Harubumi Kato; Yutaka Nishiwaki; Masahiro Fukuoka; Kouichiro Nakata; Yukito Ichinose; Masahiro Tsuboi; Soichiro Yokota; Kazuhiko Nakagawa; Moritaka Suga; Haiyi Jiang; Yohji Itoh; Alison Armour; Claire Watkins; Tim Higenbottam; Fredrik Nyberg
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 177 12 1348 - 1357 2008年06月 [査読有り]
     
    Rationale: Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib. Objectives: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. Methods: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. Measurements and Main Results: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2). Conclusions: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.
  • Shoji Kudoh; Harubumi Kato; Yutaka Nishiwaki; Masahiro Fukuoka; Kouichiro Nakata; Yukito Ichinose; Masahiro Tsuboi; Soichiro Yokota; Kazuhiko Nakagawa; Moritaka Suga; Haiyi Jiang; Yohji Itoh; Alison Armour; Claire Watkins; Tim Higenbottam; Fredrik Nyberg
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 177 12 1348 - 1357 2008年06月 [査読有り]
     
    Rationale: Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib. Objectives: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. Methods: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. Measurements and Main Results: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2). Conclusions: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.
  • Kazuhiko Nakagawa; Koichi Yamazaki; Hideo Kunitoh; Toyoaki Hida; Kenichi Gemba; Tetsu Shinkai; Yukito Ichinose; Susumu Adachi; Yoshihiro Nambu; Nagahiro Saijo; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 38 5 339 - 346 2008年05月 [査読有り]
     
    Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0-1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) (Level 1), were studied in the dose-escalation Phase I (Step 1). The RD determined in Step 1 was carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18-38. Results: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level -1 (pemetrexed 500 mg/m(2), cisplatin 60 mg/m(2)). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3-61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. Conclusion: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.
  • Kazuhiko Nakagawa; Koichi Yamazaki; Hideo Kunitoh; Toyoaki Hida; Kenichi Gemba; Tetsu Shinkai; Yukito Ichinose; Susumu Adachi; Yoshihiro Nambu; Nagahiro Saijo; Masahiro Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 38 5 339 - 346 2008年05月 [査読有り]
     
    Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0-1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) (Level 1), were studied in the dose-escalation Phase I (Step 1). The RD determined in Step 1 was carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18-38. Results: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level -1 (pemetrexed 500 mg/m(2), cisplatin 60 mg/m(2)). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3-61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. Conclusion: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.
  • Katsuyuki Kiura; Kazuhiko Nakagawa; Tetsu Shinkai; Kenji Eguchi; Yuichiro Ohe; Nobuyuki Yamamoto; Masahiro Tsuboi; Soichiro Yokota; Takashi Seto; Haiyi Jiang; Kazuto Nishio; Nagahiro Saijo; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 3 4 386 - 393 2008年04月 [査読有り]
     
    Introduction: Vandetanib (ZACTIMA (TM)) is a once-daily, oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. Vandetanib was evaluated as a monotherapy in a randomized, double-blind, dose-finding study in Japan. Patients and Methods: Eligible patients with locally advanced or metastatic (stage IIIB/lV) or recurrent non-small cell lung cancer, previously treated with chemotherapy, were randomized to receive once-daily oral vandetanib 100, 200, or 300 mg (1: 1: 1). The primary objective was to determine the objective response rate for each vandetanib dose. Results: Fifty-three patients received vandetanib (100 mg, n = 17; 200 mg, n = 18; 300 mg, n = 18). The objective response rate in each dose arm was 17.6% (3 of 17; 100 mg), 5.6% (1 of 18; 200 mg), and 16.7% (3 of 18; 300 mg). Common adverse events included rash, diarrhea, hypertension, and asymptomatic, QTc prolongation. The adverse event profile was generally consistent with that reported previously for agents that inhibit the VEGFR or EGFR signaling pathways. Among the three responders evaluated for EGFR mutation, two had no mutation, and in one case, the EGFR mutation status could not be determined by direct DNA sequencing and amplification refractory mutation system assay of EGFR exons 19-21. Baseline plasma VEGF levels appeared to be lower in patients who experienced clinical benefit after vandetanib treatment. Conclusion: In Japanese patients with advanced non-small cell lung cancer, vandetanib monotherapy (100-300 mg/d) demonstrated antitumor activity with an acceptable safety and tolerability profile.
  • Takeshi Yoshida; Isamu Okamoto; Takafumi Okabe; Tsutomu Iwasa; Taroh Satoh; Kazuto Nishio; Masahiro Fukuoka; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CANCER 122 7 1530 - 1538 2008年04月 [査読有り]
     
    Molecular inhibition of the epidermal growth factor receptor (EGFR) is a promising anticancer strategy, and monoclonal antibodies (mAbs) to EGFR are undergoing extensive evaluation in preclinical and clinical trials. However, the effects of anti-EGFR mAbs on EGFR signaling have remained unclear. We have now examined the effects of 2 anti-EGFR mAbs, matuzumab (EMD72000) and cetuximab (Erbitux), both of which are currently under assessment for treatment of various cancers, on EGFR signal transduction and cell survival in nonsmall cell lung cancer cell lines. Similar to EGF, matuzumab and cetuximab each induced phosphorylation of EGFR at several tyrosine phosphorylation sites as a result of receptor dimerization and activation of the receptor tyrosine kinase. In contrast to the effects of EGF, however, EGFR activation induced by these antibodies was not accompanied by receptor turnover or by activation of downstream signaling pathways that are mediated by Akt and Erk and are important for regulation of cell proliferation and survival. In addition, clonogenic survival assays revealed that matuzumab and cetuximab reduced the survival rate of H292 cells, in which they also inhibited the EGF-induced activation of Akt and Erk. Although we have examined only a few cell lines, our results indicate that the antitumor effects of matuzumab and cetuximab depend on inhibition of EGFR downstream signaling mediated by Akt or Erk rather than on inhibition of EGFR itself. (c) 2007 Wiley-Liss, Inc.
  • Takeshi Yoshida; Isamu Okamoto; Takafumi Okabe; Tsutomu Iwasa; Taroh Satoh; Kazuto Nishio; Masahiro Fukuoka; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CANCER 122 7 1530 - 1538 2008年04月 [査読有り]
     
    Molecular inhibition of the epidermal growth factor receptor (EGFR) is a promising anticancer strategy, and monoclonal antibodies (mAbs) to EGFR are undergoing extensive evaluation in preclinical and clinical trials. However, the effects of anti-EGFR mAbs on EGFR signaling have remained unclear. We have now examined the effects of 2 anti-EGFR mAbs, matuzumab (EMD72000) and cetuximab (Erbitux), both of which are currently under assessment for treatment of various cancers, on EGFR signal transduction and cell survival in nonsmall cell lung cancer cell lines. Similar to EGF, matuzumab and cetuximab each induced phosphorylation of EGFR at several tyrosine phosphorylation sites as a result of receptor dimerization and activation of the receptor tyrosine kinase. In contrast to the effects of EGF, however, EGFR activation induced by these antibodies was not accompanied by receptor turnover or by activation of downstream signaling pathways that are mediated by Akt and Erk and are important for regulation of cell proliferation and survival. In addition, clonogenic survival assays revealed that matuzumab and cetuximab reduced the survival rate of H292 cells, in which they also inhibited the EGF-induced activation of Akt and Erk. Although we have examined only a few cell lines, our results indicate that the antitumor effects of matuzumab and cetuximab depend on inhibition of EGFR downstream signaling mediated by Akt or Erk rather than on inhibition of EGFR itself. (c) 2007 Wiley-Liss, Inc.
  • Katsuyuki Kiura; Kazuhiko Nakagawa; Tetsu Shinkai; Kenji Eguchi; Yuichiro Ohe; Nobuyuki Yamamoto; Masahiro Tsuboi; Soichiro Yokota; Takashi Seto; Haiyi Jiang; Kazuto Nishio; Nagahiro Saijo; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 3 4 386 - 393 2008年04月 [査読有り]
     
    Introduction: Vandetanib (ZACTIMA (TM)) is a once-daily, oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling. Vandetanib was evaluated as a monotherapy in a randomized, double-blind, dose-finding study in Japan. Patients and Methods: Eligible patients with locally advanced or metastatic (stage IIIB/lV) or recurrent non-small cell lung cancer, previously treated with chemotherapy, were randomized to receive once-daily oral vandetanib 100, 200, or 300 mg (1: 1: 1). The primary objective was to determine the objective response rate for each vandetanib dose. Results: Fifty-three patients received vandetanib (100 mg, n = 17; 200 mg, n = 18; 300 mg, n = 18). The objective response rate in each dose arm was 17.6% (3 of 17; 100 mg), 5.6% (1 of 18; 200 mg), and 16.7% (3 of 18; 300 mg). Common adverse events included rash, diarrhea, hypertension, and asymptomatic, QTc prolongation. The adverse event profile was generally consistent with that reported previously for agents that inhibit the VEGFR or EGFR signaling pathways. Among the three responders evaluated for EGFR mutation, two had no mutation, and in one case, the EGFR mutation status could not be determined by direct DNA sequencing and amplification refractory mutation system assay of EGFR exons 19-21. Baseline plasma VEGF levels appeared to be lower in patients who experienced clinical benefit after vandetanib treatment. Conclusion: In Japanese patients with advanced non-small cell lung cancer, vandetanib monotherapy (100-300 mg/d) demonstrated antitumor activity with an acceptable safety and tolerability profile.
  • Fumiyoshi Ohyanagi; Atsushi Horiike; Yoshio Okano; Yukitoshi Satoh; Sakae Okumura; Yuichi Ishikawa; Ken Nakagawa; Takeshi Horai; Makoto Nishio
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 61 3 503 - 508 2008年03月 [査読有り]
     
    Purpose To investigate the activity of gemcitabine combined with irinotecan in patients with relapsed small cell lung cancer (SCLC). Patients SCLC patients who had experienced treatment failure with one prior chemotherapy were eligible. Patients were required to have a performance status of 0-2 and adequate organ function. Treatment consisted of gemcitabine (1,000 mg/m(2)) and irinotecan (150 mg/m(2)) on days 1 and 15 of a 28 day cycle. Results Thirty-one patients were enrolled and 30 patients received protocol treatment (10 had refractory disease and 20 had sensitive disease). The median age was 64 years, and the median performance status was one. An objective response was obtained in 36.7% (95% CI: 17.3.1-56.0%) of the patients. The median overall survival time was 14.4 months, and the 1 year survival rate was 51%. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%). Conclusion Gemcitabine plus irinotecan is an active regimen that seems to be well-tolerated by patients with previously treated SCLC.
  • Takafumi Okabe; Isamu Okamoto; Sayaka Tsukioka; Junji Uchida; Tsutomu Iwasa; Takeshi Yoshida; Erina Hatashita; Yuki Yamada; Taroh Satoh; Kenji Tamura; Masahiro Fukuoka; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 7 3 599 - 606 2008年03月 [査読有り]
     
    Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors.
  • Takafumi Okabe; Isamu Okamoto; Sayaka Tsukioka; Junji Uchida; Tsutomu Iwasa; Takeshi Yoshida; Erina Hatashita; Yuki Yamada; Taroh Satoh; Kenji Tamura; Masahiro Fukuoka; Kazuhiko Nakagawa
    MOLECULAR CANCER THERAPEUTICS 7 3 599 - 606 2008年03月 [査読有り]
     
    Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors.
  • Hideo Kunitoh; Harubumi Kato; Masahiro Tsuboi; Taro Shibata; Hisao Asamura; Yukito Ichonose; Nobuyuki Katakami; Kanji Nagai; Tetsuya Mitsudomi; Akihide Matsumura; Ken Nakagawa; Hirohito Tada; Nagahiro Saijo
    JOURNAL OF CLINICAL ONCOLOGY 26 4 644 - 649 2008年02月 [査読有り]
     
    Purpose To evaluate the safety and efficacy of preoperative chemoradiotherapy followed by surgical resection for superior sulcus tumors ( SSTs). Patients and Methods Patients with pathologically documented non-small-cell lung cancer with invasion of the first rib or more superior chest wall were enrolled as eligible; those with distant metastasis, pleural dissemination, and/or mediastinal node involvement were excluded. Patients received two cycles of chemotherapy every 4 weeks as follows; mitomycin 8 mg/m(2) on day 1, vindesine 3 mg/m(2) on days 1 and 8, and cisplatin 80 mg/m(2) on day 1. Radiotherapy directed at the tumor and the ipsilateral supraclavicular nodes was started on day 2 of each course, at the total dose of 45 Gy in 25 fractions, with a 1-week split. Thoracotomy was undertaken 2 to 4 weeks after completion of the chemoradiotherapy. Those with unresectable disease received boost radiotherapy. Results From May 1999 to November 2002, 76 patients were enrolled, of whom 20 had T4 disease; 75 patients were fully assessable. Chemoradiotherapy was generally well tolerated. Fifty-seven patients ( 76%) underwent surgical resection, and pathologic complete resection was achieved in 51 patients ( 68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths, including two deaths owing to postsurgical complications and one death owing to sepsis during chemoradiotherapy. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively. Conclusion This trimodality approach is safe and effective for the treatment of patients with SSTs.
  • Ken Takezawa; Isamu Okamoto; Junya Fukuoka; Kaoru Tanaka; Hiroyasu Kaneda; Hisao Uejima; Hyung-Eun Yoon; Masami Imakita; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 3 2 187 - 189 2008年02月 [査読有り]
     
    Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immuno-histochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.
  • Ken Takezawa; Isamu Okamoto; Junya Fukuoka; Kaoru Tanaka; Hiroyasu Kaneda; Hisao Uejima; Hyung-Eun Yoon; Masami Imakita; Masahiro Fukuoka; Kazuhiko Nakagawa
    JOURNAL OF THORACIC ONCOLOGY 3 2 187 - 189 2008年02月 [査読有り]
     
    Large cell neuroendocrine carcinoma (LCNEC) is a relatively new category of pulmonary neuroendocrine tumor. Although it was first detected in the lung, LCNEC has since been found in a variety of extrapulmonary sites. We now describe a patient who was diagnosed with LCNEC originating from the mediastinum, an extremely rare disorder. An increased serum concentration of alpha-fetoprotein (AFP) in the patient was reduced by chemotherapy in association with tumor shrinkage. Furthermore, the tumor was confirmed immuno-histochemically to produce AFP. To our knowledge, this is the first report of a LCNEC that produces AFP.
  • Y. Akashi; I. Okamoto; T. Iwasa; T. Yoshida; M. Suzuki; E. Hatashita; Y. Yamada; T. Satoh; M. Fukuoka; K. Ono; K. Nakagawa
    BRITISH JOURNAL OF CANCER 98 4 749 - 755 2008年02月 [査読有り]
     
    The expression and activity of the epidermal growth factor receptor (EGFR) are determinants of radiosensitivity in several tumour types, including non-small cell lung cancer (NSCLC). However, little is known of whether genetic alterations of EGFR in NSCLC cells affect the therapeutic response to monoclonal antibodies (mAbs) to EGFR in combination with radiation. We examined the effects of nimotuzumab, a humanised mAb to EGFR, in combination with ionising radiation on human NSCLC cell lines of differing EGFR status. Flow cytometry revealed that H292 and Ma-1 cells expressed high and moderate levels of EGFR on the cell surface, respectively, whereas H460, H1299, and H1975 cells showed a low level of surface EGFR expression. Immunoblot analysis revealed that EGFR phosphorylation was inhibited by nimotuzumab in H292 and Ma-1 cells but not in H460, H1299, or H1975 cells. Nimotuzumab augmented the cytotoxic effect of radiation in H292 and Ma-1 cells in a clonogenic assay in vitro, with a dose enhancement factor of 1.5 and 1.3, respectively. It also enhanced the antitumor effect of radiation on H292 and Ma-1 cell xenografts in nude mice, with an enhancement factor of 1.3 and 4.0, respectively. Nimotuzumab did not affect the radioresponse of H460 cells in vitro or in vivo. Nimotuzumab enhanced the antitumor efficacy of radiation in certain human NSCLC cell lines in vitro and in vivo. This effect may be related to the level of EGFR expression on the cell surface rather than to EGFR mutation.
  • I. Sekine; H. Nokihara; K. Takeda; Y. Nishiwaki; K. Nakagawa; H. Isobe; K. Mori; K. Matsui; N. Saijo; T. Tamura
    BRITISH JOURNAL OF CANCER 98 4 693 - 696 2008年02月 [査読有り]
     
    Patients with previously untreated extensive-disease small-cell lung cancer were treated with irinotecan 60 mgm(-2) on days 1 and 8 and cisplatin 60 mgm(-2) on day 1 with (n = 55) or without (n = 54) etoposide 50 mgm(-2) on days 1-3 with granulocyte colony-stimulating factor support repeated every 3 weeks for four cycles. The triplet regimen was too toxic to be considered for further studies.
  • [がん分子標的治療の最先端] 低分子阻害剤 サバイビンを標的とした新しい分子標的薬剤 YM155
    佐藤 太郎; 中川 和彦
    医学のあゆみ 224 1 93 - 96 2008年
  • Phase I Dose-escalation and Pharmacokinetic Trial of Lapatinib (GW572016), a Selective Oral Dual Inhibitor of ErbB-1 and -2 Tyrosine Kinases, in Japanese Patients with Solid Tumors.
    Nakagawa,K; Minami,H; Kanezaki,M; Mukaiyama,A; Minamide,Y; Uejima,H; Kurata,T; Nogami,T; Kawada,K; Mukai,H; Sasaki,Y; Fukuoka,M
    Jpn J Clin Oncol 39 2 116 - 123 2008年 [査読有り]
  • Ryotaro Morinaga; Isamu Okamoto; Kazuyuki Furuta; Yukiko Kawano; Masaru Sekijima; Kensaku Dote; Takao Satou; Kazuto Nishio; Masahiro Fukuoka; Kazuhiko Nakagawa
    LUNG CANCER 58 3 411 - 413 2007年12月 [査読有り]
     
    We report a case of small cell lung cancer (SCLC) developing after prolonged treatment (more than 2 years) for primary adenocarcinoma of the lung, and we show that both the SCLC and non-small cell lung cancer (NSCLC) tissues obtained from the same site share the same deletion in exon 19 of EGFR. This case suggests that the activating EGFR mutations may confer the pathogenesis of a subset of SCLC. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Ryotaro Morinaga; Isamu Okamoto; Kazuyuki Furuta; Yukiko Kawano; Masaru Sekijima; Kensaku Dote; Takao Satou; Kazuto Nishio; Masahiro Fukuoka; Kazuhiko Nakagawa
    LUNG CANCER 58 3 411 - 413 2007年12月 [査読有り]
     
    We report a case of small cell lung cancer (SCLC) developing after prolonged treatment (more than 2 years) for primary adenocarcinoma of the lung, and we show that both the SCLC and non-small cell lung cancer (NSCLC) tissues obtained from the same site share the same deletion in exon 19 of EGFR. This case suggests that the activating EGFR mutations may confer the pathogenesis of a subset of SCLC. (c) 2007 Elsevier Ireland Ltd. All rights reserved.
  • Yasumasa Nishimura; Kazuhiko Nakagawa; Koji Takeda; Masahiro Tanaka; Yoshihiko Segawa; Kayoko Tsujino; Shunichi Negoro; Nobukazu Fuwa; Toyoaki Hida; Masaaki Kawahara; Nobuyuki Katakami; Keiko Hirokawa; Nobuyuki Yamamoto; Masahiro Fukuoka; Yutaka Ariyoshi
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 69 3 786 - 792 2007年11月 [査読有り]
     
    Purpose: This Phase I/II trial was conducted to assess the efficacy and safety of PR-350, a novel hypoxic cell radiosensitizer, when administered with thoracic radiation therapy (RT) after induction chemotherapy (CT) for locally advanced non-small-cell lung cancer (NSCLC). Methods and Materials: Two cycles of cisplatin (80 mg/m(2)) and paclitaxel (180 mg/m(2)), or carboplatin (AUC = 6) and paclitaxel (200 mg/m(2)) were given before RT of 60 Gy in 30 fractions. In the Phase I portion, the starting dosage of PR-350 was 10 daily administrations (2000 mg/m(2)) in combination with RT, and this number was increased in increments of 10 for successive groups to 30 doses. Results: In total, 37 patients were enrolled. In Phase I (n = 20), PR-350 could be administered 30 times with concurrent thoracic RT. Thus, in Phase II (n = 17), PR-350 was administered 30 times. The major toxicity was radiation pneumonitis, with Grade 3 or more pneumonitis noted in 6 patients (16%) including 2 with treatment-related deaths. However, no Grade 3 or more esophageal toxicity was noted, and only Grade 1 peripheral neuropathy was noted in 9 patients (24%). For all 37 patients, the median survival time (MST) and the 2-year survival rate were 15.9 months and 24%, respectively. For 18 patients receiving 21 to 30 doses of PR-350, the MST and 2-year survival rate were 20.9 months and 33%, respectively. Conclusions: Thoracic RT combined with 30 daily administrations of PR-350 after induction CT was well tolerated and promising for locally advanced NSCLC. (C) 2007 Elsevier Inc.
  • Yasumasa Nishimura; Kazuhiko Nakagawa; Koji Takeda; Masahiro Tanaka; Yoshihiko Segawa; Kayoko Tsujino; Shunichi Negoro; Nobukazu Fuwa; Toyoaki Hida; Masaaki Kawahara; Nobuyuki Katakami; Keiko Hirokawa; Nobuyuki Yamamoto; Masahiro Fukuoka; Yutaka Ariyoshi
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 69 3 786 - 792 2007年11月 [査読有り]
     
    Purpose: This Phase I/II trial was conducted to assess the efficacy and safety of PR-350, a novel hypoxic cell radiosensitizer, when administered with thoracic radiation therapy (RT) after induction chemotherapy (CT) for locally advanced non-small-cell lung cancer (NSCLC). Methods and Materials: Two cycles of cisplatin (80 mg/m(2)) and paclitaxel (180 mg/m(2)), or carboplatin (AUC = 6) and paclitaxel (200 mg/m(2)) were given before RT of 60 Gy in 30 fractions. In the Phase I portion, the starting dosage of PR-350 was 10 daily administrations (2000 mg/m(2)) in combination with RT, and this number was increased in increments of 10 for successive groups to 30 doses. Results: In total, 37 patients were enrolled. In Phase I (n = 20), PR-350 could be administered 30 times with concurrent thoracic RT. Thus, in Phase II (n = 17), PR-350 was administered 30 times. The major toxicity was radiation pneumonitis, with Grade 3 or more pneumonitis noted in 6 patients (16%) including 2 with treatment-related deaths. However, no Grade 3 or more esophageal toxicity was noted, and only Grade 1 peripheral neuropathy was noted in 9 patients (24%). For all 37 patients, the median survival time (MST) and the 2-year survival rate were 15.9 months and 24%, respectively. For 18 patients receiving 21 to 30 doses of PR-350, the MST and 2-year survival rate were 20.9 months and 33%, respectively. Conclusions: Thoracic RT combined with 30 daily administrations of PR-350 after induction CT was well tolerated and promising for locally advanced NSCLC. (C) 2007 Elsevier Inc.
  • 中川 和彦; 尾崎 智博; 佐藤 太郎; 宮崎 昌樹; 明石 雄策; 寺嶋 応顕; 藤阪 保仁; 田村 友秀; 福岡 正博; 西條 長宏
    肺癌 47 4 313 - 322 日本肺癌学会 2007年08月 [査読有り]
     
    目的．肺癌貧血患者を対象に，epoetin beta（EPOCH）54000 IUを投与し，薬物動態パラメータを求め，以前の低用量での試験成績と併せて比較検討した．方法．ヘモグロビン（Hb）濃度11.0 g/dl以下の肺癌貧血患者6例にEPOCH 54000 IUを週1回8週間皮下投与した．初回投与時の薬物動態パラメータを求め，既報のEPOCH 9000 IU，18000 IU及び36000 IUの試験成績と併せて，用量との関係，反復投与時のトラフ濃度とHb濃度及び血小板数の推移，薬物動態パラメータ（Cmax，AUC）とHb濃度変化量との関係を検討した．結果．EPOCH 9000～36000 IU投与後の血清中薬物濃度は用量依存的に増加したが，54000 IU群では36000 IU群とほぼ同程度であった．一方，Hb濃度は18000 IU以上の投与で用量依存的に増加した．試験終了時にはトラフ濃度は開始レベルに回復した．結論．18000 IU以上のEPOCH皮下投与で用量依存的なHb濃度増加効果が認められた．反復投与によるEPOCHの蓄積性は認められなかった．
  • Ogawa K; Nakamura K; Hatano K; Uno T; Fuwa N; Itami J; Kojya S; Nakashima T; Shinhama A; Nakagawa T; Toita T; Sakai M; Kodaira T; Suzuki M; Ito H; Murayama S
    International journal of radiation oncology, biology, physics 68 5 1326 - 1334 2007年08月 [査読有り]
  • Tomohiro Ozaki; Kenji Tamura; Taroh Satoh; Takayasu Kurata; Toshio Shimizu; Masaki Miyazaki; Isamu Okamoto; Kazuhiko Nakagawa; Masahiro Fukuoka
    Anticancer Research 27 4 C 2657 - 2665 2007年07月 [査読有り]
     
    Background: The primary objective of this study was to determine the maximum tolerated dose (MTD), the toxicity profile and the recommended dose (RD) for phase II of a combination of S-1 and weekly administration of docetaxel. Patients and Methods: Patients with histologically diagnosed recurrent or unresectable locally advanced gastric cancer were enrolled. A fixed oral dose of 80 mg/m2 S-1 was given for 3 weeks. Docetaxel was infused intravenously on day 1, 8 and 15, repeated every 5 weeks. A pharmacokinetic study was also performed. Results: A total of 14 patients were enrolled. One dose-limiting toxicity (DLT) (grade 3 diarrhea with febrile neutropenia) occurred at level 2. DLTs occurred in 3/5 patients at level 3, (grade 3 stomatitis, with febrile neutropenia or continuous grade 4 neutropenia). The pharmacokinetic study suggested no drug interactions. Overall response and disease control rates were 20% and 80%, respectively. The response rate at the RD (level 2) was 50%. Overall survival was 9.4 months. Conclusion: RD was level 2 (80 mg/m2 of S-1 for 3 weeks and 20 mg/m2 of docetaxel on day 1, 8 and 15, every 5 weeks). Dose intensities of S-1 and docetaxel were 48 mg/m2/week and 12 mg/m2/week, respectively. This regimen showed promising activity for advanced gastric cancer.
  • Kenji Tamura; Kazuhiko Nakagawa; Takayasu Kurata; Taroh Satoh; Toshiji Nogami; Koji Takeda; Shigeki Mitsuoka; Naruo Yoshimura; Shinzoh Kudoh; Shunichi Negoro; Masahiro Fukuoka
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 60 2 285 - 293 2007年07月 [査読有り]
     
    Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses. Methods Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy <= 2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status <= 1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2. Results Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m(2)) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m(2). In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m(2). Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m(2), at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response. Conclusions When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m(2) and was lower than the value of 2.4 mg/m(2) in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.
  • Kenji Tamura; Kazuhiko Nakagawa; Takayasu Kurata; Taroh Satoh; Toshiji Nogami; Koji Takeda; Shigeki Mitsuoka; Naruo Yoshimura; Shinzoh Kudoh; Shunichi Negoro; Masahiro Fukuoka
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 60 2 285 - 293 2007年07月 [査読有り]
     
    Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of TZT-1027 (soblidotin), a dolastatin 10 analogue, in Japanese patients with advanced solid tumors when administered on days 1 and 8 in 3-week courses. Methods Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, and also met the following criteria: prior chemotherapy <= 2 regimens, Eastern Cooperative Oncology Group (ECOG) performance status <= 1, and acceptable organ function. The MTD was defined as the highest dose at which no more than one of six patients experienced a DLT during course 1. Pharmacokinetic samples were collected in courses 1 and 2. Results Eighteen patients were enrolled in the present study. Three doses (1.5, 1.65, and 1.8 mg/m(2)) were evaluated. Neutropenia was the principal DLT at doses of 1.65 and 1.8 mg/m(2). In addition, one patient also experienced grade 3 pneumonia with neutropenia, and another patient experienced grade 3 constipation, neuropathy, grade 4 neutropenia, and hyponatremia as DLTs at 1.65 mg/m(2). Phlebitis, the most frequent nonhematological toxicity, was improved by administration of additional saline after TZT-1027 administration. The MTD was 1.5 mg/m(2), at which DLT was not observed in a total of nine patients. The pharmacokinetic profile did not differ from that for the European population. One patient with metastatic esophageal cancer achieved partial response, and each of two patients with non-small cell lung cancer had a minor response. Conclusions When TZT-1027 was administered on days 1 and 8 in 3-week courses to Japanese patients, the MTD was 1.5 mg/m(2) and was lower than the value of 2.4 mg/m(2) in European patients. However, antitumor activity was observed at low doses. TZT-1027 was tolerated well at the MTD, without grade 3 nonhematological toxicities or neutropenia up to grade 2. TZT-1027 is a promising new tubulin polymerization inhibitor that requires further investigation in phase II studies.
  • Tomohiro Ozaki; Kenji Tamura; Taroh Satoh; Takayasu Kurata; Toshio Shimizu; Masaki Miyazaki; Isamu Okamoto; Kazuhiko Nakagawa; Masahiro Fukuoka
    ANTICANCER RESEARCH 27 4C 2657 - 2665 2007年07月 [査読有り]
     
    Background: The primary objective of this study was to determine the maximum tolerated dose (MTD), the toxicity profile and the recommended dose (RD) for phase II of a combination of S-1 and weekly administration of docetaxel. Patients and Methods: Patients with histologically diagnosed recurrent or unresectable locally advanced gastric cancer were enrolled. A fixed oral dose of 80 mg/m(2) S-1 was given for 3 weeks. Docetaxel was infused intravenously on day 1, 8 and 15, repeated every 5 weeks. A pharmacokinetic study was also performed. Results: A total of 14 patients were enrolled. One dose-limiting toxicity (DLT) (grade 3 diarrhea with febrile neutropenia) occurred at level 2. DLTs occurred in 315 patients at level 3, (grade 3 stomatitis, with febrile neutropenia or continuous grade 4 neutropenia). The pharmacokinetic study suggested no drug interactions. Overall response and disease control rates were 20% and 80%, respectively. The response rate at the RD (level 2) was 50%. Overall survival was 9.4 months. Conclusion: RD was level 2 (80 mg/m(2) of S-1 for 3 weeks and 20 mg/m(2) of docetaxel on day 1, 8 and 15, every 5 weeks). Dose intensities of S-1 and docetaxel were 48 mg/m(2)/week and 12 mg/m(2)/week, respectively. This regimen showed promising activity for advanced gastric cancer.
  • Atsushi Horiike; Hideharu Kimura; Kazuto Nishio; Fumiyoshi Ohyanagi; Yukitoshi Satoh; Sakae Okumura; Yuichi Ishikawa; Ken Nakagawa; Takeshi Horai; Makoto Nishio
    CHEST 131 6 1628 - 1634 2007年06月 [査読有り]
     
    Background: Somatic mutations of epidermal growth factor receptor (EGFR) are closely associated with an objective response to EGFR tyrosine kinase inhibitors. However, it is difficult to obtain sufficient tumor samples from patients with non-small cell lung cancer (NSCLC), so these diagnoses are often made using cytology procedures alone. The aim of this study was to detect EGFR mutations in transbronchial needle aspiration (TBNA) samples using both direct sequencing and a highly sensitive assay (Scorpions Amplified Refractory Mutation System; DxS; Manchester, UK) [ARMS], and to compare the sensitivity of these methods. Methods: We enrolled 94 patients (63 men and 31 women),with NSCLC in this study. Cytologic diagnoses were adenocarcinoma (n = 58), squamous cell carcinoma (n = 24), and other types of NSCLC (n = 12). We extracted DNA from the TBNA samples, and EGFR mutations were analyzed using both direct sequencing (exons 19 and 21) and the Scorpions ARMS method (E746 A750del and L858R). Results: Mutations were detected in 31 patients (33%; 14 women and 17 men). Of these, 23 patients had adenocarcinoma, 4 had squamous cell carcinoma, and 4 had other types of NSCLC. Direct sequencing detected 13 mutations (14%) in 13 patients (E746-A750del, n = 6; L858R, n = 7), and the Scorpions ARMS method detected 27 mutations (29%) in 27 patients (E746 A750del, n = 16; L858R, n = 11 patients). Conclusions: Both methods detected EGFR mutations in TBNA samples, but Scorpions ARMS is more sensitive than direct sequencing.
  • Toshio Shimizu; Taroh Satoh; Kenji Tamura; Tomohiro Ozaki; Isamu Okamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 12 3 218 - 223 2007年06月 [査読有り]
     
    Background The oxaliplatin/fluorouracil/leucovorin (FOLFOX regimen) is an effective and generally well-tolerated regimen in Western clinical studies of advanced colorectal cancer. In Japan, oxaliplatin was approved in April 2005. Methods. To evaluate the objective tumor responses and feasibility (toxicities) of FOLFOX regimens (FOLFOX4 and modified FOLFOX6, mFOLFOX6) in a predominantly Japanese population with refractory or advanced colorectal cancer in Japan, 51 consecutive patients with histologically confirmed metastatic colon or rectum cancer who were treated between April 2005 and March 2006 were enrolled in a retrospective study. FOLFOX4 was used for treatment in 39% (first-line, 45%) of these patients, and mFOLFOX6 was used for treatment in 61% (first-line, 61%). Tumor responses were assessed radiologically, and toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 regarding toxicities other than peripheral sensory neuropathy. Results. The objective response rates (in those who underwent first- or second-line therapy) were 50.0% and 8.7%, respectively. The tumor control rate (partial response [PR] + stable disease [SD]) was 80.4%. There were no toxicity-related deaths. Neutropenia grade 3 was experienced in 20% of patients, and often caused delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 78% of patients. The incidence of hypersensitivity reactions to oxaliplatin in our study was lower than that in reported in Western countries. Conclusion. Both FOLFOX regimens have good efficacy in refractory or advanced colorectal cancer in a Japanese population, with an acceptable overall toxicity profile.
  • Toshio Shimizu; Taroh Satoh; Kenji Tamura; Tomohiro Ozaki; Isamu Okamoto; Masahiro Fukuoka; Kazuhiko Nakagawa
    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 12 3 218 - 223 2007年06月 [査読有り]
     
    Background The oxaliplatin/fluorouracil/leucovorin (FOLFOX regimen) is an effective and generally well-tolerated regimen in Western clinical studies of advanced colorectal cancer. In Japan, oxaliplatin was approved in April 2005. Methods. To evaluate the objective tumor responses and feasibility (toxicities) of FOLFOX regimens (FOLFOX4 and modified FOLFOX6, mFOLFOX6) in a predominantly Japanese population with refractory or advanced colorectal cancer in Japan, 51 consecutive patients with histologically confirmed metastatic colon or rectum cancer who were treated between April 2005 and March 2006 were enrolled in a retrospective study. FOLFOX4 was used for treatment in 39% (first-line, 45%) of these patients, and mFOLFOX6 was used for treatment in 61% (first-line, 61%). Tumor responses were assessed radiologically, and toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 regarding toxicities other than peripheral sensory neuropathy. Results. The objective response rates (in those who underwent first- or second-line therapy) were 50.0% and 8.7%, respectively. The tumor control rate (partial response [PR] + stable disease [SD]) was 80.4%. There were no toxicity-related deaths. Neutropenia grade 3 was experienced in 20% of patients, and often caused delay in the subsequent treatment course. Mild to moderate cumulative peripheral sensory neuropathy affected 78% of patients. The incidence of hypersensitivity reactions to oxaliplatin in our study was lower than that in reported in Western countries. Conclusion. Both FOLFOX regimens have good efficacy in refractory or advanced colorectal cancer in a Japanese population, with an acceptable overall toxicity profile.
  • Narikazu Boku; Atsushi Ohtsu; Ichinosuke Hyodo; Kuniaki Shirao; Yoshinori Miyata; Kazuhiko Nakagawa; Takao Tamura; Kiyohiko Hatake; Yusuke Tanigawara
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 37 6 440 - 445 2007年06月 [査読有り]
     
    Background: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m(2) every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines. Methods: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m(2) every 3 weeks. Results: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1-6). The overall response rate was 9% (5/57, 95% Cl: 4-19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living. Conclusions: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients.
  • Y. Akashi; I. Okamoto; M. Suzuki; K. Tamura; T. Iwasa; S. Hisada; T. Satoh; K. Nakagawa; K. Ono; M. Fukuoka
    BRITISH JOURNAL OF CANCER 96 10 1532 - 1539 2007年05月 [査読有り]
     
    TZT-1027 is a novel anticancer agent that inhibits microtubule polymerisation and manifests potent antitumour activity in preclinical models. We have examined the effect of TZT-1027 on cell cycle progression as well as the anticancer activity of this drug both in vitro and in vivo. With the use of tsFT210 cells, which express a temperature-sensitive mutant of Cdc2, we found that TZT-1027 arrests cell cycle progression in mitosis, the phase of the cell cycle most sensitive to radiation. A clonogenic assay indeed revealed that TZT-1027 increased the sensitivity of H460 cells to gamma-radiation, with a dose enhancement factor of 1.2. Furthermore, TZT-1027 increased the radiosensitivity of H460 and A549 cells in nude mice, as revealed by a marked delay in tumour growth and an enhancement factor of 3.0 and 2.2, respectively. TZT-1027 also potentiated the induction of apoptosis in H460 cells by radiation both in vitro and in vivo. Histological evaluation of H460 tumours revealed that TZT-1027 induced morphological damage to the vascular endothelium followed by extensive central tumour necrosis. Our results thus suggest that TZT-1027 enhances the antitumour effect of ionising radiation, and that this action is attributable in part to potentiation of apoptosis induction and to an antivascular effect. Combined treatment with TZT-1027 and radiation therefore warrants investigation in clinical trials as a potential anticancer strategy.
  • Masato Ikeda; Isamu Okamoto; Kenji Tamura; Taroh Satoh; Kimio Yonesaka; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER LETTERS 248 2 292 - 298 2007年04月 [査読有り]
     
    Deregulation of survivin expression is implicated in tumorigenesis. To examine the regulation of survivin expression in response to DNA damage, we exposed A549 human lung cancer cells to ultraviolet C (UVC) radiation, which induces DNA single-strand breakage. UVC irradiation induced G(2)-M arrest that was accompanied by accumulation of p53 and subsequent down-regulation of survivin. Depletion of p53 by RNA interference prevented the UVC-induced downregulation of survivin. Furthermore, depletion of survivin resulted in G(2)-M arrest, suggesting that down-regulation of survivin by p53 contributes to the p53-dependent G(2)-M checkpoint triggered by DNA damage. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Masato Ikeda; Isamu Okamoto; Kenji Tamura; Taroh Satoh; Kimio Yonesaka; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER LETTERS 248 2 292 - 298 2007年04月 [査読有り]
     
    Deregulation of survivin expression is implicated in tumorigenesis. To examine the regulation of survivin expression in response to DNA damage, we exposed A549 human lung cancer cells to ultraviolet C (UVC) radiation, which induces DNA single-strand breakage. UVC irradiation induced G(2)-M arrest that was accompanied by accumulation of p53 and subsequent down-regulation of survivin. Depletion of p53 by RNA interference prevented the UVC-induced downregulation of survivin. Furthermore, depletion of survivin resulted in G(2)-M arrest, suggesting that down-regulation of survivin by p53 contributes to the p53-dependent G(2)-M checkpoint triggered by DNA damage. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Takafumi Okabe; Isamu Okamoto; Kenji Tamura; Masaaki Terashima; Takeshi Yoshida; Taroh Satoh; Minoru Takada; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER RESEARCH 67 5 2046 - 2053 2007年03月 [査読有り]
     
    The identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however. We have now examined 16 NSCLC cell lines, including eight newly established lines from Japanese NSCLC patients, for the presence of EGFR mutations and amplification. Four of the six cell lines that harbor EGFR mutations were found to be positive for EGFR amplification, whereas none of the 10 cell lines negative for EGFR mutation manifested EGFR amplification, suggesting that these two types of EGFR alteration are closely associated. Endogenous EGFRs expressed in NSCLC cell lines positive for both EGFR mutation and amplification were found to be constitutively activated as a result of ligand-independent dimerization. Furthermore, the patterns of both EGFR amplification and EGFR autophosphorylation were shown to differ between cell lines harboring the two most common types of EGFR mutation (exon 19 deletion and L858R point mutation in exon 21). These results reveal distinct biochemical properties of endogenous mutant forms of EGFR expressed in NSCLC cell lines and may have implications for treatment of this condition.
  • Takafumi Okabe; Isamu Okamoto; Kenji Tamura; Masaaki Terashima; Takeshi Yoshida; Taroh Satoh; Minoru Takada; Masahiro Fukuoka; Kazuhiko Nakagawa
    CANCER RESEARCH 67 5 2046 - 2053 2007年03月 [査読有り]
     
    The identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however. We have now examined 16 NSCLC cell lines, including eight newly established lines from Japanese NSCLC patients, for the presence of EGFR mutations and amplification. Four of the six cell lines that harbor EGFR mutations were found to be positive for EGFR amplification, whereas none of the 10 cell lines negative for EGFR mutation manifested EGFR amplification, suggesting that these two types of EGFR alteration are closely associated. Endogenous EGFRs expressed in NSCLC cell lines positive for both EGFR mutation and amplification were found to be constitutively activated as a result of ligand-independent dimerization. Furthermore, the patterns of both EGFR amplification and EGFR autophosphorylation were shown to differ between cell lines harboring the two most common types of EGFR mutation (exon 19 deletion and L858R point mutation in exon 21). These results reveal distinct biochemical properties of endogenous mutant forms of EGFR expressed in NSCLC cell lines and may have implications for treatment of this condition.
  • Nakagawa K
    Gan to kagaku ryoho. Cancer & chemotherapy 34 2 320 - 323 2007年02月 [査読有り]
  • Y. Ohe; Y. Ohashi; K. Kubota; T. Tamura; K. Nakagawa; S. Negoro; Y. Nishiwaki; N. Saijo; Y. Ariyoshi; M. Fukuoka
    ANNALS OF ONCOLOGY 18 2 317 - 323 2007年02月 [査読有り]
     
    Background: To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan (IP) in patients with untreated advanced non-small-cell lung cancer (NSCLC) by a non-inferiority design. Patients and methods: A total of 602 patients were randomly assigned to one of four regimens: cisplatin 80 mg/m(2) on day 1 plus irinotecan 60 mg/m(2) on days 1, 8, 15 every 4 weeks (IP) carboplatin AUC 6.0 min x mg/mL (area under the concentration-time curve) on day 1 plus paclitaxel 200 mg/m(2) on day 1 every 3 weeks (TC); cisplatin 80 mg/m(2) on day 1 plus gemcitabine 1000 mg/m(2) on days 1, 8 every 3 weeks (GP); and cisplatin 80 mg/m(2) on day 1 plus vinorelbine 25 mg/m(2) on days 1, 8 every 3 weeks (NP). Results: The response rate, median survival time, and 1-year survival rate were 31.0%, 13.9 months, 59.2%, respectively, in IP; 32.4%, 12.3 months, 51.0% in TC; 30.1%, 14.0 months, 59.6% in GP; and 33.1%, 11.4 months, 48.3% in NP. No statistically significant differences were found in response rate or overall survival, but the non-inferiority of none of the experimental regimens could be confirmed. All the four regimens were well tolerated. Conclusion: The four regimens have similar efficacy and different toxicity profiles, and they can be used to treat advanced NSCLC patients.
  • 前田 裕弘; 林 孝浩; 川畑 由美子; 大野 恭裕; 北野 雅之; 宮本 勝一; 西郷 和真; 三井 良之; 佐藤 太郎; 岡本 勇; 中川 和彦; 佐野 博幸; 船内 正憲; 辰巳 陽一; 松尾 理
    近畿大医誌 32 1 57 - 63 近畿大学 2007年 
    3年生および4年生の学生を対象として、英語教材を用いてClinical Pathological Conference(CPC)を実施した。最後のCPCを終了し、学生および教員を対象としアンケートを実施した。回収率は学生100%、教員78.5%であった。英語教材によるCPCの順序として、和訳、問題点の列挙、検査結果の解析、画像診断などがあり、3年生および4年生にとっては少しレベルが高すぎた可能性がある。しかし、教員は確実に学生の学習意欲を感じ取っており、学生の準備状況も良好であった。教員の熱意も学生は評価しており、両者にとっても有意義であった。
  • Meinoshin Okumura; Hiroyuki Shiono; Masayoshi Inoue; Hisaichi Tanaka; Hyun-Eng Yoon; Katsuhiro Nakagawa; Akihide Matsumura; Mitsunori Ohta; Keiji Iuchi; Hikaru Matsuda
    JOURNAL OF SURGICAL ONCOLOGY 95 1 40 - 44 2007年01月 [査読有り]
     
    Background and Objectives: The aim of this study was to clarify the significance of surgical treatment for recurrent thymic epithelial tumors with reference to the World Health Organization (WHO) histological classification system. Patients: Among 67 patients with tumor recurrence, 22 underwent a re-resection. There were 1 patient with a type AB tumor, 5 with type B1 tumors, 10 with type B2 tumors, 5 with type B3 tumors, and 1 with a carcinoma. Results: The 10-year survival rate following the initial resection was 70% in patients who underwent a re-resection and 35% in those who did not. The average intervals from the initial resection to re-resection were 10.3, 7.8, 6.0, 2.4, and 2.6 years for patients with type AB, 131, 132, 133 tumors, and carcinoma, respectively. The patient with a type AB tumor was alive at 2.4 years after re-resection, 12.7 years after the initial resection. The 5-year survival rates following re-resection in the patients with type 131, 132, and 133 tumors were 100, 56, and 60, respectively. The patient with a carcinoma died as a result of the tumor 2 years after re-resection. Conclusion: WHO histological classification indicates the outcome of surgical treatment for recurrent thymic epithelial tumors.
  • 前田裕弘; 林孝治; 川畑由美子; 大野恭裕; 北野雅之; 宮本勝一; 西郷和真; 三井良之; 佐藤太郎; 岡本勇; 中川和彦; 佐野博幸; 船内正憲; 辰巳陽一; 松尾理
    近畿大学医学雑誌 32 1 57 - 63 近畿大学医学会 2007年 [査読有り]
     
    3年生および4年生の学生を対象として、英語教材を用いてClinical Pathological Conference(CPC)を実施した。最後のCPCを終了し、学生および教員を対象としアンケートを実施した。回収率は学生100%、教員78.5%であった。英語教材によるCPCの順序として、和訳、問題点の列挙、検査結果の解析、画像診断などがあり、3年生および4年生にとっては少しレベルが高すぎた可能性がある。しかし、教員は確実に学生の学習意欲を感じ取っており、学生の準備状況も良好であった。教員の熱意も学生は評価しており、両者にとっても有意義であった。
  • 明石雄策; 岡本勇; 鈴木実; 田村研治; 佐藤太郎; 中川和彦; 小野公二; 福岡正博
    近畿大学医学雑誌 31 4 225 - 231 近畿大学 2006年12月 [査読有り]
     
    TZT-1027は微小管重合阻害作用を有し,高い抗腫瘍効果を持つ新規抗がん剤である.本研究で我々は,TZT-1027の細胞周期に与える影響およびTZT-1027の放射線増感効果を検討した.温度感受性Cdc2変異細胞株であるマウス乳癌細胞株tsFT210細胞を用いた細胞周期の検討では,TZT-1027は細胞周期において放射線感受性の高いG2/M期に特異的に作用することを示した.TZT-1027のこのような作用特性を考慮し,ヒト非小細胞肺癌細胞株H460細胞における放射線感受性をclonogenic assayで検討した.生存曲線より求めた,生存率0.1におけるDose Enhancement Factor(DEF)は1.2であり,TZT-1027はH460細胞の放射線に対する感受性を増強した.担癌マウスを用いた放射線感受性の検討でも,TZT-1027と放射線の併用療法は明らかな腫瘍増殖遅延効果を示した.またTZT-1027はin vitro, in vivoの両方で放射線によるアポトーシスを増強した.これらの結果からTZT-1027は放射線の抗腫瘍効果を増強し,その増感性には少なくとも部分的にアポトーシスが関連する可能性が示唆された.今後TZT-1027と放射線の併用療法の臨床応用が期待される.
  • Takayasu Kurata; Kenji Tamura; Isamu Okamoto; Taroh Satoh; Kazuhiko Nakagawa; Masahiro Fukuoka
    LUNG CANCER 54 2 241 - 242 2006年11月 [査読有り]
     
    Pemetrexed is a novel antimetabolite that targets multiple enzymes in the folate pathway, and has exhibited clear antitumor activities in the treatment of malignant pleura[ mesothelioma and non-small. cell lung cancer. Although many adverse events of pemetrexed, such as bone marrow suppression, have been reported, edema of the eyelid has been previously reported in only one case (0.2%, n = 519), according to the Pemetrexed Clinical Investigator's Brochure, April 2005 version. We experienced a patient who developed the valuable edema of the eyelid. We believe that medical oncologists should be aware of this rare adverse event, although the mechanism responsible for it is not yet known. (C) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Hiroshi Saito; Yoshiki Takada; Yukito Ichinose; Kenji Eguchi; Shinzoh Kudoh; Kaoru Matsui; Kazuhiko Nakagawa; Minoru Takada; Shunichi Negoro; Kenji Tamura; Masahiko Ando; Takuhito Tada; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 24 33 5247 - 5252 2006年11月 [査読有り]
     
    Purpose We initially conducted a randomized phase II study to compare irinotecan and cisplatin (IP) versus irinotecan, cisplatin, and etoposide (IPE) after etoposide and cisplatin (EP) with concurrent twice-daily thoracic radiotherapy (TRT) in limited-disease small-cell lung cancer (LID-SCLC). We amended the protocol to evaluate IP after EP with concurrent twice-daily TRT in a single-arm phase II study because of an unacceptable toxicity in IPE. Patients and Methods Previously untreated patients with LD-SCLC were treated intravenously with etoposide 100 mg/m(2) on days 1 through 3 and cisplatin 80 mg/m(2) on day 1 with concurrent twice-daily TRT (1.5 Gy per fraction, a total dose of 45 Gy) beginning on day 2 followed by three cycles of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 of a 4-week cycle. Results Of the 51 patients enrolled, 49 patients were assessable for response and toxicity. The overall response rate and complete response rate were 88% and 41%, respectively. The median survival time for all patients was 23 months. The 2-year and 3-year survival rates were 49% and 29.7%, respectively. The median progression-free survival was 11.8 months. The major toxicities observed were neutropenia (grade 4, 84%), febrile neutropenia (grade 3, 31%), infection (grade 3 to 4, 33%), electrolytes imbalance (grade 3 to 4, 20%), and diarrhea (grade 3 to 4, 14%). Conclusion EP with concurrent twice-daily TRT followed by the consolidation of IP appears to be an active regimen which deserves further phase III testing in patients with LD-SCLC.
  • Kazuhiko Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 58 S33 - S37 2006年11月 [査読有り]
     
    Although the initial impact of the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib may have been less than spectacular in the field of non-small cell lung cancer (NSCLC), this EGFR-TKI does offer a therapy that, at least in the short term, markedly reduces tumors without bone marrow suppression including neutropenia and without causing severe nausea and vomiting even in NSCLC patients with the worst prognosis. This raises the possibility of putting the disease under control if only temporarily. Now we must be aware that overcoming gene mutation in lung cancer is the next significant milestone for new therapeutics. This report discusses clinical trials of EGFR-TKIs focusing on Japanese contributions to current knowledge, EGFR mutation, and future directions. A Japanese phase I clinical trial saw the first super-responders to gefitinib. Two randomized phase 11 trials identified Japanese, females, and those with adenocarcinoma of the lung as specific populations sensitive to gefitinib. Unexpectedly, in the context of first-line chemotherapy four phase III trials gave completely negative results for additional clinical benefit by EGFR-TKIs combined with standard chemotherapy. However, subset analysis suggested efficacy of this treatment strategy in nonsmokers and patients harboring activated-type EGFR mutations. In the settings of second-line and later therapy, two independent randomized placebo-controlled trials, BR.21 with erlotinib and ISEL with gefitinib, revealed better duration of overall survival, time to progression, and response rate in the EGFR-TKI versus control groups, although the result was nonsignificant in the latter study. Data suggesting that adenocarcinoma, Asian race, female, and nonsmoker are associated with better response to EGFR-TKI may be closely related with phenotype of EGFR mutations, making this parameter a "response predictive marker." On the other hand, some reports have stated that gene amplification of EGFR by FISH analysis shows better correlation with clinical benefit of EGFR-TKIs than that assessed by other means in large-scale phase III trials (BR21 and ISEL). Further validation of response predictive markers is needed. Recent studies of EGFR-TKIs in NSCLC provide novel biological insights and have given birth to the concept of patient selection for this disease. Further investigation of the biological significance of EGFR mutation and its validation as response predictive marker will lead to better treatments to come for NSCLC.
  • Takayasu Kurata; Kenji Tamura; Isamu Okamoto; Taroh Satoh; Kazuhiko Nakagawa; Masahiro Fukuoka
    LUNG CANCER 54 2 241 - 242 2006年11月 [査読有り]
     
    Pemetrexed is a novel antimetabolite that targets multiple enzymes in the folate pathway, and has exhibited clear antitumor activities in the treatment of malignant pleura[ mesothelioma and non-small. cell lung cancer. Although many adverse events of pemetrexed, such as bone marrow suppression, have been reported, edema of the eyelid has been previously reported in only one case (0.2%, n = 519), according to the Pemetrexed Clinical Investigator's Brochure, April 2005 version. We experienced a patient who developed the valuable edema of the eyelid. We believe that medical oncologists should be aware of this rare adverse event, although the mechanism responsible for it is not yet known. (C) 2006 Elsevier Ireland Ltd. All rights reserved.
  • Hiroshi Saito; Yoshiki Takada; Yukito Ichinose; Kenji Eguchi; Shinzoh Kudoh; Kaoru Matsui; Kazuhiko Nakagawa; Minoru Takada; Shunichi Negoro; Kenji Tamura; Masahiko Ando; Takuhito Tada; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 24 33 5247 - 5252 2006年11月 [査読有り]
     
    Purpose We initially conducted a randomized phase II study to compare irinotecan and cisplatin (IP) versus irinotecan, cisplatin, and etoposide (IPE) after etoposide and cisplatin (EP) with concurrent twice-daily thoracic radiotherapy (TRT) in limited-disease small-cell lung cancer (LID-SCLC). We amended the protocol to evaluate IP after EP with concurrent twice-daily TRT in a single-arm phase II study because of an unacceptable toxicity in IPE. Patients and Methods Previously untreated patients with LD-SCLC were treated intravenously with etoposide 100 mg/m(2) on days 1 through 3 and cisplatin 80 mg/m(2) on day 1 with concurrent twice-daily TRT (1.5 Gy per fraction, a total dose of 45 Gy) beginning on day 2 followed by three cycles of irinotecan 60 mg/m(2) on days 1, 8, and 15 and cisplatin 60 mg/m(2) on day 1 of a 4-week cycle. Results Of the 51 patients enrolled, 49 patients were assessable for response and toxicity. The overall response rate and complete response rate were 88% and 41%, respectively. The median survival time for all patients was 23 months. The 2-year and 3-year survival rates were 49% and 29.7%, respectively. The median progression-free survival was 11.8 months. The major toxicities observed were neutropenia (grade 4, 84%), febrile neutropenia (grade 3, 31%), infection (grade 3 to 4, 33%), electrolytes imbalance (grade 3 to 4, 20%), and diarrhea (grade 3 to 4, 14%). Conclusion EP with concurrent twice-daily TRT followed by the consolidation of IP appears to be an active regimen which deserves further phase III testing in patients with LD-SCLC.
  • Makoto Hosaka; Yasuhisa Ohde; Kazuo Nakagawa; Takehiro Okumura; Toru Kameya; Haruhiko Kondo
    Japanese Journal of Thoracic and Cardiovascular Surgery 54 10 458 - 461 2006年10月 [査読有り]
     
    We report successful surgery for malignant pleural mesothelioma (MPM) in a 14-year-old boy with right aortic arch. Pleural biopsy by video-assisted thoracic surgery yielded a diagnosis of MPM, epithelial type. As the disease was not changed after combination chemotherapy with three cycles of cisplatin and gemcitabine, we performed left extrapleural pneumonectomy, including resection of the pericardium and diaphragm for MPM, and aortopexy for right aortic arch. The postoperative course was uneventful, and the patient has remained alive without disease for 10 months postoperatively. © The Japanese Association for Thoracic Surgery 2006.
  • K. Nakagawa; H. Tada; A. Akashi; T. Yasumitsu; K. Iuchi; T. Taki; K. Kodama
    BRITISH JOURNAL OF CANCER 95 7 817 - 821 2006年10月 [査読有り]
     
    We evaluated the therapeutic usefulness of adjuvant chemotherapy in patients with completely resected non-small cell lung cancer (NSCLC). We also examined the relation between DNA ploidy pattern and the response to chemotherapy. A total of 267 patients with NSCLC (pathologically documented stage I, II, or IIIA) underwent complete resection, and DNA ploidy pattern was analysed. Patients with stage I disease (n = 172) were randomly assigned to receive surgery alone (group A) or surgery followed by adjuvant chemotherapy (UFT (oral anti-cancer drug, a combination of Uracil and Tegaful) 400 mg day(-1) for 1 year after surgery; group B). Stage II or IIIA disease patients (n = 95) were randomly assigned to surgery alone (group C) or surgery followed by chemotherapy (two 28-day courses of cisplatin 80 mg m(-2) on day 1 plus vindesine 3 mg m(2) on days 1 and 8, followed by UFT 400 mg day(-1) for at least 1 year; group D). Eight-year overall survival rate in patients with stage I disease was 74.2% (95% confidence interval (CI): 64.4 -84.0%) in group B and 57.6% (95% CI: 46.4 -68.8%) in group A (P = 0.045 by log-rank test). In patients with stage II and IIIA disease, no difference was found between groups C and D. Analysis according to DNA ploidy pattern revealed no difference between the groups. Postoperative chemotherapy with UFT was suggested to be useful in patients with completely resected stage I NSCLC. No difference was seen in relation to DNA pattern in any treatment group.
  • Hiroshi Saito; Shinzoh Kudoh; Kazuhiko Nakagawa; Shunichi Negoro; Kaoru Matsui; Hiroshi Semba; Minoru Takada
    AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS 29 5 503 - 507 2006年10月 [査読有り]
     
    Objectives: The combination of irinotecan and cisplatin given every 4 weeks is one of the standard treatments for advanced nonsmall-cell lung cancer (NSCLC) in Japan. The purpose of this study is to evaluate the efficacy, safety and dose-intensity as a measure of the feasibility of 3-week scheduling of irinotecan and cisplatin in patients with advanced NSCLC in phase II study. Methods: Previously untreated patients with stage IIIB and IV NSCLC were treated intravenously with irinotecan (60 mg/m(2)) on days I and 8 and cisplatin (60 mg/m(2)) on day 1 of a 3-week cycle. Results: Of the 28 patients enrolled, 27 were evaluable for or response and toxicity. The response rate was 30% (95% confidence interval, 14-50%). The median duration of response was 16 weeks (range, 10-26 weeks). The median survival time for all patients was 52 weeks and the 1-year and 2-year survival rates were 48% and 29%, respectively. The dose-intensity of irinotecan was 34 mg/m(2)/wk (range, 19-40). The major toxicities observed were neutropenia (grade 3, 30%; 4, 30%), leukopenia (grade 3, 30%), and diarrhea (grade 3, 22%). Other toxicities were generally mild. Conclusions: Three-week scheduling of irinotecan and cisplatin is effective and feasible in advanced NSCLC.
  • Hiroshi Saito; Shinzoh Kudoh; Kazuhiko Nakagawa; Shunichi Negoro; Kaoru Matsui; Hiroshi Semba; Minoru Takada
    AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS 29 5 503 - 507 2006年10月 [査読有り]
     
    Objectives: The combination of irinotecan and cisplatin given every 4 weeks is one of the standard treatments for advanced nonsmall-cell lung cancer (NSCLC) in Japan. The purpose of this study is to evaluate the efficacy, safety and dose-intensity as a measure of the feasibility of 3-week scheduling of irinotecan and cisplatin in patients with advanced NSCLC in phase II study. Methods: Previously untreated patients with stage IIIB and IV NSCLC were treated intravenously with irinotecan (60 mg/m(2)) on days I and 8 and cisplatin (60 mg/m(2)) on day 1 of a 3-week cycle. Results: Of the 28 patients enrolled, 27 were evaluable for or response and toxicity. The response rate was 30% (95% confidence interval, 14-50%). The median duration of response was 16 weeks (range, 10-26 weeks). The median survival time for all patients was 52 weeks and the 1-year and 2-year survival rates were 48% and 29%, respectively. The dose-intensity of irinotecan was 34 mg/m(2)/wk (range, 19-40). The major toxicities observed were neutropenia (grade 3, 30%; 4, 30%), leukopenia (grade 3, 30%), and diarrhea (grade 3, 22%). Other toxicities were generally mild. Conclusions: Three-week scheduling of irinotecan and cisplatin is effective and feasible in advanced NSCLC.
  • Makoto Nishio; Fumiko Taguchi; Fumiyoshi Ohyanagi; Atushi Horikike; Yuichi Ishikawa; Yukitoshi Satoh; Sakae Okumura; Ken Nakagawa; Kazuto Nishio; Takeshi Horai
    ANTICANCER RESEARCH 26 5B 3761 - 3765 2006年09月 [査読有り]
     
    The aim of this study was to compare the relationship between HER family expression and clinical response to gefitinib. Patients and Methods: Tissues from thirty-one non-small cell lung cancer (NSCLC) patients treated with a monotherapy of gefitinib were analyzed. Expressions of HER family in 31 tumors were examined by immunohistochemistry. Results: The total expressions were 21 for EGFR (68%), 24 for HER2 (77%), 17 for HER3 (55%) and 4 for HER4 (13%). Fourteen out of 31 (45%) demonstrated triple expression of EGFR and HER2, as well as HER3 or HER4. A significantly better response rate (RR) and time to progression (TTP) were observed for the group with the triple expression than for the other groups (RR 50 vs. 11%; p < 0.05, median TTP 4.29 vs. 1.2 months; p < 0.05). Conclusion: Mutliple expression of the HER family might be related with the clinical response to gefitinib and EGFR mutation status.
  • Takayasu Kurata; Keitaro Matsuo; Minoru Takada; Masaaki Kawahara; Masahiro Tsuji; Yuka Matsubara; Nagahiro Otani; Shigeki Matsuyama; Kenya Muraishi; Tetsuya Fujita; Masato Ishikawa; Keita Koyano; Isamu Okamoto; Taroh Satoh; Kenji Tamura; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 1 7 684 - 691 2006年09月 [査読有り]
     
    Background: It is controversial whether achieving stable disease leads to a survival benefit and whether the importance of achieving stable disease differs between cytotoxic agents and molecular targeted agents. To examine these questions, the authors retrospectively reviewed phase II and III studies in the second-line setting for advanced non-small cell lung cancer using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic agents separately. Methods: The authors chose 45 trials for the chemotherapy group and nine for the EGFR TKI group by searching the PubMed database. All nine trials in the EGFR TKI group concern gefitinib and erlotinib. Results: The median survival time increased 0.0375 month with each 1% increase in stable disease rate (p = 0.039), and each 1% increase in response rate resulted in 0.0744 (p < 0.001) month of median survival time in the analysis combined with both cytotoxic agents and EGFR TKIs. Main and interaction terms for EGFR TKI treatment were not statistically significant. With respect to time to progression, only response rate showed a statistically significant relationship with survival. Conclusions: To obtain response seems to be more important than to achieve stable disease for both cytotoxic agents and EGFR TKIs, although achieving stable disease is still valuable. The relationship between survival and response or stable disease appears similar for cytotoxic agents and EGFR TKIs.
  • N Yamamoto; Y Nishimura; K Nakagawa; K Matsui; M Fukuoka
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 58 3 285 - 291 2006年09月 [査読有り]
     
    Purpose: We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly docetaxel and cisplatin (DOC/CDDP) with concurrent thoracic radiotherapy (TRT) in patients with unresectable stage III non-small-cell lung cancer (NSCLC). Materials and methods: The DOC/CDDP administration schedules consisted of a split schedule (SS) with administration in 3 out of every 4 weeks, and a continuous schedule (CS) with administration every week. TRT was given to a total dose of 60 Gy at 2 Gy per fraction over 6 weeks. Results: Twenty-one patients entered the study. The patient characteristics were: PS 0/1/2, 6/13/2; Sq/Ad, 16/5; stage IIIA/IIIB, 4/17. The principal DLT was grade3 esophagitis. The MTD of DOC on the SS and CS in combination with CDDP (25 mg/m2/week) was 25 and 20 mg/m(2)/week, respectively. We determined the RD and schedule of DOC/CDDP on the SS to be 20/25 mg/m(2)/week. The serum alpha-1-acid glycoprotein (AAG) concentration values were found to be negatively correlated with the grade of esophagitis. The median survival time was 23.1 months. Conclusion: The chemoradiation regimen tested in this study has promising activity and manageable toxicity. The continuous schedule could not be recommended due to excessive toxicity. The main DLT was esophagitis, and it significantly correlated with the plasma AAG concentration.
  • K. Nakagawa; S. Kudoh; K. Matsui; S. Negoro; N. Yamamoto; J. E. Latz; S. Adachi; M. Fukuoka
    BRITISH JOURNAL OF CANCER 95 6 677 - 682 2006年09月 [査読有り]
     
    The purpose of this study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of pemetrexed with folate and vitamin B12 supplementation (FA/VB(12)) in Japanese patients with solid tumours and to investigate the safety, efficacy, and pharmacokinetics of pemetrexed. Eligible patients had incurable solid tumours by standard treatments, a performance status 0-2, and adequate organ function. Pemetrexed from 300 to 1200 mg m(-2) was administered as a 10-min infusion on day 1 of a 21-day cycle with FA/VB(12). Totally, 31 patients were treated. Dose-limiting toxicities were alanine aminotransferase (ALT) elevation at 700 mg m(-2), and infection and skin rash at 1200 mg m(-2). The MTD/RD were determined to be 1200/1000 mg m(-2), respectively. The most common grade 3/4 toxicities were neutropenia (grade (G) 3:29, G4:3%), leucopenia (G3:13, G4:3%), lympopenia (G3:13%) and ALT elevation (G3: 13%). Pemetrexed pharmacokinetics in Japanese were not overtly different from those in western patients. Partial response was achieved for 5/23 evaluable patients (four with non-small cell lung cancer (NSCLC) and one with thymoma). The MTD/RD of pemetrexed were determined to be 1200/1000 mg m(-2), respectively, that is, a higher RD than without FA/VB12 (500 mg m(-2)). Pemetrexed with FA/VB(12) showed a tolerable toxicity profile and potent antitumour activity against NSCLC in this study.
  • N Yamamoto; Y Nishimura; K Nakagawa; K Matsui; M Fukuoka
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 58 3 285 - 291 2006年09月 [査読有り]
     
    Purpose: We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly docetaxel and cisplatin (DOC/CDDP) with concurrent thoracic radiotherapy (TRT) in patients with unresectable stage III non-small-cell lung cancer (NSCLC). Materials and methods: The DOC/CDDP administration schedules consisted of a split schedule (SS) with administration in 3 out of every 4 weeks, and a continuous schedule (CS) with administration every week. TRT was given to a total dose of 60 Gy at 2 Gy per fraction over 6 weeks. Results: Twenty-one patients entered the study. The patient characteristics were: PS 0/1/2, 6/13/2; Sq/Ad, 16/5; stage IIIA/IIIB, 4/17. The principal DLT was grade3 esophagitis. The MTD of DOC on the SS and CS in combination with CDDP (25 mg/m2/week) was 25 and 20 mg/m(2)/week, respectively. We determined the RD and schedule of DOC/CDDP on the SS to be 20/25 mg/m(2)/week. The serum alpha-1-acid glycoprotein (AAG) concentration values were found to be negatively correlated with the grade of esophagitis. The median survival time was 23.1 months. Conclusion: The chemoradiation regimen tested in this study has promising activity and manageable toxicity. The continuous schedule could not be recommended due to excessive toxicity. The main DLT was esophagitis, and it significantly correlated with the plasma AAG concentration.
  • Takayasu Kurata; Keitaro Matsuo; Minoru Takada; Masaaki Kawahara; Masahiro Tsuji; Yuka Matsubara; Nagahiro Otani; Shigeki Matsuyama; Kenya Muraishi; Tetsuya Fujita; Masato Ishikawa; Keita Koyano; Isamu Okamoto; Taroh Satoh; Kenji Tamura; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 1 7 684 - 691 2006年09月 [査読有り]
     
    Background: It is controversial whether achieving stable disease leads to a survival benefit and whether the importance of achieving stable disease differs between cytotoxic agents and molecular targeted agents. To examine these questions, the authors retrospectively reviewed phase II and III studies in the second-line setting for advanced non-small cell lung cancer using epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and cytotoxic agents separately. Methods: The authors chose 45 trials for the chemotherapy group and nine for the EGFR TKI group by searching the PubMed database. All nine trials in the EGFR TKI group concern gefitinib and erlotinib. Results: The median survival time increased 0.0375 month with each 1% increase in stable disease rate (p = 0.039), and each 1% increase in response rate resulted in 0.0744 (p < 0.001) month of median survival time in the analysis combined with both cytotoxic agents and EGFR TKIs. Main and interaction terms for EGFR TKI treatment were not statistically significant. With respect to time to progression, only response rate showed a statistically significant relationship with survival. Conclusions: To obtain response seems to be more important than to achieve stable disease for both cytotoxic agents and EGFR TKIs, although achieving stable disease is still valuable. The relationship between survival and response or stable disease appears similar for cytotoxic agents and EGFR TKIs.
  • 中川 和彦
    肺癌 46 4 345 - 352 2006年08月 [査読有り]
     
    Objective. To evaluate long-term safety, median overall and progression-free survival, of gefitinib by enrolling patients from clinical studies that had been completed or closed who may benefit from continued gefitinib monotherapy. Methods. A total of 77 patients worldwide (from 9 parent gefitinib trials), mainly with advanced NSCLC (n = 61), were enrolled into this extension trial between December 1999 and January 2002 the data cut-off was December 2002. Patients received gefitinib treatment once daily. Results. The safety profile of gefitinib reported in this trial was similar to that reported in earlier gefitinib clinical trials no new safety issues were identified and gefitinib-related toxicity was predictable, with diarrhea and skin-related adverse events being the most common. For patients entering this trial from IDEAL 1 and 2 (n = 48), similar results for both the 250 mg and 500 mg doses were observed for median overall survival (22.2 and 20.8 months, respectively) and progression-free survival (13.7 and 14.0 months, respectively). Conclusions. No new safety issues were identified following long-term treatment with gefitinib and clinical benefit observed in the parent trial was maintained in the majority of patients. © 2006 The Japan Lung Cancer Society.
  • Shinzoh Kudoh; Koji Takeda; Kazuhiko Nakagawa; Minoru Takada; Nobuyuki Katakami; Kaoru Matsui; Tetsu Shinkai; Toshiyuki Sawa; Isao Goto; Hiroshi Semba; Takashi Seto; Masahiko Ando; Taroh Satoh; Naruo Yoshimura; Shunichi Negoro; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 24 22 3657 - 3663 2006年08月 [査読有り]
     
    Purpose Docetaxel has shown activity in elderly patients with advanced non-small-cell lung cancer (NSCLC). This randomized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine (the current standard treatment) in elderly patients. Patients and Methods Chemotherapy-naive patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible. Patients randomly received docetaxel 60 mg/m(2) (day 1) or vinorelbine 25 mg/m(2) (days 1 and 8) every 21 days for four cycles. The primary end point was overall survival. Overall disease-related symptom improvement was assessed using an eight-item questionnaire. Results In total, 182 patients were enrolled. Median age was 76 years (range, 70 years to 86 years). There was no statistical difference in median overall survival with docetaxel versus vinorelbine (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138). There was a significant difference in median progression-free survival (5.5 months v 3.1 months; P < .001). Response rates were also significantly improved with docetaxel versus vinorelbine (22.7% v 9.9%1; P = .019). The most common grade 3 to 4 toxicities were neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; P = .031) and leukopenia (58.0% for docetaxel; 51.7% for vinorelbine). Other toxicities were mild and generally well tolerated. Docetaxel improved overall disease-related symptoms over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 to 3.20). Conclusion Docetaxel improved progression-free survival, response rate, and disease-related symptoms versus vinorelbine. Overall survival was not statistically significantly improved at this time. Docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.
  • Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hisao Uejima; Takahiko Sugiura; Yoshiki Takada; Shun-ichi Negoro; Kaoru Matsui; Tatsuhiko Kashii; Minoru Takada; Yoichi Nakanishi; Terufumi Kato; Masahiro Fukuoka
    CANCER 107 3 599 - 605 2006年08月 [査読有り]
     
    BACKGROUND. Combined gemcitabine and carboplatin (GC) and combined gemcitabine and vinorelbine (GV) are active and well tolerated chemotherapeutic regimens for patients with advanced nonsmall cell lung cancer (NSCLC). The authors conducted a randomized Phase II study of GC versus GV to compare them in terms of efficacy and toxicity. METHODS. One hundred twenty-eight patients with Stage IIIB or IV NSCLC were randomized to receive either carboplatin at an area under the curve of 5 on Day I combined with gemcitabine 1000 mg/m(2) on Days 1 and 8 (n = 64 patients) or vinorelbine 25 mg/m(2) combined with gemcitabine 1000 mg/m(2) on Days 1 and 8 (n = 64 patients) every 3 weeks. RESULTS. Response rates were 20.3% for the GC patients and 21.0% for the GV patients. In the GC arm, the median survival was 432 days, and the a I-year survival rate was 57.6%; in the GV arm, the median survival was 385 days, and the 1-year survival rate was 53.3% in the GV arm. The median progression-free survival was 165 days in the GC arm and 137 days in the GV arm. Severe hematologic toxicity (Grade 4) was significantly more frequent in the GC arm (45.3% vs. 25.8% in the GV arm; P = .022). Most notably, the incidence of Grade 3 or 4 thrombocytopenia was significantly higher in the GC arm (81.3% vs. 6.5% in the GV arm; P < .001). Conversely, severe nonhematologic toxicity (Grade 3 or 4) was more common in the GV arm (7.8% vs. 19.4% in the GC arm; P = .057). CONCLUSIONS. Although the GV and GC regimens had different toxicity profiles, there was no significant difference in survival among patients with NSCLC in the current study.
  • Nobuyuki Yamamoto; Kazuhiko Nakagawa; Hisao Uejima; Takahiko Sugiura; Yoshiki Takada; Shun-ichi Negoro; Kaoru Matsui; Tatsuhiko Kashii; Minoru Takada; Yoichi Nakanishi; Terufumi Kato; Masahiro Fukuoka
    CANCER 107 3 599 - 605 2006年08月 [査読有り]
     
    BACKGROUND. Combined gemcitabine and carboplatin (GC) and combined gemcitabine and vinorelbine (GV) are active and well tolerated chemotherapeutic regimens for patients with advanced nonsmall cell lung cancer (NSCLC). The authors conducted a randomized Phase II study of GC versus GV to compare them in terms of efficacy and toxicity. METHODS. One hundred twenty-eight patients with Stage IIIB or IV NSCLC were randomized to receive either carboplatin at an area under the curve of 5 on Day I combined with gemcitabine 1000 mg/m(2) on Days 1 and 8 (n = 64 patients) or vinorelbine 25 mg/m(2) combined with gemcitabine 1000 mg/m(2) on Days 1 and 8 (n = 64 patients) every 3 weeks. RESULTS. Response rates were 20.3% for the GC patients and 21.0% for the GV patients. In the GC arm, the median survival was 432 days, and the a I-year survival rate was 57.6%; in the GV arm, the median survival was 385 days, and the 1-year survival rate was 53.3% in the GV arm. The median progression-free survival was 165 days in the GC arm and 137 days in the GV arm. Severe hematologic toxicity (Grade 4) was significantly more frequent in the GC arm (45.3% vs. 25.8% in the GV arm; P = .022). Most notably, the incidence of Grade 3 or 4 thrombocytopenia was significantly higher in the GC arm (81.3% vs. 6.5% in the GV arm; P < .001). Conversely, severe nonhematologic toxicity (Grade 3 or 4) was more common in the GV arm (7.8% vs. 19.4% in the GC arm; P = .057). CONCLUSIONS. Although the GV and GC regimens had different toxicity profiles, there was no significant difference in survival among patients with NSCLC in the current study.
  • Shinzoh Kudoh; Koji Takeda; Kazuhiko Nakagawa; Minoru Takada; Nobuyuki Katakami; Kaoru Matsui; Tetsu Shinkai; Toshiyuki Sawa; Isao Goto; Hiroshi Semba; Takashi Seto; Masahiko Ando; Taroh Satoh; Naruo Yoshimura; Shunichi Negoro; Masahiro Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 24 22 3657 - 3663 2006年08月 [査読有り]
     
    Purpose Docetaxel has shown activity in elderly patients with advanced non-small-cell lung cancer (NSCLC). This randomized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine (the current standard treatment) in elderly patients. Patients and Methods Chemotherapy-naive patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible. Patients randomly received docetaxel 60 mg/m(2) (day 1) or vinorelbine 25 mg/m(2) (days 1 and 8) every 21 days for four cycles. The primary end point was overall survival. Overall disease-related symptom improvement was assessed using an eight-item questionnaire. Results In total, 182 patients were enrolled. Median age was 76 years (range, 70 years to 86 years). There was no statistical difference in median overall survival with docetaxel versus vinorelbine (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138). There was a significant difference in median progression-free survival (5.5 months v 3.1 months; P < .001). Response rates were also significantly improved with docetaxel versus vinorelbine (22.7% v 9.9%1; P = .019). The most common grade 3 to 4 toxicities were neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; P = .031) and leukopenia (58.0% for docetaxel; 51.7% for vinorelbine). Other toxicities were mild and generally well tolerated. Docetaxel improved overall disease-related symptoms over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 to 3.20). Conclusion Docetaxel improved progression-free survival, response rate, and disease-related symptoms versus vinorelbine. Overall survival was not statistically significantly improved at this time. Docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.
  • Yukitoshi Satoh; Sakae Okumura; Ken Nakagawa; Atsushi Horiike; Fumiyoshi Ohyanagi; Makoto Nishio; Takeshi Horai; Yuichi Ishikawa
    EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY 30 1 172 - 176 2006年07月 [査読有り]
     
    Background: The bronchopleural fistula (BPF) is a major complication after lung surgery. We have reviewed our experience with ischemic changes in bronchial stumps, some of which resulted in BPFs (we term this postoperative ischemic bronchitis (POIB)) and studied predisposing factors. Methods: A total of 1015 patients undergoing curative resection of lung cancers between 1991 and 2002 were reviewed. Details regarding bronchofiberscopic findings within the first 15 postoperative days were carefully reviewed with particular attention to factors possibly affecting the occurrence of POIB: the techniques for bronchial closure and mediastinal Lymph node dissection (LND). Information about clinical profiles and histologic status was also analyzed. Results: The incidence of POIB was 2.5% (29/1015), affecting 26 mates and 3 females. The most common site was the right intermediate trunk stump (n = 4; 7. 1%), followed by the left upper (n = 8; 3.4%), right tower (n = 5; 3.4%), right middle (n = 2; 3.3%), and left tower (n = 4; 3.2%) lobar bronchial stumps. BPFs eventually resulted in 3 patients (10%) out of 29 with POIB and in 4 (0.4%) out of 986 without it (p < 0.0001). Being mate, a smoker, having diabetes mellitus, having postoperative respiratory complications and subcarinal LND proved to exert a significant impact with regard to POIB. Conclusions: Surgeons must bear in mind the possibility of POIB occurrence, especially in cases undergoing particular types of lobectomy (right middle and tower, left upper, right lower or right middle) accompanied by subcarinal LND and having postoperative respiratory complications. Moreover, in appropriate groups with tumors of the right upper lobe or left upper segment, limited mediastinal LND might allow avoidance of POIB. (c) 2006 Elsevier B.V. All rights reserved.
  • Ichinosuke Hyodo; Kuniaki Shirao; Toshihiko Doi; Kiyohiko Hatake; Yasuaki Arai; Kensei Yamaguchi; Takao Tamura; Shoji Takemiya; Hiroya Takiuchi; Kazuhiko Nakagawa; Hideyuki Mishima
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 36 7 410 - 417 2006年07月 [査読有り]
     
    Background: Although the standard 3-week capecitabine regimen (1250 mg/m(2) twice daily for 2 weeks followed by a 1-week rest) has shown superior activity and improved safety over bolus 5-fluorouracil/leucovorin in two large randomized phase III trials in Europe and in the United States, only a 4-week regimen of capecitabine (828 mg/m(2) twice daily for 3 weeks) has been studied in Japan. Therefore, we performed a phase II study to investigate the 3-week regimen of capecitabine in Japanese patients with metastatic colorectal cancer (MCRC). Methods: Previously untreated patients with MCRC received oral capecitabine 1250 mg/m(2) twice daily for 2 weeks. Treatment was repeated every 3 weeks. Blood and urine samples were collected for pharmacokinetic analysis. Results: Sixty patients were enrolled. The overall response rate was 35% [95% confidence interval (CI), 23-48%], and 52% of patients had stable disease. The median time to progression was 5.5 months (95% CI, 4.2-6.7 months). The median overall survival was 20.2 months (95% CI, 16.6-27.8 months). The most frequently occurring adverse drug reaction was hand-foot syndrome (all-grade 73%; grade 3 13%). Diarrhea, anorexia, nausea and stomatitis were each seen in 37% of patients. The pharmacokinetic profiles of capecitabine and its metabolites were similar to those reported in Caucasian patients. Conclusions: The 3-week regimen of capecitabine was effective and well tolerated in Japanese patients with MCRC as well, and could be used as the basic regimen for future combination therapies.
  • Yoshinori Fujiwara; Koji Nakao; Takashi Inoue; Kenji Koishi; Yoshimasa Nishio; Ryuichirou Yagyu; Kazuhiko Nakagawa; Takehira Yarnamura
    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 21 7 1103 - 1107 2006年07月 [査読有り]
     
    Background and Aims: The relationship between gastroesophageal reflux disease and sliding hernia is controversial, especially following distal partial gastrectomy in patients with gastric cancer. The aim of this study was to examine the relationship between gastroesophageal reflux disease and sliding hernia of the esophagus after distal gastrectomy using the gastroesophageal scintigraphy and endoscopy. Methods: Forty-five distal gastrectomy patients diagnosed with cancer of the stomach were studied. Twenty-five patients presented with reflux symptoms, such as heartburn and/ or regurgitation and 20 patients exhibited no reflux symptoms. All of the patients were examined by gastroesophageal scintigraphy and their reflux indices were determined. Thirty-eight of the patients underwent upper endoscopy and both sliding hernias and reflux symptoms were classified as mild or severe. Results: Sliding hernias were diagnosed in all of the subjects and 65.8% of the patients exhibited reflux symptoms. Evidence of endoscopic esophagitis was noted in only 39.5% of the patients. The reflux indices for the mild and severe hernia groups were 5.03 +/- 2.2 and 10.3 +/- 6.4, respectively (P < 0.05). More severely symptomatic esophagitis was prevalent in the severe hernia group in comparison to the mild group (P < 0.05). Conclusion: The results suggest that the onset of gastroesophageal reflux after distal gastrectomy is induced by the surgical procedures and that hiatal hernia may be an important factor in the etiology of reflux esophagitis.
  • Ichinosuke Hyodo; Kuniaki Shirao; Toshihiko Doi; Kiyohiko Hatake; Yasuaki Arai; Kensei Yamaguchi; Takao Tamura; Shoji Takemiya; Hiroya Takiuchi; Kazuhiko Nakagawa; Hideyuki Mishima
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 36 7 410 - 417 2006年07月 [査読有り]
     
    Background: Although the standard 3-week capecitabine regimen (1250 mg/m(2) twice daily for 2 weeks followed by a 1-week rest) has shown superior activity and improved safety over bolus 5-fluorouracil/leucovorin in two large randomized phase III trials in Europe and in the United States, only a 4-week regimen of capecitabine (828 mg/m(2) twice daily for 3 weeks) has been studied in Japan. Therefore, we performed a phase II study to investigate the 3-week regimen of capecitabine in Japanese patients with metastatic colorectal cancer (MCRC). Methods: Previously untreated patients with MCRC received oral capecitabine 1250 mg/m(2) twice daily for 2 weeks. Treatment was repeated every 3 weeks. Blood and urine samples were collected for pharmacokinetic analysis. Results: Sixty patients were enrolled. The overall response rate was 35% [95% confidence interval (CI), 23-48%], and 52% of patients had stable disease. The median time to progression was 5.5 months (95% CI, 4.2-6.7 months). The median overall survival was 20.2 months (95% CI, 16.6-27.8 months). The most frequently occurring adverse drug reaction was hand-foot syndrome (all-grade 73%; grade 3 13%). Diarrhea, anorexia, nausea and stomatitis were each seen in 37% of patients. The pharmacokinetic profiles of capecitabine and its metabolites were similar to those reported in Caucasian patients. Conclusions: The 3-week regimen of capecitabine was effective and well tolerated in Japanese patients with MCRC as well, and could be used as the basic regimen for future combination therapies.
  • 清水俊雄; 田村研治; 尾崎智博; 佐藤太郎; 岡本勇; 中川和彦; 光冨徹哉; 福岡正博
    分子呼吸器病 10 4 319 - 323 2006年07月 [査読有り]
  • 中西 洋一; 中川 和彦
    肺癌 46 3 259 - 259 日本肺癌学会 2006年06月
  • I. Okamoto; J. Araki; R. Suto; M. Shimada; K. Nakagawa; M. Fukuoka
    Annals of Oncology 17 6 1028 - 1029 2006年06月 [査読有り]
  • 寺嶋応顕; 岡本勇; 田村研治; 佐藤太郎; 岡部崇記; 中川和彦; 福岡正博
    近畿大学医学雑誌 31 2 45 - 52 近畿大学 2006年06月 [査読有り]
     
    ゲフィチニブは,選択的EGFRチロシンキナーゼ阻害剤であり,EGFR遺伝子変異の存在とゲフィチニブに対する奏効率が高い相関を示すと報告されている.一方,EGFR遺伝子増幅もゲフィチニブ感受性規定因子として有用であるとする報告もあり,ゲフィチニブの効果を規定する分子メカニズムはいまだ研究段階である.本研究では,独自に樹立した9株を含む,17株のヒト非小細胞肺癌細胞株のゲフィチニブ感受性と,ゲフィチニブの標的分子であるEGFRの遺伝子変異,遺伝子増幅,蛋白発現量を調べ,相互の関連を検討した.その結果,EGFR遺伝子変異を有する細胞株は,ゲフィチニブに対して感受性を示す傾向にあり,その中でもEGFR遺伝子増幅を持つ細胞株が,高い感受性を示した.EGFR遺伝子増幅はEGFR遺伝子変異を有する細胞株のみに認められたことから,遺伝子増幅は遺伝子変異を契機に起こることが示唆された.またEGFR遺伝子変異を認める細胞株のゲフィチニブ感受性は,EGFR遣伝子増幅や,それに伴うEGFRの高発現によって決定されている可能性が示唆された.
  • H Kaneda; T Kurata; K Tamura; H Uejima; K Nakagawa; M Fukuoka
    ANTICANCER RESEARCH 26 3B 2479 - 2485 2006年05月 [査読有り]
     
    Background: A combination phase I study was conducted in a cohort of lung cancer patients to determine the maximum tolerated dose (MTD) and toxicities of irinotecan (CPT-11), a topoisomerase I inhibitor, in combination with amrubicin (AMR), a topoisomerase II inhibitor, and to observe their antitumor activities. Patients and Methods: Patients with lung cancer received AMR (35 - 40 mg/m(2) given intravenously over 5 min) for 3 consecutive days, and CPT-11 (50 - 60 mg/m(2) given intravenously over 90 min) after the completion of AMR infusion on days 1 and 8, every 3 weeks. Results: In total, eleven patients were enrolled in this study. The most frequent toxicities were bone marrow suppression, particularly leucopenia and neutropenia, followed by infection, diarrhea and pneumonitis. As a consequence of these toxicities, the MTD and the recommended dose could not be determined. There were two partial responses, which included one patient with small cell lung cancer (SCLC) who had previously received chemotherapy and the other with previously untreated non-small cell lung cancer (NSCLC). Conclusion: These data suggest that the combination of CPT-11 and AMR is not tolerated, as it mediates an unexpectedly strong myelosuppressive effect, and is inactive against both NSCLC and SCLC.
  • H Kaneda; T Kurata; K Tamura; H Uejima; K Nakagawa; M Fukuoka
    ANTICANCER RESEARCH 26 3B 2479 - 2485 2006年05月 [査読有り]
     
    Background: A combination phase I study was conducted in a cohort of lung cancer patients to determine the maximum tolerated dose (MTD) and toxicities of irinotecan (CPT-11), a topoisomerase I inhibitor, in combination with amrubicin (AMR), a topoisomerase II inhibitor, and to observe their antitumor activities. Patients and Methods: Patients with lung cancer received AMR (35 - 40 mg/m(2) given intravenously over 5 min) for 3 consecutive days, and CPT-11 (50 - 60 mg/m(2) given intravenously over 90 min) after the completion of AMR infusion on days 1 and 8, every 3 weeks. Results: In total, eleven patients were enrolled in this study. The most frequent toxicities were bone marrow suppression, particularly leucopenia and neutropenia, followed by infection, diarrhea and pneumonitis. As a consequence of these toxicities, the MTD and the recommended dose could not be determined. There were two partial responses, which included one patient with small cell lung cancer (SCLC) who had previously received chemotherapy and the other with previously untreated non-small cell lung cancer (NSCLC). Conclusion: These data suggest that the combination of CPT-11 and AMR is not tolerated, as it mediates an unexpectedly strong myelosuppressive effect, and is inactive against both NSCLC and SCLC.
  • 進行胃癌に対するTS-1とDocetaxel併用療法の第I相試験
    佐藤 太郎; 田村 研治; 尾崎 智博; 岡本 勇; 宮崎 昌樹; 清水 俊雄; 中川 和彦; 福岡 正博
    日本消化器病学会雑誌 103 臨増総会 A319 - A319 (一財)日本消化器病学会 2006年03月
  • Gyo Asai; Nobuyuki Yamamoto; Takayasu Kurata; Kenji Tamura; Hisao Uejima; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 1 3 226 - 230 2006年03月 [査読有り]
     
    The purpose of this study was to investigate the maximum tolerated doses, dose-limiting toxicities, efficacy, and pharmacokinetic profiles in the combination of irinotecan and paclitaxel. Eligibility criteria included age 75 years or younger, good performance status, adequate organ function, and unresectable non-small cell or extensive disease of small cell lung cancer. Irinotecan was administered on days I and 8 over 90 minutes, and paclitaxel was administered on day 8 over 3 hours after 90 minutes from the end of the irinotecan infusion. Irinotecan and paclitaxel were dose-escalated from 40 and 135 mg/m(2) and repeated every 4 weeks. The authors also administered a higher dosage with preventive granulocyte colony-stimulating factor support from day 9. Thirty-one patients were assessed for toxicities and responses. Dose-limiting toxicities were neutropenia and febrile neutropenia. The dose of irinotecan 60 mg/m(2) and paclitaxel 200 mg/m(2) with preventive granulocyte colony-stimulating factor support was tolerable and suitable for a phase II trial. Nine of 25 (36%) patients with non-small cell and all six patients with small cell carcinoma achieved partial response. The areas under the concentration versus time curves of irinotecan and its metabolites on day 8 were significantly higher than on day 1. This combination therapy must be planned only after careful consideration of the drug-drug interaction.
  • N Yoshimura; S Kudoh; T Kimura; S Mitsuoka; K Matsuura; K Hirata; K Matsui; S Negoro; K Nakagawa; M Fukuoka
    LUNG CANCER 51 3 363 - 368 2006年03月 [査読有り]
     
    EKB-569 is a potent, low molecular weight, selective, and irreversible inhibitor of epidermal growth factor receptor (EGFR) that is being developed as an anticancer agent. A phase 1, dose-escalation study was conducted in Japanese patients. EKB-569 was administered orally, once daily, in 28-day cycles, to patients with advanced-stage malignancies known to overexpress EGFR. Two patients with advanced non-small cell lung cancer with EGFR mutations and acquired gefitinib resistance from the phase 1 study are described in detail. Case #1 is a 63-year-old man with smoking history. He received treatment from 4 March 2004. Because he had no severe adverse events, a total of 10 courses of therapy were completed through December 16. Grade 2 skin rash and ALT elevation, and grade 1 diarrhea and nail changes developed. A chest CT scan on 4 August 2003 revealed multiple pulmonary metastases that had decreased in size. Case #2 is a 49-year-old woman with no smoking history. She received therapy from 9 February 2004. She received a total of five courses of the therapy until 22 June 2004. Grade 3 nausea and vomiting and grade 1 diarrhea and dry skin developed. A chest CT scan on March 3 revealed multiple pulmonary metastases that had decreased in size. A brain MRI on March 4 showed that multiple brain metastases also had decreased in size. Based on RECIST criteria, they had stable disease but radiographic tumor regression was observed. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
  • N Yoshimura; S Kudoh; T Kimura; S Mitsuoka; K Matsuura; K Hirata; K Matsui; S Negoro; K Nakagawa; M Fukuoka
    LUNG CANCER 51 3 363 - 368 2006年03月 [査読有り]
     
    EKB-569 is a potent, low molecular weight, selective, and irreversible inhibitor of epidermal growth factor receptor (EGFR) that is being developed as an anticancer agent. A phase 1, dose-escalation study was conducted in Japanese patients. EKB-569 was administered orally, once daily, in 28-day cycles, to patients with advanced-stage malignancies known to overexpress EGFR. Two patients with advanced non-small cell lung cancer with EGFR mutations and acquired gefitinib resistance from the phase 1 study are described in detail. Case #1 is a 63-year-old man with smoking history. He received treatment from 4 March 2004. Because he had no severe adverse events, a total of 10 courses of therapy were completed through December 16. Grade 2 skin rash and ALT elevation, and grade 1 diarrhea and nail changes developed. A chest CT scan on 4 August 2003 revealed multiple pulmonary metastases that had decreased in size. Case #2 is a 49-year-old woman with no smoking history. She received therapy from 9 February 2004. She received a total of five courses of the therapy until 22 June 2004. Grade 3 nausea and vomiting and grade 1 diarrhea and dry skin developed. A chest CT scan on March 3 revealed multiple pulmonary metastases that had decreased in size. A brain MRI on March 4 showed that multiple brain metastases also had decreased in size. Based on RECIST criteria, they had stable disease but radiographic tumor regression was observed. (c) 2005 Elsevier Ireland Ltd. All rights reserved.
  • Gyo Asai; Nobuyuki Yamamoto; Takayasu Kurata; Kenji Tamura; Hisao Uejima; Kazuhiko Nakagawa; Masahiro Fukuoka
    JOURNAL OF THORACIC ONCOLOGY 1 3 226 - 230 2006年03月 [査読有り]
     
    The purpose of this study was to investigate the maximum tolerated doses, dose-limiting toxicities, efficacy, and pharmacokinetic profiles in the combination of irinotecan and paclitaxel. Eligibility criteria included age 75 years or younger, good performance status, adequate organ function, and unresectable non-small cell or extensive disease of small cell lung cancer. Irinotecan was administered on days I and 8 over 90 minutes, and paclitaxel was administered on day 8 over 3 hours after 90 minutes from the end of the irinotecan infusion. Irinotecan and paclitaxel were dose-escalated from 40 and 135 mg/m(2) and repeated every 4 weeks. The authors also administered a higher dosage with preventive granulocyte colony-stimulating factor support from day 9. Thirty-one patients were assessed for toxicities and responses. Dose-limiting toxicities were neutropenia and febrile neutropenia. The dose of irinotecan 60 mg/m(2) and paclitaxel 200 mg/m(2) with preventive granulocyte colony-stimulating factor support was tolerable and suitable for a phase II trial. Nine of 25 (36%) patients with non-small cell and all six patients with small cell carcinoma achieved partial response. The areas under the concentration versus time curves of irinotecan and its metabolites on day 8 were significantly higher than on day 1. This combination therapy must be planned only after careful consideration of the drug-drug interaction.
  • K Yonesaka; K Tamura; T Kurata; T Satoh; M Ikeda; M Fukuoka; K Nakagawa
    INTERNATIONAL JOURNAL OF CANCER 118 4 812 - 820 2006年02月 [査読有り]
     
    Survivin is a member of the inhibitor of apoptosis protein (IAP) family that is specifically overexpressed in cancer tissues. p53 is one of the tumor suppressor genes; its induction in response to DNA damage causes apoptosis and correlates with drug sensitivity. To investigate the possible regulation of survivin by p53, we examined the level of survivin expression in lung cancer cell lines in response to adriamycin. Levels of survivin mRNA and protein in cell lines with wild-type p53 decreased dramatically after p53 induction, but no such reduction of survivin was observed in cell lines with mutated or null p53. Inhibition of wild-type p53 in A549 cells by small interfering (si) RNA. significantly upregulated the expression of survivin. Survivin inhibition by siRNA in PC9 cells with mutated p53 significantly depressed cell proliferation. To investigate the sensitivity of cancer cells to adriamycin after inhibition of survivin, we depressed survivin expression using siRNA, and then added adriamycin at an IC50 dose. After a further 48 hr incubation with adriamycin, proliferation was significantly depressed in the cells treated with siRNA targeting survivin, in comparison with siRNA targeting scramble. Furthermore, both TUNEL and pro-caspase3 expression assay showed a significant increase in apoptosis after combined treatment with adriamycin and siRNA targeting survivin. Our results demonstrate that survivin is downregulated by p53, and that siRNA targeting of survivin increases cell sensitivity to adriamycin and promotes apoptosis. siRNA targeting of survivin could be potentially useful for increasing sensitivity to anticancer drugs, especially in drug-resistant cells with mutated p53. (c) 2005 Wiley-Liss, Inc.
  • Miyako Hiramatsu; Sakae Okumura; Fumiyoshi Ohyanagi; Makoto Nishio; Yuichi Ishikawa; Ken Nakagawa
    Japanese Journal of Lung Cancer 46 1 33 - 39 2006年 [査読有り]
     
    Background. Primitive neuroectodermal tumor (PNET) and Ewing's sarcoma are relatively aggressive malignant tumors of bone and soft tissue. Their typical chromosomal translocation and chimeric protein, as a result of gene fusion, have proved their similarity and now they are thought to be identical. Since the 1980, many protocol studies have been carried out and accumulated data have demonstrated that intensive chemotherapy combined with local control is crucial to improve survival. Since primary pulmonary PNET is very rare and there are only a few cases reported in detail, there is no standard therapy for this disease and the prognosis is also unknown. Case. A 31-year old Japanese man presenting a mass adjacent to the right hilum of lung on an annual chest X-ray check up was admitted to our hospital. CT-guided needle biopsy demonstrated small, round cell proliferation and both MIC2 and PAS staining were positive, resulting in a diagnosis of PNET. Chromosomal translocation (t(11 22) (q24 q12)) together with fusion gene (EWS-FLI 1 Exon 7/Exon 5) confirmed the diagnosis. After 3 courses of chemotherapy, we performed right upper lobectomy and he recently finished an adjuvant chemotherapy course that extended over 47 weeks. © 2006 The Japan Lung Cancer Society.
  • Teruo Iwasaki; Katsuhiro Nakagawa; Motoaki Yasukawa; Hiroyuki Shiono; Teruaki Nagano; Kunimitsu Kawahara
    Japanese Journal of Thoracic and Cardiovascular Surgery 54 1 35 - 39 2006年01月 [査読有り]
     
    Ectopic cervical or cervico-mediastinal thymomas are very rare and most of them are asymptomatic, except for the presence of a cervical mass. We present the case of a 71-year-old man with an ectopic cervico-mediastinal thymoma threatening superior vena cava syndrome. He had a slight headache and presented with venous dilatation on the chest wall. A computed tomographic scan and magnetic resonance imaging of the chest demonstrated a mass extending from the right neck to the hilum, that indented the trachea and compressed and displaced the brachiocephalic veins anteriorly. Under a right hemicollar incision and median sternotomy, the mass was resected en bloc together with the thymus. The resected specimen was an encapsulated mass measuring 11×7×4 cm. The pathological diagnosis was type AB, non-invasive thymoma, confirmed by 3-color flow cytometry of tumor-derived lymphocytes. Flow cytometry using biopsy material may contribute to the preoperative diagnosis of ectopic thymoma.
  • 宮崎 昌樹; 長谷川 喜一; 森永 亮太郎; 津谷 あすか; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    気管支学 28 3 191 - 191 特定非営利活動法人 日本呼吸器内視鏡学会 2006年
  • 宮崎 昌樹; 野上 壽二; 長谷川 喜一; 森永 亮太郎; 津谷 あすか; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    気管支学 28 1 82 - 82 特定非営利活動法人 日本呼吸器内視鏡学会 2006年
  • H Asamura; T Kameya; Y Matsuno; M Noguchi; H Tada; Y Ishikawa; T Yokose; SX Jiang; T Inoue; K Nakagawa; K Tajima; K Nagai
    JOURNAL OF CLINICAL ONCOLOGY 24 1 70 - 76 2006年01月 [査読有り]
     
    Purpose Neuroendocrine (NE) tumors of the lung include typical carcinoid (TC), atypical carcinoid (AC), large-cell NE carcinoma (LCNEC), and small-cell lung carcinoma (SCLC), Their clinicopathologic profiles and relative grade of malignancy have not been defined, Patients and Methods From 10 Japanese institutes, 383 surgically resected pulmonary NE tumors were collected, The histologic diagnosis was determined by the consensus of a pathology panel consisting of six expert pathologists as TIC, AC, LCNEC, or SCLC on the basis of the WHO classification, and its relationship to clinicopathologic profiles was analyzed. Results Of the 383 tumors, 18 were excluded because of an improper specimen, The pathology panel reviewed the remaining 366 tumors, and a diagnosis of NE tumor was made in 318 patients (87.4%); 55 patients had TIC, nine had AC, 141 had LCNEC, and 113 had SCLC. The 5-year survival rates of patients with all stages were as follows: 96.2% for TC, 77.8% for AC, 40.3% for LCNEC, and 35.7% for SCLC. There was significant prognostic difference between TIC and AC as well as between AC and LCNEC+SCLC, However, there was no difference between LCNEC and SCLC, and their survival curves were superimposed, The multivarate analysis indicated that histologic type, completeness of resection, symptoms, nodal involvement, and age were significantly prognostic. Conclusion The grade of malignancy of NE tumors was upgraded in the following order: TIC, AC, LCNEC, and SCLC. No prognostic difference was noted between LCNEC and SCLC, The high-grade NE histology uniformly indicated poor prognosis regardless of its histologic type.
  • N Yamamoto; J Tsurutani; N Yoshimura; G Asai; A Moriyama; K Nakagawa; S Kudoh; M Takada; Y Minato; M Fukuoka
    ANTICANCER RESEARCH 26 1B 777 - 781 2006年01月 [査読有り]
     
    The purpose of this study was to evaluate the efficacy and toxicity of single-agent paclitaxel given weekly to patients with relapsed and refractory small cell lung cancer (SCLC). Patients were treated with 80 mg/m(2) paclitaxel administered weekly for 1 h for 6 weeks in an 8-week cycle. Twenty-two patients were enrolled, 21 of whom were eligible. The patient characteristics included: 20 males, 1 female; median age 66 years (range 48 - 75); performance status 0/1 in 19 and 2 in 5 patients. Grade 314 leukopenia and neutropenia occurred in 4.75% and 64%, respectively. Other grade 314 toxicities included infection, skin rash, neuropathy and pulmonary toxiciiy. There were 5 partial responses in 3 out of the 11 sensitive cases and 2 out of the 10 refractory cases, respectively. Paclitaxel, administered as a weekly infusion at a dose of 80 mg/m(2), was effective in treating relapsed and refractory SCLC.
  • N Yamamoto; J Tsurutani; N Yoshimura; G Asai; A Moriyama; K Nakagawa; S Kudoh; M Takada; Y Minato; M Fukuoka
    ANTICANCER RESEARCH 26 1B 777 - 781 2006年01月 [査読有り]
     
    The purpose of this study was to evaluate the efficacy and toxicity of single-agent paclitaxel given weekly to patients with relapsed and refractory small cell lung cancer (SCLC). Patients were treated with 80 mg/m(2) paclitaxel administered weekly for 1 h for 6 weeks in an 8-week cycle. Twenty-two patients were enrolled, 21 of whom were eligible. The patient characteristics included: 20 males, 1 female; median age 66 years (range 48 - 75); performance status 0/1 in 19 and 2 in 5 patients. Grade 314 leukopenia and neutropenia occurred in 4.75% and 64%, respectively. Other grade 314 toxicities included infection, skin rash, neuropathy and pulmonary toxiciiy. There were 5 partial responses in 3 out of the 11 sensitive cases and 2 out of the 10 refractory cases, respectively. Paclitaxel, administered as a weekly infusion at a dose of 80 mg/m(2), was effective in treating relapsed and refractory SCLC.
  • Y Fujiwara; N Kamikonya; T Inoue; K Koishi; R Yoshikawa; K Nakao; R Yagyu; M Nishiwaki; M Fujiwara; S Kojima; K Nakagawa; T Yamamura
    ONCOLOGY REPORTS 14 5 1177 - 1182 2005年11月 [査読有り]
     
    We conducted this study to evaluate the clinical significance of preoperative concurrent chemoradiotherapy (CRT) followed by esophagectomy in the management of T3 and T4 esophageal cancer. Thirty patients with squamous cell carcinoma of the esophagus received CRT followed by surgery. Preoperative CRT consisted of 5-fluorouracil (500 mg/m(2) by 24 h infusion for 5 days), cisplatin (15 mg/m(2) on days 1-5), and concurrent radiotherapy (a total dose of 40 Gy delivered in daily fractions of 2 Gy, 5 times per week). Esophagectomy was planned for 4-6 weeks after treatment and restaging. All 30 patients completed preoperative CRT. A clinical response (PR+CR) of the primary tumor was obtained in 82.8 %, and a response of metastatic nodes was seen in 23.1 %. Radical resection was possible in 17 of 29 operated patients (58.6%). The postoperative mortality rate was 6.9%, and the hospital mortality rate was 10.3%. Ten out of 29 operated patients (34.5%) had no residual cancer in the resected esophagus, corresponding to pathological CR. The 1-year survival rate was 80.6%, the 2-year survival rate was 62.7%, and the 3-year survival rate was 53.8%. The clinical response group and the R0 or R1 group showed better survival than other patients. Preoperative CRT should be given to patients with squamous cell carcinoma, while esophagectomy remains the standard therapy for responders and has a tolerable mortality.
  • H Matsushita; A Uenaka; T Ono; K Hasegawa; S Sato; F Koizumi; K Nakagawa; M Toda; T Shingo; T Ichikawa; Y Noguchi; T Tamiya; T Furuta; T Kawase; Date, I; E Nakayama
    CANCER SCIENCE 96 11 801 - 809 2005年11月 [査読有り]
     
    For regulatory factor X4 (RFX4), two alternatively spliced variants, RFX4-A and -B, were reported in the testis. In this study, we identified transcript variants RFX4-C, -D, -E, and -F, and demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) that RFX4-A, -B and -C mRNAs were expressed only in the testis, and RFX4-D mRNA was expressed only in normal brain tissues. In tumors, RFX4-E and -F in addition to RFX4-D mRNA were expressed in gliomas by rapid amplification of cDNA ends and RT-PCR analyses. Expression of RFX4 mRNA was not observed in other tumors, such as lung, esophageal, stomach, colon or liver cancers. Quantitative real-time RT-PCR using common primer pairs detecting all of the variant transcripts showed high expression in normal testis, low expression in the brain (1% compared to the expression in testis), and overexpression in 17 of 61 gliomas (28%). Western blot analysis using DC28 monoclonal antibody (mAb) produced against recombinant RFX4-D C-terminus protein showed expression of RFX4-A and -C proteins, but not RFX4-B protein, in the testis, and expression of RFX4-D protein in the brain. Moreover, expression of RFX4-E and -F proteins, but not RFX4-D protein, was observed in gliomas. Immunohistochemistry analysis using DC28 mAb showed positive staining in the nuclei of spermatocytes in the testis and glioma cells. Antibody against RFX4 was detected in the sera of 3 of 58 (5%) glioma patients by enzyme-linked immunosorbent assay, suggesting the immunogenicity of RFX4-E and -F proteins in glioma patients.
  • M Nishio; M Matsuda; F Ohyanagi; Y Sato; S Okumura; D Tabata; A Morikawa; K Nakagawa; T Horai
    LUNG CANCER 49 2 245 - 251 2005年08月 [査読有り]
     
    To clarify the rote of cytochrome P450 in docetaxel and cisplatin combination chemotherapy, cytochrome P450 activity was measured by simple antipyrine test, and its correlation with the drugs' pharmacodynamics was assessed. Twenty-five patients with advanced non-small cell lung cancer received an antipyrine test and were treated with docetaxel and cisplatin. Plasma antipyrine concentration (C) was measured 4 and 24 h after oral administration of 500 mg antipyrine. Antipyrine disappearance rate (ADR) was calculated by: [(C-4h - C-24h)/C-4h] x 100. ADIR correlated significantly with neutropenia nadir. ADR and alpha(1)-acid glycoprotein were selected for independent predictors of neutropenia by multiple regression analysis. In addition, 25 patients were separated into "low ADR" (<40%) and "high ADR" groups (>40%). Grade 3-4 neutropenia was observed in 7/9 "low ADR-patients (77%), whereas grade 3-4 neutropenia was observed in 5/16 "high ADR-patients (31%). We concluded that antipyrine test and cytochrome P450 play an important rote in predicting toxicities of docetaxel and cisplatin combination chemotherapy. (C) 2005 Elsevier Ireland Ltd. All rights reserved.
  • K Nakagawa; Y Matsuno; H Kunitoh; A Maeshima; H Asamura; R Tsuchiya
    CHEST 128 1 140 - 144 2005年07月 [査読有り]
     
    Study objectives: It is sometimes very difficult both clinically and pathologically to distinguish thymic epithelial tumors from primary lung carcinoma with massive anterior mediastinal involvement. The expression of KIT (CD117) in thymic epithelial tumors was investigated in order to evaluate its usefulness as a marker supporting differential diagnosis and choice of therapy. Methods: We examined the immunohistochemical expression of KIT in 70 resected thymic epithelial tumors (thymomas, 50; thymic carcinomas, 20) that had been reclassified on the basis of the World Health Organization histologic classification system. We also compared the expression of KIT and CD5 in 20 thymic carcinomas with their expression in 20 resected pulmonary squamous cell carcinomas that were spreading directly into the mediastinum. Results: Of the 50 thymomas, only 2 (4%) showed positive immunoreactivity for KIT (type A thymoma, 1; type B3 thymoma, 1), whereas 16 of the 20 thymic carcinomas (80%) showed positive immunoreactivity. Testing was positive for CD5 in 14 of the 20 thymic carcinomas (70%). In the pulmonary squamous cell carcinomas, in contrast, the immunohistochemical expression of KIT and CD5 was found in only 4 of 20 carcinomas (20%) and 3 of 20 carcinomas (15%), respectively. Furthermore, of the 40 specimens examined (either thymic or lung carcinoma) all 13 that were positive for both KIT and CD5 were thymic carcinomas, and 13 of the 16 that were negative for both were lung carcinomas. Conclusion: KIT expression is a useful immunohistochemical marker for the diagnosis of thymic carcinoma, and its examination in combination with CD5 immunohistochemistry would greatly help in the differential diagnosis of primary thymic carcinoma from pulmonary squamous cell carcinoma. Further investigations at a genetic level should be encouraged, not only to define the role of KIT in the oncogenesis of thymic epithelial tumors, but also to establish target-based therapy.
  • T Iwasaki; K Nakagawa; H Nakamura; Y Takada; K Matsui; K Kawahara
    ONCOLOGY REPORTS 13 6 1075 - 1080 2005年06月 [査読有り]
     
    Hepatoma-derived growth factor (HDGF), unrelated to hepatocyte growth factor, is a heparin-binding protein originally purified from human hepatoma HuH-7 cells. HDGF exhibits mitogenic activities for certain hepatoma cells, fibroblasts and vascular smooth muscle cells, and angiogenic activities through nuclear targeting. Recently, HDGF was found to be a mitogen for lung epithelial cells in vitro and in vivo. This suggests that HDGF may play a critical role in the development and progression of lung cancer. We investigated, immunohistochemically, the relationship between HDGF expression and clinicopathological variables, and the prognostic significance of HDGF in 102 patients with completely resected non-small-cell lung cancer (NSCLC: 70 adenocarcinomas and 32 squamous cell carcinomas). To address the mechanism of action of HDGF, we evaluated the contribution of HDGF to tumor cell proliferation and intratumor angiogenesis using anti-Ki-67 and anti-CD31 antibodies, respectively. HDGF expression was strongly detected in the nucleus of cancer cells; the HDGF-labeling index (LI) was 20-95% (median 64.5%). There was no significant association between HDGF-expression level and clinicopathological variables. Patients with NSCLC showing a high HDGF-LI ( &GE; 65%) had significantly worse overall and disease-free survivals than those with NSCLC showine, a low HDGF-LI. Multivariate analysis revealed that HDGF is a significant independent prognostic factor, more powerful than pathological stage. Moreover, HDGF expression correlated with Ki-67-LI and intraturnor microvessel density. We consider HDGF as a useful prognostic marker for patients with completely resected NSCLC and it may play a critical role in the pathobiology of lung cancer through its mitogenic and angiogenic activities.
  • M Nishio; F Ohyanagi; A Horiike; Y Ishikawa; Y Satoh; S Okumura; K Nakagawa; K Nishio; T Horai
    BRITISH JOURNAL OF CANCER 92 10 1877 - 1880 2005年05月 
    Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR, HER1/ErbB1) tyrosine kinase, has been shown to have clinical activity against non-small-cell lung cancers (NSCLCs), especially in women nonsmokers with adenocarcinomas. The aim of the present study was to clarify the relationship between androgen levels and gefitinib treatment in patients with advanced NSCLCs. Sera from 67 cases ( 36 men and 31 women) were obtained pretreatment and during treatment with gefitinib monotherapy (days 14-18) for examination of testosterone, dehydroepiandrosterone sulphate ( DHEA), and dehydroepiandrosterone sulphate (DHEAS) levels. Testosterone and DHEA during treatment were significantly lower than the pretreatment values in both women and men, and the DHEAS levels during treatment were also significantly lowered in women. Gefitinib treatment significantly suppressed androgen levels, especially in women who had no smoking history. In addition, hormone levels in women responding to gefitinib were significantly lower during the treatment than in women who did not respond. Gefitinib-associated decrease in serum androgen levels may play a role in its clinical efficacy.
  • M Nishio; F Ohyanagi; F Taguch; M Matsuda; Y Sato; S Okumura; K Nakagawa; T Horai
    LUNG CANCER 48 1 115 - 119 2005年04月 [査読有り]
     
    A phase I study combining a fixed dose of gemcitabine with differing doses of CPT-11 every two weeks for previously treated non-small cell Lung cancer (NSCLC) patients. Patients and methods: A total of 21 patients with previously treated non-small cell lung cancer were treated every two weeks with CPT-11 followed by gemcitabine. The gemcitabine dose was fixed at 1000 mg/m(2). The starting dose of CPT-11 (50 mg/ml) was then escalated different patients in 25 mg/m(2) increments until 150 mg/m(2) (level 5), the recommended dose as a single agent in Japan. Results: Dose-limiting toxicity was only observed at level 5, in three of nine patients receiving the highest dose of CPT-11. One patient had grade 3 diarrhea, and two could not continue chemotherapy with grade 1 diarrhea or grade 1 neutropenia on day 15. Hematologic toxicity with this combination regimen, however, was generally mild. No grade 4 neutropenia, and only one case of grade 3 leukopenia was noted at level 5. Compliance with the combination regimen was good and there was no cumulative toxicity with the subsequent courses. Twenty-five courses of therapy were given at level 5 and the percentage of actual delivered doses/planned doses was 82%. Conclusions: The combination chemotherapy has only very mild toxicity and dose which can be recommended with this regimen are 1000 mg/m(2) for gemcitabine and 150 mg/ml for CPT-11 every two weeks. (c) 2004 Elsevier Ireland Ltd. All rights reserved.
  • Kondo H; Okumura T; Ohde Y; Nakagawa K
    International journal of clinical oncology 10 2 81 - 85 2005年04月 [査読有り]
  • K Matsui; T Hirashima; T Nitta; M Kobayashi; Y Ogata; M Furukawa; S Kudoh; N Yoshimura; T Mukohara; S Yamauchi; S Shiraishi; H Kamoi; S Negoro; K Takeda; K Nakagawa; M Takada; T Yana; M Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 35 4 181 - 187 2005年04月 [査読有り]
     
    Objective: Gemcitabine and docetaxel are non-platinum agents with activity in non-small cell lung cancer (NSCLC). This study was conducted to determine and evaluate the recommended regimen of gemcitabine-docetaxel and evaluated its efficacy and safety in chemonaive Japanese NSCLC patients. Methods: In phase I, patients with stage IIIB/IV NSCLC were randomized and received either gemcitabine on days 1 and 8 plus docetaxel on day 1 or gemcitabine on days 1 and 8 plus docetaxel on day 8. The recommended regimen was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Efficacy and toxicity were evaluated in all patients. Results: Twenty-five patients were enrolled in phase I and six patients were given the recommended regimen; gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8. An additional 34 patients were enrolled into phase II and administered with the recommended regimen. The response rate was 32.2% [95% confidence interval (CI) 20.6-45.6%] overall and 30.0% (95% CI 16.6-46.5%) in patients with the recommended regimen (40 patients). Although grade 3 interstitial pneumonia was observed in two patients (5.0%) who received the recommended regimen, both recovered shortly after steroid treatment. No unexpected events were observed throughout this study. Conclusions: Gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8 has comparable efficacy and more tolerable toxicities than previously reported platinum-based regimens. These results should be verified by a phase III study.
  • K Matsui; T Hirashima; T Nitta; M Kobayashi; Y Ogata; M Furukawa; S Kudoh; N Yoshimura; T Mukohara; S Yamauchi; S Shiraishi; H Kamoi; S Negoro; K Takeda; K Nakagawa; M Takada; T Yana; M Fukuoka
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 35 4 181 - 187 2005年04月 [査読有り]
     
    Objective: Gemcitabine and docetaxel are non-platinum agents with activity in non-small cell lung cancer (NSCLC). This study was conducted to determine and evaluate the recommended regimen of gemcitabine-docetaxel and evaluated its efficacy and safety in chemonaive Japanese NSCLC patients. Methods: In phase I, patients with stage IIIB/IV NSCLC were randomized and received either gemcitabine on days 1 and 8 plus docetaxel on day 1 or gemcitabine on days 1 and 8 plus docetaxel on day 8. The recommended regimen was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Efficacy and toxicity were evaluated in all patients. Results: Twenty-five patients were enrolled in phase I and six patients were given the recommended regimen; gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8. An additional 34 patients were enrolled into phase II and administered with the recommended regimen. The response rate was 32.2% [95% confidence interval (CI) 20.6-45.6%] overall and 30.0% (95% CI 16.6-46.5%) in patients with the recommended regimen (40 patients). Although grade 3 interstitial pneumonia was observed in two patients (5.0%) who received the recommended regimen, both recovered shortly after steroid treatment. No unexpected events were observed throughout this study. Conclusions: Gemcitabine 1000 mg/m(2) on days 1 and 8 plus docetaxel 50 mg/m(2) on day 8 has comparable efficacy and more tolerable toxicities than previously reported platinum-based regimens. These results should be verified by a phase III study.
  • Y Ohe; S Negoro; K Matsui; K Nakagawa; T Sugiura; Y Takada; Y Nishiwaki; S Yokota; M Kawahara; N Saijo; M Fukuoka; Y Ariyoshi
    ANNALS OF ONCOLOGY 16 3 430 - 436 2005年03月 [査読有り]
     
    Background: Amrubicin, a totally synthetic 9-amino-anthracycline, demonstrated excellent single-agent activity for extensive-stage small-cell lung cancer (ED-SCLC). The aims of this trial were to determine the maximum-tolerated doses (MTD) of combination therapy with amrubicin and cisplatin, and to assess the efficacy and safety at their recommended doses (RD). Patients and methods: Eligibility criteria were patients having histologically or cytologically proven measurable ED-SCLC, no previous systemic therapy, an Eastern Cooperative Oncology Group performance status of 0-2 and adequate organ function. Amrubicin was administered on days 1-3 and cisplatin on day 1, every 3 weeks. Results: Four patients were enrolled at dose level 1 (amrubicin 40 mg/m(2)/day and cisplatin 60 mg/m(2)) and three patients at level 2 (amrubicin 45 mg/m(2)/day and cisplatin 60 mg/m(2)). Consequently, the MTD and RD were determined to be at level 2 and level 1, respectively. The response rate at the RD was 87.8% (36/41). The median survival time (MST) was 13.6 months and the 1-year survival rate was 56.1%. Grade 3/4 neutropenia and leukopenia occurred in 95.1% and 65.9% of patients, respectively. Conclusions: The combination of amrubicin and cisplatin has demonstrated an impressive response rate and MST in patients with previously untreated ED-SCLC.
  • Yasuhisa Ohde; Kazuo Nakagawa; Takehiro Okumura; Haruhiko Kondo
    Interactive Cardiovascular and Thoracic Surgery 4 1 59 - 60 2005年02月 [査読有り]
     
    We present a case of pulmonary lobar torsion secondary to pseudo-Meigs syndrome. A 45-year-old woman with colonic cancer and metastatic ovarian cancer was suffering from dyspnea. CT scan showed massive pleural effusion, air trapping and twisted bronchus of the middle lobe. At thoracotomy, the middle lobe was torqued at 180° around its bronchovascular pedicle in a counterclockwise direction. The infarcted middle lobe was resected. The pleural effusion had never recurred after resection of the metastatic ovary. This is the first report of spontaneous pulmonary torsion caused by massive pleural effusion secondary to pseudo-Meigs syndrome. © 2005 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
  • 分子標的薬gefitinibの使い方
    中川 和彦
    内科 95 1 85 - 91 2005年
  • 宮崎 昌樹; 野上 壽二; 長谷川 喜一; 岡部 崇記; 明石 雄策; 池田 昌人; 寺嶋 応顕; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    気管支学 27 5 416 - 416 特定非営利活動法人 日本呼吸器内視鏡学会 2005年 
    【目的】肺門, 縦隔病変に対するコンベックス走査式超音波気管支鏡ガイド下生検の使用経験. 【対象, 方法】2005年1月から肺門, 縦隔病変に対するコンベックス走査式超音波気管支鏡ガイド下生検を3例の症例に施行した. 【結果】症例1は79歳女性, 縦隔#3のTBNAで扁平上皮癌と診断した. 症例2は74歳男性, 気管分岐部#7のTBNAで小細胞肺癌と診断した. 症例3は68歳男性, 左肺門リンパ節のTBNAで小細胞肺癌と診断した. 【結語】コンベックス走査式超音波気管支鏡ガイド下生検は, 病変または病変周囲の血流をカラードップラーで確認し, リアルタイムの生検法であり低侵襲で, 極めて有用な検査法と考えられる.
  • 長谷川 喜一; 野上 壽二; 宮崎 昌樹; 岡部 崇記; 明石 雄策; 池田 昌人; 寺嶋 応顕; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    気管支学 27 5 416 - 417 特定非営利活動法人 日本呼吸器内視鏡学会 2005年 
    【目的】肺末梢腫瘤性病変の経気管支的診断に於けるEBUS-GS併用の有用性の検討. 【対象, 方法】2004年12月から肺野末梢の3cm以下の腫瘤性病変を有する男性20例, 女性8例の計28例の患者にEBUS-GSを用いた生検を施行した. 気管支鏡下に内視鏡用超音波プローブ(UM-S20-R, OLYM-PUS)をガイドシース(GS)を用いて病変まで誘導し病変の超音波画像を確認後, GSを留置し生検を行った. 【結果】病変部位は, 上葉13/28例, 中葉, 舌区7/28例, 下葉8/28例で, 20/28例でエコーでの描出が可能であり, 診断率は75%であった. 生検後の出血は非常に軽微なものであった. 【結語】肺末梢腫瘤性病変の経気管支的診断に際しEBUS-GS併用は, 超音波画像で病変を確認し, GSを病変部位に留置固定することにより同じ部位での生検の繰り返しが可能で, X線透視の回数を減らす事が出来た. また生検後の出血も軽微にコントロール出来た.
  • 宮崎 昌樹; 野上 壽二; 寺嶋 応顕; 池田 昌人; 津谷 あすか; 明石 雄策; 尾崎 智博; 佐藤 太郎; 岡本 勇; 田村 研治; 倉田 宝保; 中川 和彦; 福岡 正博
    気管支学 27 3 238 - 238 特定非営利活動法人 日本呼吸器内視鏡学会 2005年
  • F Koizumi; Y Noguchi; T Saika; K Nakagawa; S Sato; AMA Eldib; Y Nasu; H Kumon; E Nakayama
    MICROBIOLOGY AND IMMUNOLOGY 49 5 471 - 476 2005年 [査読有り]
     
    To evaluate the feasibility of cancer vaccine targeting XAGE-1, we investigated the expression of 4 XAGE-1 transcript variants and the humoral immune response to XAGE-1 in prostate cancer patients. XAGE-1a, b, c, d mRNA expression was analyzed in 54 prostate cancer specimens and 8 specimens of benign prostate hypertrophy (BPH) by reverse transcription-polymerase chain reaction (RT-PCR). The Immoral response to XAGE-1 was investigated in sera obtained from 278 patients with prostate cancer and 40 healthy volunteers by enzyme-linked immunosorbent assay (ELISA) using recombinant protein. XAGE-1b mRNA expression was observed in 14 of 54 (26%) prostate cancer specimens, while XAGE-1a, c, and d mRNA expressions were observed in 1, 1, and 3, respectively. None of the 4 XAGE-1 transcript variants was observed in the 8 BPH specimens. Antibody against XAGE-1 was detected in sera from 2 of 129 stage D2 patients, whereas none of sera from 149 patients with localized prostate cancer or lymph node metastasis had detectable XAGE-1 antibody. No reactivity to XAGE-1 was found in sera from the 40 healthy individuals.
  • Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin.
    Yonesaka,K; Tamura,K; Kurata,T; Satoh,T; Ikeda,M; Fukuoka,M; Nakagawa,K
    Int J Cancer 118 4 812 - 820 2005年 [査読有り]
  • Soji Kakiuchi; Yataro Daigo; Nobuhisa Ishikawa; Chiyuki Furukawa; Tatsuhiko Tsunoda; Seiji Yano; Kazuhiko Nakagawa; Takashi Tsuruo; Nobuoki Kohno; Masahiro Fukuoka; Saburo Sone; Yusuke Nakamura
    Human molecular genetics 13 24 3029 - 43 2004年12月 [査読有り]
     
    Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.
  • Soji Kakiuchi; Yataro Daigo; Nobuhisa Ishikawa; Chiyuki Furukawa; Tatsuhiko Tsunoda; Seiji Yano; Kazuhiko Nakagawa; Takashi Tsuruo; Nobuoki Kohno; Masahiro Fukuoka; Saburo Sone; Yusuke Nakamura
    Human molecular genetics 13 24 3029 - 43 2004年12月 [査読有り]
     
    Gefitinib (Iressa, ZD1839), an inhibitor of epidermal growth factor receptor-tyrosine kinase, has shown potent anti-tumor effects and improved symptoms and quality-of-life of a subset of patients with advanced non-small cell lung cancer (NSCLC). However, a large portion of the patients showed no effect to this agent. To establish a method to predict the response of NSCLC patients to gefitinib, we used a genome-wide cDNA microarray to analyze 33 biopsy samples of advanced NSCLC from patients who had been treated with an identical protocol of second to seventh line gefitinib monotherapy. We identified 51 genes whose expression differed significantly between seven responders and 10 non-responders to the drug. We selected the 12 genes that showed the most significant differences to establish a numerical scoring system (GRS, gefitinib response score), for predicting response to gefitinib treatment. The GRS system clearly separated the two groups without any overlap, and accurately predicted responses to the drug in 16 additional NSCLC cases. The system was further validated by the semi-quantitative RT-PCR, immunohistochemistry and ELISA for serological test. Moreover, we proved that the anti-apoptotic activity of amphiregulin, a protein that was significantly over-expressed in non-responders but undetectable in responders, leads to resistance of NSCLC cells to gefitinib in vitro. Our results suggested that sensitivity of a given NSCLC to gefitinib can be predicted according to expression levels of a defined set of genes that may biologically affect drug sensitivity and survival of lung cancer cells. Our scoring system might eventually lead to achievement of personalized therapy for NSCLC patients.
  • 米阪 仁雄; 田村 研治; 佐藤 太郎; 池田 昌人; 倉田 宝保; 野上 壽ニ; 中川 和彦; 福岡 正博
    近畿大学医学雑誌 29 3-4 129 - 137 近畿大学 2004年12月 
    survivin はアポトーシス阻害蛋白の一つで, 癌細胞に特異的に発現している. またp53は癌抑制遺伝子であり, DNAの障害に伴い活性化され, 抗癌剤の感受性やアポトーシスに関与する. 我々はp53による survivin の発現調節の有無を探るため, 肺癌細胞株を用いアドリアマイシン暴露後の survivin 発現量の変動を観察した. その結果, 変異型p53を有する細胞株とは対照的に, 野生型p53を有する細胞株ではp53の発現誘導に伴い survivin の発現は顕著に減少した. さらに small interfering (si) RNAを利用し, 野生型p53を有するA549肺癌細胞株のp53発現を抑制したところ, survivin 発現は有意に増加した. 次に survivin 阻害の癌細胞にもたらす影響を調べるために, 変異型p53を有する肺癌細胞株PC9の survivin 発現をsiRNAにより抑制した. その結果, 細胞増殖は有意に抑制され, さらにアドリアマイシンに対する感受性の増強と, 強いアポトーシスの誘導がみられた. 以上により, 我々は survivin 発現はp53の活性化によって抑制され, siRNAによる survivin の阻害は変異型p53を有する癌細胞の増殖を抑制し, またアドリアマイシンに対する感受性を高め, アポトーシスの惹起を促すことを確認した.
  • N Oiso; N Mizuno; K Fukai; K Nakagawa; M Ishii
    BRITISH JOURNAL OF DERMATOLOGY 151 5 1084 - 1086 2004年11月 [査読有り]
     
    Familial cylindromatosis is a rare dominantly inherited disease characterized by the development of multiple benign tumours of the skin appendages, including cylindromas, trichoepitheliomas and spiradenomas. The gene responsible was positionally cloned recently, and was designated CYLD. We describe a family with cylindromatosis, in which affected individuals have an inherited R758X nonsense mutation of CYLD. Affected members of this family manifest a relatively mild tumour phenotype; the largest tumour was only 30 mm in diameter. Thus far, there is no evident genotype-phenotype relationship in cylindromatosis, although the number of families reported with both phenotypic and genotypic data remains small.
  • H Kaneda; K Tamura; T Kurata; H Uejima; K Nakagawa; M Fukuoka
    LUNG CANCER 46 2 247 - 254 2004年11月 [査読有り]
     
    Background: The purpose of the study was to identify the potential predictive features associated with the response and survival benefit of gefitinib administration. We have retrospectively reviewed data of all patients who received a single regimen of gefitinib in our institution from August 1998 until July 2003. Methods: Overall 101 patients with non-small-cell lung cancer (NSCLC) who have received a single use of gefitinib were analyzed. Potential factors associated with the response of gefitinib included smoking index, gender, histology, performance status (PS), number of pre-treatments, age and stage. Univariate analysis was performed for these strata by Fisher's exact test and multivariate analysis was then performed using the Logistic regression model. Results: The overall response rate was 19.8%. Univariate analysis revealed that significant predictive factors were associated with the response for 'adenocarcinoma', 'female', 'good PS' (0-l) and 'non-smoker' categories. Multivariate analysis limited the predictive factors associated with the response for 'female' (P = 0.0032), 'good PS' (P < 0.02) and 'non-smoker' (P = 0.0417). In survival analyses, 'female' (P < 0.005), 'good PS' (P < 0.0001.), and a low level of the smoking index (P < 0.05) indicated significantly prolonged survival. Response and survival data in elderly patients were equivalent to those in younger patients. Adverse events (AEs) were generally mild and were almost always skin reactions and diarrhea. Interstitial lung disease (ILD)occurred in 4% of the group under observation. Conclusions: Gefitinib provided clinical benefit for the following factors 'female', 'good PS' and 'non-smoker'. A low smoking index is reported as a novel predictive prognostic factor following a single regimen of gefitinib. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
  • H Kaneda; K Tamura; T Kurata; H Uejima; K Nakagawa; M Fukuoka
    LUNG CANCER 46 2 247 - 254 2004年11月 [査読有り]
     
    Background: The purpose of the study was to identify the potential predictive features associated with the response and survival benefit of gefitinib administration. We have retrospectively reviewed data of all patients who received a single regimen of gefitinib in our institution from August 1998 until July 2003. Methods: Overall 101 patients with non-small-cell lung cancer (NSCLC) who have received a single use of gefitinib were analyzed. Potential factors associated with the response of gefitinib included smoking index, gender, histology, performance status (PS), number of pre-treatments, age and stage. Univariate analysis was performed for these strata by Fisher's exact test and multivariate analysis was then performed using the Logistic regression model. Results: The overall response rate was 19.8%. Univariate analysis revealed that significant predictive factors were associated with the response for 'adenocarcinoma', 'female', 'good PS' (0-l) and 'non-smoker' categories. Multivariate analysis limited the predictive factors associated with the response for 'female' (P = 0.0032), 'good PS' (P < 0.02) and 'non-smoker' (P = 0.0417). In survival analyses, 'female' (P < 0.005), 'good PS' (P < 0.0001.), and a low level of the smoking index (P < 0.05) indicated significantly prolonged survival. Response and survival data in elderly patients were equivalent to those in younger patients. Adverse events (AEs) were generally mild and were almost always skin reactions and diarrhea. Interstitial lung disease (ILD)occurred in 4% of the group under observation. Conclusions: Gefitinib provided clinical benefit for the following factors 'female', 'good PS' and 'non-smoker'. A low smoking index is reported as a novel predictive prognostic factor following a single regimen of gefitinib. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
  • Kazuo Tamura; Joji Utsunomiya; Takeo Iwama; Jun-Ichi Furuyama; Tetsuya Takagawa; Naohisa Takeda; Yoshihiro Fukuda; Takayuki Matsumoto; Takashi Nishigami; Kiyoshi Kusuhara; Ken Sagayama; Kazuhiko Nakagawa; Takehira Yamamura
    International Journal of Clinical Oncology 9 4 232 - 245 2004年08月 [査読有り]
     
    It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson's two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive.
  • Inoue M; Ohta M; Iuchi K; Matsumura A; Ideguchi K; Yasumitsu T; Nakagawa K; Fukuhara K; Maeda H; Takeda S; Minami M; Ohno Y; Matsuda H; Thoracic Surgery; Study Group of; Osaka University
    The Annals of thoracic surgery 78 1 238 - 244 2004年07月 [査読有り]
     
    BACKGROUND: A pulmonary metastasectomy for colorectal carcinoma is a generally accepted procedure, although several prognostic predictors have been reported. The aim of this study is to define the patients who benefit from pulmonary metastasectomy for colorectal carcinoma. METHODS: Retrospective survival analysis was performed using 128 patients who underwent curative pulmonary resection. RESULTS: The overall 5-year survival rate was 45.3%. Univariate analysis showed the number of metastases, location (unilateral or bilateral), prethoracotomy carcinoembryonic antigen (CEA) level, hilar or mediastinal lymph-node metastasis, and Dukes' stage to be considerable prognostic factors. Among these, Dukes' A for the primary lesion and unilateral pulmonary metastasis were shown to be independent predictors of longer survival by multivariate analysis (p = 0.0093 and p = 0.0182, respectively). In patients treated with both pulmonary and hepatic metastastasectomies, a better prognosis was observed in those who received metachronous resection. Recurrence after a pulmonary metastasectomy frequently occurred in the thorax and the 3-year survival rate was 44.6% in patients who underwent a repeat thoracotomy. CONCLUSIONS: Patients with unilateral metastasis and Dukes' A for the primary tumor benefit most from the resection of pulmonary metastasis from colorectal carcinoma. Further, the number of metastases, prethoracotomy CEA level, and hilar or mediastinal lymph-node involvement should be considered to determine the operative indication. Finally, periodic follow-up examinations for thoracic recurrence should be carefully performed as these patients may have a heightened risk of requiring a repeat thoracotomy.
  • Nakagawa K
    Nihon rinsho. Japanese journal of clinical medicine 62 7 1312 - 1320 2004年07月 [査読有り]
  • T Kurata; K Tamura; N Yamamoto; T Nogami; T Satoh; H Kaneda; K Nakagawa; M Fukuoka
    BRITISH JOURNAL OF CANCER 90 11 2092 - 2096 2004年06月 [査読有り]
     
    To establish the toxicities and maximum tolerated dose (MTD) of nedaplatin with gemcitabine, and to observe their antitumour activity, we conducted a combination phase I study in advanced non-small-cell lung cancer (NSCLC). Patients received nedaplatin (60-100 mg m(-2) given intravenously over 90 min) on day 1, and gemcitabine (800-1000 mg m(-2) given intravenously over 30 min) on days 1, 8, every 3 weeks. In total, 20 patients with locally advanced or metastatic NSCLC who received no prior chemotherapy or one previous chemotherapy regimen were enrolled. The most frequent toxicities were neutropenia and thrombocytopenia; nonhaematological toxicities were generally mild. Three out of six patients experienced dose-limiting toxicities (neutropenia, thrombocytopenia and delayed anaemia) at dose level 4, 100 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine, which was regarded as the MTD. There were three partial responses, for an overall response rate of 16.7%. The median survival time and 1-year survival rate were 9.1 months and 34.1%, respectively. This combination is well tolerated and active for advanced NSCLC. The recommended dose is 80 mg m(-2) nedaplatin with 1000 mg m(-2) gemcitabine. This combination chemotherapy warrants a phase II study and further evaluation in prospective randomised trials with cisplatin- or carboplatin-based combinations as first-line chemotherapy for advanced NSCLC. (C) 2004 Cancer Research UK.
  • Yutaka Nishiwaki; Seiji Yano; Tomohide Tamura; Kazuhiko Nakagawa; Shinzoh Kudoh; Takeshi Horai; Kazumasa Noda; Ichiro Takata; Koshiro Watanabe; Hideo Saka; Koji Takeda; Fumio Imamura; Kaoru Matsui; Nobuyuki Katakami; Akira Yokoyama; Yoshiyuki Sawa; Minoru Takada; Katsuyuki Kiura; Takahiko Sugiura; Masahiro Fukuoka; Hirohiko Uchida
    Gan to kagaku ryoho. Cancer & chemotherapy 31 4 567 - 73 2004年04月 [査読有り]
     
    The multinational, multi-institutional clinical Phase II trial of gefitinib monotherapy, IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) 1, included Japanese and non-Japanese patients with advanced non-small-cell lung cancer (NSCLC) pretreated with one or more chemotherapy regimens, at least one including platinum. To investigate whether survival is affected by gender or histological type of cancer, a retrospective, exploratory subset analysis was conducted including only Japanese patients from IDEAL 1 (n = 102 in total, 51 each in 250 and 500 mg/day groups). The median survival time of the 102 patients was 12.0 months and the one year survival rate was 50%. The median survival time was 13.8 months for the 250 mg/day group and 11.2 months for the 500 mg/day group and the one-year survival rate was 57% and 45% respectively. Survival was longer in patients with adenocarcinoma than those with other histological types of cancer, and was longer in those with symptom improvement than without. The median survival time in females was longer than that in males. The results suggest that gefitinib could be superior to classical anticancer agents with regard to not only the response rate but also survival time in patients with NSCLC, particularly adenocarcinoma, previously treated with chemotherapy. Further studies are needed to identify factors affecting survival.
  • 非小細胞肺癌患者に対するGefitinib IDEAL 1試験の日本人サブセット解析
    西脇裕; 矢野聖二; 田村友秀; 中川和彦; 工藤新三; 宝来威; 野田和正; 高田一郎; 渡邊古志郎; 坂英雄; 武田晃司; 今村文生; 松井薫; 片上信之; 横山晶; 澤祥幸; 高田實; 木浦勝行; 杉浦孝彦; 福岡正博; 内田寛彦
    癌と化学療法 31 4 567 - 573 2004年04月 [査読有り]
  • 中川 和彦
    臨床薬理 = JAPANESE JOURNAL OF CLINICAL PHARMACOLOGY AND THERAPEUTICS 35 2 293S  一般社団法人 日本臨床薬理学会 2004年03月
  • Hisao Asamura; Kazuo Nakagawa; Yoshihiro Matsuno; Kenji Suzuki; Shun-Ichi Watanabe; Ryosuke Tsuchiya
    Interactive Cardiovascular and Thoracic Surgery 3 1 163 - 167 2004年03月 [査読有り]
     
    Despite the wide use of the Masaoka staging system for thymoma, the distribution of survival by stage group is not well balanced. The new staging systems for testing were defined as follows: stage I was created by merging Masaoka's stages I and II, and stage IV remained unchanged. Stages II and III were defined as thymomas with invasive growth and the following combinations of tumor diameter and number of involved structures/organs. Scheme 1: stage II included tumors less than 10 cm in diameter and involving one neighboring structure/organ. Stage III included tumors with all combinations of diameter and number of involved structures/organs other than those in stage II. Scheme 2: stage II included tumors of all combinations other than those in stage III. Stage III included tumors 10 cm or more in diameter and involving two or more structures/organs. The survival curves were assessed for 138 patients treated at the National Cancer Center, Tokyo. The 10-year survival rates for each stage according to the Masaoka, Scheme 1, and Scheme 2 systems were as follows: stage I (100%, 100%, 100%), stage II (100%, 86%, 83%), stage III (70%, 64%, 34%), and stage IV (34%, 34%, 34%), respectively. The survival curves for Scheme 1 gave the most balanced distribution of survival in each staging group. By considering both tumor diameter and number of involved structures/organs, Masaoka's stages I-III could be rearranged with more balanced distribution of survival. © 2003 Elsevier B.V. All rights reserved.
  • N Sawabata; M Ohta; A Matsumura; K Nakagawa; H Hirano; H Maeda; H Matsuda
    ANNALS OF THORACIC SURGERY 77 2 415 - 420 2004年02月 [査読有り]
     
    Background. Complete excision of nonsmall cell lung cancer is necessary during a limited resection procedure, as a malignant positive margin can lead to margin relapse. Because there is scant information available regarding the optimal size of a malignant negative margin, we conducted a multicenter, prospective study to more fully elucidate this area of concern. Methods. Two hundred five pulmonary tumors (22 nonsmall cell lung cancers and 183 undiagnosed lesions) were excised, of which 118 nonsmall cell lung cancer lesions were analyzed. Malignant status was considered positive when either a cytologic or histologic technique revealed the margin to be malignant. Maximum tumor diameter (from 4 to 45 mm with an average of 15.3 mm), margin distance (from 0 to 25 mm with an average of 9.3 mm), tumor location, extent of stapling carried out, and performance of a thoracotomy were the variables. Results. Seventy-two of the sample tissues (61%) were malignant negative. The negative group had smaller maximum tumor diameter, greater margin distance, lesions in more easily resectable regions, and more often required stapling only. Using a multivariate analysis, maximum tumor diameter and margin distance were found to be independent factors. The number of malignant negative margins was 7/7 (100%) when the margin distance was greater than 20 mm, and the number of malignant negative margins was 21 of 21 (100%) when the resected tumors had a margin distance greater than the maximum tumor diameter. Conclusions. Malignant positive margins were not found when the margin distance was greater than the maximum tumor diameter, which was considered to be the optimal margin distance for prevention against margin relapse. (C) 2004 by The Society of Thoracic Surgeons.
  • AM Ali Eldib; T Ono; M Shimono; M Kaneko; K Nakagawa; R Tanaka; Y Noguchi; E Nakayama
    INTERNATIONAL JOURNAL OF CANCER 108 4 558 - 563 2004年02月 [査読有り]
     
    By serologic identification of antigens by recombinant expression cloning (SEREX) analysis using an autologous lung adenocarcinoma cell line, OU-LU-6, as a cDNA library source, we demonstrated that XAGE-1 was the dominant antigen recognized by serum from a patient. By immuno-screening, we obtained 38 positive cDNA clones consisting of 16 genes designated as OY-LC-1 to -OY-LC-16. OY-LC-1, represented by 18 clones, was identical to XAGE-1. OY-LC-2 to -16, represented by either a single or 2 clones, were identical to known genes shown to be ubiquitously expressed in various normal tissues. RT-PCR analysis showed that of 4 XAGE-I transcripts-XAGE-1a, b, c and d-XAGE-1b was expressed in OU-LU-6 dominantly. Furthermore, XAGE-1b mRNA was expressed in 4 of 10 lung cancer tissues, whereas no expression was observed in normal tissues. Of 4 XAGE-1b mRNA positive cancer tissues, 3 were adenocarcinoma and one was poorly differentiated squamous cell carcinoma. Of 32 sera from lung cancer patients, 8 sera were reactive with the XAGE-1b product. Those 8 sera were from patients with adenocarcinoma. These findings indicated strong immunogenicity of XAGE-1 b in lung adenocarcinoma and suggested its potential use as a target for vaccine-based immunotherapies. (C) 2003 Wiley-Liss, Inc.
  • T Kurata; K Tamura; H Kaneda; T Nogami; H Uejima; G Asai; K Nakagawa; M Fukuoka
    ANNALS OF ONCOLOGY 15 1 173 - 174 2004年01月 [査読有り]
  • N Yamamoto; M Fukuoka; SI Negoro; K Nakagawa; H Saito; K Matsui; M Kawahara; H Senba; Y Takada; S Kudoh; T Nakano; N Katakami; T Sugiura; T Hoso; Y Ariyoshi
    BRITISH JOURNAL OF CANCER 90 1 87 - 92 2004年01月 [査読有り]
     
    Docetaxel plus cisplatin and docetaxel plus irinotecan are active and well-tolerated chemotherapy regimens for advanced non-small-cell lung cancer (NSCLC). A randomised phase II study compared their efficacy and toxicity in 108 patients with stage IIIb/IV NSCLC, who were randomised to receive docetaxel 60 mg m(-2) and cisplatin 80 mg m(-2) on day 1 (DC; n=51), or docetaxel 60 mg m(-2) on day 8 and irinotecan 60 mg m(-2) on day 1 and 8 (DI; n=57) every 3 weeks. Response rates were 37% for DC and 32% for DI patients. Median survival times and 1- and 2-year survival rates were 50 weeks (95% confidence interval: 34-78 weeks), 47 and 25% for DC, and 46 weeks (95% confidence interval: 37-54 weeks), 40 and 18% for DI, respectively. The progression-free survival time was 20 weeks (95% confidence interval: 14-25 weeks) with DC and 18 (95% confidence interval: 12-22 weeks) with DI. Significantly more DI than DC patients had grade 4 leucopenia and neutropenia (P<0.01); more DC patients had grade &GE;2 thrombocytopenia (P<0.01). Nausea and vomiting was more pronounced with DC (P<0.01); diarrhoea was more common with DI (P=0.01). Three treatment-related deaths occurred in DC patients. In conclusion, although the DI and DC regimens had different toxicity profiles, there was no significant difference in survival.
  • ヒト肺癌株移植ヌ－ドマウスにおけるゲフィチニブとビノレルビン併用における抗腫瘍効果の検討
    宮﨑 昌樹; 田村 研治; 米阪 仁雄; 中川 和彦; 福岡 正博
    近畿大学医学雑誌 28 4 337 - 386 2003年12月 [査読有り]
  • Nakao K; Fujiwara Y; Koishi K; Nishizaki K; Nakagawa K; Ooiwa N; Yamamura T
    Gan to kagaku ryoho. Cancer & chemotherapy 30 10 1505 - 1509 2003年10月 [査読有り]
  • Masahiro Fukuoka; Seiji Yano; Giuseppe Giaccone; Tomohide Tamura; Kazuhiko Nakagawa; Jean-Yves Douillard; Yutaka Nishiwaki; Johan Vansteenkiste; Shinzoh Kudoh; Danny Rischin; Richard Eek; Takeshi Horai; Kazumasa Noda; Ichiro Takata; Egbert Smit; Steven Averbuch; Angela Macleod; Andrea Feyereislova; Rui-Ping Dong; José Baselga
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21 12 2237 - 46 2003年06月 [査読有り]
     
    PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]
  • Masahiro Fukuoka; Seiji Yano; Giuseppe Giaccone; Tomohide Tamura; Kazuhiko Nakagawa; Jean-Yves Douillard; Yutaka Nishiwaki; Johan Vansteenkiste; Shinzoh Kudoh; Danny Rischin; Richard Eek; Takeshi Horai; Kazumasa Noda; Ichiro Takata; Egbert Smit; Steven Averbuch; Angela Macleod; Andrea Feyereislova; Rui-Ping Dong; José Baselga
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology 21 12 2237 - 46 2003年06月 [査読有り]
     
    PURPOSE: To evaluate the efficacy and tolerability of two doses of gefitinib (Iressa [ZD1839]; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with pretreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This was a randomized, double-blind, parallel-group, multicenter phase II trial. Two hundred ten patients with advanced NSCLC who were previously treated with one or two chemotherapy regimens (at least one containing platinum) were randomly assigned to receive either 250-mg or 500-mg oral doses of gefitinib once daily. RESULTS: Efficacy was similar for the 250- and 500-mg/d groups. Objective tumor response rates were 18.4% (95% confidence interval [CI], 11.5 to 27.3) and 19.0% (95% CI, 12.1 to 27.9); among evaluable patients, symptom improvement rates were 40.3% (95% CI, 28.5 to 53.0) and 37.0% (95% CI, 26.0 to 49.1); median progression-free survival times were 2.7 and 2.8 months; and median overall survival times were 7.6 and 8.0 months, respectively. Symptom improvements were recorded for 69.2% (250 mg/d) and 85.7% (500 mg/d) of patients with a tumor response. Adverse events (AEs) at both dose levels were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent in the higher-dose group. Withdrawal due to drug-related AEs was 1.9% and 9.4% for patients receiving gefitinib 250 and 500 mg/d, respectively. CONCLUSION: Gefitinib showed clinically meaningful antitumor activity and provided symptom relief as second- and third-line treatment in these patients. At 250 mg/d, gefitinib had a favorable AE profile. Gefitinib 250 mg/d is an important, novel treatment option for patients with pretreated advanced NSCLC [corrected]
  • K Nakagawa; T Yasumitu; K Fukuhara; H Shiono; M Kikui
    ANNALS OF THORACIC SURGERY 75 6 1740 - 1744 2003年06月 [査読有り]
     
    Background. We evaluated the prognosis of adenosquamous carcinoma of the lung after lung resection in comparison with other types of carcinoma. Methods. We retrospectively reviewed charts of patients who underwent lung resection for lung cancer. Results. Surgical outcomes for 30 patients with adenosquamous carcinoma of the lung, who were treated between 1976 and 1998, were compared with the surgical results for 1,219 patients similarly treated for adenocarcinoma or squamous cell carcinoma during the same period. Adenosquamous carcinoma comprised only 2.1% of 1,408 lung cancer cases treated by resection. The overall cumulative 5-year survival rate was only 6.2% for the patients with adenosquamous carcinoma, indicating a significantly poorer prognosis than for adenocarcinoma or squamous cell carcinoma. Conclusions. The cumulative survival rate for patients with adenosquamous carcinoma in pathologic stages IA to IIB was similar to that of patients with stage IIIA adenocarcinoma or squamous cell carcinoma. (Ann Thorac Surg 2003;75:1740-4) (C) 2003 by The Society of Thoracic Surgeons.
  • K Nakagawa; T Tamura; S Negoro; S Kudoh; N Yamamoto; N Yamamoto; K Takeda; H Swaisland; Nakatani, I; M Hirose; RP Dong; M Fukuoka
    ANNALS OF ONCOLOGY 14 6 922 - 930 2003年06月 [査読有り]
     
    Background: This phase I dose-escalating study investigated the tolerability and toxicity of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid tumors. Thirty-one patients were included. Patients and methods: Patients initially received a single oral dose of gefitinib followed by 10-14 days of observation. Oral gefitinib was subsequently administered on 14 consecutive days, every 28 days. Dose escalation was from 50 mg/day to a maximum of 925 mg/day or dose-limiting toxicity (DLT). Results: Most adverse events were mild (grade 1/2); the most frequent were an acne-like rash and gastrointestinal effects. Two of six patients at 700 mg/day had DLT; no further dose escalation occurred. C-max was reached within 3-7 h and exposure to gefitinib increased with dose. Mean terminal half-life following multiple dosing was 50.1 h (range 27.8-79.7 h). A partial response (duration 35-361 days) was observed in five of the 23 patients with non-small-cell lung cancer over a range of doses (225-700 mg/day), and seven patients with a range of tumors had disease stabilization (duration 40-127 days). Conclusions: In conclusion, gefitinib showed a favorable tolerability profile in Japanese patients. The safety profile, pharmacokinetic parameters and antitumor activity observed in our study are comparable to those observed in patients from the USA and Europe.
  • Y Shintani; M Ohta; H Hirabayashi; H Tanaka; K Iuchi; K Nakagawa; H Maeda; T Kido; S Miyoshi; H Matsuda
    INTERNATIONAL JOURNAL OF CANCER 104 6 790 - 795 2003年05月 [査読有り]
     
    Thymidylate synthase (TS) is an enzyme that catalyzes an important DNA biosynthesis process. The gene expression of TS has not been reported in non-small-cell lung cancer (NSCLC) patients. To clarify the correlation between TS mRNA levels and clinicopathological features of NSCLC, we examined 70 Stage I and II NSCLC patients for intra-tumoral expression of TS using TaqMan reverse transcription polymerase chain reaction (RT-PCR) assay and immunohistochemistry methods. We also investigated the TS promoter 28 bp polymorphism in 48 cancer tissues using PCR amplification of genomic DNA. Lung cancer tissue showed higher TS mRNA levels than normal lung tissue (Mann-Whitney U-tests; p = 0.0020). Further, TS mRNA expression was correlated with immunohistochemical TS expression (p = 0.029). We obtained 2 different DNA fragments, which indicated triple-repeat (3R) and double-repeat (211) type alleles. Cancer tissues with the 3R/3R genotype showed significantly higher TS mRNA levels as compared to those with other genotypes (p = 0.0019). The TS genotype was also correlated with immunohistochemical TS expression (chi(2) test; p = 0.0079). The disease-free survival of the low TS mRNA level group was significantly better than those with high TS mRNA levels (log-rank test; p = 0.010), however, there were no significant differences found by immunohistochemical evaluation (p = 0.34) or TS genotype analysis (p = 0.11). A multivariate analysis revealed that high TS mRNA levels independently contributed to disease-free survival. The quantitation of TS mRNA levels is clinically more sensitive and useful for determining the prognosis of Stage I and 11 NSCLC patients than an immunohistochemical evaluation. (C) 2003 Wiley-Liss, Inc.
  • K Nakao; Y Fujiwara; R Itoh; K Nakagawa; T Yamamura
    HEPATO-GASTROENTEROLOGY 50 51 893 - 896 2003年05月 [査読有り]
     
    Afferent loop obstruction after distal gastrectomy is rare. We present a case of a 59-year-old women who under-went distal partial gastrectomy with Billroth-II, reconstruction added Braun anastomosis for cancer of the stomach. On the 10th postoperative day, she had high-grade fever and complained of abdominal pain. We diagnosed the afferent loop obstruction by computed tomography scan. Re-operation was performed to decompress the afferent loop. New Braun anastomosis was created, but because the decompression of the biliary tract was insufficient, percutaneous transhepatic biliary drainage was performed on the 52nd postoperative day. Her clinical course subsequently improved and she was discharged on the 104th postoperative day. This paper describes the details of this unusual condition, and we discuss a review of the literature.
  • Yukito Ichinose; Keiichiro Genka; Teruaki Koike; Harubumi Kato; Yoh Watanabe; Takashi Mori; Sogo Iioka; Akira Sakuma; Mitsuo Ohta; M. Kawamura; K. Yokoi; T. Sakuma; N. Tsubota; M. Yoshimura; N. Yanai; F. Nagasaka; K. Nakagawa; T. Tojo; T. Sato; S. Ohta; N. Yamaoka; Y. Matsuzaki; S. Fujimura; K. Nagai; H. Miyamoto; K. Kobayashi; H. Saito; J. Isobe; T. Yasumitsu; O. Doi; O. Kuwahara; T. Hatta; N. Katakami; S. Maebeya; N. Shimizu; J. Nakagawa; A. Motohiro; T. Hirata
    Journal of the National Cancer Institute 95 8 605 - 610 2003年04月 [査読有り]
     
    Background: Bestatin is a potent aminopeptidase inhibitor that has immunostimulant and antitumor activity. We conducted a prospective randomized, double-blind, placebo-controlled trial to determine whether postoperative adjuvant treatment with bestatin could prolong the survival of patients with completely resected stage I squamous-cell lung carcinoma. Methods: Patients with confirmed, resected stage I squamous-cell lung carcinoma were randomly assigned to receive either bestatin (30 mg) or placebo daily by mouth for 2 years. We assessed whether bestatin treatment was associated with overall survival and 5-year cancer-free survival and assessed its safety. All statistical tests were two-sided. Results: From July 8, 1992, through March 30, 1995, 402 patients were entered in the study, 202 in the bestatin group and 198 in the placebo group. The median follow-up for surviving patients was 76 months (range = 58-92 months). The 5-year overall survival was 81% in the bestatin group and 74% in the placebo group for a difference of 7% (95% confidence interval [CI] = -1.4% to 15.0%). The 5-year cancer-free survival was 71 % in the bestatin group and 62% in the placebo group for a difference of 9% (95% CI = -0.7% to 17.8%). Overall survival (P = .033, log-rank test) and cancer-free survival (P = .017, log-rank test) were statistically significantly different by Kaplan-Meier analysis. Few adverse events were observed in either group. Conclusions: Survival was statistically significantly better for patients with completely resected stage I squamous-cell lung carcinoma who were treated with bestatin as a postoperative adjuvant therapy than for those who received a placebo. This result requires confirmation in other phase III trials.
  • T Komiya; N Fusetani; S Matsunaga; A Kubo; FJ Kaye; MJ Kelley; K Tamura; M Yoshida; M Fukuoka; K Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 51 3 202 - 208 2003年03月 [査読有り]
     
    Purpose: Ritterazine B, one of the ritterazine analogues extracted from Ritterella tokioka, has been shown to be chemically similar to cephalostatin 1, and among the ritterazine derivatives is the most cytotoxic to P388 murine leukemia cells. The objective of this study was to determine the cytotoxicity of ritterazine B to non-small-cell lung cancer (NSCLC) cells in vitro and its effects on the cell cycle and apoptosis. Methods: The cytotoxicity of ritterazine B against PC14 NSCLC cells was investigated using a 4-day MTT assay. Morphological changes in cells after exposure to this compound were evaluated by phase-contrast microscopy. The effects on the cell cycle of HL-60 leukemia cells and PC14 cells were elucidated by flow cytometry and an in vitro CDK/cyclin kinase assay. Induction of apoptosis in HL-60 cells was assessed using the TUNEL assay and Hoechst 33342 staining. In addition, molecules involved in apoptosis were evaluated by Western blotting. Results: Ritterazine B exerted strong cytotoxic effects against PC14 cells with a mean GI(50) of 75.1 nM. Cell cycle analysis showed that ritterazine B caused accumulation of HL-60 and PC14 cells at the G2/M checkpoint. Furthermore, ritterazine B-treated HL-60 cells became multinucleated, and at a concentration of 20 nM this resulted in the onset. of apoptosis. Neither cleavage of caspase target molecules nor phosphorylation of bcl-2 were observed in ritterazine B-treated HL-60 cells. Conclusions: These results indicate that ritterazine B might be a potent inducer of apoptosis acting via a novel antimitotic mechanism.
  • T Komiya; N Fusetani; S Matsunaga; A Kubo; FJ Kaye; MJ Kelley; K Tamura; M Yoshida; M Fukuoka; K Nakagawa
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 51 3 202 - 208 2003年03月 [査読有り]
     
    Purpose: Ritterazine B, one of the ritterazine analogues extracted from Ritterella tokioka, has been shown to be chemically similar to cephalostatin 1, and among the ritterazine derivatives is the most cytotoxic to P388 murine leukemia cells. The objective of this study was to determine the cytotoxicity of ritterazine B to non-small-cell lung cancer (NSCLC) cells in vitro and its effects on the cell cycle and apoptosis. Methods: The cytotoxicity of ritterazine B against PC14 NSCLC cells was investigated using a 4-day MTT assay. Morphological changes in cells after exposure to this compound were evaluated by phase-contrast microscopy. The effects on the cell cycle of HL-60 leukemia cells and PC14 cells were elucidated by flow cytometry and an in vitro CDK/cyclin kinase assay. Induction of apoptosis in HL-60 cells was assessed using the TUNEL assay and Hoechst 33342 staining. In addition, molecules involved in apoptosis were evaluated by Western blotting. Results: Ritterazine B exerted strong cytotoxic effects against PC14 cells with a mean GI(50) of 75.1 nM. Cell cycle analysis showed that ritterazine B caused accumulation of HL-60 and PC14 cells at the G2/M checkpoint. Furthermore, ritterazine B-treated HL-60 cells became multinucleated, and at a concentration of 20 nM this resulted in the onset. of apoptosis. Neither cleavage of caspase target molecules nor phosphorylation of bcl-2 were observed in ritterazine B-treated HL-60 cells. Conclusions: These results indicate that ritterazine B might be a potent inducer of apoptosis acting via a novel antimitotic mechanism.
  • Kazuo Nakagawa; Hisao Asamura; Yoshihiro Matsuno; Kenji Suzuki; Haruhiko Kondo; Arafumi Maeshima; Etsuo Miyaoka; Ryosuke Tsuchiya
    Journal of Thoracic and Cardiovascular Surgery 126 4 1134 - 1140 2003年 [査読有り]
     
    Objective: This study explored the relationship between the histologic subtype of thymoma according to the new World Health Organization histologic classification and the clinical findings, as well as the prognostic significance of the classification. Methods: A total of 130 patients with thymoma, who underwent resection at the National Cancer Center Hospital, Tokyo, from 1962 to 2000, were studied retrospectively. The histologic subtype of thymoma was determined according to the new World Health Organization histologic classification. The stage was also determined according to a modified Masaoka's classification as stage I, II, III, IVa, or IVb. To determine the factors that may affect the prognosis of thymoma, a multivariate analysis with Cox's proportional hazards regression model was performed. Results: The distribution of histologic subtype was type A (n = 18), type AB (n = 56), type B1 (n = 15), type B2 (n = 29), and type B3 (n = 12). A close correlation was seen between the histologic subtype and stage (P = .000). The overall survivals at 5 and 10 years were 92% and 91%, respectively. The 5- and 10-year survivals according to stage were 100% and 100% (stage I, n = 40 stage II, n = 54), 81% and 76% (stage III, n = 25), and 47% and 47% (stage IV, n = 11), respectively. The difference in survival between stage III and stage IV was significant (P = .000). Patients with type A or AB thymoma demonstrated a 100% survival at both 5 and 10 years. Recurrences were seen in 12 patients with complete resection. According to a multivariate analysis, tumor size (P = .001), completeness of resection (P = .002), histologic subtype (P = .011), and stage (P = .00) were significant prognostic factors. Conclusion: The World Health Organization histologic classification significantly correlated with the clinical stage. Tumor size, completeness of resection, histologic subtype, and stage predicted the prognosis of thymoma.
  • Koji Takeda; Shunichi Negoro; Toshiyuki Sawa; Kazuhiko Nakagawa; Masaaki Kawahara; Takeshi Isobe; Shinzoh Kudoh; Noriyuki Masuda; Hisanobu Niitani; Masahiro Fukuoka
    Clinical Lung Cancer 4 4 224 - 228 2003年 [査読有り]
     
    An early phase II study of topotecan produced favorable results in a small number of untreated and previously treated patients with small-cell lung cancer (SCLC). This multicenter study was conducted in patients with relapsed SCLC at 19 medical institutions in Japan. Topotecan 1.0 mg/m2/day was administered for 5 consecutive days every 3 weeks. Fifty-three patients were enrolled in the study. One patient was withdrawn before the commencement of study treatment, and 2 patients were unable to continue study treatment due to an interruption in the supply of study medication. The response rate was 26.0% in 13 of the 50 evaluable patients who were eligible and completed protocol-specified treatment and procedures. The median time to progression and overall survival were 133 days and 262 days, respectively. The most frequently reported toxicity was reversible myelosuppression, such as leukopenia, neutropenia, anemia (decreased hemoglobin), and thrombocytopenia. Nonhematological toxicity was also reported but the incidence of grade 3/4 symptoms was low. The results of this study indicate that topotecan is effective against relapsed SCLC with good tolerability.
  • Koji Takeda; Shunichi Negoro; Toshiyuki Sawa; Kazuhiko Nakagawa; Masaaki Kawahara; Takeshi Isobe; Shinzoh Kudoh; Noriyuki Masuda; Hisanobu Niitani; Masahiro Fukuoka
    Clinical Lung Cancer 4 4 224 - 228 2003年 [査読有り]
     
    An early phase II study of topotecan produced favorable results in a small number of untreated and previously treated patients with small-cell lung cancer (SCLC). This multicenter study was conducted in patients with relapsed SCLC at 19 medical institutions in Japan. Topotecan 1.0 mg/m2/day was administered for 5 consecutive days every 3 weeks. Fifty-three patients were enrolled in the study. One patient was withdrawn before the commencement of study treatment, and 2 patients were unable to continue study treatment due to an interruption in the supply of study medication. The response rate was 26.0% in 13 of the 50 evaluable patients who were eligible and completed protocol-specified treatment and procedures. The median time to progression and overall survival were 133 days and 262 days, respectively. The most frequently reported toxicity was reversible myelosuppression, such as leukopenia, neutropenia, anemia (decreased hemoglobin), and thrombocytopenia. Nonhematological toxicity was also reported but the incidence of grade 3/4 symptoms was low. The results of this study indicate that topotecan is effective against relapsed SCLC with good tolerability.
  • N Sawabata; A Matsumura; M Ohota; H Maeda; H Hirano; K Nakagawa; H Matsuda
    ANNALS OF THORACIC SURGERY 74 6 1953 - 1957 2002年12月 [査読有り]
     
    Background. We have developed a novel test for the surgical margin of pulmonary malignant tumor using a cytologic technique (the run-across method in which a glass slide is run across the staple site), and we have assessed whether this method is useful in predicting margin relapse and prognosis. Methods. From April 1996 to March 1999,15 lesions of stage I non-small cell lung cancer (NSCLC) (maximum diameter ranged from 10 to 35 mm with a median of 20 mm) from 15 patients with cardiopulmonary impairment were excised without additional proximal resections. The surgical margin was examined using the run-across method. There were 8 male 7 female patients whose ages ranged from 51 to 80 years. One patient underwent video-assisted thoracic surgery and 14 underwent thoracotomy. The preoperative diagnoses of the patients were 13 adenocarcinomas, 2 squamous cell carcinomas, and 1 undiagnosed lesion (1 adenocarcinoma). The follow-up period ranged from 37 to 63 months. Results. The rate of positive cytology was 47% in comparison with the rate of positive histology of 20%. There were 4 patients with margin relapse (3 of them contained negative histology margins) at a rate of 57% among the positive cytology patients in comparison with 0% among the negative cytology patients (p = 0.03). In a comparison of survival between the negative cytology group and the positive cytology group, there were no statistically significant differences. Conclusions. The run-across method is also useful in confirming complete resection. A positive cytology margin could lead to margin relapse even if a non-small cell lung cancer is resected with a negative histology margin.
  • 築山正嗣; 西尾和人; 田村研治; 中川和彦; 福岡正博
    近畿大学医学雑誌 27 3-4 215 - 221 2002年12月 [査読有り]
  • 秋山慶太; 田村研治; 宮崎昌樹; 中川和彦; 福岡正博
    近畿大学医学雑誌 27 2 69 - 77 近畿大学 2002年10月 [査読有り]
     
    P-糖蛋白やMRP (multidrug resistance-associated protein)などのABC(ATP binding cassette)蛋白は,種々の抗癌剤の薬剤耐性に関与しており,抗癌化学療法において大きな問題の一つである.ABC蛋白の一種であり,K^+イオンの輸送に関与するSUR(sulfonylurea receptor) 1, 2が抗癌剤の薬剤耐性に関与している可能性を考え,癌細胞株(PC-14, SBC-3, A-549, MCF-7, K562)に各種抗癌剤(adriamycin, cisplatin, CPT-11, SN-38, taxol, Vp-16)を暴露し,これら抗癌剤によるSUR1, 2のmRNA発現誘導をreal time RT一PCR 定量法を用いて検索した.その結果, adriamycinを暴露した肺癌細胞株については,濃度・時間依存的に有意な発現誘導を認めた.さらに, adriamycinの薬剤耐性との関連性を明らかにするために, SBC-3, MCF-7, K562とそれぞれのadriamycin耐性株においてSUR2のmRNA発現量を比較した.その結果, SBC-3, MCF-7のadriamycin耐性株において親株と比較してSUR2の有意な過剰発現を確認した.これらの結果より,SUR2がadriamycinに対する耐性に関与している可能性が示唆された.
  • 再発ないし前治療無効小細胞肺癌に対するパクリタキセル毎週投与の第II相試験
    倉田 宝保; 鶴谷 純司; 山本 信之; 田村 研治; 野上 壽二; 植島 久雄; 高田 実; 工藤 新三; 河原 正明; 中川 和彦; 福岡 正博
    日本癌治療学会誌 37 2 293 - 293 (一社)日本癌治療学会 2002年09月
  • M Yamada; S Kudoh; H Fukuda; K Nakagawa; N Yamamoto; Y Nishimura; S Negoro; K Takeda; M Tanaka; M Fukuoka
    BRITISH JOURNAL OF CANCER 87 3 258 - 263 2002年07月 [査読有り]
     
    Dose-escalation study was performed to evaluate the maximum tolerated dose, recommended dose and toxicity profile of weekly irinotecan with daily carboplatin and concurrent thoracic radiotherapy in patients with locally advanced non-small-cell lung cancer, Thirty-one previously untreated patients with unresectable stage III non-small-cell lung cancer were enrolled in this study. Patients received weekly irinotecan plus carboplatin (20 mg m(-2) daily for 5 days a week) for 4 weeks and thoracic radiotherapy (60 Gy in 30 fractions). The irinotecan dose was escalated from 30 mg m(-2) in increments of 10 mg m(-2). Four irinotecan dose levels were given and 30 patients were assessable. Their median age was 62 years (range: 52 - 72 years), 28 had a performance status of 0 - 1 and two had a performance status of 2, 12 had stage IIIA disease and 18 had IIIB disease. There were 19 squamous cell carcinomas, 10 adenocarcinomas, and one large cell carcinoma. The dose-limiting toxicities were pneumonitis, esophagitis, thrombocytopenia and neutropenia. The maximum tolerated dose of irinotecan was 60 mg m(-2), with two patients developing grade 4 pulmonary toxicity and one patient died of pneumonitis (grade 5). The recommended dose of irinotecan was 50 mg m(-2). Other grade 3 or 4 toxicities were nausea and vomiting. Three patients achieved complete remission and 15 had partial remission, for an objective response rate of 60.0%. The median survival time was 14.9 months, and the 1- and 2-year survival rates were 5 1.6% and 34.2%, respectively. The study concluded that the major toxicity of this regimen was pneumonitis. This therapy may be active against unresectable non-small-cell lung cancer and a phase II study is warranted. (C) 2002 Cancer Research UK.
  • Inoue M; Kimura K; Hasegawa K; Fujiwara K; Nakagawa K; Yasumitsu T
    The Japanese journal of thoracic and cardiovascular surgery : official publication of the Japanese Association for Thoracic Surgery = Nihon Kyobu Geka Gakkai zasshi 50 4 165 - 167 2002年04月 [査読有り]
  • Y Ichinose; R Tsuchiya; T Koike; T Yasumitsu; K Nakamura; H Tada; H Yoshimura; T Mitsudomi; K Nakagawa; K Yokoi; H Kato
    JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY 123 4 695 - 699 2002年04月 [査読有り]
     
    Background: The prognosis of patients with resected non-small cell lung cancer without carcinomatous pleuritis whose intrapleural cancer cells were detected by means of a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy has been reported to be poor. Methods: The Japan Clinical Oncology Group conducted a phase III trial for a 3-year period starting from October 1994 to determine whether intraoperative intrapleural hypotonic cisplatin treatment could effectively control pleural disease and thereby prolong the survival of these patients. The patients were randomized to receive either intraoperative intrapleural hypotonic cisplatin treatment or no treatment before closure of the open thorax. The intraoperative intrapleural hypotonic cisplatin treatment consisted of exposing the entire thorax to cisplatin (50 mug/mL) in distilled water for 15 minutes. Results: Because of the slow registration pace, the study was prematurely terminated in January 1998. During the 41-month period from the start of the registration, 49 patients were entered into the study, and all were eligible. Twenty-five and 24 patients were randomly assigned to the treatment and control groups, respectively. No statistically significant difference in the overall survival and disease-free survival between the 2 groups was observed. However, the appearance of carcinomatous pleuritis was suppressed by the hypotonic cisplatin treatment (42% of the control group vs 8% of the treatment group, P = .008). Conclusions: Although the randomized trial was prematurely terminated, the intraoperative intrapleural hypotonic cisplatin treatment was found to effectively suppress the appearance of carcinomatous pleuritis in resected patients who demonstrated a positive pleural lavage cytology finding.
  • Gondo N; Nakagawa K; Yanagi H; Yamamura T
    Gan to kagaku ryoho. Cancer & chemotherapy 29 4 532 - 538 2002年04月 [査読有り]
  • J Tsurutani; T Nitta; T Hirashima; T Komiya; H Uejima; H Tada; N Syunichi; A Tohda; M Fukuoka; K Nakagawa
    LUNG CANCER 35 3 299 - 304 2002年03月 [査読有り]
     
    Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top I occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
  • J Tsurutani; T Nitta; T Hirashima; T Komiya; H Uejima; H Tada; N Syunichi; A Tohda; M Fukuoka; K Nakagawa
    LUNG CANCER 35 3 299 - 304 2002年03月 [査読有り]
     
    Reverse transcription polymerase chain reaction (RT-PCR) single-strand conformation polymorphism analysis was used to detect topoisomerase I (top1) mutations in total RNA from 16 specimens that were excised during surgery from eight patients with non-small cell lung cancer (NSCLC) who had received preoperative chemotherapy consisting of irinotecan (CPT-11) and cisplatin. PCR single-strand conformation polymorphism and subsequent DNA sequencing analysis showed two nucleotide substitutions resulting in Trp736stop (TGG to TGA) and Gly737Ser (GGT to AGT) in one tumor specimen. The mutations were located near a site in top1 that was previously reported to harbor a mutation in the human lung cancer cell line PC7/CPT, which was selected for CPT resistance. These results demonstrate that mutations in top I occur after chemotherapy with CPT-11 in NSCLC patients and suggest that development of resistance to CPT-11 in some patients may involve mutation of top1. However, the significance of top1 mutations to CPT resistance needs to be further investigated. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
  • 日本人進行性非小細胞肺癌患者におけるエルロチニブ単剤療法の第II相試験統合解析
    岡本浩明; 渡辺古志郎; 後藤功一; 田村友秀; 高橋利明; 一瀬幸人; 中川和彦; 畝川芳彦; 西條長宏; 福岡正博
    日本呼吸器学会誌 1 3 190 - 119 2002年03月 [査読有り]
  • 既治療無効小細胞肺癌に対するパクリタキセル毎週投与の第II相試験
    倉田 宝保; 鶴谷 純司; 田村 研治; 山本 信之; 梁 尚志; 高田 実; 工藤 新三; 河原 正明; 中川 和彦; 福岡 正博
    日本内科学会雑誌 91 臨増 217 - 217 (一社)日本内科学会 2002年02月
  • AUC finding Study of Daily Carboplatin Combined with Concurrent Thoracic Radiotherapy for Elderly Non-Small Cell Lung Cancer patients
    家田 泰浩; 山本信之; 中川 和彦; 西村 恭昌; 福岡 正博
    Acta Med Kinki Univ Acta Med Kinki Univ 26 2 35 - 44 近畿大学医学部 2002年 
    CBDCAの投与量を， Calvert 式より総投与量を算出し，それを25分割し1回投与量とした，高齢者非小細胞肺癌（Non-Small Cell Lung Cancer：NSCLC）に対する少量Carboplatin(CBDCA)連日投与と胸部放射線療法(TRT)の治療方法は，高齢者NSCLCに対して，毒性を予測・制御でき，安全でかつ，治療効果を高めることが期待できると考えらる．
  • Masayoshi Inoue; Katsuhiro Nakagawa; Makoto Kameda; Kyoichiro Toyoshima; Tsutomu Yasumitsu
    Japanese Journal of Thoracic and Cardiovascular Surgery 50 10 439 - 442 2002年 [査読有り]
     
    We treated a 15-year-old patient with spontaneous pneumothorax associated with Swyer-James syndrome using video-assisted thoracoscopic surgery (VATS). Thoracic computed tomography showed hyperlucent areas in the bilateral lungs. Due to major air leakage continuing for a week, we conducted VATS bullectomy. Because the opposite lung suffered hypoplasia, intermittent bilateral pulmonary ventilation was required to sustain an adequate PaO2 in arterial blood gas analysis during surgery. Because of recurrent pneumothorax, we performed reoperation 10 months later, finding a few newly generated bullae. To the best of our knowledge, this is the first report of VATS used to treat a Swyer-James syndrome patient with pneumothorax.
  • 清水 俊雄; 梁 尚志; 池田 昌人; 寺嶋 応顕; 高田 実; 今北 正美; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 24 3 190 - 190 特定非営利活動法人 日本呼吸器内視鏡学会 2002年
  • 三原 雅史; 梁 尚志; 池田 昌人; 清水 俊雄; 寺嶋 応顕; 高田 実; 今北 正美; 尹 亨彦; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 24 3 189 - 189 特定非営利活動法人 日本呼吸器内視鏡学会 2002年
  • 植島 久雄; 小宮 武文; 宮崎 昌樹; 田村 研治; 浅井 暁; 倉田 宝保; 野上 壽二; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 24 3 168 - 168 特定非営利活動法人 日本呼吸器内視鏡学会 2002年
  • J Tsurutani; T Komiya; H Uejima; H Tada; N Syunichi; M Oka; S Kohno; M Fukuoka; K Nakagawa
    LUNG CANCER 35 1 11 - 16 2002年01月 [査読有り]
     
    Recently, several studies have suggested that a major mechanism of resistance to paclitaxel might involve mutations in the beta-tubulin gene in tumor cells. To investigate the frequency of beta-tubulin mutations in Japanese patients with small and non-small cell lung cancer, direct sequence analysis following reverse transcription-polymerase chain reaction (RT-PCR) of the beta-tubulin gene was performed using total RNA from 20 lung cancer cell lines and 22 specimens from lung cancer patients. First-strand cDNA sequence analysis of the 42 samples showed silent mutations at codon 180 of the beta-tubulin gene, which encodes the GTP-binding site of the protein, and codons 195 and 217. However, neither missense nor non-sense mutations affecting microtubule dynamics, within or near the GTP-binding site of the beta-tubulin gene, were detected. These results indicate that beta-tubulin gene mutations might not play a major role in the mechanism of resistance to paclitaxel in Japanese lung cancer patients. Further investigations are needed to clarify the mechanism of drug resistance. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
  • J Tsurutani; T Komiya; H Uejima; H Tada; N Syunichi; M Oka; S Kohno; M Fukuoka; K Nakagawa
    LUNG CANCER 35 1 11 - 16 2002年01月 [査読有り]
     
    Recently, several studies have suggested that a major mechanism of resistance to paclitaxel might involve mutations in the beta-tubulin gene in tumor cells. To investigate the frequency of beta-tubulin mutations in Japanese patients with small and non-small cell lung cancer, direct sequence analysis following reverse transcription-polymerase chain reaction (RT-PCR) of the beta-tubulin gene was performed using total RNA from 20 lung cancer cell lines and 22 specimens from lung cancer patients. First-strand cDNA sequence analysis of the 42 samples showed silent mutations at codon 180 of the beta-tubulin gene, which encodes the GTP-binding site of the protein, and codons 195 and 217. However, neither missense nor non-sense mutations affecting microtubule dynamics, within or near the GTP-binding site of the beta-tubulin gene, were detected. These results indicate that beta-tubulin gene mutations might not play a major role in the mechanism of resistance to paclitaxel in Japanese lung cancer patients. Further investigations are needed to clarify the mechanism of drug resistance. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
  • Makoto Yoshida; Toshihiro Suzuki; Takefumi Komiya; Erina Hatashita; Kazuto Nishio; Nakagawa Kazuhiko; Masahiro Fukuoka
    International Journal of Cancer 94 3 432 - 437 2001年11月 
    Acquired anticancer drug resistance in cancer cells is often a result of an increase in levels of the ATP binding cassette (ABC) transporters that export anticancer drugs from cancer cells, suggesting that anticancer drugs may induce genes that mediate drug resistance in cancer cells. In this study, the induction of anticancer drug transporter gene expression by Adriamycin was examined in human lung cancer cell lines. Increased expression of MDRI, MRP5 and SMRP mRNA was observed 48 hr after the initiation of Adriamycin exposure in human lung cancer PC-14 cells and cisplatin-resistant PC-14/CDDP cells, in a dose-dependent manner as measured by TaqMan real-time RT-PCR. The levels of MRP-1, MRP2 and LRP mRNA were not altered by Adriamycin exposure. The biologic functions of the MRP5 and SMRP genes have not been fully clarified. To elucidate the relationship between Adriamycin resistance and MRP5 and SMRP, mRNA levels of MRP5 and SMRP in Adriamycin-resistant cell lines were compared with the parental cells. Increased expression of MRP5 and SMRP mRNA was observed in all 3 cell lines (SBC-3/ADM, AdR MCF7 and K562/ADM) by Northern blot analysis and RNase protection assay. These results suggest that subacute exposure of lung cancer cells to Adriamycin induced MRP5 and SMRP and that long-term exposure with Adriamycin selected the MRP5- and SMRP-overexpressing lung cancer cells. MRP5 and SMRP is a candidate molecule for acquired Adriamycin resistance in addition to MDRI. © 2001 Wiley-Liss, Inc.
  • M Yoshida; T Suzuki; T Komiya; E Hatashita; K Nishio; N Kazuhiko; M Fukuoka
    INTERNATIONAL JOURNAL OF CANCER 94 3 432 - 437 2001年11月 [査読有り]
     
    Acquired anticancer drug resistance in cancer cells is often a result of an increase in levels of the ATP binding cassette (ABC) transporters that export anticancer drugs from cancer cells, suggesting that anticancer drugs may induce genes that mediate drug resistance in cancer cells. In this study, the induction of anticancer drug transporter gene expression by Adriamycin was examined in human lung cancer cell lines. Increased expression of MDR1, MRP5- and SMRP mRNA was observed 48 hr after the initiation of Adriamycin exposure in human lung cancer PC-14 cells and cisplatin-resistant PC-14/CDDP cells, in a dose-dependent manner as measured by TaqMan real-time RT-PCR. The levels of MRP-1, MRP2 and LRP mRNA were not altered by Adriamycin exposure. The biologic functions of the MRP5 and SMRP genes have not been fully clarified. To elucidate the relationship between Adriamycin resistance and MRP5 and SMRP, mRNA levels of MRP5 and SMRP in Adriamycin-resistant cell lines were compared with the parental cells. Increased expression of MRPS and SMRP mRNA was observed in all 3 cell lines (SBC-3/ADM, AdR MCF7 and K562/ADM) by Northern blot analysis and RNase protection assay. These results suggest that subacute exposure of lung cancer cells to Adriamycin induced MRP5 and SMRP and that long-term exposure with Adriamycin selected the MRP5- and SMRP-overexpressing lung cancer cells. MRP5 and SMRP is a candidate molecule for acquired Adriamycin resistance in addition to MDR1. (C) 2001 Wiley-Liss, Inc.
  • 非小細胞肺癌株PC14におけるCYP3A4の発現誘導
    築山 正嗣; 中川 和彦; 小宮 武文; 吉田 誠; 鶴谷 純司; 山本 信之; 植島 久雄; 秋山 慶太; 田村 研治; 倉田 宝保
    日本癌学会総会記事 60回 67 - 67 (一社)日本癌学会 2001年09月
  • 肺癌細胞におけるSulfonylurea receptor 1,2の発現誘導
    秋山 慶太; 田村 研治; 鶴谷 純司; 築山 正嗣; 浅井 暁; 小宮 武文; 倉田 宝保; 植島 久雄; 山本 信之; 中川 和彦
    日本癌学会総会記事 60回 233 - 233 (一社)日本癌学会 2001年09月
  • T Hirashima; O Yoshitaka; T Nitta; S Sasada; M Kobayashi; N Masuda; K Matsui; K Nakagawa; T Yasumitsu; Y Takada; M Kikui; Kawase, I
    ANTICANCER RESEARCH 21 5 3685 - 3689 2001年09月 [査読有り]
     
    To examine the correlation between telomerase activity and clinical features in patients with lung cancer, we examined 86 patients with endoscopically visible lung cancer including 61 with non-small cell lung cancer (NSCLC) and 25 with small cell lung cancer (SCLC). Telomerase activity was detected by using Telomerase ELISA Kit (Bohringer Manheim, Germany). The median and interquartile ranges of telomerase activity in normal lung, NSCLC and SCLC were 65 and 51-75, 106 and 58-349 and 285 and 117-2214, respectively. Normal lung, NSCLC and SCLC had significantly different telomerase activity (p<0.0001). Between NSCLC and SCLC, SCLC exhibited higher telomerase activity than did NSCLC (p=0.0029). A cut-off level of absorbance [A(450)nm-A(690)nm] of 86 derived from 90% specificity in normal lung was used, sensitivity for overall lung cancer, NSCLC and SCLC was 62.8%, 54.1% and 84.0%, respectively. There was no significant difference in telomerase activity between each stage in NSCLC (p=0.9243). In SCLC, however, the median and interquartile range of telomerase activity in extensive disease (2128 and 292-2681) was significantly higher than those in limited disease (207 and 97252) (p=0.0285).
  • Y Ichinose; R Tsuchiya; T Koike; O Kuwahara; K Nakagawa; Y Yamato; K Kobayashi; Y Watanabe; M Kase; K Yokoi
    LUNG CANCER 32 1 55 - 60 2001年04月 [査読有り]
     
    Objective: the purpose of this study was to clarify the prognosis of resected non-small cell lung cancer (NSCLC) patients with carcinomatous pleuritis of minimal disease which might be considered as the next advanced stage of positive pleural lavage cytology. Method: the data were collected from a questionnaire survey on the survival of the patients with carcinomatous pleuritis found at thoracotomy from 1985 to December 1994 which was conducted by the Japan Clinical Oncology Group (JCOG). Results: out of 227 patients with carcinomatous pleuritis found at thoracotomy who had available information on a survival, 100 patients who underwent a resection of the primary tumor had carcinomatous pleuritis of minimal disease defined based on the criteria of the Japan Lung Cancer Society. The mean malignant fluid volume (+/- S.E.) was 37.1 (6.3) mi and the mean number of pleural disseminated nodules was 5.6 (0.9). A lobectomy was performed in 79 patients, a pneumonectomy in ii and a limited resection in ten. The 3- and 5-year survival rates were 31.8 and 22.8%, respectively. Conclusions: the prognosis of resected NSCLC patients with carcinomatous pleuritis of minimal disease was unexpectedly good. This indicates that no fine line may exist between positive pleural lavage cytology findings and the aforementioned lesion. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
  • 肺癌細胞における各種抗癌剤によるトランスポーター遺伝子の発現誘導
    吉田誠; 西尾和人; 中川和彦; 福岡正博
    近畿大学医学雑誌 26 1 9 - 21 2001年04月 [査読有り]
  • 局所進行肺癌の集学的治療班
    多田弘人; 貴志彰宏; 麻田博輝; 中川和彦; 福岡正博
    大阪市勤務医師会研究年報 29 191 - 193 2001年03月 [査読有り]
  • 池田 昌人; 寺嶋 応顕; 清水 俊雄; 梁 尚志; 高田 実; 今北 正美; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 23 6 574 - 574 特定非営利活動法人 日本呼吸器内視鏡学会 2001年
  • 寺嶋 広顕; 池田 昌人; 高田 実; 梁 尚志; 清水 俊雄; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 23 6 572 - 572 特定非営利活動法人 日本呼吸器内視鏡学会 2001年
  • Y Ichinose; R Tsuchiya; T Yasumitsu; T Koike; Y Yamato; K Nakagawa; H Tada; K Yokoi; K Nagai; M Kase
    LUNG CANCER 31 1 37 - 41 2001年01月 [査読有り]
     
    Objective: The purpose of this study was to clarify the prognosis of non-small cell lung cancer patients without pleural effusion whose intrapleural cancer cells were detected by a cytologic examination of pleural lavage fluid obtained immediately after a thoracotomy. Method: A questionnaire survey on the survival of the patients with positive pleural lavage cytology from January 1985 to December 1994 was performed by the Japan Clinical Oncology Group. Results: According to the data collected from lj institutions, 1890 non-small cell lung cancer patients without pleural effusion underwent pleural lavage cytology immediately after thoracotomy and 142 (7.8%) of them were found to have intrapleural cancer cells detected by the cytological analysis. The information of survival on 113 patients was available. This comprised of 64 males and 49 females with a mean age of 64.6 years. The predominant histologic type was adenocarcinoma (74%). Out of these 113 patients, 109 (97%) underwent a surgical resection. The 5-year survival rate was 30% in all patients, 49%, in pathological stage I (n = 35). 23%, in stage II (n = 20) and 26% in stage IIIA (n = 34). Conclusion: Patients with a positive pleural lavage cytology in pathological stage I or II appear to have a poor 5-year survival rate. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.
  • HJ Kuh; S Nakagawa; J Usuda; K Yamaoka; N Saijo; K Nishio
    JAPANESE JOURNAL OF CANCER RESEARCH 91 12 1303 - 1313 2000年12月 
    Most anticancer agents induce cell cycle arrest (cytostatic effect) and cell death (cytotoxic effect), resulting in the inhibition of population growth of cancer cells. When asynchronous cells are to be examined, the currently used flow cytometric method can not provide checkpoint-specific and quantitative information on the drug-induced cell cycle arrest. Hence, despite its significance, no good method to analyze in detail the mechanism of cell cycle arrest and its contribution to overall growth inhibition induced by an anticancer agent has yet been established. We describe in this study the development of a discrete time (Markov model)-based computational model for cell cycle progression/arrest with transition probability (TPi) as a model parameter. TPi was calculated using model equations that include easily measurable parameters such as the fraction of cells in each cell cycle phase and population doubling time. The TPi was then used to analyze checkpoint-specific and quantitative changes in cell cycle progression. We also used TPi in a Monte-Carlo simulation to predict growth inhibition caused by cell cycle arrest only. Human SCLC cells (SBC-3) exposed to UCN-01 were used to validate the model. The model-predicted growth curves agreed with the observed data for SBC-3 cells not treated or treated at a cytostatic concentration (0.2 muM) of UCN-01, indicating validity of the present model. The changes in TPi indicated that UCN-01 reduced the G(i)-to-S transition rate and increased the S-to-G(2)/M and G(2)/M-to-G(1) transition rates of SBC-3 cells in a concentration- and time-dependent manner. When the model-predicted growth curves were compared with the observed data for cells treated at a cytotoxic concentration (2 muM), they suggested that 22% out of 65% and 32% out of 73% of the growth inhibition could be attributed to the cell cycle arrest effect after 48 h and 72 h exposure, respectively. In conclusion, we report here the establishment of a novel method of analysis that can provide checkpoint-specific and quantitative information about cell cycle arrest induced by an anticancer agent and that can be used to assess the contribution of cell cycle arrest effect to the overall growth inhibition.
  • M Inoue; K Nakagawa; K Fujiwara; K Fukuhara; T Yasumitsu
    ANNALS OF THORACIC SURGERY 70 5 1620 - 1623 2000年11月 [査読有り]
     
    Background. The significance of mediastinoscopy for small cell lung cancer is unclear owing to the small number of surgical cases. Methods. To determine the N component of the TNM staging system, computed tomographic findings and the results of mediastinoscopy were compared with the pathologic examination of surgical specimens. Results. Four cases among 37 patients (10.8%) were determined as inoperable by mediastinoscopy because of mediastinal lymph node metastasis. A thoracotomy was performed in 33 patients. Six patients (18.2%) who had been judged to have no metastasis by mediastinoscopy were found to have N2 disease after examination of the surgical specimens. In the identification of all mediastinal metastases, mediastinoscopy was 40.0% sensitive, 100% specific, and 83.8% accurate. When the superior mediastinal, paratracheal, pretracheal, tracheobronchial, and subcarinal lymph nodes were defined as approachable nodes, mediastinoscopy was 66.7% sensitive, 100% specific, and 94.6% accurate in the evaluation of these restricted nodes. Four cases among 8 patients with cN1 lesions resulted in a designation as pN2. Conclusions. Mediastinoscopy is useful for the diagnosis of an approachable mediastinal lymph node in small cell lung cancer cases. This exploration is necessary for patients with small cell lung cancer who are diagnosed as cN1 before thoracotomy. (Ann Thorac Surg 2000;70:1620-3) (C) 2000 by The Society of Thoracic Surgeons.
  • パクリタキセル(タキソール)がイリノテカンの薬物動態に及ぼす影響
    浅井 暁; 山本 信之; 小宮 武文; 森山 あづさ; 児玉 圭司; 鶴谷 純司; 吉田 誠; 築山 正嗣; 秋山 慶太; 中川 和彦
    日本癌学会総会記事 59回 233 - 233 2000年09月
  • 新規抗がん剤ritterazineB
    小宮 武文; 鶴谷 純司; 吉田 誠; 山本 信之; 植島 久雄; 福岡 正博; 伏谷 伸宏; 中川 和彦
    日本癌学会総会記事 59回 187 - 187 (一社)日本癌学会 2000年09月
  • ヒト小細胞肺癌株におけるβtubulin遺伝子異常
    鶴谷 純司; 小宮 武文; 植島 久雄; 山本 信之; 中川 和彦; 福岡 正博; 平島 智徳
    日本癌学会総会記事 59回 185 - 185 (一社)日本癌学会 2000年09月
  • 各種抗癌剤による薬剤耐性遺伝子発現誘導
    吉田 誠; 中川 和彦; 小宮 武文; 畑下 恵理奈; 鶴谷 純司; 植島 久雄; 山本 信之; 福岡 正博
    日本癌学会総会記事 59回 193 - 193 (一社)日本癌学会 2000年09月
  • 固形癌に対するNon-Platinum Tripletの臨床第I相試験
    児玉 圭司; 山本 信之; 秋山 慶太; 築山 正嗣; 鶴谷 純司; 浅井 暁; 森山 あづさ; 小宮 武文; 植島 久雄; 中川 和彦
    日本癌治療学会誌 35 2 449 - 449 (一社)日本癌治療学会 2000年09月
  • 局所進行型非小細胞肺がんに対するweekly Taxotere(TXT)+Cisplatin(CDDP)と胸部放射線の同時併用療法の第I相試験
    平島 智徳; 山本 信之; 中川 和彦; 野上 壽二; 植島 久雄; 小宮 武文; 森山 あづさ; 浅井 暁; 児玉 圭司; 鶴谷 純司
    日本癌治療学会誌 35 2 446 - 446 (一社)日本癌治療学会 2000年09月
  • 武田晃司; 根来俊一; 中川和彦; 工藤新三; 吉村成央; 田村友秀; KELLY H; 福岡正博
    Japanese Journal of Cancer Research 91 Supplement (Sept) 231 - 232 2000年09月
  • M Inoue; Y Kotake; K Nakagawa; K Fujiwara; K Fukuhara; T Yasumitsu
    ANNALS OF THORACIC SURGERY 70 2 380 - 383 2000年08月 [査読有り]
     
    Background. This study aims to clarify which patients would benefit by surgery for pulmonary metastases from colorectal carcinoma. Methods. A retrospective study was undertaken in 25 patients who had undergone complete resection. In all cases, prethoracotomy carcinoembryonic antigen (CEA) level was measured and mediastinal or hilar lymph nodes were histologically examined. Results. Overall 5-year survival was 39.2%. The 5-year survival rate for patients with a normal CEA level was 61.1%, as compared with 19.0% for patients with an elevated CEA level (p = 0.0423). The 5-year survival rate for patients without a lymph node metastasis was 49.5%, as compared with 14.3% for patients with a lymph node metastasis (p = 0.0032). No lymph node metastasis was a predictor of longer survival by univariate and multivariate analyses. The primary site, disease-free interval, and number and size of the metastasis were not significant prognostic factors. Conclusions. A resection for pulmonary metastasis from colorectal carcinoma is effective in patients with a normal CEA level and without a lymph node metastasis. (C) 2000 by The Society of Thoracic Surgeons.
  • N Masuda; S Negoro; S Kudoh; T Sugiura; K Nakagawa; H Saka; M Takada; H Niitani; M Fukuoka
    JOURNAL OF CLINICAL ONCOLOGY 18 16 2996 - 3003 2000年08月 [査読有り]
     
    Purpose: We conducted a phase I trial of docetaxel, a new antimicrotubule agent, combined with irinotecan (CPT-11), a topoisomerase I inhibitor. The aim was to determine the maximum-tolerated dose (MTD) of docetaxel combined with CPT-11. as well as the dose-limiting toxicities (DLTs) of this combination in advanced non-small-cell lung cancer (NSCLC) patients. Patients and Methods: Thirty-two patients with stage IIIB or IV NSCLC were treated at 4-week intervals with docetaxel (60 minutes, day 2) plus CPT-11 (90 minutes, days 1, 8, and 15), The starting doses of docetaxel/CPT-11 were 30/40 mg/m(2), and doses were escalated in 10-mg/m(2) increments until the MTD was reached. Results: The MTD of docetaxel/CPT-11 was 50/60 mg/m(2) (level 5A), or 60/50 mg/m(2) (level 5B). Neutropenia and diarrhea were the DLTs, CPT-11 did not affect the pharmacokinetics of docetaxel. There were 11 (37%) partial responses among 30 patients. The median survival time wets 48 weeks, and the 1-year survival rate was 44.9%. Conclusion: The combination of docetaxel and CPT-11 seems to be active against NSCLC, with acceptable toxicity. The recommended dose for phase II studies is 50 mg/m(2) of CPT-11 (days 1, 8, and 15) and 50 mg/m(2) of docetaxel (day 2) administered every 28 days. (C) 2000 by American Society of Clinical Oncology.
  • 日本における臨床腫瘍研究 限局型小細胞肺癌に対するDose Intensive Weekly化学療法とCisplatin+Etoposide+胸部放射線同時照射併用のPilot Study
    礒部威; 福岡正博; 根来俊一; 杉浦孝彦; 河原正明; 工藤新三; 荒木潤; 中川和彦; 横崎典哉; 山木戸道郎; 有吉寛; 西日本肺癌治療共同研究グループ
    癌と化学療法 27 8 1091 - 1096 2000年07月 [査読有り]
  • N Masuda; K Matsui; N Yamamoto; T Nogami; K Nakagawa; S Negoro; K Takeda; N Takifuji; M Yamada; S Kudoh; T Okuda; S Nemoto; K Ogawa; H Myobudani; S Nihira; M Fukuoka
    CLINICAL CANCER RESEARCH 6 6 2288 - 2294 2000年06月 [査読有り]
     
    2'-deoxy-2'-methylidenecytidine (DMDC) is a potent deoxycytidine analogue. Preclinical studies of DMDC demonstrated activity against a variety of murine and human tumors in cell cultures and murine models and indicate enhanced antitumor activity of DMDC when it was administered in a manner that provided prolonged systemic expo sure, In view of this observation, this study was designed to determine the toxicities, maximum-tolerated dose, and pharmacokinetic profile of DMDC. DMDC was given p.o. under fasting conditions for 14 consecutive days every 4 weeks in patients with advanced solid tumors. The starting dose was 12 mg/m(2)/day, Pharmacokinetic studies were carried out on days 1 and 14 of the first cycle. Fourteen patients received 22 courses of DMDC. The dose-limiting toxicities were anorexia, leukopenia, thrombocytopenia, and anemia. General fatigue was the common nonhematological toxicity, The maximum-tolerated dose was 18 mg/m(2)/day, at which two of six patients developed grade 3 toxicities. This dose level could also be considered for Phase II testing with this schedule. At the 18-mg/m(2)/day dose level, the mean terminal half-life, maximum plasma concentration (C-max), the area under the plasma drug concentration-time curve (AUC(0-infinity)) on day 1 were 1.7496 h, 112.9 ng/ml, and 399.8 ng.h/ml, respectively. Forty to 50% of the administered dose was recovered in the urine, indicating a good bioavailability and resulting significant systemic exposure to the drug, which may enable chronic oral treatment.
  • 家田泰浩; 山本信之; 坂井幸子; 吉田誠; 小宮武文; 野上壽二; 植島久雄; 中川和彦; 福岡正博
    肺癌 40 3 185 - 189 日本肺癌学会 2000年06月 [査読有り]
     
    cisplatin (CDDP)またはirinotecan (CPT-11)を含む化学療法が無効であった非小細胞肺癌(Non-Small Cell Lung Cancer, NSCLC)に対するDocetaxel 60mg / m^2のPilot studyを施行した.12例が登録され, 全例が評価可能であった.前化学療法の効果は, no change (NC)7例, progressive disease (PD)2例であった.5 / 12例にGrade4の好中球減少に認めた.他の毒性は軽微であった.全体の奏効率は16.2%, Median survival time (MST)は170日, 1年生存率は11%. Performance status (PS) 間の比較では, PSが良好である群(PS0, 1)の方が予後が良好であった.(MST:PS0, 1 / 2 ; 285日 / 116日, P=0.024). この結果は, PSが良好であればCDDP又は, CPT-11に抵抗性のNSCLCに対する治療に, Docetaxel 60mg / m^2の投与が有効であることを示唆している.
  • T Komiya; Kawase, I; T Nitta; T Yasumitsu; M Kikui; M Fukuoka; K Nakagawa; T Hirashima
    INTERNATIONAL JOURNAL OF ONCOLOGY 16 6 1173 - 1177 2000年06月 [査読有り]
     
    To investigate the prognostic role of hTERT expression in non-small cell lung cancer (NSCLC), we examined the expression of hTERT mRNA in tumor specimens from 68 patients with NSCLC using RT-PCR. The expression of hTERT was detected in 34 (50%) of 68 cancer tissues. There were no correlations between hTERT status and any common clinical features except age. Patients with hTERT expression had shorter survival than those without hTERT expression. Multivariate analysis showed that hTERT expression was an independent negative prognostic factor. These results suggest that expression of hTERT may be an independent prognostic factor for NSCLC patients.
  • T Hirashima; T Komiya; T Nitta; Y Takada; M Kobayashi; N Masuda; K Matui; M Takada; M Kikui; T Yasumitu; A Ohno; K Nakagawa; M Furuoka; Kawase, I
    ANTICANCER RESEARCH 20 3B 2181 - 2187 2000年05月 [査読有り]
     
    This study was performed to evaluate the prognostic significance of alteration in telomere length in pathological stage (p-stage) I-IIIA non-small cell lung cancer (NSCLC). Paired cancer and normal lung tissues were obtained from 72 patients with histologically confirmed p-stage I-III4 NSCLC. Terminal restriction fragment (TRF) length, which indicates telomere length, was measured by Southern blot analysis. Tumor telomerase activity was also assayed by non-radioactive PCR-ELISA in 55 patients. TRF length (mean+/-SD) in normal tissue was 6.2+/-1.1 Kb. Therefore, upper and lower limits of normal range in TRF length was set at 8.4 (mean+2SD) Kb and 4.0 (mean-2SD) Kb, respectively. A tumor showing TRF length over normal range was defined as positive for the alteration. In 72 patients, 25 (34.7%) with alteration in TRF length had significantly shorter survival durations than those of the others. Telomerase activity did not correlate with survival duration. In multivariate analysis, alteration in TRF length (P=0.0033) was second to p-stage (P=0.0004) in importance among the various parameters.
  • 非小細胞肺癌に対するweekly CDDP+docetaxel concurrent thoracic radiotherapyの第I/II相試験
    児玉 圭司; 山本 信之; 中川 和彦; 植島 久雄; 小宮 武文; 浅井 暁; 飯田 あずさ; 家田 泰浩; 鶴谷 純司; 坂井 幸子
    日本呼吸器学会雑誌 38 増刊 212 - 212 (一社)日本呼吸器学会 2000年03月
  • がん患者への臨床検査技師の取り組みを考える がん患者と家族を対象とした「がん治療と臨床検査」の講演後のアンケート報告から
    古垣内美智子; 今野元博; 金星智世; 米本圭佑; 鷹家優美子; 下川てるみ; 井本真由美; 森嶋祥之; 内藤昭智; 上硲俊法; 荷掛恵; 七條恵; 松林輝代子; 加戸聖美; 原聡; 中川和彦; 西村恭昌; 奥野清隆; 塩崎均
    癌と化学療法 37 3 555 - 558 2000年03月 [査読有り]
  • 森山 あづさ; 坂井 幸子; 小宮 武文; 植島 久雄; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 22 3 208 - 208 特定非営利活動法人 日本呼吸器内視鏡学会 2000年
  • 森山 あづさ; 小宮 武文; 植島 久雄; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 22 4 317 - 317 特定非営利活動法人 日本呼吸器内視鏡学会 2000年
  • A Kubo; K Nakagawa; RK Varma; NK Conrad; JQ Cheng; WC Lee; Testa, JR; BE Johnson; FJ Kaye; MJ Kelley
    CLINICAL CANCER RESEARCH 5 12 4279 - 4286 1999年12月 [査読有り]
     
    Loss of p16 functional activity leading to disruption of the p16/cyclin-dependent kinase (CDK) 4:cyclin D/retinoblastoma pathway is the most common event in human tumorigenesis, suggesting that compounds with CDK4 kinase inhibitory activity may be useful to regulate cancer cell growth. To identify such inhibitors, the 60 cancer cell lines of the National Cancer Institute drug screen panel were examined for p16 alterations (biallelic deletion, intragenic mutations, or absent p16 protein), and the growth-inhibitory activity of more than 50,000 compounds against these 60 cell lines was compared with their p16 status. One compound, 3-amino thioacridone (3-ATA; NSC 680434), whose growth-inhibitory activity correlated with the p16 status of the cell lines had an IC50 of 3.1 mu M in a CDK4 kinase assay. In addition, four compounds structurally related to 3-ATA inhibited CDK4 kinase with IC(50)s ranging from 0.2-2.0 mu M. All five of these compounds were less potent inhibitors of cell division cycle 2 and CDK2 kinases, with IC(50)s 30- to 500-fold higher than that for CDK4. ATP competition experiments demonstrated a noncompetitive mode of inhibition for 3-ATA (K-i = 5.5 mu M) and a linear mixed mode for benzothiadiazine (NSC 645787; K-i = 0.73 mu M). We have successfully demonstrated a novel approach to identify specific CDK4 kinase inhibitors that may selectively induce growth inhibition of p16-altered tumors.
  • 【Chemoradiotherapyの有用性と問題点】限局型小細胞癌に対するInitial dose intensive chemotherapy(CODE)療法後のcisplatin+etoposide・放射線同時併用のパイロットスタディー
    川口 知哉; 礒部 威; 福岡 正博; 根来 俊一; 杉浦 孝彦; 河原 正明; 工藤 新三; 中川 和彦; 山木戸 道郎; 有吉 寛
    日本癌治療学会誌 34 2 41 - 41 (一社)日本癌治療学会 1999年10月
  • 野上 壽二; 吉田 誠; 沢口 博千代; 浅井 暁; 飯田 あずさ; 岩永 賢司; 小宮 武文; 山本 信之; 中川 和彦; 福岡 正博
    気管支学 21 5 371 - 371 特定非営利活動法人 日本呼吸器内視鏡学会 1999年
  • Y Fujiwara; K Nakagawa; M Kusunoki; T Hatada; T Yamamura; J Utsunomiya
    HEPATO-GASTROENTEROLOGY 46 25 290 - 294 1999年01月 [査読有り]
     
    Chylothorax is an uncommon but well recognized complication of esophagectomy. We present the case of a 57 year-old man with squamous cell carcinoma of the abdominal esophagus who underwent subtotal esophagectomy by right thoracotomy. Post-operatively, the volume of pleural effusion from the right chest was increased (1600-2000ml/day). The effusion was straw colored, not changing to milky after meals. The characteristics and composition of the pleural fluid were similar to those of chyle. We therefore treated this patient using methods for treatment of chylothorax, conservatively, by administration of OK-432 and minocycline/hydrochloride into the pleural cavity from the chest tube with success. We discuss the pathophysiology of this unusual condition and its treatment.
  • Clinical significance of K-ras point mutations in advanced adenocarcinoma or large cell carcinoma of the lung.
    Nakagawa,K; Hirashima,T; Nitta,T; Yoshikawa,A; Fukuoka,M; Ando,M
    Kumamoto Medical Journal, 46 33 - 39 1999年 [査読有り]
  • Shoji Hirasaki; Norio Koide; Yasuo Shima; Kazuhiko Nakagawa; Atsuhiko Sato; Jun Mizuo; Hiromichi Ogawa; Kozo Ujike; Takao Tsuji
    Journal of Gastroenterology 33 5 734 - 738 1998年10月 [査読有り]
     
    Paraduodenal hernia is a rare condition in which the small bowel loops are herniated into an unusual fossa in the periduodenal area. We treated a patient with paraduodenal hernia diagnosed preoperatively. A 28-year-old woman was admitted to our hospital because of intermittent abdominal pain. Abdominal ultrasonography revealed a large tumor adjacent to the pancreas. Provisional diagnosis made according to computed tomography (CT) findings was tumor of the pancreas tail. However, on a CT scan performed after the administration of diatrizoate meglumine/diatrizoate sodium (Gastrografin, Schering, Berlin, Germany) the mass was shown as a jejunum loop located between the stomach and the pancreas body. Subsequent laparotomy revealed that the jejunum loop was herniated into an unusually large mesocolic fossa and that the hernial orifice was covered by the adhesion between the transverse and descending colons. It seemed that the small intestine within the mesocolic fossa was strangulated by this adhesion. The patient's abdominal pain resolved postoperatively. These observations suggest that paraduodenal hernia should be suspected in patients with chronic, atypical abdominal pain, regardless of the findings for small bowel obstruction.
  • N Masuda; M Fukuoka; A Fujita; Y Kurita; S Tsuchiya; K Nagao; S Negoro; H Nishikawa; N Katakami; K Nakagawa; H Niitani
    BRITISH JOURNAL OF CANCER 78 2 251 - 256 1998年07月 [査読有り]
     
    A phase I trial of the combination of irinotecan (CPT-11) with cisplatin in advanced non-small cell lung cancer (NSCLC) showed a very promising response rate of 54% in previously untreated NSCLC patients, This study was conducted to confirm the activity and toxicities of CPT-11 and cisplatin combination for previously untreated NSCLC in a multi-institutional phase II study. Seventy patients with stage IIIB or IV NSCLC received CPT-11 60 mg m(-2) intravenously (IV) on days 1, 8 and 15, and cisplatin 80 mg m(-2) (IV) on day 1 every 4 weeks. Assessments were made of response, survival and toxicities. Sixty-nine were eligible, and evaluable for toxicities and survival, and 64 patients evaluable for response, Thirty-three patients (52%; 95% confidence interval 39-64%) achieved an objective response, with one complete response (2%) and 32 partial responses (50%), The median duration of response was 19 weeks and the overall median survival time was 44 weeks. The 1-year survival rate was 33%. The major toxic effects were leucopenia and diarrhoea. Grade 3 or 4 leucopenia, neutropenia, and diarrhoea occurred in 32 patients (46%), 53 patients (80%), and 13 patients (19%) respectively A combination of CPT-11 and cisplatin is very effective against non-small-cell lung cancer with acceptable toxicities.
  • T Komiya; Y Hosono; T Hirashima; N Masuda; T Yasumitsu; K Nakagawa; M Kikui; A Ohno; M Fukuoka; Kawase, I
    CLINICAL CANCER RESEARCH 3 10 1831 - 1835 1997年10月 [査読有り]
     
    Although p21 WAF1/Cip1 expression has been detected immunohistochemically in non-small cell lung cancer (NSCLC), the associations between p21 expression and clinical characteristics are unknown, To determine the association between p21 expression and clinical features, p21 expression was immunohistochemically analyzed in paraffin-embedded tumor samples from 137 patients with curatively resected NSCLC, p21 expression, indicating normal p21 function, was detected in 48 (35.0%) of the 137 patients with curatively resected NSCLC and was detected more frequently in patients with stage I or II disease (40.2%) than in those with stage IIIA disease (22.5%; P = 0.0483). There was no difference in the positive rate between squamous cell carcinoma [SCC; 15 of 48 (31.3%)] and adenocarcinoma [30 of 77 (39.0%)]. For SCC, patients with tumors expressing p21 survived longer than did those with tumors negative for p21 expression; however, the corresponding survival time was not significant for adenocarcinoma, On the other hand, p53 expression, detected in 58 (42.3%) of these patients, did not act as any predictor for prognosis in either SCC or adenocarcinoma. Our findings suggest that the presence of p21 expression is associated with favorable prognosis in SCC and may be useful in obtaining candidates for adjuvant therapies from among patients with SCC.
  • T Komiya; Y Kusunoki; M Kobayaski; T Hirashima; T Yana; N Masuda; K Matsui; M Takada; K Nakagawa; Y Kotake; T Yasumitsu; M Kikui; Kawase, I
    ACTA RADIOLOGICA 38 5 821 - 825 1997年09月 [査読有り]
     
    Purpose: To evaluate the usefulness of transcutaneous needle biopsy (TCNB). Material and Methods: From Mat 1988 to December 1994, we performed TCNB under fluoroscopic control in 408 patients with mass lesions of the peripheral lung. The Surecut needle (1.5 mm) was selected mainly because of its ability to obtain specimens large enough for histological examination. Of the 408 patients, 286 had had previous bronchofiberscopic examinations but no definite diagnosis had been reached. Results: A definite diagnosis was obtained by TCNB in 305 (74.7%) of 408 cases (251 malignant neoplasms, 54 benign lesions). In malignant neoplasms, the pathological diagnosis based on cytology and histology together was more reliable than that based on cytology alone. Although the complications of this procedure (such as pneumothorax) were within the range of acceptability, care should be taken to avoid air embolism and the seeding of cancer cells along the needle tract. Conclusion: TCNB with the Surecut needle is a useful procedure with relatively low risk.
  • T Komiya; T Hirashima; M Takada; N Masuda; T Yasumitsu; K Nakagawa; Y Hosono; M Kikui; S Tsuji; M Fukuoka; Kawase, I
    ANTICANCER RESEARCH 17 5B 3721 - 3724 1997年09月 [査読有り]
     
    Background: The prognostic significance of serum p53-Abs positivity for non-small cell lung cancer (NSCLC) is still unknown. Patients and methods: To determine the prognostic value of serum p53-Abs status, we determined serum p53-Abs and immunohistochemistry in 140 patients with stage I-IIIA NSCLC. Results: p53-Abs were detected in 12.1% of all patients and in 17.6% of those with squamous cell carcinoma (SCC). Neither p53-Abs nor p53 overexpression alone was correlated with survival for all patients. When these factors were combined for SCC, seronegative patients with tumors overexpressing p53 survived significantly longer than did those with p53-Abs or p53-nonexpressing tumors. In multivariate analysis, p53-Abs status and p53 overexpression were independent prognostic factors for SCC (p = 0.0337). Conclusions: These findings suggest that the combination of p53Abs seropositivity and p53 overexpression may be a prognostic factor for SCC.
  • A Ohno; T Hirashima; A Kubo; N Masuda; M Takada; H Fujiwara; T Yasumitsu; M Kikui; M Fukuoka; K Nakagawa
    INTERNATIONAL JOURNAL OF ONCOLOGY 10 3 521 - 528 1997年03月 [査読有り]
     
    To investigate the role of p53 abnormalities in predicting the survival of patients with non-small cell lung cancer (NSCLC), polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and immunohistochemical analyses were performed on 74 and 67 tumor samples, respectively, from patients with pathological stage I-IIIa NSCLC. An abnormally migrating SSCP band was observed in 21 of 74 (28%) tumor specimens. DNA sequence analysis revealed 23 intragenic mutations including 3 small deletions and 20 point mutations. Immunohistochemical analysis using the DO-7 monoclonal antibody showed abnormal expression of p53 in 27 of 67 (40%) patients. The concordance rate between immunohistochemical and PCRSSCP analyses was 73% (49/67) in this study. Univariate and multivariate analyses demonstrated that abnormal expression of p53 may be associated with prolonged survival (p=0.0997 and 0.0099, respectively). In contrast, no relationship was observed between p53 mutation and overall survival (0.6968). These results suggest that p53 status and the survival outcome changes between immunohistochemical and mutational analyses in stage I-IIIa NSCLC.
  • MJ Kelley; K Nakagawa; NK Conrad; J LeRiche; N Murray; JS Lee; JY Ro; EG Shaw; MA Tucker; BE Johnson
    CLINICAL CANCER RESEARCH 2 7 1103 - 1105 1996年07月 [査読有り]
     
    We performed genetic analysis on 12 second primary non-small cell lung cancers in patients surviving small cell lung cancer to assess the potential contribution of smoking to the development of these tumors, Mutations of TP53 were found in three (25%) tumors, KRAS2 in three (25%) tumors, and CDKN2 in two (18%) tumors, Four (50%) mutations (one each in TP53 and CDKN2 and two in KRAS2) were G:C to T:A transversions on the coding strand, a mutation accounting for approximately one-third of mutations in smoking-related tumors but uncommonly found in lung cancers not associated with smoking, The genetic changes in these second lung cancers are more representative of smoking-associated malignancies than lung cancers arising in patients occupationally exposed to irradiation and atomic bomb survivors.
  • A Kubo; A Yoshikawa; T Hirashima; N Masuda; M Takada; J Takahara; M Fukuoka; K Nakagawa
    CANCER RESEARCH 56 6 1232 - 1236 1996年03月 [査読有り]
     
    Reverse transcription-PCR-single-strand conformation polymorphism analysis was performed to detect topoisomerase II alpha mutations using total RNA from 19 bronchial biopsy specimens obtained from 13 patients with small cell lung cancer. An abnormally migrating single-strand conformation polymorphism band was observed in one tumor sample from a patient treated with etoposide-containing chemotherapy. DNA sequence analysis of this tumor showed two transversions at codons 486 (G to A) and 494 (A to G), resulting in two missense mutations (Arg to Lys and Glu to Gly, respectively). The codon 486 mutation was identical to that previously found in two cell lines selected for amsacrine resistance. These results demonstrate that mutations of topoisomerase II alpha occur in patients with small cell lung cancer. The significance of these mutations in the development of resistance to etoposide needs further investigation.
  • K NAKAGAWA; NK CONRAD; JP WILLIAMS; BE JOHNSON; MJ KELLEY
    ONCOGENE 11 9 1843 - 1851 1995年11月 [査読有り]
     
    The CDKN2 tumor suppressor gene encodes an inhibitor of type D cyclin dependent kinases. CDKN2 is homozygously deleted in approximately 25% of nonsmall cell lung cancer (NSCLC) cell lines and these deletions are associated with advanced stage cancer. Conflicting reports of the frequency of CDKN2 alterations in NSCLC tumors prompted us to examine the relationship of these alterations and those of the related gene, MTS2, with patient stage and site of cancer. One hundred twenty-five NSCLC samples (71 cell lines and 54 tumors) were examined by PCR-SSCP. Twenty of 71 (28%) tumor cell lines had homozygous deletions, and six (8%) had point mutations compared to 4 (7%) with point mutations among 54 tumor samples. All mutations mere observed in tumors or cell lines from patients with stage III or IV disease. Two patients with no mutations in their primary tumor had a CDKN2 point mutation detected in a metastatic tumor. Point mutations were G:C to T:A transversion on the coding strand in five of 10 and resulted in nonsense mutations in seven of 10. Undetectable CDKN2 mRNA, in the absence of detectable genetic alteration, was noted in a similar fraction of cell lines derived from patients with stage I or IZ disease [two of seven (29%)] and stage Hi or TV disease [15 of 49 (31%)]. Homozygous deletion of MTS2 was found in 17 of 20 cell lines with CDKN2 deletions; no point mutations of MTS2 were identified by SSCP in the 125 samples. Thus, CDKN2 is a frequent target of genetic alterations at 9p21 in NSCLC. Both deletions and point mutations of CDKN2 are closely associated with tumor dissemination.
  • MJ KELLEY; K NAKAGAWA; SM STEINBERG; JL MULSHINE; A KAMB; BE JOHNSON
    JOURNAL OF THE NATIONAL CANCER INSTITUTE 87 10 756 - 761 1995年05月 [査読有り]
     
    Background: The CDKN2 gene encodes the human cyclin-dependent kinase 4 inhibitor. This inhibitor protein is believed to be a tumor suppressor that plays an essential role in cell cycle regulation. One half of all cancer cell lines and one fourth of lung cancer cell lines examined to date contain homozygous deletions (i.e., both alleles lost) of CDKN2. However, the relative frequency of homozygous CDKN2 deletions in non-small-cell lung cancers (NSCLC) and in small-cell lung cancers (SCLC) has not been determined. Inactivation or loss of another tumor suppressor encoded by the retinoblastoma gene (the Rb protein) is more common in SCLC than in NSCLC. Purpose: We measured the frequency of homozygous CDKN2 deletions in 77 NSCLC and in 93 SCLC tumor cell lines. In addition, possible associations were explored between CDKN2 gene loss, the presence or absence of Rb protein, and the clinical status of lung cancer patients. Methods: DNA was isolated from each tumor cell line and from the primary tumor and normal tissue of one NSCLC patient. Sequences corresponding to exons 1 and 2 of the CDKN2 gene were amplified by use of the polymerase chain reaction, and the resulting amplification products were analyzed by agarose gel electrophoresis and DNA blotting. Genomic DNA blotting was also used to evaluate CDKN2 gene deletions. The frequency of homozygous CDKN2 loss and the presence or absence of functional Rb protein (reported previously) in the cell lines were compared. Results: Homozygous deletion of CDKN2 was detected in 18 (23%) of 77 cell lines established from patients with NSCLC, compared with one (1%) of 93 cell lines established from patients with SCLC (P<.001). No CDKN2 gene loss was observed in the normal tissue of an NSCLC patient whose tumor cell line showed homozygous deletion of the gene; however, the primary tumor from this patient had evidence of CDKN2 loss. Homozygous CDKN2 deletion was detected in 13 (28%) of 46 tumor cell lines from patients with stage III or stage IV NSCLC, compared with zero of 10 tumor cell lines from patients with stage I or stage II NSCLC. Coincident loss of CDKN2 genes and functional Rb protein was rarely observed (in two of 135 cell lines). Conclusion: The frequency of homozygous CDKN2 gene deletion in NSCLC cell lines is greater than that observed for any other known, or candidate, tumor suppressor gene. Implication: Further study of the role of CDKN2 gene alteration in the pathogenesis of NSCLC is needed.
  • S KUDOH; M FUKUOKA; N MASUDA; A YOSHIKAWA; Y KUSUNOKI; K MATSUI; S NEGORO; N TAKIFUJI; K NAKAGAWA; T HIRASHIMA; T YANA; M TAKADA
    JAPANESE JOURNAL OF CANCER RESEARCH 86 4 406 - 413 1995年04月 [査読有り]
     
    Two phase I trials of irinotecan (CPT-11) in combination with cisplatin were conducted. In both cases, the dose-limiting toxicities were leukopenia and/or diarrhea. During these trials the pharmacokinetics of CPT-11 and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were investigated to evaluate the relationship between pharmacokinetic parameters and diarrhea, since this is an unpredictable and severe toxicity of combination chemotherapy using CPT-11 and cisplatin. Twenty-three previously untreated patients with advanced lung cancer were evaluated in the pharmacokinetic study. Ten patients received CPT-11 at 80 or 90 mg/m(2) plus cisplatin at 60 mg/m(2). The other 13 patients received CPT-11 at 80 or 90 mg/m(2) plus cisplatin at 80 mg/m(2) with the granulocyte colony-stimulating factor support (2 mu g/kg X 16 days). CPT-11 was given as a 90-min intravenous infusion on days 1, 8, and 15. Cisplatin was given on day 1. The pharmacokinetics of CPT-11 and SN-38 were analyzed on day 8 during the first course of treatment. The maximum tolerated dose of CPT-11 Has 90 mg/m(2) in both phase I trials. The severity of diarrhea was best correlated with the peak plasma concentration of SN-38 among the pharmacokinetic parameters tested. In addition, patients with a plasma SN-38 level > 12.4 ng/ml at 1.75 h after the start of CPT-11 infusion had a higher incidence of Eastern Cooperative Oncology Group grade 3-4 diarrhea than those with a lower SN-38 level (P=0.0003). stepwise logistic regression analysis identified the SN-38 concentration as a significant contributor to the development of diarrhea (P=0.0021). We conclude that there is a clear relationship between the SN-38 concentration and diarrhea during chemotherapy with CPT-11 plus cisplatin.
  • 久保昭仁; 中川和彦; 宮本裕介
    日本癌治療学会誌 30 4 664 - 679 1995年04月 [査読有り]
  • M TAKADA; N MASUDA; E MATSUURA; Y KUSUNOKI; K MATUI; K NAKAGAWA; T YANA; TUYUGUCHI, I; OOHATA, I; M FUKUOKA
    BRITISH JOURNAL OF CANCER 71 1 160 - 165 1995年01月 [査読有り]
     
    Soluble cytokeratin fragment 19 levels were measured with an enzyme immunoassay method developed by Boehringer Mannheim (Enzymun-Test CYFRA 21-1) in the serum of 185 patients with lung cancer [149 with non-small-cell lung cancer (NSCLC) and 36 with small-cell lung cancer (SCLC)] and 97 patients with benign lung diseases in order to determine its clinical usefulness in the diagnosis of lung cancer and follow-up of treatment. We used the cut-off value of 3.5 ng ml(-1), established by the Japan CYFRA research group. This cut-off value is based on calculations using the receiver operating characteristic approach instead of using the 95% specificity approach recommended by other authors. The resulting sensitivity and specificity for the group of all lung cancer patients were 65.4% and 84.5% respectively. The sensitivity was highest (76.1%) for squamous cell carcinoma and lowest (44.4%) for SCLC. For NSCLC patients, when CYFRA 21-1 levels were analysed by node (N) factor, patients who presented with mediastinal lymph node metastasis (N2 or N3) demonstrated higher serum CYFRA 21-1 levels (5.6; interquartile range 3.2-11.5 ngml(-1)) than patients without mediastinal node metastasis (N0 or N1, 3.9; interquartile range 2.2-10.0 ng ml(-1); Mann-Whitney U-test, P = 0.0373). We compared the discriminatory power of CYFRA 21-1 with that of other tumour markers including carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and neuron-specific enolase (NSE). The area under the curve (AUG) of each ROC curve was calculated using the CLABROC program for statistical analysis. CYFRA 21-1 appeared to have the most discriminatory power of the markers tested in the diagnosis of lung cancer. In serial measurements of 14 patients receiving chemotherapy or radiotherapy, a high degree of correlation was noted between serum levels of CYFRA 21-1 and extent of clinical response (Wilcoxon, P = 0.0093).
  • N MASUDA; M FUKUOKA; S KUDOH; K MATSUI; Y KUSUNOKI; M TAKADA; K NAKAGAWA; T HIRASHIMA; H TSUKADA; T YANA; A YOSHIKAWA; A KUBO; E MATSUURA; T NITTA; N TAKIFUJI; K TERAKAWA; S NEGORO
    JOURNAL OF CLINICAL ONCOLOGY 12 9 1833 - 1841 1994年09月 [査読有り]
     
    Purpose: We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with etoposide, a topoisomerase II inhibitor, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) support because of the overlapping neutrophil toxicity of both drugs. The aim was to determine the maximum-tolerated dose of CPT-11 combined with a fixed dose of etoposide in patients with advanced lung cancer, as well as the dose-limiting toxicities of this combination. Patients and Methods: Twenty-five patients with stage III or IV lung cancer, 15 (60%) with prior chemotherapy, were treated at 4-week intervals using CPT-11 (90-minute intravenous infusion on days 1, 8, and 15) plus etoposide (80 mg/m(2) intravenously on days 1 to 3). In addition, rhG-CSF (2 mu g/kg/d) was given from day 4 to day 21, except on the days of CPT-11 administration. The starting dose of CPT-11 was 60 mg/m(2), and it was escalated in 10-mg/m(2) increments until the maximum-tolerated dose was reached. Results: The maximum-tolerated dose of CPT-11 was 90 mg/m(2), since two of the three patients developed grade 3 to 4 leukopenia or grade 3 to 4 diarrhea during the first cycle of treatment at this dose level. Diarrhea and leukopenia were the dose-limiting toxicities, while thrombocytopenia was only a moderate problem. Elimination of CPT-11 was biphasic, with a mean +/- SD beta half-life of 18.17 +/- 9.09 hours. The mean terminal half-life of 7-ethyl-10-hydroxycamptothecin (SN-38; the major metabolite of CPT-11) was 43.40 +/- 37.84 hours. There was one complete response (5%) and eight partial responses (38%) among 21 assessable patients, for an overall response rare of 43%. The response rates for small-cell lung cancer (SCLC) and non-smell-cell lung cancer (NSCLC) were 58% (seven of 12 patients) and 22% (two of nine patients), respectively. Conclusion: The combination of CPT-11 and etoposide with rhG-CSF support seems to be active against lung cancer, especially SCLC, with acceptable toxicity. The recommended dose for phase H studies in previously untreated patients is 80 mg/m(2) of CPT-11 (days 1, 8, and 15) and 80 mg/m(2) of etoposide (days 1 to 3) plus 2 mu g/kg of rhG-CSF (days 4 to 21, except when CPT-11 is given). In addition, 70 mg/m(2) of CPT-11 appears to be the appropriate dose for previously treated patients receiving this regimen. (C) 1994 by American Society of Clinical Oncology.
  • 阿部 庄作; 中川 和彦; 飯鉢 尚子; 瀬戸 貴司; 杉山 温人; 武田 晃司; 田中 泰之; 福岡 和也; Gabazza E.; 梅木 茂宣; 肥山 淳一郎; 宮武 和代; 日高 紀子; 千場 博
    日本胸部疾患学会雑誌 32 421 - 424 The Japanese Respiratory Society 1994年
  • 大森 久紀; 楠 洋子; 平島 智徳; 玉野井 優水; 梁 尚志; 松井 薫; 益田 典幸; 中川 和彦; 高田 実; 菊井 正紀; 森野 英男; 瀧藤 伸英; 今村 純孝; 福岡 正博
    気管支学 16 1 11 - 20 特定非営利活動法人 日本呼吸器内視鏡学会 1994年 
    中枢気道発生のいわゆるLow-grade malignant tumorとされている自験例(中心型カルチノイド10例, 腺様嚢胞癌5例, 唾液腺型混合腫瘍 : 以下混合腫瘍3例)について, 気管支鏡所見および臨床経過を検討した。カルチノイドは, 気管支腔内への増殖が主体で, 全例ポリープ型を示し, 周囲粘膜への明らかな浸潤所見は見られず, 蒼白ないし赤色調で, 壊死を伴うものがみられた。腺様嚢胞癌は, より中枢側の気管・気管支より発生し, 形態はポリープ型から粘膜下浸潤型まで様々であったが, いずれも強い長軸進展の傾向がみられ, 腫瘍周囲の気管支壁粘膜下への浸潤を認めたものが多かった。全例蒼白調で粘膜に被われた凹凸不整を呈し, 樹枝状の血管怒張の著明なものが多かった。混合腫瘍では形態的な特徴は指摘できないが, 周囲粘膜下への浸潤は認めなかった。中心型カルチノイドには進行癌は見られなかったが, 腺様嚢胞癌の3例, 混合腫瘍の1例にIII, IV期の進行癌が見られ, それらは全例癌死であった。手術を施行した症例の生存期間は6∿153ヵ月(平均60ヵ月)で全例生存中であるが, 全体の5年生存率は, カルチノイド, 腺様嚢胞癌, 混合腫瘍でそれぞれ67%, 30%, 67%と低値であった。low-grade malignant tumorといえども進行例や非手術例の予後は悪く, 早期発見が重要であると考えられた。
  • 梁 尚志; 楠 洋子; 高田 実; 松井 薫; 益田 典幸; 中川 和彦; 瀧藤 伸英; 福岡 正博
    気管支学 16 3 233 - 233 特定非営利活動法人 日本呼吸器内視鏡学会 1994年
  • 梁 尚志; 楠 洋子; 高田 実; 松井 薫; 益田 典幸; 中川 和彦; 牛島 淳; 瀧藤 伸英; 福岡 正博
    気管支学 16 8 803 - 805 特定非営利活動法人 日本呼吸器内視鏡学会 1994年
  • Japan PDT Lung Cancer Study Group; 飯田 邦夫; 楠 洋子; 梁 尚志; 高田 実; 平島 智徳; 久保 昭仁; 吉川 厚子; 田村 研治; 吉田 勉; 中川 和彦; 益田 典幸; 松井 薫; 河原 正明; 古瀬 清行; 福岡 正博
    気管支学 16 4 411 - 412 特定非営利活動法人 日本呼吸器内視鏡学会 1994年
  • 田村 研治; 吉田 勉; 飯田 邦夫; 吉川 厚子; 久保 昭仁; 平島 智徳; 梁 尚志; 中川 和彦; 益田 典幸; 松井 薫; 楠 洋子; 高田 実; 山口 竜司; 多田 卓仁; 安光 勉; 古武 弥宏; 福岡 正博
    気管支学 16 3 261 - 261 特定非営利活動法人 日本呼吸器内視鏡学会 1994年
  • N MASUDA; M FUKUOKA; S KUDOH; Y KUSUNOKI; K MATSUI; K NAKAGAWA; T HIRASHIMA; M TAMANOI; T NITTA; T YANA; S NEGORO; N TAKIFUJI; M TAKADA
    JOURNAL OF CLINICAL ONCOLOGY 12 1 90 - 96 1994年01月 [査読有り]
  • N MASUDA; M FUKUOKA; S KUDOH; Y KUSUNOKI; K MATSUI; N TAKIFUJI; K NAKAGAWA; M TAMANOI; T NITTA; T HIRASHIMA; S NEGORO; M TAKADA
    BRITISH JOURNAL OF CANCER 68 4 777 - 782 1993年10月 [査読有り]
     
    We have conducted a Phase I trial to determine the maximum tolerated dose of CPT-11 together with a fixed dose of cisplatin in patients with advanced lung cancer, and the dose-limiting toxicities of this combination. Fourteen previously untreated patients with stage IIIB or IV disease were treated with CPT-11 (90-min intravenous infusion on days 1, 8, and 15) plus cisplatin (60 mg m-2, intravenously on day 1). The starting dose of CPT-11 was 60 mg m-2, and diarrhea was the dose-limiting toxicity at the 90 mg m-2 dose level. All three patients (all four cycles) given 90 mg m-2 of CPT-11 experienced grade 3 diarrhea. Hematologic toxicity was relatively mild. Elimination of CPT-11 was biphasic with a mean (+/- s.d.) beta half-life of 11.36 +/- 7.26 h. The mean terminal half-life of the major metabolite (7-ethyl-10-hydroxycamptothecin; SN-38) was 22.13 +/- 13.28 (s.d.) h, and modest escalation of the CPT-11 dose from 80 mg m-2 to 90 mg m-2 resulted in a statistically significant apparent increase in the plasma concentrations of SN-38. There were one complete response (7%) and five partial responses (36%) among the 14 patients for an overall response rate of 43%. The recommended dose for Phase 11 studies is 80 mg m-2 of CPT-11 and 60 mg m-2 of cisplatin.
  • M NISHIOKA; M FUKUOKA; K NAKAGAWA; K MATSUI; T NAKAJIMA
    CHEST 104 1 160 - 163 1993年07月 [査読有り]
     
    Spontaneous pneumothorax following chest irradiation is thought to occur in patients with radiation fibrosis several months or more after the completion of therapy. In the four patients presented herein, spontaneous pneumothorax was seen during or immediately after therapeutic radiation of lung cancer. All patients had bronchoscopic findings of bronchial obstruction by the tumor before treatment and radiographic improvement of atelectasis was observed during therapy. The interval between the improvement of atelectasis and the development of pneumothorax varied by less than three weeks. These common findings suggest that rupture of alveoli or emphysematous bullae and subsequent pneumothorax might be due to overinflation of the affected lung caused by partial bronchial obstruction. We should be aware of the occurrence of spontaneous pneumothorax following partial resolution of total bronchial obstruction.
  • S KUDOH; M TAKADA; N MASUDA; K NAKAGAWA; K ITOH; Y KUSUNOKI; S NEGORO; K MATSUI; N TAKIFUJI; H MORINO; M FUKUOKA
    JAPANESE JOURNAL OF CANCER RESEARCH 84 2 203 - 207 1993年02月 [査読有り]
     
    The objective of this study was to evaluate the antitumor efficacy of combined use of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and cisplatin (CDDP). The antitumor activities of CPT-11, CDDP and their combination against 3 human lung tumor xenografts were estimated using congenitally athymic BALB/c (nu/nu) mice. The doses were 47 mg/kg for CPT-11 and 6 mg/kg for CDDP on days 1, 5 and 9. In combination therapy, half of the single dosage of each agent was used. The doses were administered intraperitoneally. The antitumor activity and toxicity were evaluated in terms of the tumor volume and body weight change of mice, respectively. The combination therapy resulted in a statistically significant tumor regression compared to the use of only CPT-11 or CDDP in two tumor xenografts out of three. The toxicity of the combination therapy was no higher than that of CPT-11 or CDDP alone. These results suggest that the antitumor activity of the combination of CPT-11 and CDDP is superior to that of CPT-11 or CDDP alone.
  • 松浦 悦子; 塚田 裕子; 吉川 厚子; 新田 隆; 平島 智徳; 玉野井 優水; 梁 尚志; 松井 薫; 益田 典幸; 中川 和彦; 楠 洋子; 高田 実; 福岡 正博; 古武 彌宏; 安光 勉; 森野 英男
    気管支学 15 4 364 - 364 特定非営利活動法人 日本呼吸器内視鏡学会 1993年
  • 梁 尚志; 玉野井 優水; 塚田 裕子; 松浦 悦子; 吉川 厚子; 新田 隆; 平島 智徳; 高田 実; 益田 典幸; 中川 和彦; 松井 薫; 楠 洋子; 福岡 正博; 瀧藤 伸英
    気管支学 15 4 360 - 360 特定非営利活動法人 日本呼吸器内視鏡学会 1993年
  • 塚田 裕子; 吉川 厚子; 松浦 悦子; 新田 隆; 平島 智徳; 玉野井 優水; 梁 尚志; 松井 薫; 中川 和彦; 益田 典幸; 楠 洋子; 高田 実; 福岡 正博; 森野 英男; 根来 俊一; 瀧藤 伸英
    気管支学 15 4 361 - 361 特定非営利活動法人 日本呼吸器内視鏡学会 1993年
  • 吉川 厚子; 中川 和彦; 平島 智徳; 新田 隆; 塚田 裕子; 松浦 悦子; 梁 尚志; 玉野井 優水; 楠 洋子; 松井 薫; 益田 典幸; 高田 実; 福岡 正博
    気管支学 15 4 354 - 354 特定非営利活動法人 日本呼吸器内視鏡学会 1993年
  • 楠 洋子; 梁 尚志; 玉野井 優水; 高田 実; 松井 薫; 中川 和彦; 益田 典幸; 平島 智徳; 吉川 厚子; 田村 研治; 牛島 淳; 東条 尚; 河原 正明; 古瀬 清行; 福岡 正博
    気管支学 15 8 738 - 744 特定非営利活動法人 日本呼吸器内視鏡学会 1993年 
    Nd-YAGレーザー(以下YAGレーザーと略す)は速攻性の組織昇華作用をもち, 気道の閉塞や狭窄に対して, 現時点では極めて有効な手段とされている。一方, 強力ゆえに重篤な合併症を起こす可能性がある。今回私達は自験例51例を基に, YAGレーザー治療の適応と限界について検討を行った。治療の目的別頻度は, 1)救命, 31%, 2)気道の開大, 51%, 3)根治的治療, 12%, 4)その他, 6%であった。効果判定はその初期の目的が達せられた程度により行った。目的1)においては著効が44%, 有効が31%, 2)ではそれぞれ69%, 15%, 3)においては68%, 16%となり, 全体では著効61%, 有効22%で計83%に有効性が認められた。また呼吸機能の%FVCと%FEV_<1.0>の治療前後におけるt検定はそれぞれp=0.0096, p=0.009の有意差で改善が認められた。一方合併症は, 非接触型YAGレーザー施行例38例中, 心肺機能上重篤な合併症や大量出血, 気道穿孔など14例(37%), のべ33例にみられ, うち治療関連死3例を認めた。接触型YAGレーザーの合併症の頻度は13例中5例(23%)であったが, 救急処置を要したものはなかった。基礎疾患に心血管障害を有する場合での心肺機能障害の発生頻度は, 無い症例に比べp<0.01の有意差で高率であった。有効な治療を施行するためと合併症の予防のために三次元CT等が有用であった。YAGレーザーの根治的治療への応用として, PDTとの併用で, 閉塞性病変を有する肺門部早期癌をCRに導入させる方法が期待される。
  • 梁 尚志; 玉野井 優水; 塚田 裕子; 松浦 悦子; 吉川 厚子; 新田 隆; 平島 智徳; 高田 実; 益田 典幸; 中川 和彦; 松井 薫; 楠 洋子; 福岡 正博; 瀧藤 伸英
    気管支学 15 5 496 - 497 特定非営利活動法人 日本呼吸器内視鏡学会 1993年
  • H. Tanaka; N. Takifuji; N. Masuda; M. Takada; S. Kudo; K. Nakagawa; K. Matsui; K. Ito; Y. Kusunoki; M. Fukuoka
    Japanese Journal of Thoracic Diseases 31 4 492 - 497 1993年 [査読有り]
     
    Small cell lung (SCLC) is rapidly progressive, but is sensitive to chemotherapy. The incidence of brain metastasis is high in patients with this disease. The management of brain metastases is an important problem in SCLC patients, because brain tumors have been regarded as being inaccessible to anti-cancer agents due to the blood-brain-barrier (BBB). Of 15 SCLC patients with brain metastasis at diagnosis who were treated with chemotherapy, 3 achieved a complete response (CR) and 4 had a partial response (PR), giving a response rate of 47%. Of 17 SCLC patients with brain metastasis at relapse, 1 achieved a CR and 6 had a PR by chemotherapy, with a response rate of 30%. The response rate of brain metastasis in SCLC patients treated with chemotherapy was similar to those of primary lesions and other metastatic lesions. SCCL patients with brain metastasis at diagnosis had the same response rate and median survival time as other ED-SCLC patient. The BBB may not be an impending factor in systemic chemotherapy of brain metastasis in SCLC. Systemic chemotherapy may be the treatment of choice for SCLC patients with brain metastasis.
  • N MASUDA; M FUKUOKA; M TAKADA; Y KUSUNOKI; S NEGORO; K MATSUI; S KUDOH; N TAKIFUJI; K NAKAGAWA; S KISHIMOTO
    JOURNAL OF CLINICAL ONCOLOGY 10 11 1775 - 1780 1992年11月 [査読有り]
  • N MASUDA; M FUKUOKA; Y KUSUNOKI; K MATSUI; N TAKIFUJI; S KUDOH; S NEGORO; M NISHIOKA; K NAKAGAWA; M TAKADA
    JOURNAL OF CLINICAL ONCOLOGY 10 8 1225 - 1229 1992年08月 [査読有り]
  • 大森久紀; 松井薫; 中川和彦
    日本胸部疾患学会雑誌 30 6 1085 - 1090 1992年06月 [査読有り]
  • S KUBO; M MATSUTANI; K NAKAGAWA; T OGURA; H ESUMI; N SAIJO
    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 118 4 244 - 248 1992年04月 [査読有り]
     
    Poly(ADP-ribose) polymerase has been generally assumed to be involved in DNA repair. The level of the enzyme in various lung cancer cell lines was examined to determine if it is involved in drug resistance. Among nine cell lines of lung cancer tested, small-cell lung cancer lines, which showed higher sensitivity to cisplatin and etoposide, were unexpectedly found to contain significantly higher poly(ADP-ribose) polymerase activity than five non-small-cell lung cancer cell lines. This activity inversely correlated with IC50 values of lung cancer cell lines to etoposide, an inhibitor of topoisomerase II. The polymerase activity was also examined in several cisplatin-resistant variants of the cell lines. However, no difference was observed between parental and cisplatin-resistant cells. There was no significant relation between poly(ADP-ribose) polymerase activity and IC50 values for cisplatin and carboplatin. Although this enzyme was considered to play some role in the resistance to specific drugs, it might not be a critical factor in cisplatin-induced cytotoxicity.
  • K MINATO; T MANABE; N OKUYAMA; Y SASAKI; K NAKAGAWA; N SAIJO
    ONCOLOGY 49 2 143 - 146 1992年03月 [査読有り]
     
    The purpose of the present study was to determine with two-dimensional electrophoresis whether two sublines (high and low metastatic potential to lymph nodes) of rat fibrosarcoma induced by methylcholanthrene have differences in cellular proteins. The high metastatic potential subline had a specific protein in the protein map of the whole cell lysate. Its isoelectric point was 6.4 and the molecular weight was 18,000. This specific protein appeared in maps of the precipitate of 1,000 g centrifugation and in the supernatant from treatment with 0.5% Nonidet P-40 (NP-40). But this specific protein was not stained by five lectins, concanavalin A, wheat germ agglutinin, Ulex europeus agglutinin-1, Dolichis biflorus agglutinin, and Ricinus communis agglutinin. Apparently, this high metastatic potential subline has a specific protein in the plasma membrane which has no glycochain.
  • 中川 和彦; 西尾 和人; 大森 亨; 瀧川 奈義夫; 松村 正; 太田 斉
    日本胸部疾患学会雑誌 30 400 - 401 The Japanese Respiratory Society 1992年
  • 新田 隆; 楠 洋子; 瀧藤 伸英; 高田 実; 松井 薫; 工藤 新三; 益田 典幸; 伊藤 和信; 中川 和彦; 玉野井 優水; 児嶋 真治; 平島 智徳; 福岡 正博; 安光 勉; 古武 弥宏; 森野 英男
    気管支学 14 8 765 - 769 特定非営利活動法人 日本呼吸器内視鏡学会 1992年 
    1976年10月から1992年3月までに当院で経験した原発性多発肺癌は48例で全原発性肺癌4007例の1.2%であった。その内肺門部早期肺癌を含む多発肺癌は14例で同時期の全肺門部早期肺癌62例の23%を占めていた。同時性多発肺癌は29例(60%), 異時性多発肺癌は19例(40%)であった。組織型の組合わせは1例を除く全例にSqを含んでおり, 特にSq-Sqの組み合せが44%と最多を占めた。それぞれの病巣の病期は0とI期が全体の78%を占めた。異時性の第2癌発生までの期間の中央値は47ヵ月であった。治療は初回に手術を施行した場合と非観血的治療, 特にPhotodynamic therapy (PDT)を施行した場合とでは生存に有意差がなかった。予後因子としては, 第2癌発生時期と, 組織型の組み合せ(Sq-Sq)が有意であった。
  • H. Oomori; K. Matsui; K. Nakagawa; N. Masuda; K. Itoh; S. Kudoh; S. Takifuji; Y. Kusunoki; M. Takada; S. Negoro; M. Fukuoka
    Japanese Journal of Thoracic Diseases 30 6 1085 - 1090 1992年 [査読有り]
  • S NIIMI; K NAKAGAWA; Y SUGIMOTO; K NISHIO; Y FUJIWARA; S YOKOYAMA; Y TERASHIMA; N SAIJO
    CANCER RESEARCH 52 2 328 - 333 1992年01月 [査読有り]
     
    We established a cisplatin-resistant human ovarian cancer cell line (HAC2/0.1) from the parent cell line (HAC2/P) by continuous exposure of HAC2/P to 0.1-mu-g of cisplatin/ml. Drug sensitivity determined by colony assay revealed that HAC2/0.1 was 2.4 times as resistant to cisplatin as the parental cell line. HAC2/0.1 was 12.1 and 2.0 times as resistant to (4s)4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)-carbonyloxy]dione hydrochloride trithydrate (CPT-11) and 7-ethyl-10-hydroxy-CPT (SN-38; an active metabolite of CPT-11), respectively, than HAC2/P. We studied the mechanism of cross-resistance to CPT-11 in HAC2/0.1. The glutathione (GSH) content was higher in HAC2/0.1 than in HAC2/P. The activity of DNA topoisomerase I and the accumulation of CPT-11 and SN-38 were also the same. On the other hand, the conversion of CPT-11 to SN-38 in HAC2/0.1 was about 3-fold less than in HAC2/P. Treatment of the parent and resistant cell lines with buthionine sulfoxamine (BSO) decreased the GSH content of both cell lines and decreased the 50% inhibitory concentrations of all the tested drugs for HAC2/0.1. The accumulation of CPT-11 in HAC2/0.1 but not in HAC2/P was increased by BSO treatment. On the other hand, in HAC2/P the 50% inhibitory concentrations of SN-38 and CPT-11 were not influenced by BSO treatment. The 50% inhibitory concentration of CPT-11 for HAC2/0.1 was not reduced by BSO treatment to the level for HAC2/P, even though the GSH content had been reduced more than in HAC2/P. These results show that there is no clear relationship between GSH and resistance to CPT-11. The decreased conversion of CPT-11 to SN-38 is considered to be the main cause of resistance to CPT-11 in this cell line.
  • N MASUDA; M FUKUOKA; K MATSUI; Y KUSUNOKI; S KUDOH; S NEGORO; N TAKIFUJI; M FUJISUE; H MORINO; K NAKAGAWA; M NISHIOKA; M TAKADA
    JOURNAL OF THE NATIONAL CANCER INSTITUTE 83 23 1743 - 1748 1991年12月 [査読有り]
     
    We studied tumor samples from 39 patients, who entered our study from January 1989 to May 1990, to assess whether the ability to establish a continually growing tumor cell line from fresh tumor specimens can be associated with decreased survival times in patients with small-cell lung cancer. The tumor samples were used to establish cell lines in culture using a serum-free medium supplemented with hydrocortisone, insulin, transferrin, estrogen, and selenium (HITES). Thirty-three of these specimens were obtained by fiberoptic bronchoscopy from primary sites during routine diagnostic procedures. A total of 11 (28%) cell lines were established: seven (21%) from 33 primary tumors and four (80%) from rive peripheral lymph nodes. Survival times of the 11 patients whose tumor cell specimens continually grew in culture at any time during their clinical course were significantly shorter than those of the 28 patients whose tumor cell specimens did not grow in vitro (median survival time of 26 weeks versus 73 weeks; P = .0068). Cox's proportional hazards model, including sex, age, Eastern Cooperative Oncology Group performance status, stage, source of specimen, treatment, and in vitro tumor cell growth in the overall patient group, showed that cell line establishment (P = .0017) and no therapy (P = .0015) were the most important factors indicating poor survival time. For the subgroup of 23 primary tumor patients, the important factors (in decreasing order) that indicated decreased survival times were the establishment of a cell line (P = .0112) and treatment with cyclophosphamide-doxorubicin-vincristine alternating with cisplatin-etoposide, versus cisplatin-vincristine-doxorubicin-etoposide therapy (P = .0463). Our study demonstrates that in vitro tumor cell growth is an adverse predominant prognostic factor in patients with small-cell lung cancer.
  • T NAKAMURA; Y IWAMURA; M KANEKO; K NAKAGAWA; K KAWAI; K MITAMURA; T FUTAGAWA; H HAYASHI
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 21 5 325 - 329 1991年10月 [査読有り]
     
    The retinoblastoma gene (Rb) is one of the tumor suppressor genes to have already been cloned. Deletions and inactivations of the gene have been widely observed in various types of hyman tumor. To study the generality of Rb alteration in human tumors, 121 cases of tumor DNAs were examined for abnormalities in the gene structure by blot hybridization. Deletions of both alleles were detected in hepatocellular carcinoma, insulinoma and neuroblastoma. Rearrangements and allelic deletions of the Rb gene were, moreover, observed in some brain tumors and hepatocellular carcinomas, respectively. All were surgically resected tumors. The observations suggest the inactivation of Rb through structural alterations sometimes to correlated with the development or progression of these types of human tumor.
  • N MASUDA; M FUKUOKA; M TAKADA; S NEGORO; K MATSUI; N TAKIFUJI; S KUDOH; KAZUNOBU, I; K NAKAGAWA; Y KUSUNOKI
    AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS 14 4 322 - 327 1991年08月 [査読有り]
     
    Most patients with small-cell lung cancer usually relapse within 1 to 2 years. Relapses after a 5-year disease-free interval occur extremely rarely. This report describes a patient with limited-stage small-cell lung cancer who had achieved a complete response to combination chemotherapy followed by chest irradiation but developed small-cell lung cancer 9.4 years after the beginning of therapy. Small-cell lung cancer recurred in the same side of the lung, in the mediastinal nodes, and in the liver. The pattern of development of small-cell lung cancer suggests that the patient had a relapse rather than a metachronous lung cancer. To our knowledge, this is the second-latest relapse of small-cell lung cancer in the literature.
  • S NIIMI; K NAKAGAWA; J YOKOTA; Y TSUNOKAWA; K NISHIO; Y TERASHIMA; M SHIBUYA; M TERADA; N SAIJO
    BRITISH JOURNAL OF CANCER 63 2 237 - 241 1991年02月 [査読有り]
     
    NIH3T3 cells transfected with c-H-ras and/or c-myc genes were examined for differences in drug sensitivity. The five transfectants used were N8, NIH3T3-nm-1, pT22-3-nm-2, pP1-4 and pT22-3. They were transfected with pKOneo alone, pKOneo and c-myc, pKOneo and c-myc plus activated c-H-ras, normal c-H-ras and activated c-H-ras genes, respectively. The IC50s of cisplatin, 4-hydroperoxycyclophosphamide, adriamycin, melphalan, and CPT-11 were significantly higher for NIH3T3-nm-1 and pT22-3-nm-2 than for the parental NIH3T3 and N8 cells. Transfection with normal and activated C-H-ras oncogenes only led to increases in the IC50s of alkylating agents. There was no significant difference between the IC50s of N8 and those of NIH3T3 parental cells to any of these anticancer agents. These results strongly suggest that the expression of the c-myc gene plays a role in the acquisition of drug resistance. The c-myc gene may therefore provide us with an important clue in determining the mechanism of drug resistance.
  • 楠 洋子; 瀧藤 伸英; 高田 実; 松井 薫; 益田 典幸; 工藤 新三; 伊藤 和信; 中川 和彦; 今村 純孝; 福岡 正博
    気管支学 13 92 - 97 特定非営利活動法人 日本呼吸器内視鏡学会 1991年 
    肺野末梢陰影を呈し, 内視鏡的に不可視であった561例を対象として, 経気管支的腫瘍生検法(transbronchial tumor biopsy : TBTB)の手順や成績を示し, 気管支鏡検査の妥当性を検討した。TBTBとして病巣擦過法(TBC), 組織生検法(TBB), 組織生検後細胞診(TBB-C)の各方法を使用し84%に確診ができた。各々の陽性率は, 原発性肺癌324例中270例(83%), 転移性肺癌15例中7例(47%), 良性疾患209例中110例(53%)であった。原発性肺癌については, 腫瘍径2cm以上, 以下で陽性率に差はなかったが, 特に2cm以下では上の3方法を同時に施行した35例については, いずれかの1方法のみで陽性であったのが21%もあり, 確診には出来うる限り全ての方法を併用する必要性を確認した。また我々が常用している器具についても述べた。
  • 今村 純孝; 福岡 正博; 楠 洋子; 瀧藤 伸英; 根来 俊一; 高田 実; 松井 薫; 益田 典幸; 工藤 新三; 伊藤 和信; 中川 和彦; 山本 信之; 加藤 治文; 早田 義博
    気管支学 13 137 - 137 特定非営利活動法人 日本呼吸器内視鏡学会 1991年
  • 山本 信之; 福岡 正博; 楠 洋子; 根来 俊一; 高田 実; 松井 薫; 益田 典幸; 瀧藤 伸英; 工藤 新三; 伊藤 和信; 中川 和彦; 今村 純孝; 古武 彌宏; 安光 勉; 森野 英男; 南條 輝志男
    気管支学 13 114 - 114 特定非営利活動法人 日本呼吸器内視鏡学会 1991年
  • Imamura Sumitaka; Fukuoka Masahiro; Masuda Noriyuki; Kusunoki Yoko; Matsui Kaoru; Takifuji Nobuhide; Kudoh Sinzoh; Fujisue Mamoru; Negoro Shunichi; Nakagawa Kazuhiko; Takada Minoru
    気管支学 13 123 - 123 特定非営利活動法人 日本呼吸器内視鏡学会 1991年
  • F OSHITA; T TAMURA; A KOJIMA; K YAMADA; M FUKUDA; K NAKAGAWA; Y OHE; Y SASAKI; K EGUCHI; T SHINKAI; R ONO; K HARA; N SAIJO
    EUROPEAN JOURNAL OF CANCER 27 4 427 - 430 1991年 [査読有り]
     
    123 patients with small cell lung cancer (SCLC) presented to the National Cancer Center Hospital (Tokyo) between 1978 and 1986. 22 of 71 patients with limited stage disease (LD) and none of 52 patients with extensive disease (ED) survived for 3 years. 15 of the 22 three year survivors had significant late complications. All patients received chemotherapy and either thoracic irradiation, resection or both. No prophylactic cranial irradiation was given. 4 patients developed cardiac failure, 2 with a dilated cardiomyopathy, despite the fact that no patient received over 420 mg/m2 of doxorubicin. 12 patients of the 17 who received thoracic irradiation developed radiation pneumonitis and 3 required hospitalisation for severe haemoptysis (2) or cavity formation (1). 1 patient who received nimustine developed a fatal myelodysplastic syndrome and 2 additional patients developed second primary tumours in the oesophagus (1) and stomach (1). Mild peripheral neuropathy (WHO grade 1) was persistent in 3 patients and asymptomatic azotemia (WHO grade 1) in 7. Despite advances in the treatment of SCLC there are very few asymptomatic long-term survivors.
  • Fumihiro Oshita; Tomohide Tamura; Akira Kojima; Kohzo Yamada; Masaaki Fukuda; Kazuhiko Nakagawa; Yuichiro Ohe; Yasutsuna Sasaki; Kenji Eguchi; Tetsu Shinkai; Ryosuke Ono; Kohei Hara; Nagahiro Saijo
    European Journal of Cancer and Clinical Oncology 27 4 427 - 430 1991年 [査読有り]
     
    123 patients with small cell lung cancer (SCLC) presented to the National Cancer Center Hospital (Tokyo) between 1978 and 1986. 22 of 71 patients with limited stage disease (LD) and none of 52 patients with extensive disease (ED) survived for 3 years. 15 of the 22 three year survivors had significant late complications. All patients received chemotherapy and either thoracic irradiation, resection or both. No prophylactic cranial irradiation was given. 4 patients developed cardiac failure, 2 with a dilated cardiomyopathy, despite the fact that no patient received over 420 mg/m2 of doxorubicin. 12 patients of the 17 who received thoracic irradiation developed radiation pneumonitis and 3 required hospitalisation for severe haemoptysis (2) or cavity formation (1). 1 patient who received nimustine developed a fatal myelodysplastic syndrome and 2 additional patients developed second primary tumours in the oesophagus (1) and stomach (1). Mild peripheral neuropathy (WHO grade 1) was persistent in 3 patients and asymptomatic azotemia (WHO grade 1) in 7. Despite advances in the treatment of SCLC there are very few asymptomatic long-term survivors. © 1991.
  • 悪性腫瘍 肺癌 Medicament News
    中川和彦; 福岡正博
    1318 36 - 37 1991年01月 [査読有り]
  • 剤耐性遺伝子MDR研究について
    森蔭俊彦; 中川和彦; 西條長宏
    実験医学 8 17 2227 - 2230 1990年12月 [査読有り]
  • Y OHE; T SHINKAI; K EGUCHI; Y SASAKI; T TAMURA; K NAKAGAWA; A KOJIMA; K YAMADA; F OSHITA; T MIYA; N SAIJO
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 20 4 364 - 368 1990年12月 [査読有り]
     
    Fourteen patients with inoperable or recurrent non-small cell lung cancer (NSCLC) were treated with 5-fluorouracil (5-FU) plus high-dose leucovorin (LV). The administration schedule was 2 h infusion of LV at a dose of 500 mg/m2 and 30 min infusion of 5-FU at a dose of 600 mg/m2 given 1 h after the start of the LV infusion. This regimen was followed weekly, six times. No objective (complete or partial) response was seen in any of the patients. Ten patients showed no change and there were four with progressive disease. One patient experienced grade 3 leukopenia after two courses of treatment. Another experienced grade 2 leukopenia. One patient experienced grade 2 vomiting and six, skin pigmentation. Other myelosuppressive effects and non-hematologic toxicities, including diarrhea and mucositis, were mild. It was concluded that the schedule of 5-FU with high-dose LV therapy employed could not be expected to produce a response rate greater-than-or-equal-to 20% against NSCLC. 5-FU plus high-dose LV therapy was, therefore, considered to be ineffective against NSCLC with the schedule of administration followed.
  • K EGUCHI; T SHINKAI; Y SASAKI; T TAMURA; Y OHE; K NAKAGAWA; M FUKUDA; K YAMADA; A KOJIMA; F OSHITA; M MORITA; K SUEMASU; N SAIJO
    JAPANESE JOURNAL OF CANCER RESEARCH 81 11 1168 - 1174 1990年11月 [査読有り]
  • K NISHIO; Y SUGIMOTO; K NAKAGAWA; S NIIMI; Y FUJIWARA; M BUNGO; K KASAHARA; H FUJIKI; N SAIJO
    BRITISH JOURNAL OF CANCER 62 3 415 - 419 1990年09月 [査読有り]
  • F KANZAWA; Y SUGIMOTO; K MINATO; K KASAHARA; M BUNGO; K NAKAGAWA; Y FUJIWARA; LF LIU; N SAIJO
    CANCER RESEARCH 50 18 5919 - 5924 1990年09月 [査読有り]
  • 薬剤耐性因子としてのGlutathione S-Transferase π
    中川和彦; 西條長宏
    組織培養 16 7 235 - 239 1990年06月 [査読有り]
  • M SAKURAI; M IIGO; Y SASAKI; K NAKAGAWA; Y FUJIWARA; T TAMURA; Y OHE; M BUNGO; N SAIJO
    ONCOLOGY 47 3 251 - 256 1990年05月 [査読有り]
  • M BUNGO; Y FUJIWARA; K KASAHARA; K NAKAGAWA; Y OHE; Y SASAKI; S IRINO; N SAIJO
    CANCER RESEARCH 50 9 2549 - 2553 1990年05月 [査読有り]
  • シスプラチン耐性肺癌細胞株におけるシスプラチン耐性機構
    豊後雅巳; 中川和彦; 西條長宏
    癌と化学療法 17 3-2 515 - 516 1990年03月 [査読有り]
  • K NAKAGAWA; N SAIJO; S TSUCHIDA; M SAKAI; Y TSUNOKAWA; J YOKOTA; M MURAMATSU; K SATO; M TERADA; KD TEW
    JOURNAL OF BIOLOGICAL CHEMISTRY 265 8 4296 - 4301 1990年03月 [査読有り]
  • Y SASAKI; M FUKUDA; M MORITA; T SHINKAI; K EGUCHI; T TAMURA; Y OHE; K YAMADA; A KOJIMA; K NAKAGAWA; T OHMORI; N SAIJO
    JAPANESE JOURNAL OF CANCER RESEARCH 81 2 196 - 200 1990年02月 [査読有り]
  • 山田 耕三; 江口 研二; 児島 章; 尾下 文浩; 中川 和彦; 大江 裕一郎; 田村 友秀; 佐々木 康綱; 新海 哲; 池田 茂人; 西條 長宏
    気管支学 12 118 - 118 特定非営利活動法人 日本呼吸器内視鏡学会 1990年
  • 佐々木 康綱; 新海 哲; 江口 研二; 田村 友秀; 大江 裕一郎; 中川 和彦; 藤原 康弘; 豊後 雅巳; 笠原 寿郎; 大森 亨; 西條 長宏
    臨床薬理 21 1 75 - 76 The Japanese Society of Clinical Pharmacology and Therapeutics 1990年
  • K MINATO; F KANZAWA; K NISHIO; K NAKAGAWA; Y FUJIWARA; N SAIJO
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 26 5 313 - 317 1990年 [査読有り]
  • Cancer Chemother. Pharmacol.
    Minato,K; Kanzawa,F; Nishio,K; Nakagawa,K; Fujiwara,Y; Saijo,N. Characterization of; a; is; cell; lung cancer cell line
    Cancer Chemother. Pharmacol., 26 313 - 317 1990年 [査読有り]
  • T SHINKAI; N SAIJO; K EGUCHI; Y SASAKI; T TAMURA; Y FUJIWARA; A KOJIMA; K NAKAGAWA; K MINATO; T NAKAJIMA; K SUEMASU
    JAPANESE JOURNAL OF CANCER RESEARCH 80 8 783 - 786 1989年08月 [査読有り]
  • Y OHE; K NAKAGAWA; Y FUJIWARA; Y SASAKI; K MINATO; M BUNGO; S NIIMI; N HORICHI; M FUKUDA; N SAIJO
    CANCER RESEARCH 49 15 4098 - 4102 1989年08月 [査読有り]
  • T SHINKAI; M SAKURAI; K EGUCHI; Y SASAKI; T TAMURA; Y FUJIWARA; M FUKUDA; K YAMADA; A KOJIMA; S SASAKI; Y SOEJIMA; Y AKIYAMA; K MINATO; K NAKAGAWA; R ONO; N SAIJO
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 19 2 135 - 141 1989年06月 [査読有り]
  • T SHINKAI; N SAIJO; K EGUCHI; Y SASAKI; T TAMURA; Y FUJIWARA; M MAE; M FUKUDA; Y OHE; S SASAKI; K NAKAGAWA; K MINATO; WS HONG; K SUEMASU
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 19 1 40 - 44 1989年03月 [査読有り]
  • T TAMURA; T SHINKAI; K EGUCHI; Y SASAKI; Y FUJIWARA; M FUKUDA; Y OHE; K NAKAGAWA; K MINATO; N SAIJO
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 19 1 51 - 55 1989年03月 [査読有り]
  • A OHTSU; Y SASAKI; T TAMURA; Y FUJIWARA; Y OHE; K MINATO; K NAKAGAWA; M BUNGO; N SAIJO
    JAPANESE JOURNAL OF CANCER RESEARCH 80 3 265 - 270 1989年03月 [査読有り]
  • K. Nakagawa; H. Fujiwara
    Optics Communications 70 2 73 - 76 1989年02月 [査読有り]
     
    Both real-time and double-exposure phase-conjugate interferometries are demonstrated with an eosin-doped gelatin film. The eosin-doped film can generate phase conjugate waves simultaneously or separately by degenerate four-wave mixing (DFWM) and holographic processes. The holographic process differs from the DFWM process in the respect that the eosin-doped film can record spatial information on light like a hologram. The DFWM component has a response time in the order of milliseconds, which is by a factor of four faster than that of the holographic component. The difference in their response times in the two processes is important in real-time and double-exposure phase-conjugate interferometries. © 1989.
  • T TAMURA; Y SASAKI; T SHINKAI; K EGUCHI; M SAKURAI; Y FUJIWARA; K NAKAGAWA; K MINATO; M BUNGO; N SAIJO
    CANCER RESEARCH 49 3 730 - 735 1989年02月 [査読有り]
  • Yuichiro Ohe; Tetsu Shinkai; Kenji Eguchi; Yasutsuna Sasaki; Tomohide Tamura; Akira Kojima; Kouzou Yamada; Kazuhiko Nakagawa; Masaaki Fukuda; Yasuhiro Fujiwara; Nagahiro Saijo
    CHEMOTHERAPY 37 10 1277 - 1281 1989年 [査読有り]
     
    Eight patients with NSCLC and three with metastatic colon cancer of the lung were entered into a phase I study of 5-FU plus high-dose LV. The starting dose of 5-FU was 600 mg/m2/week, which was increased to 800mg/m2/week. The administration schedule was a 2-hour infusion of LV (500 mg/m2) and an IV bolus of 5-FU (600 or 800mg/m2), given 1 hour after the beginning of LV infusion. This regimen was repeated 5-6 times weekly. Five patients received 600 mg/m2 of 5-FU with no doselimiting toxicity. Six patients subsequently received 800 mg/m2 of 5-FU. One patient with NSCLC who was resistant to CDDP achieved a PR at 800 mg/m2 of 5-FU plus high-dose LV. At 800 mg/m2 of 5-FU, severe diarrhea (2/6), myelosuppression (2/6), mucositis (2/6), and dermatitis (1/6) were observed. This dose of 5-FU plus high-dose LV was considered intolerable. Based on this study the recommended dose of 5-FU with high-dose LV for a phase II study was 600 mg/m2/week. © 1989, Japanese Society of Chemotherapy. All rights reserved.
  • N SAIJO; K NAKAGAWA; M BUNGO; Y SASAKI; Y FUJIWARA; WS HONG
    ANTICANCER DRUGS 191 315 - 328 1989年 [査読有り]
  • Application of miniaturized improved nucleic acid precursor incorporation assay to in vitro evaluation of new drugs.
    Nakano,H; Saijo,N; Nakagawa,K; Sasaki,Y; Fujiwara,Y; MInato,K; Bungo,M; Kasahara,K; Hong,W.-S
    Cancer J. 2 267 - 270 1989年 [査読有り]
  • Y SASAKI; T TAMURA; K EGUCHI; T SHINKAI; Y FUJIWARA; M FUKUDA; Y OHE; M BUNGO; N HORICHI; S NIIMI; K MINATO; K NAKAGAWA; N SAIJO
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 23 4 243 - 246 1989年 [査読有り]
  • 『〔癌治療学(上)〕化学療法 化学療法剤とその薬理学 薬剤耐性機構
    中川和彦
    日本臨床 46 増刊 164 - 169 1988年10月 [査読有り]
  • A OZAKI; H NAKANO; K MINATO; K NAKAGAWA; Y SASAKI; N SAIJO
    EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY 24 6 1055 - 1060 1988年06月 [査読有り]
  • F KANZAWA; Y MATSUSHIMA; H NAKANO; K NAKAGAWA; H TAKAHASHI; Y SASAKI; N SAIJO
    ANTICANCER RESEARCH 8 3 323 - 327 1988年05月 [査読有り]
  • M SAKURAI; M IIGO; T TAMURA; A OTSU; Y SASAKI; H NAKANO; K NAKAGAWA; K MINATO; Y OHE; N SAIJO
    CANCER IMMUNOLOGY IMMUNOTHERAPY 26 2 109 - 113 1988年04月 [査読有り]
  • J ISHIHARA; N SAIJO; F KANZAWA; Y MATSUSHIMA; Y SASAKI; H TAKAHASHI; H NAKANO; K NAKAGAWA; WS HONG; A HOSHI; T TAKAHASHI
    EUROPEAN JOURNAL OF CANCER & CLINICAL ONCOLOGY 24 3 497 - 499 1988年03月 [査読有り]
  • T TAMURA; N SAIJO; T SHINKAI; K EGUCHI; Y SASAKI; M SAKURAI; Y FUJIWARA; H NAKANO; K NAKAGAWA; K MINATO; WS HONG
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 18 1 27 - 32 1988年03月 [査読有り]
  • WS HONG; N SAIJO; Y SASAKI; K MINATO; H NAKANO; K NAKAGAWA; Y FUJIWARA; K NOMURA; PR TWENTYMAN
    INTERNATIONAL JOURNAL OF CANCER 41 3 462 - 467 1988年03月 [査読有り]
  • K NAKAGAWA; J YOKOTA; M WADA; Y SASAKI; Y FUJIWARA; M SAKAI; M MURAMATSU; T TERASAKI; Y TSUNOKAWA; M TERADA; N SAIJO
    JAPANESE JOURNAL OF CANCER RESEARCH 79 3 301 - 304 1988年03月 [査読有り]
  • T SHINKAI; N SAIJO; K EGUCHI; Y SASAKI; T TAMURA; M SAKURAI; J SUGA; H NAKANO; K NAKAGAWA; WS HONG; T NAKAJIMA
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 21 3 203 - 207 1988年 [査読有り]
  • T SANO; N SAIJO; Y SASAKI; T SHINKAI; K EGUCHI; T TAMURA; M SAKURAI; H TAKAHASHI; H NAKANO; K NAKAGAWA; WS HONG
    JAPANESE JOURNAL OF CANCER RESEARCH 79 1 131 - 143 1988年01月 [査読有り]
  • N HORIUCHI; K NAKAGAWA; Y SASAKI; K MINATO; Y FUJIWARA; K NEZU; Y OHE; N SAIJO
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 22 3 246 - 250 1988年 [査読有り]
  • N. Saijo; T. Shinkai; K. Eguchi; Y. Sasaki; T. Tamura; Y. Fujiwara; K. Nakagawa; M. Fukuda; K. Minao; Y. Ohe
    Japanese Journal of Cancer and Chemotherapy 15 4 977 - 983 1988年 [査読有り]
  • 〔肺癌 最新の診療〕抗癌剤耐性肺癌細胞の分子生物学的研究の現状
    中川和彦; 藤原康弘; 佐々木康綱
    臨床医 14 1 24 - 27 1988年01月 [査読有り]
  • WS HONG; N SAIJO; Y SASAKI; T SHINKAI; K EGUCHI; M SAKURAI; H TAKAHASHI; H NAKANO; K NAKAGAWA; PR TWENTYMAN
    JAPANESE JOURNAL OF CANCER RESEARCH 78 11 1274 - 1280 1987年11月 [査読有り]
  • J TAGUCHI; N SAIJO; K MIURA; T SHINKAI; K EGUCHI; Y SASAKI; T TAMURA; M SAKURAI; K MINATO; Y FUJIWARA; H NAKANO; K NAKAGAWA; WS HONG
    JAPANESE JOURNAL OF CANCER RESEARCH 78 9 977 - 982 1987年09月 [査読有り]
  • C CHIANG; F KANZAWA; Y MATSUSHIMA; H NAKANO; K NAKAGAWA; H TAKAHASHI; M TERADA; S MORINAGA; R TSUCHIYA; Y SASAKI; N SAIJO
    JOURNAL OF PHARMACOBIO-DYNAMICS 10 9 431 - 435 1987年09月 [査読有り]
  • F KANZAWA; Y MATSUSHIMA; CD CHIANG; H NAKANO; K NAKAGAWA; H TAKAHASHI; Y SASAKI; N SAIJO
    JOURNAL OF PHARMACOBIO-DYNAMICS 10 9 449 - 451 1987年09月 [査読有り]
  • J ISHIHARA; N SAIJO; Y SASAKI; H NAKANO; A OZAKI; H TAKAHASHI; M SAKURAI; K NAKAGAWA; M IIGO; F KANZAWA; A HOSHI; WS HONG; JETT, JR; T TAKAHASHI
    CANCER IMMUNOLOGY IMMUNOTHERAPY 24 3 185 - 189 1987年06月 [査読有り]
  • T AKIBA; N SAIJO; K MIYAMOTO; J TAGUCHI; H TAITO; M SAKURAI; T TAMURA; Y SASAKI; K EGUCHI; T SHINKAI; Y UEI; H TAKAHASHI; H NAKANO; K NAKAGAWA; WS HONG
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 17 2 173 - 178 1987年06月 [査読有り]
  • T AKIBA; N SAIJO; K MIYAMOTO; M SAKURAI; T TAMURA; Y SASAKI; K EGUCHI; T SHINKAI; Y UEI; Y FUJIWARA; H NAKANO; K NAKAGAWA; WS HONG
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 17 2 165 - 172 1987年06月 [査読有り]
  • WS HONG; JETT, JR; Y SASAKI; H TAKAHASHI; H NAKANO; K NAKAGAWA; A HOSHI; N SAIJO
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 17 1 49 - 55 1987年03月 [査読有り]
  • K. Nakagawa; H. Fujiwara
    Proceedings of SPIE - The International Society for Optical Engineering 813 527 - 528 1987年01月 [査読有り]
     
    Recently there has been some interest in the phase conjugation by the degenerate four-wave mixing in organic materials1). Xanthene dyes such as eosin, erythrosin and fluorescein, having a strong absorption at the wavelengths of an Ar-ion laser and a relatively long lifetime of their triplet states, can generate cw phase conjugate (PC) wave at the intensity of less than 0.5 w/cm2. On the other hand, these dye-doped films have been used as holographic recording materials for self-development because of photochemically induced changes in absorption and/or refractive index under the action of light2), 3) We revealed that the xanthene dyes fixed in gelatin can generate simultaneously the PC waves by not only the DFWM process with a fast response time (5msec) but also the holographic process with a slow response time (40 sec) and then can store the light information as a hologram4)'5). © 1987 SPIE.
  • H. Nakamura; T. Hashimoto; T. Taguchi; H. Oi; K. Nakagawa; K. Inoue; K. Seki; S. Mizumoto; H. Akashi; I. Tsukaguchi
    Japanese Journal of Cancer and Chemotherapy 14 5 1656 - 1663 1987年 [査読有り]
  • M SAKURAI; T SHINKAI; K EGUCHI; Y SASAKI; T TAMURA; K MIURA; Y FUJIWARA; A OTSU; N HORIUCHI; H NAKANO; K NAKAGAWA; WS HONG; N SAIJO
    JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY 113 6 563 - 566 1987年 [査読有り]
  • H TAKAHASHI; Y SASAKI; N SAIJO; M SAKURAI; H NAKANO; K NAKAGAWA; A HOSHI; JETT, JR; WS HONG
    CANCER CHEMOTHERAPY AND PHARMACOLOGY 19 3 197 - 200 1987年 [査読有り]
  • Y SASAKI; F KANZAWA; H TAKAHASHI; Y MATSUSHIMA; H NAKANO; K NAKAGAWA; WS HONG; K MINATO; Y FUJIWARA; N SAIJO
    INVESTIGATIONAL NEW DRUGS 5 4 353 - 359 1987年 [査読有り]
  • Chemotherapy for small cell lung cancer
    Saijo,N; Shinkai,T; Eguchi,K; Sasaki,Y; Tamura,T; Sakurai,M; Takahashi,H; Nakano,H; Nakagawa,K; Hong,W.S; Fukuoka,M; Furuse,K; Nishiwaki,Y; Ikegami,H; Suemasu,K
    Excerpta Medica 2 162 - 172 1987年 [査読有り]
  • F KANZAWA; Y MATSUSHIMA; CD CHIANG; H NAKANO; K NAKAGAWA; H TAKAHASHI; S MORINAGA; R TSUCHIYA; Y SASAKI; K EGUCHI; N SAIJO
    INVESTIGATIONAL NEW DRUGS 5 4 339 - 343 1987年 [査読有り]
  • JETT, JR; N SAIJO; WS HONG; Y SASAKI; H TAKAHASHI; H NAKANO; K NAKAGAWA; M SAKURAI; K SUEMASU; M TESADA
    INVESTIGATIONAL NEW DRUGS 5 2 155 - 159 1987年 [査読有り]
  • 中川和彦; 西條長宏
    医学のあゆみ 141 9 533 - 537 1987年 [査読有り]
  • T SHINKAI; N SAIJO; K EGUCHI; Y SASAKI; T TAMURA; K TOMINAGA; M SAKURAI; T SANO; H TAITO; H TAKAHASHI; H NAKANO; K NAKAGAWA; K SUEMASU
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 16 3 279 - 287 1986年09月 [査読有り]
  • H TAKAHASHI; N SAIJO; T SHINKAI; K EGUCHI; Y SASAKI; T TAMURA; T SANO; H NAKANO; K NAKAGAWA; M SAKURAI; WS HONG; A HOSHI; Y HAYATA
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 16 3 253 - 260 1986年09月 [査読有り]
  • J SUGA; N SAIJO; T SHINKAI; K EGUCHI; Y SASAKI; T TAMURA; M SAKURAI; T SANO; R ONO; H TAKAHASHI; H NAKANO; K NAKAGAWA; A HOSHI; JETT, JR
    JAPANESE JOURNAL OF CLINICAL ONCOLOGY 16 3 309 - 315 1986年09月 [査読有り]
  • H. Fujiwara; K. Nakagawa
    Optics Communications 55 6 386 - 390 1985年10月 [査読有り]
     
    Phase conjugation is performed in a fluorescein film by a cw Ar ion laser of the wavelength 0.488 μm in a degenerate four-wave mixing (DFWM) configuration. It becomes apparent that the phase conjugate wave is generated simultaneously by not only DFWM but also a holographic process and that the DFWM and holographic components of the phase conjugate wave have different time constants. © 1985.
  • K. Aozasa; M. Tsujimoto; A. Inoue; K. Nakagawa; J. Hanai; A. Kurata; J. Nosaka
    Oncology 42 2 97 - 103 1985年 [査読有り]
     
    Clincopathologic findings in 102 patients with primary gastrointenstinal lymphomas were reviewed. Abdominal pain was the common presenting symptom. The primary sites of the tumors were: 67 in the stomach, 24 in the small intestine, 7 in the ileocecal region, 3 in the large intestine, and 1 in the esophagus. The disease more frequently affected males than females and showed peak incidence in the 5th decade of life. Gastric lymphomas usually presented with a single lesion, but multiple lesions were frequent in the small intestine. The body and/or antrum of the stomach were the commonest sites of the lymphomas. Gastric lymphomas were diagnosed at an earlier stage than intestinal lymphomas. There was 1 case with Hodgkin's disease. The remaining 101 patients with non-Hodgkin's lymphomas were classified according to the Rappaport and the Kiel classifications. The proportion of nodular lymphomas in the present series was 7%. The frequencies of diffuse histiocytic type and germinal center cell tumors were 62 and 74%, respectively. Cox's multivariate analysis for prognostic factors revealed that the stage of the tumor, sex, and age were prognostically significant.
  • 肺癌細胞株におけるultraviolet C照射時のsurvivin発現調節機構とその生物学的役割
    池田昌人; 岡本勇; 田村研治; 佐藤太郎; 寺嶋応顕; 明石雄策; 米阪仁雄; 野上壽二; 中川和彦; 福岡正博
    近畿大学医学雑誌 30 2 19 - 25 [査読有り]

書籍

  • 入門腫瘍内科学
    西條 長宏; 中川 和彦; 西尾 和人; 荒尾 徳三; 石岡 千加史; 田村 和夫; 南 博信; 古瀬 純司; 赤座 英之; 中西 洋一; 木浦 勝行 (担当:共著範囲:)篠原出版新社 2009年

講演・口頭発表等

  • WJOGの現状と今後の展望
    中川和彦; 武田晃司; 室 圭; 高野利実; 山本信之
    第94回日本胃癌学会総会 2022年03月 口頭発表（招待・特別）
  • Distinctive characteristics MSI-H in chemo;immune therapy for gastric cancer
    Hisato Kawakami; Kei Muro; Kazuhiko Nakagawa
    第94回日本胃癌学会総会 2022年03月 シンポジウム・ワークショップパネル（公募）
  • FOLRα positive gastric cancer exhibits chemorisistance that is overcome by a novel ADC,MoRAb-202
    Hisato Kawakami; Hitomi Sakai; Tekashi Teramura; Yuuta Onodera; Erizabeth Somers; Keiji Furuuchi; Yoshimitsu Uenaka; Ryoji Kato; Kazuhiko Nakagawa
    第94回日本胃癌学会総会 2022年03月 シンポジウム・ワークショップパネル（公募）
  • Genomic and Transcriptomic Features of Response to Immune Checkpoint Inhibitors in Small Cell Lung Cancer
    金村宙昌; 林 秀敏; 冨田秀太; 谷崎潤子; 鈴木慎一郎; 川中雄介; 津谷あす香; 福田 泰; 金田裕靖; 工藤慶太; 高濱隆幸; 今井亮介; 原谷浩司; 千葉康敬; 大谷知之; 伊藤彰彦; 坂井和子; 西尾和人; 中川和彦
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • Primary Data;from DESTINY-Lun;A Phase;Trial of Trastuzumab Deruxtecan in HE;Mutated Metastatic NSCLC
    後藤 悌; T. Li Bob; F. Smit Egbert; 中川 和彦; 宇田川 響; Mazières Julien; Nagasaka Misako; Bazhenova Lyudmila; Saltos Andreas N; Felip Enriqueta; Pacheco Jose M; Pérol Maurice; Paz-Ares Luis; Saxena Kapil; 志賀 遼太; Cheng Yingkai; Acharyya Suddhasatta; Shahidi Javad; Planchard David; A. Jänne Pasi
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): A Phase 2 Study (DESTINY-Lung02)
    後藤 功一; F. Smit Egbert; T. Li Bob; Mazieres Julian; Planchard David; 中川 和彦; Paz-Ares Luis; Novello Silvia; Yang James Chih-Hsin; Ahn Myung-Ju; Liu Geoffrey; O’Byrne Kenneth; Aregay Mehreteab; 志賀 遼太; Saxena Kapil; Pereira Kaline; Meinhardt Gerold; A. Janne Pasi
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • 新規ADCであるMORAb-202は FOLRα-PHB2-MDM2 axisによる化学療法抵抗性を有するがんに有効である
    川上尚人; 酒井 瞳; 寺村岳士; 小野寺勇太; Elizabeth Somers; 古内恵司; 上仲俊光; 加藤了資; 中川和彦
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • First-line nivolumab + platinum chemotherapy + bevacizumab in advanced NSQ NSCLC: Subgroup analysis on OS in TASUKI-52
    乾 直輝; 菅原俊一; 樋田豊明; 吉田達哉; 田中洋史; 熊谷 融; 加藤晃史; 寺岡俊輔; 岡本 勇; 細見幸生; 福原達朗; 仲 剛; 関 順彦; 西尾誠人; 大江 裕一郎; 田村友秀; 山本信之; 赤松弘朗; 高橋 滋; 中川和彦
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • がん疼痛に対するオピオイド選択のためのバイオマーカーを用いたランダム化比較試験;Relief Study
    松岡弘道; 鶴谷純司; 千葉康敬; 藤田至彦; 酒井清裕; 吉田健史; 大武陽一; 小山敦子; 西尾和人; 中川和彦
    第19回日本臨床腫瘍学会学術集会 2022年02月 シンポジウム・ワークショップパネル（公募）
  • A rP2 study comparing Nivo with CBDCA-PEM for EGFRm NSCLC acquired TKI-resistance not due to T790M (WJOG8515L)
    中村 敦; 林 秀敏; 上村剛大; 光岡茂樹; 伊藤健太郎; 内田純二; 田村洋輔; 岩本康男; 沖 昌英; 北園 聡; 長谷川 喜一; 久保昭仁; 猶木克彦; 池田 慧; 渡邊景明; 千葉康敬; 坂井和子; 西尾和人; 山本信之; 中川和彦
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • The significance of;ultra-low EGFR;M mutations on;EGFR-TKI efficacy in;patients with;NSCLC -the WJOG13119L study-
    益田 武; 三浦 理; 高祖英典; 柳原一広; 岡本龍郎; 庄田浩康; 清水淳市; 金地伸拓; 原 聡志; 坂田晋也; 時任高章; 柏原光介; 西川和男; 渡辺 洋; 前野健; 鈴木繁紀; 早川乃介; 山本信之; 中川和彦; 服部 登
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • 口演 EGFR遺伝子変異陽性非扁平上皮非小細胞肺癌に対するオシメルチニブ+ベバシズマブ併用とオシメルチニブ単剤を比較するランダム化第2相試験; WJOG9717L
    加藤晃史; 釼持広知; 和久田 一茂; 盛 啓太; 菅原俊一; 桐田圭輔; 岡本 勇; 東 公一; 西野和美; 寺岡俊輔; 小山 良; 益田 健; 林 秀敏; 豊澤 亮; 三浦 理; 佐藤悠城; 中川和彦; 山本信之; 高橋利明
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • 特発性肺線維症合併進行非小細胞肺癌に対するニンテダニブ＋化学療法と化学療法単独を比較するランダム化第3相試験（J-SONIC）
    大坪孝平; 岸本淳司; 安藤昌彦; 釼持広知; 峯岸裕司; 堀之内秀仁; 加藤晃史; 市原英基; 近藤征史; 安宅信二; 田宮基裕; 池田 慧; 原田敏之; 竹本真之輔; 林 秀敏; 山本信之; 中川和彦; 中西洋一; 岡本 勇プレジデンシャルセッション
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（招待・特別）
  • ;Intestinal microbiota;gene expression reveal similarity;dissimilarity between irAE colitis and UC
    坂井和子; デベラスコ マルコ; 永井知行; 上嶋一臣; 筑後孝章; 倉 由吏恵; 高濱隆幸; 林 秀敏; 中川和彦; 工藤正俊; 西尾和人
    第19回日本臨床腫瘍学会学術集会 2022年02月 口頭発表（一般）
  • 大腸癌の腫瘍免疫微小環境におけるM;発現の影響
    幕谷悠介; 川上尚人; 千葉康敬; 伊藤彰彦; 吉村佳奈子; 辻川敬裕; 原谷浩司; 川村純一郎; 中川 和彦
    第19回日本臨床腫瘍学会学術集会 ポスター発表
  • 非小細胞肺癌に対する免疫チェックポイント阻害薬投与中に免疫関連有害事象である血球貪食症候群を発症した一例
    黒崎 隆; 谷﨑潤子; 萩原 智; 角谷宏明; 三谷誠一郎; 大倉將生; 広川恵寿輝; 林 秀敏; 中川和彦
    第19回日本臨床腫瘍学会学術集会 ポスター発表
  • 当院における閉経前転移再発乳癌に対するCDK4/6阻害剤の有効性の検討
    岩朝 勤; 中川和彦; 竹久志穂; 藤原きみこ; 菰池佳史; 広川恵須輝; 渡邊諭美
    第19回日本臨床腫瘍学会学術集会 ポスター発表
  • Immune-based Tumor Characteristics of Non-Small-Cell Lung Cancer
    磯本晃佑; 原谷浩司; 辻川敬裕; 幕谷悠介; 中川和彦
    第19回日本臨床腫瘍学会学術集会 ポスター発表
  • 増悪病変に対する局所治療を併用することで免疫チェックポイント阻害薬の長期奏効が得られているMSI-H固形癌の1例
    佐藤千尋; 中川和彦
    第19回日本臨床腫瘍学会学術集会 ポスター発表
  • 非小細胞肺癌に対する免疫治療中に免疫関連有害事象である血球貪食症候群を発症した1例
    黒崎 隆; 谷﨑潤子; 三谷誠一郎; 大倉將生; 広川恵寿輝; 林 秀敏; 中川和彦
    第234回日本内科学会近畿地方会 2021年12月
  • 中咽頭癌への化学療法後gastoroparesisを発症した1例
    中山智裕; 渡邊諭美; 黒崎 隆; 原谷浩司; 田中 薫; 中川和彦
    第234回日本内科学会近畿地方会 2021年12月
  • 初診時悪性黒腫と診断された淡明細胞肉腫の1例
    梨木真美子; 谷﨑潤子; 三谷誠一郎; 大倉將生; 広川恵寿輝; 林 秀敏; 中川和彦
    第234回日本内科学会近畿地方会 2021年12月
  • irAE脳髄膜炎;腎炎に対してステロイドパルス治療が著効した1例
    大倉將生; 谷﨑潤子; 三谷誠一郎; 広川恵寿輝; 林 秀敏; 中川和彦
    第234回日本内科学会近畿地方会 2021年12月
  • 労作性狭心症と肺癌の合併で心配停止状態になるも積極的により救命できた1例
    川中雄介; 田中 薫; 岩朝 勤; 髙濱隆幸; 佐藤千尋; 中川和彦; 髙瀬 徹; 杉本啓史郎; 副島奈央子
    第234回日本内科学会近畿地方会 2021年12月
  • 耐性化したEGFR遺伝子変異陽性非小細胞肺癌に対するNivolumabとCBDCA+PEMの第2相比較臨床試験（WJOG8515L）
    福田 泰; 林 秀敏; 菅原俊一; 佐藤悠城; 三浦 理; 大田恵一; 小澤雄一; 原 聡志; 谷﨑潤子; 東 公一; 大森翔太; 立原素子; 西野和美; 別所昭宏; 原谷浩司; 坂井和子; 西尾和人; 山本信之; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • 日本肺癌学会による既存肺がん臨床試験データの統合とデータベース化，及びその共有と再利用体制の構築
    小澤雄一; 伊藤健太郎; 釼持広知; 宿谷威仁; 林 秀敏; 藤本大智; 大江裕一郎; 岡本浩明; 木浦勝行; 菅原俊一; 中川和彦; 仁保誠治; 吉野一郎; 弦間昭彦; 山本信之
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • オンコマイン検査成功率改善に向けた検査内製化と検査工程の見直し
    白石 直樹; 田中 薫; 高濱隆幸; 鈴木慎一郎; 金村宙昌; 磯本晃佑; 林 秀敏; 米阪仁雄; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • MET-amplifiedによるKRASG12C阻害薬の獲得耐性とメカニズム
    鈴木 慎一郎; 米阪仁雄; 寺村岳士; 竹原俊幸; 加藤了資; 酒井瞳; 原谷浩司; 谷﨑潤子; 川上尚人; 林 秀敏; 坂井和子; 西尾和人; 中川 和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • 肺癌学会としてのオンコマインデータ収集事業について
    宿谷威仁; 藤本大智; 林 秀敏; 伊藤健太郎; 小澤雄一; 釼持広知; 中川和彦; 光冨徹哉; 弦間昭彦; 山本信之
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • ICIが有効であった進行・再発非小細胞肺がんに対するニボルマブの第II相試験（WJOG9616L）
    高森信吉; 赤松弘朗; 寺岡俊輔; 林 秀敏; 三浦 理; 秦 明登; 戸井之裕; 白石祥理; 豆鞘伸昭; 佐藤悠城; 古屋直樹; 洪 泰浩; 山本信之; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • EGFR-TKI augments HER;expression;enhances the efficacy of HE;targeting patritumab deruxtecan
    米阪仁雄; 谷﨑潤子; 前西 修; 川上尚人; 田中 薫; 林 秀敏; 坂井和子; 後藤大輝; 小林真季; 吉本龍人; 大塚絵里; 沖田弘明; 舟橋 賢記; 橋本悠里; 廣谷賢志; 明松隆志; 西尾和人; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • PD-L1高発現非扁平上皮非小細胞肺癌に対するアテゾリズマブ;ベバシズマブ併用臨床第II相試験
    村上晴泰; 瀬戸貴司; 野崎 要; 下川元継; 豊澤 亮; 菅原俊一; 林 秀敏; 加藤晃史; 仁保誠治; 坂 英雄; 沖 昌英; 吉岡弘鎮; 岡本 勇; 駄賀晴子; 東 公一; 田中洋史; 西野和美; 東内理恵; 山本信之; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • EGFR変異陽性術後NSCLCに対するシスプラチン＋ビノレルビンとゲフィチニブの第3相比較試験（WJOG6410L）
    岩本康男; 多田弘人; 光冨徹哉; 杉尾賢二; 坪井正博; 岡本 勇; 坂倉範昭; 菅原俊一; 安宅信二; 高橋利明; 林 秀敏; 岡田守人; 井野川英利; 吉岡弘鎮; 高橋和久; 東山聖彦; 吉野一郎; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • 非小細胞肺癌における腫瘍微小免疫環境の検討
    磯本晃佑; 原谷浩司; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • 遺伝子異常未検出の非小細胞肺癌を対象とするGuardant360による遺伝子解析の前向き観察研究：WJOG13620L,横浜,ハイブリット開催2021年11月26日～28日(28日)"
    上村剛大; 釼持広知; 福田悟史; 宮脇太一; 羽間大祐; 神戸寛史; 寺岡俊輔; 松尾規和; 山口哲平; 益田武; 横山俊秀; 大坪孝平; 橋本大哉; 山本信之; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 口頭発表（一般）
  • 進展型小細胞肺癌における腫瘍微小免疫環境の網羅的解析
    金村宙昌; 林 秀敏; 大谷知之; 冨田秀太; 鈴木慎一郎; 原谷浩司; 谷﨑潤子; 津谷あす香; 福田 泰; 金田裕靖; 工藤慶太; 高濱 隆幸; 今井亮介; 千葉康敬; 西尾和人; 伊藤彰彦; 中川和彦
    第62回日本肺癌学会学術集会 2021年11月 シンポジウム・ワークショップパネル（公募）
  • 再発小細胞肺がんに対するペムブロリズマブ＋アムルビシンの多施設共同第II相試験
    寺岡 俊輔; 赤松弘朗; 林 秀敏; 藤本大智; 早田敦志; 原谷浩司; 小澤雄一; 吉田健司; 岩朝 勤; 下川敏雄; 富井啓介; 中川和彦; 山本信之
    第62回日本肺癌学会学術集会 2021年11月 シンポジウム・ワークショップパネル（公募）
  • ベンダムスチン塩酸塩経口剤(SyB C-0501)の進行性固形がん患者に対する第1相臨床試験
    武田 真幸; 中川 和彦; 林 秀敏; 岩朝 勤; 川上 尚人; 渡邉 諭美; 山本 昇; 米盛 勧; 小山 隆文; 佐藤 潤; 田村 研治; 菊池 圭一; 赤池 健一郎; 竹田 志保; 清水 俊雄
    第59回日本癌治療学会学術集会
  • MET-amplifiedによるKRASG12C阻害薬の獲得耐性とそのメカニズム
    鈴木慎一郎; 米阪仁雄; 谷﨑潤子; 川上尚人; 林 秀敏; 坂井和子; 西尾和人; 中川和彦
    第80回日本癌学会学術総会 2021年10月
  • EGFR阻害剤によるHER3の発現亢進及び抗HER3パトリツマブデルクステカン抗腫瘍効果の増強
    米阪仁雄; 谷﨑潤子; 前西修; 坂井和子; 後藤大輝; 橋本悠里; 廣谷賢志; 明松隆志; 西尾和人; 中川和彦
    第80回日本癌学会学術総会 2021年10月
  • Primary results of a randomized phase II study of osimertinib plus bevacizumab versus osimertinib monotherapy for untreated patients with non-squamous non-small-cell lung cancer harboring EGFR mutations; WJOG9717L study.
    On the behalf of West Japan; Oncology Group; Hirotsugu Kenmotsu; Kazushige Wakuda; Keita Mori; Terufumi Kato; Shunichi Sugawara; Keisuke Kirita; Isamu Okamoto; Koichi Azuma; Kazumi Nishino; Shunsuke Teraoka; Ryo Koyama; Ken Masuda; Hidetoshi Hayashi; Ryo Toyozawa; Satoru Miura; Yuki Sato; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Toshiaki Takahashi
    2021 European Society of Medical Oncology
  • On behalf of the DESTINY-Lung01 investigatorsPrimary Data from DESTINY-Lung01:A Phase 2 Trial of Trastuzumab Deruxtecan (T-DXd) in Patients With HER2-Mutated (HER2m) Metastatic Non–Small Cell Lung Cancer (NSCLC)
    Bob T. Li; MD, PhD; MPHa; Egbert F. Smit; Yasushi Goto; Kazuhiko Nakagawa; Hibiki Udagawa; Julien Mazières; Misako Nagasaka; yudmila Bazhenova; Andreas N. Saltos; Enriqueta Felip; Jose M.Pacheco; Maurice Pérol; Luis Paz-Ares; Kapil Saxena; Ryota Shiga; Yingkai Cheng; Suddhasatta Acharyya; Javad Shahidi; David Planchard; Pasi A. Jänne
    2021 European Society of Medical Oncology
  • A phase II study of Nivolumab Rechallenge therapy in advanced NSCLC patients who responded to prior PD-1/L1 inhibitors (West Japan Oncology Group 9616L)
    Shunsuke Teraoka; Hiroaki Akamatsu; Shinkichi Takamori; Hidetoshi Hayashi; Satoru Miura; Akito Hata; Yukihiro Toi; Yoshimasa Shiraishi; Nobuaki Mamesaya; Yuki Sato; Naoki Furuya; Yasuhiro Koh; Takeharu Yamanaka; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    2021 European Society of Medical Oncology
  • RELAY, Ramucirumab plus Erlotinib (RAM+ERL) in Untreated Metastatic EGFR-Mutant NSCLC (EGFR+ NSCLC): Association between TP53 Status and Clinical Outcome
    Makoto Nishio; Luis Paz-Ares; Martin Reck; Kazuhiko Nagakawa; Edward B. Garon; Matteo Ceccarelli; Sameera R Wijayawardana; Talia Muram; Carla Visseren-Grul; Silvia Novello
    2021 European Society of Medical Oncology
  • Trastuzumab Deruxtecan (T-DXd) in Patients With HER2-Mutated (HER2m) Metastatic Non–Small Cell Lung Cancer (NSCLC): A Phase 2 Study (DESTINY-Lung02)
    Egbert F. Smit; Bob T. Li; Julien Mazieres; David Planchard; Kazuhiko Nakagawa; Koichi Goto; Luis Paz-Ares; Silvia Novello; James Chih-Hsin Yang; Myung-Ju Ahn; Geoffrey Liu; Kenneth O’Byrne; Mehreteab Aregay; Ryota Shiga; Kapil Saxena; Kaline Pereira; Gerold Meinhardt; Pasi A. Jänne
    2021 European Society of Medical Oncology
  • 根治切除後のStageⅡ MSI-H胃癌におけるS-1術後補助化学療法の有用性
    佐藤千尋; 川上尚人; 中川和彦; 佐藤太郎
    日本消化会病学会近畿支部第115回例会 2021年09月 シンポジウム・ワークショップパネル（公募）
  • lP50.01 RELAY, Erlotinib Plus Ramucirumab in Untreated, EGFR-Mutated,Metastatic NSCLC: Outcomes by EGFR Exon 19-del Variants.
    K. Nishino; J. Shih; C. Lovly; K. Nakagawa; M. Reck; E. Garon; M. Ceccarelli; S. Wijayawardana; C. Visseren-Grul; E. Nada
    2021 World Conference on Lung Cancer
  • 気管支鏡検査時の迅速細胞診;ROSE;の成功に関連する因子の検討
    金村宙昌; 田中 薫; 鈴木慎一郎; 黒崎 隆; 磯本晃佑; 岩朝 勤; 白石直樹; 林 秀敏; 武田真幸中川和彦
    第44回日本呼吸器内視鏡学会学術集会
  • Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive nonsmall cell lung cancer (NSCLC): First results from the J-ALTA tyrosine kinase inhibitor (TKI)-naive expansion cohort.
    Masashi Kondo; Shunichi Sugawara; Toshihide Yokoyama; Toru Kumagai; Makoto Nishio; Koichi Goto; Yuichiro Ohe; Takashi Seto; Nobuyuki Yamamoto; Kentarou Kudou; Takayuki Asato; Pingkuan Zhang; Kazuhiko Nakagawa
    2021 American Society of Clinical Oncology Annual Meeting
  • A randomized phase II/III study comparing carboplatin and irinotecan with carboplatin and etoposide for the treatment of elderly patients with extensivedisease small cell lung cancer (JCOG1201/TORG1528).
    Tsuneo Shimokawa; Yuki Misumi; Hiroaki Okamoto; Yukio Hosomi; Isamu Okamoto; Hiroshi Tanaka; Shinji Atagi; Toyoaki Hida; Koichi Goto; Hiroaki Akamatsu; Kaoru Kubota; Kazuhiko Nakagawa; Hidehito Horinouchi; Masahiko Ando; Ryunosuke Machida; Junko Eba; Tomoko Kataoka; Yuichiro Ohe
    2021 American Society of Clinical Oncology Annual Meeting
  • Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+NSCLC).
    Hiroshige Yoshioka; Toyoaki Hida; Hiroshi Nokihara; Masahiro Morise; Young Hak Kim; Koichi Azuma; Takashi Seto; Yuichi Takiguchi; Makoto Nishio; Toru Kumagai; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Miyako Satouchi; Toshiyuki Kozuki; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Takuya Yoshimoto; Tomohide Tamura
    2021 American Society of Clinical Oncology Annual Meeting
  • A randomized phase II study comparing nivolumab (NIVO) with carboplatinpemetrexed (CbPEM) for patients (pts) with EGFR mutation-positive non-small cell lung cancer (NSCLC) who acquire resistance to tyrosine kinase inhibitors (TKIs) not due to a secondary T790M mutation (WJOG8515L).
    Hidetoshi Hayashi; Shunichi Sugawara; Yasushi Fukuda; Yuki Sato; Satoru Miura; Keiichi Ota; Yuichi Ozawa; Satoshi Hara; Junko Tanizaki; Koichi Azuma; Shota Omori; Motoko Tachihara; Kazumi Nishino; Shinobu Hosokawa; Yasutaka Chiba; Koji Haratani; Kazuko Sakai; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    2021 American Society of Clinical Oncology Annual Meeting
  • Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT,WJOG6410L): A randomized phase 3 trial
    Hirohito Tada; Tetsuya Mitsudomi; Takeharu Yamanaka; Kenji Sugio; Masahiro Tsuboi; Isamu Okamoto; Yasuo Iwamoto; Noriaki Sakakura; Shunichi Sugawara; Shinji Atagi; Toshiaki Takahashi; Hidetoshi Hayashi; Morihito Okada; Hiroshige Yoshioka; Hidetoshi Inokawa; Kazuhisa Takahashi; Masahiko Higashiyama; Ichiro Yoshino; Kazuhiko Nakagawa
    2021 American Society of Clinical Oncology Annual Meeting
  • 肺癌におけるTP53変異はhigh tumor mutation burden(TMB)と関連する
    西尾和人; 坂井和子; 中川和彦; 杉尾賢二; 山本信之
    第25回日本がん分子標的治療学会学術集会 2021年05月
  • 非小細胞肺癌に対するオンコマインDxTTを用いたドライバー遺伝子検査に関する他施設共同後ろ向き研究：WJOG13019L
    中村 敦; 坂田晋也; 大坪孝平; 伊藤健太郎; 寺岡俊輔; 松本直久; 白石祥理; 原谷浩司; 田宮基裕; 池田慧; 益田 武; 時任高章; 立原素子; 髙濱隆幸; 吉田寿子; 山本信之; 中川和彦
    第61回日本呼吸器学会学術講演会 2021年04月 口頭発表（一般）
  • 進行再発肺腺癌におけるエルロチニブとゲフィチニブのランダム化第III相試験の長期生存成績
    庄田浩康; 岩本康男; 里内美弥子; 山本信之; 中川和彦; 片上信之
    第61回日本呼吸器学会学術講演会 2021年04月 口頭発表（一般）
  • Phase III trial of Site-Specific Treatment Based on Gene Expression and Mutation Profiling by NGS for Patients with Cancer of Unknown Primary (CUP)
    新井誠人; 林 秀敏; 南 博信; 滝口裕一; 渡邊諭美; 豊田昌徳; 秋吉宏平; 畝川芳彦; 上田弘樹; 岩本康男; 増田 淳; 向井博文; 久保寿夫; 富樫庸介; 坂井和子; 藤田至彦; 冨田秀太; 千葉康敬; 西尾和人; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • EGFR T790M 変異陽性肺癌患者におけるオシメルチニブ治療とctDNAモニタリング(WJOG8815L）
    加藤晃史; 坂井和子; 髙濱隆幸; 下川元継; 東 公一; 武田真幸; 岡本 勇; 駄賀晴子; 寺岡俊輔; 高橋利明; 大平達夫; 横山俊秀; 山本信之; 中川和彦; 西尾和人
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Osimertinib for RT-naïve CNS Metastasis of EGFRm NSCLC: pii OCEAN Study (LOGIK1603/WJOG 9116L), Part of T790M cohort.
    知花賢治; 山口博之; 和久田一茂; 福田 実; 剱持広知; 吉村健一; 井上孝治; 三浦 理; 中川和彦; 山本信之; 杉尾賢二
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Phase 2 trial of the alternative therapy with osimertinib and afatinib for NSCLC with EGFR mutation.
    川嶋庸介; 林 秀敏; 米阪仁雄; 白石祥理; 寺岡俊輔; 別所昭宏; 谷﨑潤子; 光岡茂樹; 沖 昌英; 小野 哲; 原 聡志; 福田悟史; 井谷英敏; 坂井和子; 千葉康敬; 西尾和人; 山本信之; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • 西尾誠人,西尾和人,Martin Reck,Edward B Garon,今村文生,川口知哉,山口博之,池田彗,平野勝也,Carla Visseren-Grul,Matteo Ceccareli, Sameera R Wijayawardana, Annamaria Zimmermann,本間剛介,松井朋子,江夏総太郎,中川和彦
    西尾誠人; 西尾和人; Martin Reck,Edward; B Garon; 今村文生; 川口知哉; 山口博之; 池田彗; 平野勝也; Carla Visseren-Grul; Matteo Ceccareli; Sameera R Wijayawardana; Annamaria Zimmermann; 本間剛介; 松井朋子; 江夏総太郎; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Gene profiling of circulating tumor DNA(ctDNA) in RAS wild-type mCRC patients who are refractory to anti-EGFR antibody.
    伊澤直樹; 西尾和人; 舛石俊樹; 高橋直樹; 庄司広和; 山本祥之; 松本俊彦; 杉山圭司; 梶原猛史; 奥田博介; 青松直撥; 川上尚人; 江崎奏斗; 成田有季哉; 原 浩樹; 砂川 優; 朴 成和; 森脇俊和; 中島貴子; 室 圭
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • A multi-institutional, signal-arm phase II study of pembrolizumab plus amrubicin in related small cell lung cancer.
    原谷浩司; 赤松弘朗; 寺岡俊輔; 林 秀敏; 早田敦志; 吉田健史; 小澤雄一; 岩朝 勤; 藤本大智; 下川敏雄; 富井啓介; 中川和彦; 山本信之
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Effect of the COVID-19 pandemic on cancer care: A questionnaire survey for Japanese oncologists. COVID-19のパンデミックががん診療に与えた影響に関する日本のがん治療医へのアンケート調査
    酒井 瞳; 岩朝 勤; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Trastuzumab deruxtecan in HER2-overexpressing metastatic non-small cell lung cancer: interim results of DESTINY-Lung01
    中川和彦; Misako Nagasaka; Enriqueta Felip; Jose M. Pacheco; Christina Baik; 後藤 悌; Andreas Saltos; Bob T. Li; 宇田川響; Shirish Gadgeel; 村上晴奏; David Planchard; Lyudmila Bazhenova; Luis Paz-Ares; Maurice Perol; Julien Mazieres; Fabrice Barlesi; 志賀遼太; Janne; Pasi; A.Egbert; F.Smit
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Efficacy of Adjuvant S-1 monotherapy in MSI-H Stage II Gastric Cancer.
    佐藤千尋; 川上尚人; 木村 豊; 田中 亮; 佐竹悠良; 藤田淳也; 川端良平; 佐藤太郎
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • ５－Year Survival Update of KEYNOTE-024 Japan Subset: Pembrolizumab for Advanced Non-Small-Cell Lung Cancer With PD-L1 TPS ≥50％
    高橋利明; 里内美弥子; 野崎要; 中川和彦; 青江啓介; 倉田宝保; 関根朗雅; 堀池 篤; 福原達朗; 菅原俊一; 梅村茂樹; 坂 英雄; 岡本 勇; 山本信之; 酒井 洋; 岸 一馬; Shi Rong Han; 野口一夫; Bin Zhao; 堀田勝幸
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Phase 2 trial of Atezolizumab with Bevacizumab for patients with PD-L1 high non-Sq NSCLC(WJOG10718L/At Be Study)
    中村 敦; 瀬戸貴司; 林 秀敏; 村上晴奏; 仁保誠治; 加藤晃史; 坂 英雄; 吉岡弘鎮; 岡本 勇; 東 公一; 駄賀晴子; 三浦 理; 西野和美; 東内理恵; 山本信之; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Safety of immune checkpoint inhibitors in paatients with advanced malignancy complicated with rhumatoid arthritis.(関節リウマチ合併進行固形がんに対する免疫チェックポイント阻害薬の安全性の検討)
    工藤慶太; 中島早希; 上島成也; 堀内哲也; 中西文彦; 宇都宮琢秀; 垣内万依; 山口真美; 大島至郎
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Rand-phase 2 study of osimertinib +/- Bev in advanced lung adenocarcinoma patients with EGFR T790M mutation (WJOG8715L)
    田中 薫; 赤松弘朗; 戸井之裕; 藤本大智; 立原泰子; 古屋直樹; 大谷咲子; 清水淳一; 片上信之; 東 公一; 三浦奈央子; 西野和美; 原 聡志; 寺岡俊輔; 森田智視; 中川和彦; 山本信之
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Clinical Applicantion of the Foundation One Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors.進行性固形癌患者の治療方針決定へのFoundation Oneの臨床応用
    武田真幸; 髙濱隆幸; 坂井和子; 清水重樹; 渡邊諭美; 川上尚人; 田中 薫; 福岡和也; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • A phase II study on the efficacy of Nivolumab in patients with cancer of unknown primary (CUP) (NivoCUP)
    野口瑛美; 谷﨑潤子; 秋吉宏平; 豊田昌徳; 上田弘樹; 滝口裕一; 尾崎由紀範; 畝川芳彦; 高橋 信; 沖川佳子; 木寺康裕; 福岡和也; 中村靖司; 千葉康敬; 坂井和子; 米盛 勧; 南 博信; 西尾和人; 中川和彦; 林 秀敏
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Brigatinib activity in aletinib-resistant ALK-positive NSCLC according to ALK plasma mutation status from J-ALTA trial.
    下川路伊亮; 片山量平; 吉田達哉; 熊谷 融; 桶田豊明; 豊澤 亮; 後藤功一; 中川和彦; 大江裕一郎; 瀬戸貴司; 山本信之; 朝戸臣敬; 平岡 圭; 张 平宽; 西尾誠人
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • ミニオーラルセッション A multicenter restrospective study of Oncomine Dx Target Test Multi-CDx system for genetic profiling of NSCLC:WJOG13019L
    伊藤健太郎; 坂田晋也; 大坪孝平; 中村 敦; 寺岡俊輔; 松本直久; 白石祥理; 原谷浩司; 田宮基裕; 池田 彗; 三浦 理; 谷﨑潤子; 大森翔太; 吉岡弘鎮; 秦 明登; 吉田寿子; 山本信之; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Mini-Oral Session4 / ミニオーラル4 『EGFR inhibtor upregulates HER3 expression and enhances the efficacy of anti-HER3 antibody drug conjugate U3-1402.』
    米阪仁雄; 谷﨑潤子; 前西 修; 川上尚人; 田中 薫; 林 秀敏; 武田真幸; 坂井和子; 小林真季; 吉本龍人; 後藤大輝; 船橋賢記; 橋本悠里; 廣谷賢志; 明松隆志; 西尾和人; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Oral Session4 TR・遺伝子プロファイリング・ゲノム医療 『Association of TMB with outcome in patients with select advanced solid tumors treated with pembrolizumab in KEYNOTE-158』
    中川和彦; Aurelin Marabelle,Marwan, Fakih; Juanita Lopez; Manisha Shah; Ronnie Shapira-Frommer; Hyun cheol Chung; Hedy Kindler; Jose A. Lopez-Martin; Wilson H.Miller Jr; Antonio Italiano; Steven Kao; Sarina Piha-Paul Jean-Pierre Delord,Robert Mcwilliams; Deepti Aurora-Garg; Menghui Chen; Fan Jin; Kevin Norwood; Yung-Jue Bang
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Presidential Session 『Two phase II trials of PD-1 inhibitors in patients with plumonary sarcomaoid carcinoma.(NCCH1603/NCH1703)』
    板橋耕太; 後藤 悌; 藤原 豊; 大熊裕介; 豊澤 亮; 倉田宝保; 横山俊秀; 軒原 浩; 横井 崇; 山口哲平; 岡本 勇; 武田真幸; 時任高章; 中村 敦; 細見幸生; 大江裕一郎
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • Presidential Session 『Phase III trial of nivolumab+platinum chemotherapy +bevacizumab in untreated advanced NSQ NSCLC:Japanese subanalysis』
    桶田豊明; 菅原俊一; 乾 直輝; 吉田達哉; 田中洋史; 熊谷 融; 加藤晃史; 寺岡俊輔; 岡本 勇; 細見幸生; 福原達朗; 仲 剛; 関 順彦; 西尾誠人; 大江裕一郎; 田村友秀; 山本信之; 赤松弘朗; 住吉直樹; 中川和彦
    第18回日本臨床腫瘍学会総会,京都 2021年02月
  • 在宅緩和移行へ上手くつなぐことが出来たAYA世代小細胞肺癌患者の一例
    岩朝 勤; 酒井清裕; 竹久志穂; 五味恵美; 遠藤美幸; 津田美沙緒; 川口明範; 辰巳愛子; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Successful treatment of a case of hormone receptor-positive metastatic extramammary Paget disease with tamoxifen.
    磯本晃佑; 原谷浩司; 渡邊諭美; 武田真幸; 岩朝 勤; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Gastroparesis as a rare but important cause of servere gastrointestinal adverse event during chemotherapy for solid cancer.
    中山智裕; 原谷浩司; 黒崎 隆; 田中 薫; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Interstitial lung disease associated with capmatinib therapy in a NSCLC patient with MET exon 14 skipping mutations
    金村宙昌; 武田真幸; 清水重喜; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Promotion of Advance care Plannning in the University Hospital. 大学病院におけるアドバンス・ケア・プランニング推進の取り組む
    吉田健史; 酒井清裕; 柏田孝美; 藤野 崇; 南 直宏; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Shortened infusion duration for ramucirumab：Safety evaluation using pooled clinical trial detasets.
    三谷誠一郎; 陳 祐晟; 井上晃一; 森 丈治; Gao Ling; Lau Yiu Keung; Wei Ran; Long Amanda; Abada Paolo B; 若林 聡
    第18回日本臨床腫瘍学会総会,京都
  • A single -institution experience of pembrolizumab for Patients with Recurrent or Metastatic Headand Neck Cancer. 再発転移頭頚部癌に対するペムブロリズマブの使用経験
    田中 薫; 佐藤千尋; 原谷浩司; 文田壮一; 吉田健史; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • The efficacy of salvage chemotherapy after immune checkpoint inhibitors in patients with head and neck canccer.
    黒崎 隆; 三谷誠一郎; 田中 薫; 鈴木慎一郎; 金村宙昌; 原谷浩司; 文田壮一; 岩朝 勤; 林 秀敏; 吉田健史; 石川一樹; 北野睦三; 大月直樹; 西村恭昌; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Efficacy of Trastuzumab deruxtecan in a HERE2 positive breast canccer patients with plumonary lymphangitis carcinomatosis.
    広川恵寿輝; 岩朝 勤; 酒井 瞳; 渡邊諭美; 菰池佳史; 中川和彦
    第18回日本臨床腫瘍学会総会,京都
  • Efficacy and safety of consolidation therapy in stage III NSCLC with preeexisting intertitial lung disease.
    川中雄介; 安田有斗; 谷﨑潤子; 岩嶋大介; 野長瀬祥兼; 上桝 潔; 平山 寛; 高橋憲一; 尾崎智博
    第18回日本臨床腫瘍学会総会,京都
  • MSI-H 進行胃癌に対する１次治療としてのニボルマブと低用量イピリムマブ併用の第Ⅱ相試験(NO LIMIT試験)
    川上尚人; 小松嘉人; 藪崎 裕; 原 浩樹; 平田賢郎; 平野秀和; 町田 望; 牧山明資; 門脇重憲; 杉本直俊; 津田政弘; 茶山一彰; 江崎奏斗; 廣中秀一; 室 圭
    第18回日本臨床腫瘍学会総会,京都
  • Serum β 2-microglobulin with pembrolizumab in non-small cell lung cancer.
    大田隆代; 工藤慶太; 内野順治; 瀬戸友利恵; 寺嶋応顕; 中野雄介; 岡部嵩記; 杦浦孝宗; 長谷川喜一; 津谷あす香; 林 秀敏; 黒崎 隆; 佃 博; 松井 薫; 益田典幸; 福岡正博
    第18回日本臨床腫瘍学会総会,京都
  • 特別講演２ がん治療の変貌 ー進行非小細胞肺癌をモデルとしてー
    中川和彦
    第42回日本病院薬剤師会近畿学術大会 2021年01月
  • Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01
    Egbert F Smit; Kazuhiko Nakagawa; Misako Nagasaka; Enriqueta Felip; Yasushi Goto; Bob T. Li; Jose M Pacheco; Haruyasu Murakami; Fabrice Barlesi; Andreas N Saltos; Maurice Perol; Hibiki Udagawa; Kapil Saxena; Ryota Shiga; Ferdinand Guevara; Suddhasatta Acharyya; Javad Shahidi; David Planchard; Pasi Antero Jänne
    WCLC 2020/2020 World Conference on Lung Cancer, WEB Meeting , Singapore 2021年01月
  • Trastuzumab Deruxtecan in HER2-Mutated Metastatic Non-Small Cell Lung Cancer (NSCLC): Interim Results of DESTINY-Lung01
    Kazuhiko Nakagawa; Misako Nagasaka; Enriqueta Felip; Yasushi Goto; Bob T. Li; Jose M Pacheco; Haruyasu Murakami; Fabrice Barlesi; Andreas N Saltos; Maurice Perol; Hibiki Udagawa; Kapil Saxena; Ryota Shiga; Ferdinand Guevara; Suddhasatta Acharyya; Javad Shahidi; David Planchard; Pasi Antero Jänne
    WCLC 2020 2020 World Conference on Lung Cancer, WEB Meeting , Singapore 2021年01月
  • Safety and Efficacy of First-Line Dacomitinib in Advanced Non-Small Cell Lung Cancer by EGFR Mutation SUBtype in ARCHER 1050
    Yi-long Wu; Ying Cheng; Xiangdong Zhou; Maria Rita Migliorino; Seiji Niho; Kazuhiko Nakagawa; Ki Hyeong Lee; Jesus Corral; Rafael Rosell; Rolf Linke; Yiyun Tang; Malaika Pastel; Keith D Wilner; Tony S. Mok
    WCLC 2020 / 2020 World Conference on Lung Cancer, WEB Meeting , Singapore
  • Activity of Brigatinib in Alectinib-Resistant ALK-Positive NSCLC According to ALK Plasma Mutation Status From J-ALTA Trial.
    Ryohei Katayama; Makoto Nishio; Tatsuya Yoshida; Toru Kumagai; Ryo Toyozawa; Tadasuke Shimokawaji; Koichi Goto; Kazuhiko Nakagawa; Takashi Seto; Nobuyuki Yamamoto; Takayuki Asato; Kei Hiraoka; Pingkuan Zhang; Yuichiro Ohe
    WCLC 2020 / 2020 World Conference on Lung Cancer, WEB Meeting , Singapore
  • Phase 2 Trial of the Alternating Therapy with Osimertinib and Afatinib for Treatment-Naive Patients with EGFR-Mutated Advanced Non–Small Cell Lung Cancer (WJOG10818L/Alt Trial)
    Hidetoshi Hayashi; Kimio Yonesaka; Shunichi Sugawara; Yuki Sato; Koichi Azuma; Shinya Sakata; Motoko Tachihara; Satoshi Ikeda; Toshihide Yokoyama; Osamu Hataji; Yukihiro Yano; Katsuya Hirano; Haruko Daga; Hideaki Okada; Kazuko Sakai; Yasutaka Chiba; Kazuto Nishio; Nobuyuki Yamamoto; Kazuhiko Nakagawa
    WCLC 2020 / 2020 World Conference on Lung Cancer, WEB Meeting , Singapore
  • Alectinib内服中に妊娠合併し治療中断したが無事出産し得た進行ALK陽性肺癌の1例
    田中 薫; 葉 宜慧; 小西悠平; 竹久志穂; 辰巳愛子; 梶原都香紗; 松村謙臣; 中川和彦
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • 日本肺癌学会による臨床試験データの統合とデータベース化 世界に対抗できるデータベース構築を目指して
    小澤雄一; 山中竹春; 伊藤健太郎; 剱持広知; 大江裕一郎; 木浦勝行; 菅原俊一; 中川和彦; 吉野一郎; 弦間昭彦; 山本信之
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • 未治療進行非小細胞肺癌における化学療法の治療効果と総腫瘍量の関連性
    鈴木慎一郎; 原谷浩司; 林 秀敏; 加藤了資; 川中雄介; 谷﨑潤子; 尾崎智博; 黒崎隆; 長谷川喜一; 岡部崇記; 明石雄策; 千葉康敬; 伊藤敦彦; 中川和彦
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • EGFR T790M変異陽性肺癌患者におけるオシメルチニブ治療とctDNAモニタリング(WJOG8815L)
    岩間映二; 坂井和子; 髙濱隆幸; 下川元継; 東 公一; 武田真幸; 加藤晃史; 駄賀晴子; 寺岡俊輔高橋利明; 大平達夫; 横山俊秀; 山本信之; 中川和彦; 西尾和人
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • 悪性腫瘍に対する気道インターベンションの検討
    高畠弘幸; 楠本英則; 塩野裕之; 髙濱隆幸; 岡部崇記; 明石雄策; 井上恵理; 福田浩平
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • EGFR－TKI治療後CNSPDもしくはプラチナ治療既治療(T790M-)EGFR+NSCLCに対するオシメルチニブの第２相試験
    武田真幸; 下川元継; 中村 敦; 野崎 要; 渡辺恭孝; 加藤晃史; 早川乃介; 田中洋史; 高橋利明; 沖 昌英; 立原素子; 藤本大智; 山口覚博; 野上尚之; 岡本 勇; 東 公一; 長谷川一男; 山本信之; 中川和彦
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • EGFR陽性の切除不能・局所進行NSCLCに対するゲフィチニブ+胸部放射線同時併用の第Ⅱ相試験(WJOG6911L)
    赤松弘朗; 村上晴奏; 原田英幸; 林 秀敏; 駄賀晴子; 長谷川喜一; 金 永学; 加藤晃史; 徳永障二; 西村恭昌; 中川和彦; 山本信之
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • EGFR－TKI憎悪後のEGFR T790M陽性進行肺腺癌に対するオシメルチニブ+/-ベバシズマブの第２相試験(WJOG8715L)
    赤松弘朗; 戸井之裕; 林 秀敏; 藤本大智; 立原素子; 古屋直樹; 大谷咲子; 清水淳市; 片上信之; 東 公一; 三浦奈保子; 西野和美; 原 聡志; 寺岡俊輔; 森田智視; 中川和彦; 山本信之
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • 脳転移(放射線未治療)のあるNSCLCに対するOsimertinibの第Ⅱ相試験：OCEAN study(LOGIK1603/WJOG9116L)
    伊藤健太郎; 和久田一茂; 山口博之; 剱持広知; 福田 実; 三浦 理; 知花賢治; 中川和彦; 山本信之; 杉尾賢二
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • 実臨床下における進展型小細胞肺癌に対するカルボプラチン+エトポシド+アテゾリズマブの治療成績
    金村宙昌; 林 秀敏; 磯本晃佑; 鈴木慎一郎; 田中薫; 吉田健史; 武田真幸; 中川和彦
    第61回日本肺癌学会学術集会, 岡山 2020年11月
  • Treatment with abemaciclib for hormone receptor–positive breast cancer in real-world use: 2-year data in a single institution
    Takashi Kurosaki; Tsutomu Iwasa; Satomi Watanabe; Hitomi Sakai; Yukihiko Hashimoto; Yoshifumi Komoike; Kazuhiko Nakagawa
    第28回日本乳癌学会学術総会
  • 当院における外国人患者への薬物療法の取り組みに関して
    岩朝 勤; 竹久志穂; 川口明範; 渡邊諭美; 酒井瞳; 新崎亘; 橋本幸彦; 菰池佳史; 中川和彦
    第28回日本乳癌学会総会
  • JSCO / JCA / JSMO Joint Symposium 『新薬開発の最近の進歩』
    中川和彦
    第58回日本癌治療学会学術集会, 京都 2020年10月
  • EGFRT790M変異陽性肺癌患者におけるオシメルチニブ治療中の循環腫瘍のDNAのモニタリング(WJOG8815L)
    坂井和子; 髙濱隆幸; 東 公一; 武田真幸; 岡本 勇; 小野哲; 中川和彦; 西尾和人
    第24回日本がん分子標的治療学会学術集会,徳島
  • CDDPを使用できない食道癌患者に対する3剤併用術前化学療法の検討
    木村豊; 白石 治; 安田卓司; 川上尚人
    日本消化器病学会近畿支部 第113回例会 , 大阪 2020年10月
  • KEYNOTE-024試験における日本人サブセットの3年生存解析
    里内美弥子; 野崎要; 高橋利明; 中川和彦; 青江啓介; 倉田宝保; 関根朗雅; 堀池篤; 福原達朗; 菅原俊一; 梅村茂樹; 坂 英雄; 岡本 勇; Shi Rong Han; 野口和夫; 堀田勝幸
    第60回日本呼吸器学会学術講演会,神戸 2020年09月
  • 切除不能進行・再発胃癌に対するニボルマブ単剤療法の臨床的効果予測因子の検討
    黒崎 隆; 川上 尚人; 中川 和彦
    第106回日本消化器病学会総会
  • 頭頸部癌における免疫チェックポイント阻害剤後のセツキシマブ使用の有効性および安全性
    三谷誠一郎; 田中薫; 鈴木慎一郎; 原谷浩司; 文田壮一; 川上尚人; 吉田健史; 林秀敏; 北野睦三; 石川一樹; 土井勝美; 西村恭晶; 中川和彦
    第44回日本頭頸部癌学会総会
  • 当院における分化型甲状腺癌および未分化癌に対するレンバチニブの使用経験
    吉田健史; 田中薫; 中川和彦
    第44回日本頭頸部癌学会総会
  • 当院での進行頭頸部癌に対するニボルマブの有効性と安全性
    鈴木慎一郎; 田中薫; 佐藤千尋; 金村宙昌; 磯本晃佑; 加藤了資; 原谷浩司; 三谷誠一郎; 林秀敏; 北野睦三; 石川一樹; 土井勝美; 西村恭晶; 中川和彦
    第44回日本頭頸部癌学会総会
  • 当院の非小細胞肺癌患者に対する遺伝子パネル検査の使用経験
    田中 薫; 鈴木慎一郎; 金村宙昌; 渡邊諭美; 吉田健史; 武田真幸; 林 秀敏; 清水重喜; 伊藤彰彦; 中川和彦
    第43回日本呼吸器内視鏡学会学術集会,北海道 2020年06月
  • 遺伝子パネル導入において当院での気管支鏡検査における対応策
    鈴木慎一郎; 田中 薫; 金村宙昌; 磯本晃佑; 原谷浩司; 林 秀敏; 武田真幸; 中川和彦
    第43回日本呼吸器内視鏡学会学術集会,北海道 2020年06月
  • NGSCUP: Phase II trial of site-specific treatment based on gene expression and mutation profiling by next generation sequencing (NGS) for patients (pts) with cancer of unknown primary site (CUP).
    Hidetoshi Hayashi; Yuichi Takiguchi; Hironobu Minami; Kohei Akiyoshi; Yoshihiko Segawa; Hiroki Ueda; Yasuo Iwamoto; Chihiro Nakayama Kondoh; Koji Matsumoto; Shin Takahashi; Hisateru Yasui; Toshiyuki Sawa; Yusuke Onozawa; Yasutaka Chiba; Yosuke Togashi; Kazuko Sakai; Yoshihiko Fujita; Shuta Tomida; Kazuto Nishio; Kazuhiko Nakagawa
    American Society of Clinical Oncology, WEB Meeting
  • Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): Interim results of DESTINY-Lung01.
    Egbert F. Smit; Kazuhiko Nakagawa; Misako Nagasaka; Enriqueta Felip; Yasushi Goto; Bob T. Li; Jose Maria Pacheco; Haruyasu Murakami; Fabrice Barlesi; Andreas Nicholas Saltos; Maurice Perol; Hibiki Udagawa; Kapil Saxena; Ryota Shiga; Ferdin; M. Guevara; Suddhasatta Acharyya; Javad Shahidi; David Planchard; Pasi A. Janne
    American Society of Clinical Oncology, WEB Meeting
  • NivoCUP: An open-label phase II study on the efficacy of nivolumab in cancer of unknown primary.
    Junko Tanizaki; Kan Yonemori; Kohei Akiyoshi; Hironobu Minami; Hiroki Ueda; Yuichi Takiguchi; Chihiro Nakayama Kondoh; Yoshihiko Segawa; Shin Takahashi; Yasuo Iwamoto; Yasuhiro Kidera; Kazuya Fukuoka; Yasushi Nakamura; Yasutaka Chiba; Kazuto Nishio; Kazuhiko Nakagawa; Hidetoshi Hayashi
    American Society of Clinical Oncology, WEB Meeting
  • A phase II study of osimertinib for patients with radiotherapy-naïve CNS metastasis of non-small cell lung cancer harboring EGFR mutations: The OCEAN study (LOGIK 1603/WJOG 9116L).
    Kazushige Wakuda; Hiroyuki Yamaguchi; Hirotsugu Kenmotsu; Minoru Fukuda; Noriyuki Ebi; Takayuki Suetsugu; Koji Inonue; Kentaro Tanaka; Toshihide Yokoyama; Keisuke Kirita; Osamu Hataji; Satoru Miura; Kenji Chibana; Kenichi Yoshimura; Kazuhiko Nakagawa; Nobuyuki Yamamoto; Kenji Sugio
    American Society of Clinical Oncology, WEB Meeting
  • Brigatinib in Japanese ALK positive NSCLC patients previously treated with ALK tyrosine kinase inhibitors: J-ALTA.
    Tatsuya Yoshida; Makoto Nishio; Toru Kumagai; Toyoaki Hida; Ryo Toyozawa; Tadasuke Shimokawaji; Koichi Goto; Kazuhiko Nakagawa; Yuichiro Ohe; Nobuyuki Yamamoto; Kentarou Kudou; Takayuki Asato; Pingkuan Zhang; Takashi Seto
    American Society of Clinical Oncology, WEB Meeting
  • RELAY study of erlotinib (ERL) + ramucirumab (RAM) or placebo (PL) in EGFR-mutated metastatic non-small cell lung cancer Poster Session (NSCLC): Biomarker analysis using circulating tumor DNA (ctDNA) in Japanese patients (pts).
    Kazuto Nishio; Kazuko Sakai; Takashi Seto; Makoto Nishio; Edward B. Garon; Martin Reck; Koichi Goto; Terufumi Kato; Yoichi Nakanishi; Toshiaki Takahashi; Nobuyuki Yamamoto; Katsuyuki Kiura; Yuichiro Ohe; Tomohide Tamura; Carla M Visseren-Grul; Rebecca R. Hozak; Sameera R. Wijayawardana; Sotaro Enatsu; Kazuhiko Nakagawa
    American Society of Clinical Oncology, WEB Meeting
  • RELAY+: Exploratory study of ramucirumab plus gefitinib in untreated patients (pts) with epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC).
    Makoto Nishio; Kazuto Nishio; Martin Reck; Edward; B. Garon; Fumio Imamura; Tomoya Kawaguchi; Hiroyuki Yamaguchi; Satoshi Ikeda; Katsuya Hirano; Carla M Visseren-Grul; Ryan C Widau; Annamaria H. Zimmermann; Gosuke Homma; Sotaro Enatsu; Kazuhiko Nakagawa
    American Society of Clinical Oncology, WEB Meeting
  • RELAY, ramucirumab plus erlotinib versus placebo plus erlotinib in patients (pts) with previously untreated, EGFR-mutated, metastatic NSCLC: clinical outcomes by EGFR mutation type type.
    K.Nakagawa; E. Nadal; E. Garon; M. Nishio; T. Seto; N.Yamamoto; K. Park; J-Y. Shih; B. frimodt-Moller; A-M. Zimmerman; C. Visseren-Grul; M. Reck
    European Lung Cancer Congress in Geneva 2020年04月
  • irAE大腸炎を契機にICIの関与が疑われたStevens-Johnson症候群の1例
    黒崎 隆; 川上尚人; 文田壮一; 三谷誠一郎; 中川和彦
    第117回日本内科学会講演会,東京 2020年04月
  • 切除不能進行再発胃癌に対するニボルマブ単独療法の臨床的予後予測因子の検討
    黒崎 隆; 川上尚人; 三谷誠一郎; 中川和彦
    日本消化器病学会近畿支部 第112回例会 2020年02月
  • HER3リガンド・ヘレグリン陽性肺癌のEGFRチロシンキナーゼ(EGFR－TKI)への治療抵抗性について
    米阪仁雄; 林 秀敏; 鈴木慎一郎; 加藤了資; 武田真幸; 中川和彦; 岩間映二; 岡本 勇; 安宅信二; 西尾和人
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • PD-L1高発現未治療進行非小細胞肺癌におけるPembrolizmabの治療効果と総腫瘍量の関連性
    鈴木慎一郎; 原谷浩司; 加藤了資; 林 秀敏; 中川和彦; 谷﨑潤子; 尾崎智博; 岡部嵩記; 明石雄策; 長谷川喜一; 西尾和人; 伊藤彰彦
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • 免疫チェックポイント阻害薬奏効後に転移巣増大を来した肺癌症例の遺伝子的検討
    佐藤千尋; 林 秀敏; 田中 薫; 武田真幸; 中川和彦; 坂井和子; 西尾和人
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • 末期腎不全で維持血液透析中の非小細胞肺癌患者に対し安全にペムブロリズマブ単独療法を施行できた一例
    黒崎隆; 武田真幸; 鈴木慎一郎; 磯本晃佑; 金村宙昌; 林 秀敏; 米阪仁雄; 中川和彦
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • 当院の非小細胞肺癌患者に対する遺伝子パネル検査の使用経験
    田中 薫; 鈴木慎一郎; 金村宙昌; 渡邊諭美; 吉田健史; 武田真幸; 林 秀敏; 清水重喜; 伊藤彰彦; 中川和彦
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • アテゾリズマブによる重症肝炎に対して血漿交換を使用した一例
    金村宙昌; 林 秀敏; 原谷浩司; 米阪仁雄; 中川和彦; 萩原 智; 工藤正俊; 大谷知之; 伊藤彰彦
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺がんの腫瘍微小環境への影響
    磯本晃佑; 原谷浩司; 林 秀敏; 加藤了資; 田中 薫; 武田真幸; 中川和彦; 清水重喜; 伊藤彰彦; 冨田秀太; 丹羽 崇; 小倉高志; 横山俊秀; 福田 泰; 石田 直; 千葉康敬; 谷﨑潤子
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • CAPP－Seqを用いたLiquid biopsyによるT790M陽性非小細胞肺癌のオシメルチニブ耐性因子の検討
    加藤了資; 林 秀敏; 原谷浩司; 田中 薫; 吉田健史; 武田真幸; 米阪仁雄; 中川和彦; 坂井和子; 西尾和人; 髙濱隆幸; 谷﨑潤子; 野長瀬祥兼; 金田裕靖
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • 非小細胞肺癌患者における免疫チェックポイント阻害薬による消化管irAEにおけるヒト・腸内細菌叢の病態と炎症性腸疾患の類似性に関する検討
    西尾和人; 坂井和子; 櫻井俊治; 上嶋一臣; 永井知行; 林 秀敏; 川上尚人; 髙濱隆幸; 武田真幸; 中川和彦
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • 肺線維症をもつ悪性胸膜忠脾腫患者へのニボルマブ使用報告
    岩朝 勤; 黒崎 隆; 鈴木慎一郎; 田中 薫; 武田真幸; 中川和彦
    第111回日本肺癌学会関西支部会学術集会 2020年02月
  • Soluble immune-checkpoint factors as a predictive biomarker for nivolumab treatment in advanced NSCLC patients.
    茶本健司; 林 秀敏; 冨樫庸介; 福岡和也; 波多江龍亮; 後藤 恵; 千葉康敬; 谷崎潤子; 原谷浩司; 高濱隆幸; 田中 薫; 武田真幸; 坂井和子; 樋口景子; 宇賀 均; 西尾和人; 本庶 佑; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年12月
  • EGFR変異陽性肺がんにおけるHER3リガンド・ヘリグリン発現とEGFR－TKIの治療効果との関係
    米阪仁雄; 岩間映二; 林 秀敏; 髙濱隆幸; 谷﨑潤子; 武田真幸; 東 公一; 安宅信二; 岡本 勇; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • The role of soluble immune-checkpoint factors in advanced NSCLC.
    林 秀敏; 茶本健司; 富樫庸介; 中川和彦; 本庶 佑
    第６０回日本肺癌学会学術集会 2019年12月
  • Impact of Co-Mutations in EGFR-Mutated NSCLC Before EGFR-TKIs on T790M Mutation Status After TKIs
    武田真幸; 坂井和子; 林 秀敏; 田中 薫; 原谷浩司; 髙濱隆幸; 加藤了資; 米阪仁雄; 西尾和人; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • CAPP-Seqを用いたLiquid biopsyによるT790M陽性非小細胞肺癌のオシメルチニブ耐性因子の検討
    加藤了資; 林 秀敏; 米阪仁雄; 原谷浩司; 酒井 瞳; 髙濱隆幸; 岩朝 勤; 田中 薫; 吉田健史; 武田真幸; 金田裕靖; 清水重喜; 坂井和子; 伊藤彰彦; 西尾和人; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • 切除不能Ⅲ期非小細胞肺癌に対する胸部放射線と第２.３世代抗癌剤同時併用療法の長期生存解析：WJOG0105LFS
    里内美弥子; 善家義貴; 坪井正博; 千葉康敬; 光岡茂樹; 清水淳市; 駄賀晴子; 藤本大智; 森 雅秀; 青木琢也; 澤 祥幸; 大森翔太; 山本信之; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • 局所進行非小細胞肺癌に対するシスプラチン/nab-パクリタキセル+放射線化学療法の第I/Ⅱ相試験
    横山俊秀; 丹羽 崇; 林 秀敏; 小倉昌和; 谷﨑潤子; 尾崎智博; 吉岡弘鎮; 倉田宝保; 田村洋輔; 藤阪保仁; 田中 薫; 長谷川喜一; 千葉康敬; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • Pem maintenance with Bev prolonged the survival, with adv EGFR-wild nSQ-NSCLC treated Car+Pem+Bev.
    中村 敦; 瀬戸貴司; 山中竹春; 東 公一; 吉岡弘鎮; 小野 哲; 安宅信二; 岩本康男; 林 秀敏; 岡本 勇; 坂 英雄; 光岡茂樹; 藤本大智; 西野和美; 堀池 篤; 駄賀晴子; 曽根 崇; 山本信之; 中川和彦; 中西洋一
    第６０回日本肺癌学会学術集会 2019年12月
  • Preliminary results of brigatinib in Japanese who previously received alectinib.
    里内美弥子; 村上修司; 瀬戸貴司; 西尾誠人; 林 秀敏; 中川和彦; 朝戸臣敬; 橋上美香; Pingkuan Zhang; 大江裕一郎
    第６０回日本肺癌学会学術集会 2019年12月
  • 進行非小細胞肺がんに対するPD-1阻害薬投与後の化学療法の有効性を検討する大規模比較研究(WJOG10217L)
    清水淳一; 加藤了資; 林 秀敏; 千葉康敬; 宮脇英里子; 尾崎智博; 藤本大智; 豊澤 亮; 坂本信二郎; 新屋智之; 知花賢治; 横井 崇; 岡田秀明; 秦 明登; 福山誠一; 田幡江利子; 長島聖二; 濱元陽一郎; 山本信之; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • U3-1402,a HER3-targeting ADC,sensitizes tumors with HER3 expression to PD-1 blockade
    原谷浩司; 米阪仁雄; 高村史記; 前西 修; 宮澤正顯; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響
    磯本晃佑; 原谷浩司; 林 秀敏; 清水重喜; 冨田秀太; 丹羽 崇; 横山俊秀; 福田 泰; 千葉康敬; 加藤了資; 谷﨑潤子; 田中 薫; 武田真幸; 小倉高志; 石田 直; 伊藤彰彦; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • 肺がんステージ3に罹患した患者の復職支援の事例から
    竹内伸一郎; 中川和彦; 西井智恵子; 林 真紀子; 浜谷通代; 和田照平; 辰巳愛子; 新城美香子; 荒木愛理; 中出知佐; 仲川紋子; 金津真由美
    第６０回日本肺癌学会学術集会 2019年12月
  • PD-L1高発現の進行NSCLCにおける総腫瘍径とICIによる治療効果の関係性を検討する観察研究
    鈴木慎一郎; 加藤了資; 原谷浩司; 林 秀敏; 谷﨑潤子; 尾崎智博; 長谷川喜一; 大田隆代; 千葉康敬; 伊藤彰彦; 坂井和子; 西尾和人; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • 辺縁系脳炎によるPS4のSCLCStage3Bに対し化学療法が著効し逐次的放射線療法後予防的全能照射を施行した一例
    川中雄介; 鈴木慎一郎; 加藤了資; 原谷浩司; 林 秀敏; 中川和彦; 楠 進; 山岸裕子; 寺山敦之
    第６０回日本肺癌学会学術集会 2019年12月
  • 固形がんに対する腫瘍遺伝子網羅的解析結果に関する観察研究
    杉本 藍; 福井朋也; 佐々木治一郎; 石原未希子; 日吉康弘; 井川 聡; 坂井和子; 武田真幸; 髙濱隆幸; 中川和彦; 西尾和人; 楢木克彦
    第６０回日本肺癌学会学術集会 2019年12月
  • EGFR変異陽性非小細胞肺がんにおける組織、血漿中AXL・GAS６発現レベルに関する研究
    野長瀬祥兼; 武田真幸; 東 公一; 林 秀敏; 原谷浩司; 田中 薫; 米阪仁雄; 石井秀宜; 星野友昭; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • ALK融合遺伝子陽性非小細胞肺癌におけるALK-TKI耐性機序に関する検討
    田中 薫; 谷﨑潤子; 野長瀬祥兼; 原谷浩司; 酒井 瞳; 加藤了資; 渡邊諭美; 吉田健史; 佐藤千尋; 林 秀敏; 坂井和子; 西尾和人; 中川和彦
    第６０回日本肺癌学会学術集会 2019年12月
  • 免疫チェックポイント阻害薬奏功後に転移巣増大を来した時肺癌奨励の遺伝子的検討
    佐藤千尋; 林 秀敏; 坂井和子; 田中 薫; 武田真幸; 西尾和人; 中川和彦
    第94回日本呼吸器学会/第124回日本結核病学会 近畿地方会 2019年11月
  • がん治療が変わるー肺癌治療の変遷を中心にー
    中川和彦
    2019年度日本内科学会生涯教育講演会 Bセッション 2019年10月
  • Impact of Coexisting Gene Mutations in EGFR-Mutated Non-Small Cell Lung Cancer Before Treatment on EGFR T790 Mutation Status After EGFR-TKIs
    M. Takeda; K. Sakai; H. Hayashi; K.Tanaka; K. Haratani; T. Takahama; R. Kato; K.Yonesaka; K. Nishio; K. Nakagawa
    2019 World Conference on Lung Cancer,Barcelona,Spain 2019年09月
  • Ph3 Study of Maintenance Therapy with S-1 vs BSC After Induction Therapy with Carboplatin ＋ S-1 for Advanced Squamous Cell Lung Cancer (WJOG7512L)
    K.Tanaka; S.Morita; M.Ando; T. Yokoyama; A.Nakamura; H.Yoshioka; T. Ishiguro; S. Miura; R. Toyozawa; T. Oguri; H. Daga; R. Ko; A. Bessho; M.Tachihara; Y.Iwamoto; K.Hirano; Y. Nakanishi; K.Nakagawa; N. Yamamoto; I. Okamoto
    2019 World Conference on Lung Cancer,Barcelona,Spain 2019年09月
  • The Sequential Therapy of Crizotinib Followed by Alectinib:Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L)
    S.Watanabe; T.Yamanaka; K.Ito; S. Sakata; H Daga; T. Kijima; K. Hirono; I. Okamoto; A. Nakamura; T. Hattori; K. Nakagawa; N. Yamamoto
    2019 World Conference on Lung Cancer,Barcelona,Spain 2019年09月
  • Chemotherapy after PD-1 inhibitors vesus chemotherapy alone in patients with Non-small cell lung cancer.(WJOG10217L)
    E. Miyawaki; R. Kato; H. Hayashi; Y. Chiba; J. Shimizu; T. Ozaki; D. Fujimoto; R. Toyozawa; Y. Akazawa; M. Okuno; S. Morikawa; T. Ohira; T. Harada; R. Ushio; A. Kubo; T. Harada; N. Kimura; H. Yamaguchi; K. Nishikawa; N. Yamamoto; K. Nakagawa
    2019 World Conference on Lung Cancer,Barcelona,Spain
  • Preliminary results of brigatinib in Japanese patients(PTS) who previously received alectinib: Brigatinib-2001 study.
    S. Murakami; T. Seto; M. Satouchi; M. Nishio; H. Hayashi; Y. Ohe; T. Asato; P. Zhang; K. Nakagawa
    2019 World Conference on Lung Cancer,Barcelona,Spain
  • RELAY EU/US Subset Ramucirumab plus erlotinib plus erlotinib improves progression -free survival in first-line EGFR mutation-positive NSCLC.
    S. Aix; S. Novello; E. Garon; K. Nakagawa; E. Nadal; D. Moro; Sibilot, M. Alonso Garcia; E. Fabre; B. Frimodt-M
    2019 World Conference on Lung Cancer,Barcelona,Spain
  • Clinicopathological Features of MSI-H Colorectal Cancer:A Case Series in a Single Institute
    川上尚人; 武川直樹; 野長瀬祥兼; 奥野達哉; 家根由規; 吉岡康多; 牛嶋北斗; 大東弘治; 所 忠男; 上田和樹; 高濱隆幸; 武田真幸; 川村純一郎; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Efficacy of targeting therapy for recurrence or metastatic breast cancer patient after chemotherapy treatment.
    岩朝 勤; 広川恵須輝; 酒井 瞳; 渡邊諭美; 東 千尋; 田中由美子; 新崎 亘; 橋本幸彦; 菰池佳史; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Impact of Coexisting Gene Mutations in EGFR-Mutated NSCLC Before EGFR-TKI on EGFR T790M Mutation Status After EGFR-TKI
    武田真幸; 坂井和子; 林 秀敏; 田中 薫; 原谷浩司; 高濱隆幸; 加藤了資; 米阪仁雄; 西尾和人; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • A retrospective comparison of Paclitaxel Vs Paclitaxel + Ramcirumab for patients with advanced gastric cancer
    奥野達哉; 植田勲人; 藤原季美子; 武川直樹; 野長瀬祥兼; 川上尚人; 林 秀敏; 武田真幸; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • 高齢の進行食道癌患者に対する3剤併用術前化学療法の検討
    木村 豊; 白石 治; 岩間 密; 加藤寛章; 川上尚人; 奥野達哉; 平木洋子; 安田 篤; 新海政幸; 今野元博; 中川和彦; 安田卓司
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • 原発不明癌に対するNivolumabの有効性を検討する第II相試験（NivoCUP）
    谷崎潤子; 林 秀敏; 南 博信; 新井誠人; 高橋 信; 畝川芳彦; 増田 淳; 上田弘樹; 秋吉宏平; 岩本 康男; 米盛 勧; 木寺康裕; 福岡和也; 西尾和人; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Retrospective analysis of efficacy in breast cancer patients requiring dose reduction in palbociclib due to neutropenia.
    広川 恵寿輝; 岩朝 勤; 酒井 瞳; 渡邊 諭美; 菰池 佳史; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • A randomized pII trial of site-specific therapy based on gene expression vs CBDCA+PTX for cancer of unknown primary site.
    林 秀敏; 倉田宝保; 滝口裕一; 新井誠人; 武田晃司; 秋吉宏平; 松本光史; 尾上琢磨; 向井博文; 松原伸晃; 南 博信; 豊田昌徳; 小野澤祐輔; 小野 哲; 藤田至彦; 坂井和子; 洪 泰浩; 大橋靖雄; 西尾和人; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • The association of baseline tumor size with pembrolizumab efficacy in patients with NSCLC with high PD-L1 expression
    鈴木慎一郎; 原谷浩司; 林 秀敏; 谷﨑潤子; 尾崎智博; 長谷川喜一; 大田隆代; 工藤慶太; 横山俊秀; 福田 泰; 明石雄策; 岡部崇記; 丹羽 崇; 千葉康敬; 伊藤彰彦; 坂井和子; 西尾和人; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Efficacy of re-treatment with immune checkpoint inhibitors in patients with pretreated advanced NSCLC.
    高濱隆幸; 武田真幸; 田中 薫; 岩朝 勤; 林 秀敏; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Updated results of phase 1 study of [fam-] trastuzumab deruxtecan in HER2-expressing or -mutated advanced NSCLC or -mutated advanced NSCLC.
    中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Efficacy and Safety of Nivolumab in Previously Treated Patients with Head and Neck Cancer.
    田中 薫; 加藤了資; 野長瀬祥兼; 武川直樹; 谷﨑潤子; 吉田健史; 林 秀敏; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Phase I/II study of nab-paclitaxel with cisplatin（ C） and radiotherapy in pts with unresectable stage III NSCLC （ABCDRT）
    林 秀敏; 小倉昌和; 丹羽 崇; 横山俊秀; 谷崎潤子; 尾崎智博; 吉岡弘鎮; 倉田宝保; 田村 洋輔; 藤阪保仁; 田中 薫; 長谷川喜一; 工藤慶太; 千葉康敬; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Exploratory analysis of JFCM: Predictive value of rash, EGFR expression, and EGFR copy for necitumumab in squamous NSCLC
    後藤 悌; 西尾誠人; 山本信之; 大江裕一郎; 鎌田 亜美; 鈴川和己; 江夏総太郞; 中川和彦; 田村友秀
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Population PK/PD Analysis of Necitumumab: Dose justification for Squamous Cell Lung Cancer (SqCLC) Patients in Japan.
    三村 花華; Amanda Long; Emmanuel Chigutsa; Johan Wallin; 江夏総太郎; 中川和彦; 田村友秀
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Anti-EGFR antibody-resistant head and neck squamous cell carcinoma maintained sensitivity to pan-HER inhibitor afatinib.
    米阪仁雄; 田中 薫; 北野睦三; 坂井和子; 林 秀敏; 西尾和人; 土井勝美; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Updated results of phase 1 study of [fam-] trastuzumab deruxtecan in HER2-expressing or -mutated advanced NSCLC
    中川和彦; 土井 俊彦; 髙橋 俊二; 葉 清隆; 鶴谷 純司; Park Haeseong; Modi Shanu; Krop Ian E; Waqar Saiama; Li Bob T; 平良 眞一郎; 齊藤 格; 藤崎 良彦; 慈幸 貴洋; Singh Jasmeet; 杉原 匡周; Pasi A. Janne
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • PD-1 Inhibitors Followed by Subsequent Chemotherapy versus Chemotherapy Alone in Patients with NSCLC （WJOG10217L）
    加藤了資; 林 秀敏; 千葉康敬; 宮脇英里子; 清水淳市; 尾崎智博; 藤本大智; 野崎 要; 福田 泰; 青木琢也; 宮本信吾; 立原素子; 日下 圭; 猪又峰彦; 杉野安輝; 柏原光介; 長谷川剛生; 田中文啓; 山本信之; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • U3-1402, a HER3-targeting ADC, sensitizes tumors with HER3 expression to PD-1blockade: A preclinical research.
    原谷浩司; 米阪仁雄; 高村史記; 前西 修; 加藤了資; 武川直樹; 川上尚人; 田中 薫; 林 秀敏; 武田真幸; 前田尚之; 明松隆志; 廣谷賢志; 鶴谷純司; 西尾和人; 宮澤正顕; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Phase II trial of amrubicin and cisplatin chemotherapy for invasive thymoma: WJOG5509L
    小野 哲; 工藤慶太; 西尾誠人; 白石祥理; 岡本 勇; 岩本康夫; 大熊裕介; 奥田勝裕; 秋吉宏平; 西野和美; 光岡茂樹; 東公一; 上野清伸; 入来豊久; 杉尾賢二; 千葉康敬; 向井 清; 石川雄一; 中川和彦; 山本 信之
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Laparoscopic adrenal gland biopsy showed recurrent adenocarcinoma after chemoradiotherapy for LD-SCLC.
    吉田健史; 西本 光寿; 大關 孝之; 田中 伴典; 清水 重喜; 植村 天受; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Phase III study of CBDCA/PEM followed by PEM versus DOC in elderly pts with advanced non-sq NSCLC (JCOG1210/WJOG7813L)
    軒原 浩; 岡本 勇; 葉 清隆; 菅原俊一; 堀之内秀仁; 東 公一; 米嶋康臣; 村上晴泰; 駄賀晴子; 細見幸生; 安宅信二; 尾崎智博; 堀池 篤; 藤田結花; 岡本浩明; 安藤昌彦; 野村尚吾; 山本信之; 大江裕一郎; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Tumor tissue and plasma level of AXL and GAS6 in EGFR mutation positive non-small cell lung cancer
    野長瀬祥兼; 武田真幸; 林 秀敏; 田中 薫; 原谷浩司; 米阪仁雄; 東 公一; 石井秀宣; 星野友昭; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Comparison of molecular biological characteristics and clinical outcome of extramammary
    渡邊諭美; 原谷浩司; 高濱隆幸; 武田真幸; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • The Impact of EGFR-TKIs Treatment on Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small-Cell Lung Cancer
    磯本晃佑; 原谷浩司; 林 秀敏; 清水重喜; 冨田秀太; 丹羽 崇; 横山俊秀; 福田 泰; 千葉康敬; 加藤了資; 谷崎潤子; 田中 薫; 武田真幸; 小倉高志; 石田 直; 伊藤彰彦; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Circulating Tumor DNA Identifies Osimertinib Resistance Mechanisms in EGFR T790Mpositive lung cancer
    加藤了資; 林 秀敏; 米阪仁雄; 原谷浩司; 高濱隆幸; 酒井 瞳; 谷崎潤子; 岩朝 勤; 田中 薫; 吉田健史; 武田真幸; 金田裕靖; 清水重喜; 酒井和子; 伊藤彰彦; 西尾和人; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Impact of cytotoxic chemotherapy on PD-L1 expression in patients with NSCLC negative for EGFR mutation and ALK fusion
    酒井 瞳; 小山敦子; 田中 薫; 渡邊諭美; 名倉美樹; 保田紀子; 林 真紀子; 遠藤美幸; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • A questionnaire survey about psychosocial effects due to appearance change amongJapanese cancer patients(日本人がん患者における外見変化の心理社会的影響の質問紙調査)
    酒井 瞳; 武田 真幸; 坂井 和子; 中村 靖司; 伊藤 彰彦; 林 秀敏; 田中 薫; 西尾 和人; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • A randomized phase III study of maintenance Bev with or without Pem after CBDCA, Pem, and Bev for nSQ-NSCLC (WJOG5610L)
    東 公一; 瀬戸貴司; 山中竹春; 菅原俊一; 吉岡弘鎮; 小野 哲; 安宅信二; 岩本康男; 林 秀敏; 岡本 勇; 坂 英雄; 光岡茂樹; 藤本大智; 西野和美; 堀池 篤; 駄賀晴子; 曽根 崇; 山本信之; 中川和彦; 中西洋一
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • 西日本がん研究機構(WJOG)における医師主導治験の取り組みと問題点
    武田晃司; 澤 和彦; 下村 満; 中村慎一郎; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • RELAY: Global Ph3 study of erlotinib + ramucirumab or placebo in metastatic NSCLC with EGFR mutation ? East Asian subset.
    西尾 誠人; 瀬戸 貴司; Martin Reck; Edward; B. Garon; Chao-Hua Chiu; 葉 清隆; 今村 文生; Keunchil Park; Jin-Yuan Shih; Carla Visseren-Grul; Bente Frimodt-Moller; Annamaria Zimmermann; 本間剛介; 江夏総太郞; 中川和彦
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • 非小細胞肺癌を対象としたカルボプラチン+ペメトレキセド+アテゾリズマブへのベバシズマブの上乗せ効果を検証する第III相試験
    白石 祥理; 駄賀 晴子; 池田 慧; 秦 明登; 水谷 英明; 阪本 智宏; 齋藤 春洋; 畑地 治; 田中 洋史; 堀池 篤; 坂 英雄; 下川 恒生; 森 雅秀; 平野 勝也; 東 公一; 光冨 徹哉; 瀬戸 貴司; 山本 信之; 中川和彦; 岡本 勇
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • Phase 2 study of [fam-] trastuzumab deruxtecan (DS-8201a) in HER2-overexpressing or -mutated advanced NSCLC
    後藤 悌; 中川和彦; 宇田川 響; 村上晴泰; 藤原 豊; Li Bob T; Planchard David; 志賀 遼太; Lee Caleb; Wang Kongming; Pasi A. Janne
    第17回日本臨床腫瘍学会学術集会 2019年07月
  • DAS59を用いたがん治療による外見変化の心理社会的影響と情報ニーズ・ケアニーズの実態調査
    酒井 瞳; 名倉美樹; 保田紀子; 岩朝 勤; 渡邊諭美; 林 真紀子; 遠藤美幸; 菰池佳史; 小山敦子; 中川和彦
    第27回日本乳癌学会学術総会 2019年07月
  • 化学療法後の分子標的治療薬の奏効に関する検討
    岩朝 勤; 広川恵須輝; 酒井 瞳; 渡邊諭美; 東 千尋; 田中由美子; 新崎 亘; 橋本幸彦; 菰池佳史; 中川和彦
    第27回日本乳癌学会学術総会 2019年07月
  • パルボシクリブによる好中球減少症を経験した28症例から考えた至適容量の検討
    広川恵寿輝; 岩朝 勤; 酒井 瞳; 渡邊諭美; 菰池佳史; 中川和彦
    第27回日本乳癌学会学術総会 2019年07月
  • HER2陽性乳癌細胞株における抗HER3抗体パトリツマブと抗HER2抗体トラスツズマブ/ペルツズマブの3剤併用治療
    渡邊諭美; 鶴谷純司; 広川恵寿輝; 酒井 瞳; 岩朝 勤; 中川和彦
    第27回日本乳癌学会学術総会 2019年07月
  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌のPD-L1発現率への影響
    磯本晃佑; 原谷浩司; 林 秀敏; 清水重喜; 冨田秀太; 丹羽 崇; 横山俊秀; 福田 泰; 千葉康敬; 加藤了資; 谷﨑潤子; 田中 薫; 武田真幸; 小倉高志; 石田 直; 伊藤彰彦; 中川和彦
    第110回日本肺癌学会関西支部会学術集会 2019年06月
  • PD-L1発現陰性/TMB Highの肺腺癌に対して化学療法とペムブロリズマブの併用療法を施行した一例
    金村宙昌; 林 秀敏; 武田真幸; 髙濱隆幸; 田中 薫; 坂井和子; 西尾和人; 中川和彦
    第110回日本肺癌学会 関西支部会学術集会 2019年06月
  • CAPP-Seqを用いたLiquid biopsyによるT790M陽性非小細胞肺癌のオシメルチニブ耐性因子の検討
    加藤了資; 米阪仁雄; 髙濱隆幸; 武田真幸; 坂井和子; 西尾和人; 中川和彦
    第23回がん分子標的治療学会学術講演会 2019年06月
  • EGFR変異陽性非小細胞肺癌における組織、血漿中のAXL・GAS6発現レベルに関する研究
    野長瀬祥兼; 武田真幸; 米阪仁雄; 東 公一; 中川和彦
    第23回がん分子標的治療学会学術講演会 2019年06月
  • HER2陽性乳癌細胞株における抗HER３抗体パトリツマブと抗HER2抗体トラツズマブ/ペルツヅマブの３剤併用療法
    渡邊諭美; 米阪仁雄; 武田真幸; 中川和彦
    第23回がん分子標的治療学会学術講演会 2019年06月
  • 抗EGFR抗体耐性頭頚部癌におけるPan-HERファミリー阻害剤アファチニブの有用性について
    米阪仁雄; 坂井和子; 西尾和人; 中川和彦
    第23回がん分子標的治療学会学術講演会 2019年06月
  • HER２遺伝子増幅を持たないヘテロなHER2タンパク発現大腸癌に対する[fam-]tratuzumab deruxtecanの抗腫瘍効果の検討
    川上尚人; 米阪仁雄; 武田真幸; 中川和彦
    第23回がん分子標的治療学会学術講演会 2019年06月
  • がんクリニカルシーケンスに於ける知識ベースキュレーションシステムの比較検討
    武田真幸; 坂井和子; 髙濱隆幸; 米阪仁雄; 中川和彦; 西尾和人
    第23回がん分子標的治療学会学術講演会 2019年06月
  • がん治療が変わる～肺癌治療の変遷を中心に～
    中川和彦
    日本内科学会生涯教育講演会 2019年06月
  • Pembrolizumab (pembro) for advanced biliary adenocarcinoma: Results from the KEYNOTE-028 (KN028) and KEYNOTE-158 (KN158) basket studies.
    Yung-Jue Bang; Makoto Ueno; David Malka; Hyun Cheol Chung; Adnan Nagrial; Robin Kate Kelley; Sarina Anne Piha-Paul; Willeke Ros; Antoine Italiano; Kazuhiko Nakagawa; Hope S. Rugo; Filippo G. De Braud; Andrea I. Varga; Aaron Richard Hansen; Chao Gao; Suba Krishnan; Kevin Norwood; Toshihiko Doi
    ASCO2019，Chicago 2019年06月
  • A randomized phase III study of continuous maintenance bevacizumab with or without pemetrexed after induction therapy with carboplatin (Car), pemetrexed (Pem), and bevacizumab (Bev) for advanced non-squamous non-small cell lung cancer (nSQ-NSCLC) without sensitizing EGFR mutations: The COMPASS study (WJOG5610L).
    Takashi Seto; Koichi Azuma; Takeharu Yamanaka; Shunichi Sugawara; Hiroshige Yoshioka; Akira Ono; Shinji Atagi; Yasuo Iwamoto; Hidetoshi Hayashi; Isamu Okamoto; Hideo Saka; Mitsuoka Shigeki; Daichi Fujimoto; Kazumi Nishino; Atsushi Horiike; Haruko Daga; Takashi Sone; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Yoichi Nakanishi
    ASCO2019，Chicago 2019年06月
  • RELAY:A multinational, double-blind, randmized Phase 3 study of erlotinib (ERL) in combination with ramucirmab (RAM) or placebo (PL) in previously untreasted patients with epidermal growth factor receptor mutation-positive (EGFRm) metadtatics non-small cell lung cancer (NSCLC).
    Kazuhiko Nakagawa; Edward B. Garon; Takashi Seto; Makoto Nishio; Santiago Ponce Aix; Chao-Hua Chiu; Keunchil Park; Silvia Novello; Ernest Nadal; Fumio Imamura; Kiyotaka Yoh; Jin-Yuan Shih; Kwok Hung Au; Denis Moro-Sibilot; Sotaro Enatsu; Annamaria H. Zimmermann; Bente Frimodt-Moller; Carla M. Visseren Grul; Martin Reck
    ASCO2019，Chicago 2019年06月
  • Phase I study on preliminary safety and efficacy of rovalpituzumab tesirine in Japanese patients (pts) with advanced, recurrent small cell lung cancer (SCLC).
    Hiroaki Akamatsu; Hibiki Udagawa; Kentaro Tanaka; Masayuki Takeda; Shintaro Kanda; Keisuke Kirita; Shunsuke Teraoka; Kazuhiko Nakagawa; Yutaka Fujiwara; Ikuko Yasuda; Sumiko Okubo; Masayuki Shintani; Rachel S Leibman; Charity D. Scripture; Tomohide Tamura; Isamu Okamoto
    ASCO2019，Chicago 2019年06月
  • The impact of sequential therapy of crizotinib followed by alectinib: Real-world data analysis of 840 ALK-inhibitor naïve patients with NSCLC harboring ALK-rearrangement (WJOG9516L).
    Kentaro Ito; Takeharu Yamanaka; Satomi Watanabe; Yoshihiro Hattori; Kazumi Nishino; Haruki Kobayashi; Yuko Oya; Toshihide Yokoyama; Takashi Seto; Koichi Azuma; Tomoya Fukui; Toshiyuki Kozuki; Atsushi Nakamura; Isamu Okamoto; Katsuya Hirano; Takashi Yokoi; Haruko Daga; Shinya Sakata; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    ASCO2019，Chicago 2019年06月
  • Blood tumor mutational burden (bTMB) and tumor PD-L1 as predictive biomarkers of survival in MYSTIC: First-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic (m) NSCLC.
    Naiyer A. Rizvi; Byoung Chul Cho; Niels Reinmuth; Ki Hyeong Lee; Alexander Luft; Myung-Ju Ahn; Michel van den Heuvel; Manuel Cobo Dols; David Vicente; Alexey Smolin; Vladimir Moiseyenko; Scott Joseph Antonia; Kazuhiko Nakagawa; Sarah B. Goldberg; Edward; S. Kim; Jill Walker; Rajiv Raja; Feng Liu; Urban J. Scheuring; Solange Peters
    ASCO2019，Chicago 2019年06月
  • A multicenter, open label, randomized phase III study of atezolizumab with platinum-pemetrexed and with or without bevacizumab for patients with advanced nonsquamous non-small cell lung cancer (WJOG11218L APPLE Study).
    Yoshimasa Shiraishi; Haruko Daga; Satoshi Ikeda; Akito Hata; Hideaki Mizutani; Tomohiro Sakamoto; Haruhiro Saito; Osamu Hataji; Hiroshi Tanaka; Atsushi Horiike; Hideo Saka; Tsuneo Shimokawa; Masahide Mori; Katsuya Hirano; Koichi Azuma; Tetsuya Mitsudomi; Takashi Seto; Nobuyuki Yamamoto; Kazuhiko Nakagawa; Isamu Okamoto
    ASCO2019，Chicago 2019年06月
  • Randomized phase III study comparing carboplatin plus pemetrexed followed by pemetrexed versus docetaxel in elderly patients with advanced non-squamous non-small-cell lung cancer (JCOG1210/WJOG7813L).
    Isamu Okamoto; Hiroshi Nokihara; Kiyotaka Yoh; Shunichi Sugawara; Hidehito Horinouchi; Koichi Azuma; Yasuto Yoneshima; Haruyasu Murakami; Haruko Daga; Yukio Hosomi; Shinji Atagi; Tomohiro Ozaki; Atsushi Horiike; Yuka Fujita; Hiroaki Okamoto; Masahiko Ando; Shogo Nomura; Nobuyuki Yamamoto; Yuichiro Ohe; Kazuhiko Nakagawa
    ASCO2019，Chicago 2019年06月
  • Final PFS analysis and safety data from the phase III J-ALEX study of alectinib (ALC) vs. crizotinib (CRZ) in ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC).
    Takashi Seto; Makoto Nishio; Toyoaki Hida; Hiroshi Nokihara; Masahiro Morise; Young Hak Kim; Koichi Azuma; Yuichi Takiguchi; Hiroshige Yoshioka; Toru Kumagai; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Miyako Satouchi; Toshiyuki Kozuki; Kazuhiko Nakagawa; Tetsuya Mitsudomi; Nobuyuki Yamamoto; Takashi Asakawa; Tomohide Tamura
    ASCO2019，Chicago 2019年06月
  • 肺がん薬物療法の発展とOnco-Cardiology
    中川和彦
    第7回腫瘍循環器研究会 2019年05月
  • Alectinibによる長期の腫瘍制御が可能であった末期腎不全合併ALK融合遺伝子陽性肺腺癌の1例
    鈴木慎一郎; 原谷浩司; 渡邉諭美; 高濱隆幸; 武川直樹; 林 秀敏; 武田真幸; 米阪仁雄; 中川和彦
    第116回日本内科学会総会・講演会 2019年04月
  • 出血性NSAID潰瘍を契機にニボルマブによる後天性血友病Aを診断した肺扁平上皮癌の1例
    加藤了資; 林 秀敏; 佐野圭吾; 半田康平; 中川和彦
    第116回日本内科学会総会・講演会 2019年04月
  • EGFR遺伝子変異を有する非扁平上皮非細胞肺癌に対する，ペメトレキセド＋ゲフィチニブとゲフィチニブ単剤の無作為化第Ⅱ相試験：全生存期間の最終報告
    中川和彦; 村上晴泰; 江夏総太郎; Xin Wang; Trun Puri; Maruo Orlando; Ying Cheng; Pan-Chyr Yang; Jianxing He; Jin Hyoung Kang; Joo-Hang Kim; James Chin-Hsin Yang
    第59回日本呼吸器学会学術講演会 2019年04月
  • GLCC国際調査2017にみる肺癌症状認知度と国民収入の検討
    澤 祥幸; 中川和彦; 中西洋一
    第59回日本呼吸器学会学術講演会 2019年04月
  • がん治療が変わる～がんゲノム医療とがん免疫療法の話
    中川和彦
    大阪地域連携情報交換会 2019年03月
  • ポスターセッション 当科におけるオシメルチニブの使用成績と血漿中ｃｆDNAの有効性に関する検討  [通常講演]
    加藤了資; 林 秀敏; 米阪仁雄; 原谷浩司; 高濱隆幸; 谷?潤子; 岩朝 勤; 田中 薫; 吉田健史; 武田真幸; 金田裕靖; 清水重喜; 坂井和子; 伊藤彰彦; 西尾和人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • 一般口演 原発不明がんにおける腫瘍微小免疫環境と予後の関連性  [通常講演]
    原谷浩司; 林 秀敏; 高濱隆幸; 澤田貴宏; 中村靖司; 伊藤彰彦; 千葉康敬; 谷崎潤子; 藤田至彦; 坂井和子; 西尾和人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション 日本人の肺がん症状認識度と肺癌患者への姿勢―国際アンケート調査解析  [通常講演]
    澤 祥幸; 中西洋一; 中川和彦; 吉田 勉; 石黒 崇; 堀場あかね; 二村洋平; フォックス・ジャスミ; オディジェ・キャロライン; ピータース・マシュー
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション Nivolumab induced Acute Granulomotous Tubulointerstitial Nephritis in a Patient with Gastric Cancer  [通常講演]
    川上尚人; 中谷嘉寿; 市川昌志; 山本祥代; 大塚康生; 益子晃子; 高島康利; 伊藤彰彦; 有馬秀二; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション 出血性NSAIDｓ潰瘍を契機にニボルマブによる後天性血友病Aを診断した肺扁平上皮癌の1例  [通常講演]
    加藤了資; 林 秀敏; 米阪仁雄; 佐野圭吾; 半田康平; 植田勲人; 奥野達哉; 川上尚人; 武田真幸; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション ALK融合遺伝子陽性非小細胞肺癌に於けるALK−TKI耐性機序に関する検討  [通常講演]
    田中 薫; 谷?潤子; 野長瀬祥兼; 原谷浩司; 酒井 瞳; 林 秀敏; 坂井和子; 西尾和人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション 当院における高齢者への化学慮法施行の現状に関して  [通常講演]
    岩朝 勤; 中川和彦; 鶴谷純司; 酒井 瞳; 渡邉諭美; 菰池佳史; 橋本幸彦; 新崎 亘
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション Incidence of reduced relative dose intensity of dose dense chemotherapy in patients with early stage breast cancer  [通常講演]
    酒井 瞳; 岩朝 勤; 鶴谷純司; 加藤了資; 原谷浩司; 谷?潤子; 菰池佳史; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • 一般口演 原発不明癌に対するNivolumabの有効性を検討する第?相試験(NivoCUP)  [通常講演]
    谷?潤子; 林 秀敏; 南 博信; 新井誠人; 高橋 信; 畝川芳彦; 尾崎由紀範; 上田弘樹; 秋吉宏平; 岩本康男; 米盛 勧; 木寺康裕; 福岡和也; 西尾和人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • シンポジウム CAPP seqのもたらすリキッドバイオプシーの可能性と臨床応用の展望  [通常講演]
    高濱隆幸; 坂井和子; 中川和彦; 西尾和人
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション The antitumor efficacy of DS-8201a is dependent on the expression levels of HER2 in KRAS mutated colorectal cancer cells  [通常講演]
    武川直樹; 川上尚人; 鶴谷純司; 米阪仁雄; 原谷浩司; 野長瀬祥兼; 加藤了資; 酒井 瞳; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション EGFR遺伝子変異陽性の非小細胞肺癌に対する２つオシメルチニブ±ベバシズマブのランダム化第?相試験(WJOG8715LとWJOG9717L)  [通常講演]
    剱持広知; 赤松弘朗; 和久田一茂; 森田智視; 盛 啓太; 坂井和子; 西尾和人; 中川和彦; 高橋利明; 山本信之
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション 再発および遠隔転移食道癌を対象としたUDON併用療法の第?相試験  [通常講演]
    野長瀬祥兼; 植田勲人; 武川直樹; 奥野達哉; 川上尚人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション 進行食道癌患者に対する５-FU+docetaxel+nedaplatin(UDON)療法による術前化学療法の検討  [通常講演]
    木村 豊; 白石 治; 川上尚人; 植田勲人; 奥野達哉; 岩間 密; 加藤寛章; 平木洋子; 安田 篤; 新海政幸; 今野元博; 今本治彦; 中川和彦; 安田卓司
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ポスターセッション 当科における切除不能進行再発胃癌患者に対するパクリタキセル+ラムシルマブ併用療法の有効性、安全性の検討  [通常講演]
    奥野達哉; 植田勲人; 藤原季美子; 武川直樹; 野長瀬祥兼; 川上尚人; 林 秀敏; 武田真幸; 鶴谷純司; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • シンポジウム４ 『「7大学連携個別化がん医療実践者養成プラン」』におけるゲノム医療人材育成  [通常講演]
    中川和彦; 福岡和也
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • セミプレナリーセッション 血漿EGFR T790M遺伝子変異陽性/既治療非小細胞肺癌患者におけるosimertinibの有効性を検討する第二相試験(WJOG8815L/LPS)  [通常講演]
    高濱隆幸; 東 公一; 下川元継; 加藤晃史; 駄賀晴子; 岡本 勇; 赤松弘明; 高橋利明; 太平達夫; 横山俊秀; 平野勝也; 白石祥理; 姫路大輔; 山本信之; 西尾和人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • 一般口演 Clinical characteristics of non-small cell lung cancer harboring exon 20 mutation of EGFR or HER2  [通常講演]
    武田真幸; 坂井和子; 林 秀敏; 田中 薫; 谷?潤子; 高濱隆幸; 原谷浩司; 西尾和人; 中川和彦
    第16回日本臨床腫瘍学会学術集会，神戸 2018年
  • ペンブロリズマブ投与終了後の緩和照射直後に肺蔵炎を発症した肺腺癌の1例  [通常講演]
    中島早希; 宇都宮琢秀; 吉野谷清和; 本多英弘; 工藤慶太
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • 肉芽腫様所見を伴った縦隔腫瘍の2例  [通常講演]
    太谷知之; 清水重喜; 榎木英介; 林 秀敏; 武本智樹; 中川和彦; 光冨徹哉; 佐藤隆夫; 伊藤彰彦
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • 出血性NSAIDｓ潰瘍を契機にニボルマブによる後天性血友病Aを診断した肺扁平上皮癌の1例  [通常講演]
    加藤了資; 林 秀敏; 佐野圭吾; 半田康平; 米阪仁雄; 中川和彦
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • 気胸を契機にサルベージ手術を施行し得た左上葉肺癌の1例  [通常講演]
    伊藤龍一; 中嶋 隆; 濱 誠; 水口真二郎; 野村奈央; 山本良二; 津谷あす香; 駄賀晴子
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • 非小細胞におけるPD−１阻害剤への耐性バイオマーカーについて  [通常講演]
    米阪仁雄; 高村史記; 大和美智子; 中川和彦
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • PD-L１高発現の進行非小細胞肺癌患者における初回治療選択の現状  [通常講演]
    坪口裕子; 中谷有貴; 秋吉宏平; 上田眞也; 津谷あす香; 岡崎俊介; 徳永伸也; 駄賀晴子
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • ALK融合遺伝子陽性非小細胞肺癌におけるALK−TKI耐性機序に関する検討  [通常講演]
    田中 薫; 谷?潤子; 野長瀬祥兼; 原谷浩司; 酒井 瞳; 林 秀敏; 阪井和子; 西尾和人; 中川和彦
    第108回日本肺癌学会関西支部学術集会，大阪 2018年
  • ポスター 原発不明がんの治療のための標的分子  [通常講演]
    藤田至彦; 坂井和子; 倉田宝保; 中川和彦; 西尾和人
    第22回日本がん分子標的治療学会学術集会，東京 2018年
  • ワークショップ 固形癌に対する腫瘍遺伝子網羅的解析結果に基づく分子標的治療薬選択が与える影響  [通常講演]
    高濱隆幸; 武田真幸; 坂井和子; 中川和彦; 西尾和人
    第22回日本がん分子標的治療学会学術集会，東京 2018年
  • ワークショップ EGFR又はHER2 exon 20変異陽性非小細胞肺癌の臨床的特徴  [通常講演]
    武田真幸; 坂井和子; 高濱隆幸; 中川和彦; 西尾和人
    第22回日本がん分子標的治療学会学術集会，東京 2018年
  • ワークショップ 非小細胞肺癌における腫瘍免疫関連分子B7-H3による抗PD-1治療への抵抗性とその克服について  [通常講演]
    米阪仁雄; 西尾和人; 中川和彦
    第22回日本がん分子標的治療学会学術集会，東京 2018年
  • Oralセッション EGFR遺伝子変異陽性肺癌における血漿検体と組織検体でのT790M変異検査の比較検討  [通常講演]
    田中 薫; 加藤了資; 高濱隆幸; 谷?潤子; 岩朝 勤; 林 秀敏; 武田真幸; 中川和彦
    第41回日本呼吸器内視鏡学会学術集会，東京 2018年
  • ランチョンセミナー ?期非小細胞肺癌治療、今なにが課題か -放射線療法後のがん免疫環境から、次の一手を探る-  [通常講演]
    田中 薫; 後藤 悌
    第41回日本呼吸器内視鏡学会学術集会 2018年
  • ポスター掲示 初発骨転移症例の予後規定因子の検討  [通常講演]
    菰池佳史; 東 千尋; 田中裕美子; 濱田未佳; 新崎 亘; 橋本幸彦; 北條敏也; 乾 浩己; 鶴谷純司; 岩朝 勤; 酒井 瞳; 大宗久; 金泉博文; 山村順
    第２６回日本乳癌学会学術総会，京都 2018年
  • ポスター掲示 当院における高齢者への化学療法施行の現状に関して  [通常講演]
    岩朝 勤; 鶴谷純司; 酒井 瞳; 渡邉諭美; 新崎 亘; 安積達也; 橋本幸彦; 菰池佳史
    第２６回日本乳癌学会学術総会，京都 2018年
  • 厳選口演 乳癌化学療法により外見変化に対する医師の認識と介入の実態  [通常講演]
    酒井 瞳; 岩朝 勤; 鶴谷純司; 菰池佳史
    第２６回日本乳癌学会学術総会，京都 2018年
  • 推薦口演 Phase II trial of Eribulin/S-1 combination therapy for advanced/recurrent breast cancer  [通常講演]
    鶴谷純司; 岩朝勤; 水野豊; 小島康幸; 高島勉; 松並展輝; 森本 卓; 山村順; 大谷彰一郎; 田辺裕子; 渡辺諭美; 加藤了資; 高野利美; 菰池佳史; 中川和彦
    第２６回日本乳癌学会学術総会，京都 2018年
  • ミニシンポジウム 既治療３B/4期非小細胞肺癌に対するエルロチニブ/ドセタキセル併用療法の第１/２相臨床試験：WJOG4708L  [通常講演]
    木村達郎; 川口知哉; 工藤新三; 千葉康敬; 丹羽崇; 渡部克也; 木島貴志; 小暮啓人; 小栗鉄也; 笠井 尚; 林 秀敏; 小野哲; 田中洋史; 吉岡弘鎮; 矢野聖二; 山本信之; 中西洋一; 中川和彦
    第58回日本呼吸器学会学術講演会，大阪 2018年
  • ミニシンポジウム KEYNOTE−025：日本人既治療PD-L1陽性非小細胞肺がんに対するペムブリズマブPhaseIb試験  [通常講演]
    西尾誠人; 高橋利明; 吉岡弘鎮; 中川和彦; 福原達朗; 山田一彦; 一木昌郎; 田中洋史; 瀬戸貴司; 酒井 洋; 笠原寿郎; 里内美弥子; 野口一夫; 嶋本隆司; 加藤晃史
    第58回日本呼吸器学会学術講演会，大阪 2018年
  • ポスター 悪性リンパ腫放射線治療後、2次発癌として進行食道癌を併発した1例  [通常講演]
    奥野達哉; 植田勲人; 武川直樹; 野長瀬祥兼; 川上尚人; 谷?潤子; 林 秀敏; 田中 薫; 武田真幸; 鶴谷純司; 中川和彦
    第104回日本消化器病学会総会，東京 2018年
  • 口演 ショートレクチャー 大学病院における早期からの緩和ケア・地域連携の実践〜腫瘍内科と緩和ケアの融合の試み〜  [通常講演]
    吉田健史
    第90回日本呼吸器学会 近畿地方会 2017年
  • ポスターセッション 関節リウマチ合併扁平上皮肺がん患者へのキートールダﾞ使用経験の一例  [通常講演]
    岩朝 勤; 武田真幸; 田中 薫; 谷?潤子; 加藤了資; 林 秀敏; 吉田健史; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • ポスターセッション ニボルマブ投与後に腫瘍周囲のすりガラス陰影とともにpseudprogressionを呈した肺腺癌の1例  [通常講演]
    加藤了資; 林 秀敏; 谷?潤子; 田中 薫; 武田真幸; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • ポスターセッション Trousseau症候群とDICを合併した肺腺癌にgefitinibが奏効した1例  [通常講演]
    野長瀬祥兼; 武田真幸; 田中 薫; 吉田健史; 林 秀敏; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • ポスターセッション ペメトレキセドが長期著効したRET融合遺伝子陽性非小細胞肺癌の1例  [通常講演]
    武田真幸; 林 秀敏; 田中 薫; 中川和彦; 坂井和子; 西尾和人
    第90回日本呼吸器学会 近畿地方会 2017年
  • ポスターセッション 肺胞蛋白症の診断をきかっけに骨髄異形成症候群が判明し、その後急速な転機をたどった1例  [通常講演]
    吉野谷清和; 岡本充史; 中島早希; 本多英弘; 星田義彦; 武田真幸; 工藤慶太
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション 近畿大学おける免疫チェックポイント阻害薬チーム医療の試み(iMNETs)  [通常講演]
    林 秀敏; 中川和彦; 佐野博幸; 東田有智; 西村恭昌; 光冨徹哉; 藤原季実子; 林 真紀子
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション 当院における肺癌在宅患者の看取りに関する因子の検討  [通常講演]
    新田 隆; 中川和彦; 工藤慶太; 平島智徳; 鶴谷純司; 武田真幸; 吉田健史; 林 秀敏; 岩朝 勤; 田中 薫
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション 当院通院治療センターでのカルボプラチン投与時のアプレピタント併用による悪心の変化  [通常講演]
    林 真紀子; 山崎里花; 柳江正嗣; 藤原季美子; 石田洋子; 武田真幸; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション 治療前後肺線維症・間質性肺炎合併肺癌の治療方針の検討  [通常講演]
    高濱隆幸; 武田真幸; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション ニボルマブによる肝障害の画像及び病理所見の特徴  [通常講演]
    林 秀敏; 川上尚人; 谷?潤子; 田中 薫; 原谷浩司; 鎌田 研; 竹中 完; 木村雅友; 筑後孝章; 佐藤隆夫; 工藤正俊; 伊藤彰彦; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション 非小細胞肺癌におけるニボルマブ治療効果と免疫関連有害事象(irAE)の関連性(他施設向き観察研究)  [通常講演]
    原谷浩司; 林 秀敏; 加藤了資; 田中 薫; 武田真幸; 米阪仁雄; 金田裕靖; 工藤慶太; 長谷川喜一; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション 非小細胞肺がんにおけるニボルマブの効果予測因子としての末梢血マーカーの検討  [通常講演]
    谷?潤子; 原谷浩司; 林 秀敏; 千葉康敬; 中村靖司; 米阪仁雄; 工藤慶太; 金田裕靖; 長谷川喜一; 田中 薫; 武田真幸; 伊藤彰彦; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション T790M陽性肺癌細胞株における第三世代EGFR−TKIとSrc阻害薬ダサチニブの併用効果の検討  [通常講演]
    吉田健史; 渡邉諭美; 川上尚人; 武川直樹; 野長瀬祥兼; 谷?潤子; 林 秀敏; 武田真幸; 鶴谷純司; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • オーラルセッション EGFR遺伝子変異陽性肺癌に於ける血漿検体でのT790M変異検査の検討  [通常講演]
    田中 薫; 加藤了資; 原谷浩司; 野長瀬祥兼; 酒井 瞳; 高濱隆幸; 谷?潤子; 吉田健史; 岩朝 勤; 林 秀敏; 武田真幸; 中川和彦
    第90回日本呼吸器学会 近畿地方会 2017年
  • Iternational Poster Session1 Clinical evaluation of palliative chemoradiotherapy for metastasis asophageal cancer.  [通常講演]
    H.Ueda,M. Takeda; S. Ueda; H.Kawakami; T. Okuno; H. Hayashi; J. Tsurutani; T. Tamura; K. Ishikawa; Y.Nimura; K.Nakagawa
    第25回日本消化器関連学会週間 2017年
  • ポスター ペメトレキセド長期著効したRET融合遺伝子陽性非小細胞肺癌の1例  [通常講演]
    武田真幸; 林 秀敏; 田中 薫; 坂井和子; 西尾和人; 中川和彦
    第58回日本肺癌学会学術集会 2017年
  • 一般口演 EAST-LC試験―70歳以上におけるサブグループ解析  [通常講演]
    高橋利明; 中川和彦; 山本信之; 軒原 浩; 大江裕一郎; 西尾誠人; 新行内雅斗; 後藤功一; 今村文生; 一瀬幸人; 瀬戸貴司; 吉岡弘鎮; 弦間昭彦; 坂 英雄; 井上 彰; 武田晃司; 岡本 勇; 木浦勝行; 田村友秀
    第58回日本肺癌学会学術集会 2017年
  • 一般口演 既治療進行・再発非小細胞肺癌に対するラムシルマブとドセタキセル併用投与：奏効までの期間の解析  [通常講演]
    田中 薫; 樋田豊明; 吉岡弘鎮; 鈴川和己; 江夏総太郎; 中村 隆; 田村友秀; 中川和彦
    第58回日本肺癌学会学術集会 2017年
  • 一般口演 進行非小細胞肺癌に対する微量心嚢水の予後に関する検討  [通常講演]
    加藤了資; 林 秀敏; 千葉康敬; 田中 薫; 武田真幸; 中川和彦
    第58回日本肺癌学会学術集会 2017年
  • ワークショップ T790M陽性肺癌細胞株における第三世代EGFR−TKIとSｒｃ阻害薬ダサチニブの併用効果の検討  [通常講演]
    吉田健史; 渡邉諭美; 武川直樹; 川上尚人; 中川和彦
    第58回日本肺癌学会学術集会 2017年
  • ワークショップ 扁平上皮癌のアクショナブル遺伝子異常  [通常講演]
    西尾和人; 金田裕靖; 谷?潤子; 坂井和子; 濱隆幸; 武田真幸; 光冨徹哉; 中川和彦; 岡本勇
    第58回日本肺癌学会学術集会 2017年
  • アンコールセッション EGFR変異陽性肺癌患者に関するgefitinibとpemetrexed併用療法の比較第?相試験：Translational ｒeserch  [通常講演]
    James Yang; Ying Cheng; Haruyasu Murakami; Pan-Chyr Yang,Jianxing He; 中川和彦; Jin Kang; Joo-Hang; Kim; Rebecca Hozak; Tuan Nguyen; Xin Wang; 江夏総太郎; Tarun Puri; Maruo Orlando
    第58回日本肺癌学会学術集会 2017年
  • メディカルセミナー Discussion,Treatment strategy for T790M mutation positive lung cancer. 討論、T790M変死陽性肺癌の治療戦略  [通常講演]
    赤松弘朗; 林 秀敏
    第15回日本臨床腫瘍学会学術集会 2017年
  • シンポジウム 臨床試験現場の立場から  [通常講演]
    中川和彦
    第15回日本臨床腫瘍学会学術集会 2017年
  • ポスター heregulin発現HER2陽性乳癌・胃癌における抗HER2薬ラパチニブ、トラスツズマブ、T-DM1の感受性に関する研究  [通常講演]
    野長瀬 祥兼; 米阪仁雄; 川上尚人; 渡邉諭美; 原谷浩司; 高濱隆幸; 武川直樹; 植田勲人; 谷崎潤子; 林 秀敏; 吉田健史; 武田真幸; 千葉康敬; 田村孝雄; 中川和彦; 鶴谷純司
    第25回日本乳癌学会総会，福岡 2017年
  • ポスターディスカッション 当院におけるエリブリン使用74例の検討  [通常講演]
    岩朝 勤; 鶴谷純司; 酒井 瞳; 渡邊諭美; 新崎 亘; 安積達也; 橋本幸彦; 菰池佳史; 中川和彦
    第25回日本乳癌学会総会，福岡 2017年
  • 厳選ポスター T-DM1 de novo耐性HER2陽性乳癌の臨床病理学的検討  [通常講演]
    酒井 瞳; 岩朝勤; 菰池佳史; 鶴谷純司; 坂井和子; 西尾和人; 中川和彦
    第25回日本乳癌学会総会，福岡 2017年
  • ニボルマブ投与後に腫瘍周囲のすりガラス陰影とともにpseudoprogressionを呈した肺腺癌の1例  [通常講演]
    加藤了資; 林 秀敏; 谷?潤子; 田中 薫; 武田真幸; 中川和彦
    第１０６回日本肺癌学会関西支部会学術集会 2017年
  • ペメトレキセドが長期著効したRET融合遺伝子陽性非小細胞肺癌の1例  [通常講演]
    武田真幸; 林 秀敏; 田中 薫; 中川和彦; 坂井和子; 西尾和人
    第１０６回日本肺癌学会関西支部会学術集会 2017年
  • Alectinibによる長期の腫瘍制御が可能であった末期腎不全合併ALK融合遺伝子陽性肺腺癌の1例  [通常講演]
    原谷浩司; 林 秀敏; 西田諭美; 武川直樹; 武田真幸; 中川和彦
    第１０６回日本肺癌学会関西支部会学術集会 2017年
  • Trousseau症候群とDICを合併した肺腺癌にGefitinibが奏効した１例  [通常講演]
    野長瀬祥兼; 武田真幸; 田中 薫; 林 秀敏; 吉田健史; 林 秀敏; 中川和彦
    第１０６回日本肺癌学会関西支部会学術集会 2017年
  • 気管支鏡を施行したニボルマブによる肺障害の検討  [通常講演]
    西山 理; 山崎 亮; 西川祐作; 佐野安子; 山縣俊之; 佐野博幸; 岩永賢司; 東本有司; 東田有智; 中川和彦
    第40回日本呼吸器内視鏡学会学術集会 2017年
  • 一般口演 セツキシマブ耐性の大腸癌患者における血漿によるHER2遺伝子増幅の検出  [通常講演]
    武川直樹
    第103回日本消化器病学会総会 2017年
  • 326免疫checkpoint阻害剤で汎下垂体昨日不全を来した悪性黒色腫の1例  [通常講演]
    奥野達哉; 酒井 瞳; 武友保憲; 岩朝 勤; 田中 薫; 武田真幸; 鶴谷純司; 田村孝雄; 池上博司; 中川和彦
    第113回日本内科学会 2017年
  • ポスターセッション Pleural effusionで発症しMesotheliomaで診断できた2例  [通常講演]
    藤田悦生; 太田文典; 清井めぐみ; 圧嶋健作; 川畑仁貴; 青木達也; 川端大輝; 橋本忠幸; 阪中啓一郎; 仲地健一郎; 阪中謙司; 鷲森美希; 山村理沙; 北村要輔; 山口雄太; 上村和久; 山下実輝; 流田智史; 濱隆幸; 坂田好史; 稲田佳紀; 小澤 悟; 小林良平; 嶋田浩介; 寒川浩道; 高畑昌弘; 匹本樹寿; 小林克暢; 星屋博信; 山本勝廣
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション 皮膚筋炎合併の胸腺癌患者に対する全人的苦痛の緩和に  [通常講演]
    河野 恵; 岩朝 勤; 中西良子; 森田さやか; 徳留由貴; 川上尚人; 吉田健史; 三瀬博之; 宮?巳美; 尾崎公俊
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション 肺癌患者の診断から在宅療養を継続した支援の取り組み  [通常講演]
    西林和美; 藤木智子; 宮内豊路子; 西山登志子; 藤田悦生; 太田典文; 濱隆幸
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション ニボルマブによるIrAE対応に向けた院内体制構築の試み  [通常講演]
    米本加奈子; 荒木順子; 森脇 静; 西山登志子; 太田文典; 濱隆幸
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • メディカルスタッフ・患者向け教育セミナー 『誰でも分かる肺癌個別化治療』  [通常講演]
    武田真幸
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • 基調講演 『ALK阻害剤の使い分け「セリチニブの果たす役割」』  [通常講演]
    林 秀敏
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション 予後因子、その他 進行非小細胞肺癌に対する微量心嚢水の予後に関する検討  [通常講演]
    加藤了資; 林 秀敏; 酒井 瞳; 原谷浩司; 濱隆幸; 岩朝 勤; 田中 薫; 武田真幸; 中川和彦; 千葉康敬
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション 予後因子、その他 FGFR遺伝子異常を有する肺扁平上皮癌の術後再発生存期間に対する影響とマルチキナーゼ阻害薬に対する感受性  [通常講演]
    西尾和人; 金田裕靖; 谷?潤子; 坂井和子; 冨樫庸介; 寺嶋雅人; デベラスコ・マルコ; 藤田至彦; 坂野恵里; 中村 雄; 武田真幸; 伊藤彰彦; 光冨徹哉; 岡本 勇; 中川和彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション チーム医療２ がん相談支援センターにおける現状と今後の課題  [通常講演]
    石田洋子; 武田真幸; 中川和彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション チーム医療２ 大学医病院における早期からの緩和ケア・地域連携の実践  [通常講演]
    吉田健史; 松岡弘道; 小山敦子; 鶴谷純司; 中川和彦; 三瀬博之; 尾崎公俊; 前田宗之; 新田 隆
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション 7大学連携SP(模擬患者)を用いた職種横断的臨床課題演習  [通常講演]
    光岡茂樹; 川口知哉; 中川和彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • アワードセッション EGFR遺伝子変異陽性小細胞肺癌におけるニボルマブの有効性と効果予測因子の解析  [通常講演]
    原谷浩司; 林 秀敏; 武田真幸; 中川和彦; 坂井和子; 西尾和人; 金田裕靖
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • 一般演題 Alectinib(Alec)に耐性化したALK陽性肺癌にCeritinib(Cer)が奏効した一例  [通常講演]
    幕内陽介; 林 秀敏; 原谷浩司; 谷?潤子; 武田真幸; 中川和彦; 坂井和子; 西尾和人; 清水重喜; 伊藤彰彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション LCNEC、SCLC 全身化学療法により神経症状が著名に改善したLambert-Eaton筋無力症状群合併進展型小細細胞肺癌の一例  [通常講演]
    國田裕貴; 原谷浩司; 田中 薫; 中川和彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • 一般演題 A病院通院治療センターでの安全確保への取り組み〜看護師・薬剤師協働の疑義照会から〜  [通常講演]
    林 真紀子; 山?里花; 石田洋子; 藤原季実子; 林 秀敏; 武田真幸; 中川和彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション EGFR、ALK肺癌 組織型転化を来したEGFR陽性肺癌症例の臨床的検討  [通常講演]
    田中 薫; 加藤了資; 原谷浩司; 武川直樹; 濱隆幸; 岩朝 勤; 林 秀敏; 武田真幸; 中川和彦; 清水重喜; 伊藤彰彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • ポスターセッション オシメルチニブ2 osimertinibが奏効したEGFR T790M 変異陽性肺腺癌、癌性髄膜炎の一例  [通常講演]
    酒井 瞳; 林 秀敏; 岩朝 勤; 武田真幸; 中川和彦
    第105回日本肺癌学会関西支部学術集会，大阪， 2017年
  • Ｈｅｒｇｕｌｉｎ-ｉｎｄｕｃｅｄ ｒｅｓｉｓｔａｎｃｅ ａｇａｉｎｓｔ ＨＥＲ２-targeted therapies in HER2 positive breast and gastric cancer in vitro and in vino  [通常講演]
    Nonagase Y; Yonesaka K; Kawakami H; Watanabe S; Haratani K; Takahama T; Takegawa N; Ueda H; Tanizaki J; Hayashi H; Yoshida T; Takeda M; Chiba Y; Tamura T; Nakagawa K; Tsurutani J
    107ｔｈ American Association for Cancer Research Annual Meeting, New Orleans, U.S.A. 2016年
  • HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer  [通常講演]
    Takegawa N; Yonesaka K; Sakai K; Ueda H; Watanabe S; Nonagase Y; Okuno T; Takeda M; Maenishi O; Tsurutani J; Satoh T; Okamoto I; Nishio K; Tamura T; Nakagawa K
    107ｔｈ American Association for Cancer Research Annual Meeting, New Orleans, U.S.A. 2016年
  • ポスター 『EGFR−TKI既治療EGFR遺伝子変異陽性非小細胞肺癌におけるニボルマブの治療成績』  [通常講演]
    林 秀敏; 原谷浩司; 田中 薫; 長谷川喜一; 工藤慶太; 金田裕靖; 武田真幸; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • ポスター 『肺癌に於ける次世代シークエンサーを用いた変異解析に基づく分子標的薬適応決定』  [通常講演]
    武田真幸; 坂井和子; 林 秀敏; 田中 薫; 吉田健史; 岩朝 勤; 高濱隆幸; 野長瀬祥兼; 西尾和人; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • ポスター 『ニボルマブ治療によりpseudoprogressionを認めた肺腺癌の2例』  [通常講演]
    谷?潤子; 林 秀敏; 加藤了資; 原谷浩司; 高濱隆幸; 田中 薫; 岩朝 勤; 武田真幸; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • 一般口演 『血漿遊離DNAからT790M遺伝子変異陽性の確認された患者に対する第三世代EGFRTKIを用いた第II相試験の計画』  [通常講演]
    高濱隆幸; 坂井和子; 山本信之; 西尾和人; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • 一般口演 『肺がん医療向上委員会の活動と今後の課題〜web-poll結果から』 第  [通常講演]
    澤 祥幸; 中西洋一; 清水英治; 鈴木 実; 瀬戸貴司; 滝口裕一; 中川和彦; 伊藤眞由美; 澤昭浩; 光冨徹哉
    57回日本肺癌学会学術集会， 福岡 2016年
  • 一般口演 『Phase I/II study of nab-paclitaxel with CDDP and TRT in patients with locally advanced NSCLC』  [通常講演]
    倉田宝保; 林 秀敏; 小倉昌和; 丹羽 崇; 横井 崇; 田村洋輔; 藤阪保仁; 金田裕靖; 吉岡弘鎮; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • 一般口演 『統合解析：切除不能局所進行非小細胞肺癌に対するS-1+CDDP+胸部放射線療法(SP+TRT)の臨床試験』  [通常講演]
    山中竹春; 瀬戸貴司; 佐々木智成; 大柳文義; 小塚拓洋; 高橋利明; 原田英幸; 西尾誠人; 一瀬幸人; 西村恭昌; 山本信之; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • 一般口演 『抗B7-H3抗体治療薬により抗PD-L1抗体への増感治療について』  [通常講演]
    米阪仁雄; 前西 修; 廣谷賢志; 金田裕靖; 西尾和人; 中川和彦
    第57回日本肺癌学会学術集会， 福岡 2016年
  • 一般口演 『A real world evidence of 1,660 Japanese patients with NSCLC harboring EGFR mutation』  [通常講演]
    金 永学; 井上 彰; 吉田和史; 熊谷 融; 中川和彦; 山本信之; 瀬戸貴司; 岡本 勇; 森田智視; 武藤哲史; 福岡正博
    第57回日本肺癌学会学術集会， 福岡 2016年
  • アンコールセッション 『ALK陽性肺癌を対象としてアレクチニブ(ALC)とクリゾチニブ(CRZ)』の比較第?相試験(J-ALEX試験)  [通常講演]
    東 公一; 樋田豊明; 軒原 浩; 近藤征史; 金 永学; 瀬戸貴司; 滝口裕一; 西尾誠人; 吉岡弘鎮; 今村文生; 保田勝幸; 渡部 聡; 後藤功一; 中川和彦; 光冨徹哉; 山本信之; 田中智宏; 田村友秀
    第57回日本肺癌学会学術集会， 福岡 2016年
  • プレナリーセッション 『プラチナ既治療非小細胞肺癌に対するS-1とドセタキセルのランダム化比較第3相試験(EAST-LC)』  [通常講演]
    菅原俊一; 中川和彦; 山本信之; 軒原 浩; 大江裕一郎; 西尾誠人; 高橋利明; 後藤功一; 前門戸 任; 一瀬幸人; 瀬戸貴司; 酒井 洋; 弦間昭彦; 坂 英雄; 井上 彰; 武田晃司; 岡本 勇; 木浦勝行; 田村友秀
    第57回日本肺癌学会学術集会， 福岡 2016年
  • シンポジウム 希少がんんの新治療法確率に向けての課題  [通常講演]
    武田真幸
    第54回日本癌治療学会学術集会，横浜 2016年
  • ポスター 『原発不明癌の治療のための標的分子の探索-Exploration of novel target molecules for treatment of cancer of unknown primary.』  [通常講演]
    藤田至彦; 坂井和子; 倉田宝保; 寺嶋雅人; 林 秀敏; 中川和彦; 西尾和人
    第75回日本癌学会学術総会，横浜 2016年
  • 一般口演 肺癌に於ける次世代シーケンサ―を用いた変異解析に基づく分子標的薬適応決定-Clinical application of amplicon-based next-generation sequencing to therapeutic decision making in lung cancer  [通常講演]
    武田真幸; 坂井和子; 林 秀敏; 田中 薫; 高濱隆幸; 吉田健史; 岩朝 勤; 光冨徹哉; 伊藤彰彦; 西尾和人; 中川和彦
    第75回日本癌学会学術総会，横浜 2016年
  • 一般口演 局所進行非小細胞肺癌に対するシスプラチン/nab-パクリタキセル＋胸部放射線同時併用化学療法の第1/2相試験（第1相パート）  [通常講演]
    林 秀敏; 小倉昌和; 丹羽 崇; 横井 崇; 田村洋輔; 藤阪保仁; 金田裕靖; 倉田宝保; 吉岡弘鎮; 中川 和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ミニシンポジウム4 次世代シーケンサーを用いた原発巣推定  [通常講演]
    林 秀敏; 冨田秀太; 藤田至彦; 寺嶋雅人; 冨樫庸介; 坂井和子; 西尾和人; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • Anticancer activities of various EGFR-TKIs against uncommon EGFR-mutated non-small cell lung cancer  [通常講演]
    冨樫 庸介; 千葉真人; 坂野恵里; 小林祥久; 林 秀敏; 光冨撤哉; 西尾和人
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター 患者向けガイドブック「よくわかる肺がんQ＆A」は必要か？  [通常講演]
    澤 祥幸; 中川和彦; 山本信之; 瀬戸貴司; 金田裕靖; 林 秀敏; 赤松弘朗; 北口聡一; 立原素子; 光冨 徹哉; 西日本がん研究機構
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター Clinical significance of concurrent chemoradiotherapy for advanced esophageal cancer  [通常講演]
    植田勲人; 武田真幸; 上田眞也; 川上尚人; 武川直樹; 田村孝雄; 石川一樹; 西村恭昌; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター Long-term treatment with nintedanib of NSCLC associated with CCDC6-RET rearrangemen  [通常講演]
    武田真幸; 坂井和子; 岡本邦男; 林 秀敏; 田中 薫; 清水俊雄; 西尾和人; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • アンコールセッション ALK融合遺伝子陽性進行・再発非小細胞肺癌を対象としたアレクチニブとクリゾチニブの有効性及び安全性を比較する第III相試験（J-ALEX試験）  [通常講演]
    近藤征史; 樋田豊明; 軒原浩; 金 永学; 中川和彦; 光冨徹哉; 山本信之; 西尾誠人; 田中智宏; 田村友秀
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • International Session 抗B7-H3抗体治療薬による免疫チェックポイント阻害剤への増感治療について  [通常講演]
    米阪仁雄; 前西 修; 坂井和子; 廣谷賢志; 西尾和人; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • 一般口演 上皮間葉移行（EMT）によりEGFR-TKIへの獲得耐性を示す非小細胞肺癌におけるZEB1の重要性  [通常講演]
    吉田健史; Song Lanxi; Haura Eric B; Gemmill Robert; Drabkin Harry A; 浦本秀隆; 田中文啓; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • International Sympoｓium HER2 genomic amplification in circulating tumor DNA from patients with cetuximab-resistant colorectal cancer  [通常講演]
    Naoki Takegawa; Kimio Yonesaka; Kazuko Sakai; Yoshikane Nonagase; Hiroto Ueda; Osamu Maenishi; Junji Tsurutani; Kazuto Nishio; Takao Tamura; Kazuhiko Nakagawa
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター ALK融合遺伝子陽性肺癌のFISH陽性率はALK阻害剤の治療効果と関連する  [通常講演]
    田中 妙; 吉岡弘鎮; 林 秀敏; 岡本邦男; 金田俊彦; 横山俊秀; 武田真幸; 金田裕靖; 中川和彦; 石田 直
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター HER2陽性乳癌・胃癌における抗HER2薬に対するHeregulinによる薬剤耐性に関する研究  [通常講演]
    野長?祥兼; 米阪仁雄; 渡邉諭美; 武川直樹; 川上尚人; 林 秀敏; 武田真幸; 田村孝雄; 中川和彦; 鶴谷純司
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター Phase I investigator initiated trial of YM155 in combination with elrotnib in patients with EGFR-mutant advanced NSCLC  [通常講演]
    清水俊雄; 西尾和人; 坂井和子; 林 秀敏; 岡本邦男; 武田真幸; 岩朝 勤; 田中 薫; 青山幸司; 森下 麻依子; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスター Survival analysis of patients with ALK rearrangement?positive NSCLC treated sequentially with crizotinib and alectinib  [通常講演]
    渡邉諭美; 林 秀敏; 岡本邦男; 藤原 季美子; 長谷川喜一; 金田裕靖; 田中薫; 武田真幸; 福岡正博; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスターフリーディスカッション Afatinib抵抗性の脳転移に対して、全脳照射後にErlotinibが長期奏効したEGFR変異陽性進行非小細胞肺癌の一例  [通常講演]
    野長?祥兼; 岡本邦男; 渡邉諭美; 原谷浩司; 高濱隆幸; 武川直樹; 植田勲人; 田村孝雄; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスターフリーディスカッション Two cases of Lung Ad with EGFR mutation transformed into SCC: successful treatment of one case with rociletinib  [通常講演]
    原谷浩司; 林 秀敏; 渡邉諭美; 金田裕靖; 吉田健史; 武田真幸; 清水俊雄; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスターフリーディスカッション HER-2陽性乳房外Paget病に対するbeyond PDでの抗HER2治療が奏効した一例  [通常講演]
    渡邉諭美; 武田真幸; 高濱隆幸; 谷崎潤子; 岩朝 勤; 鶴谷純司; 林 秀敏; 清水俊雄; 和田仁孝; 中川 和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスターフリーディスカッション ｓ状結腸がん肝転移治癒切施行後、StageI小細胞肺癌を合併した1例  [通常講演]
    奥野達哉; 野長瀬祥兼; 武川直樹; 植田勲人; 田中 薫; 林 秀敏; 武田真幸; 清水俊雄; 鶴谷純司; 田村孝雄; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスターフリーディスカッション アレクチニブ耐性後に小細胞癌転化をしたALK融合遺伝子陽性の肺腺癌の一例  [通常講演]
    武川直樹; 林 秀敏; 飯塚徳重; 高濱隆幸; 植田勲人; 田中 薫; 武田真幸; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • ポスターフリーディスカッション cell freeDNAを用いてEGFRT790M遺伝子変異が確認されたEGFR-TKI既治療NSCLCに対するAZD9291を用いた非盲検第二相試験  [通常講演]
    高濱 隆幸
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • 一般口演 Phase II trial of Eribulin/S-1 combination therapy for advanced/recurrent breast cancer  [通常講演]
    Tsutomu Iwasa; Yoshifumi Komoike; Junji Tsurutani; Kazuhiko Nakagawa; Yutaka Mizuno; Nobuki Matsunami; Jun Yamamura; Shoichiro Otani; Yasuyuki Kojima; Satomi Watanabe
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • 一般口演 Clinical application of amplicon-based next-generation sequencing to therapeutic decision-making in lung cancer  [通常講演]
    武田真幸; 坂井和子; 林 秀敏; 田中 薫; 岩朝 勤; 西郷和真; 伊藤彰彦; 光冨徹哉; 西尾和人; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • 一般口演 当院における非小細胞肺癌に対するre-biopsyの検討  [通常講演]
    田中 薫; 渡邊諭美; 原谷浩司; 野長瀬祥兼; 高濱隆幸; 吉田健史; 岩朝 勤; 林 秀敏; 武田真幸; 金田裕靖; 中川和彦
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • インターナショナルシンポジウム Integration of medical oncology and palliative care for early and continues palliative care in the university hospital.  [通常講演]
    Takeshi Yoshida; Hiromasa Izumi; Chihiro Makimura; Hiroyuki Mise; Kimitoshi Ozaki; Muneyuki Maeda; Takashi Nitta; Hiromichi Matsuoka; Jyunji Tsurutani; Atsuko Koyama; Kazuhiko Nakagawa
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • 一般口演 EGFR T790M 変異陽性肺腺癌，癌性髄膜炎にosimertinibを投与した一例  [通常講演]
    酒井 瞳; 林 秀敏; 岩朝 勤; 武田真幸; 中川和彦
    第104回日本肺癌学会関西支部学術集会，大阪 2016年
  • 一般口演 肺がん２ 尿崩症を初発症状とした肺小細胞癌下垂体転移の1例  [通常講演]
    加藤了資; 酒井 瞳; 原谷浩司; 高濱隆幸; 谷?潤子; 吉田健史; 岩朝 勤; 田中 薫; 林 秀敏; 武田真幸; 中川和彦; 古川健太郎; 奥田武司
    第104回日本肺癌学会関西支部学術集会，大阪 2016年
  • 要望演題 ニボルマブ投与でpseudoprogressionを認めた肺腺癌の2例  [通常講演]
    谷?潤子; 林 秀敏; 田中 薫; 岩朝 勤; 武田真幸; 中川和彦
    第104回日本肺癌学会関西支部学術集会，大阪 2016年
  • 一般口演 ALK融合遺伝子陽性NSCLCに対するクリゾチニブ、アレクチニブ逐次療法の生存解析  [通常講演]
    渡邉諭美; 林 秀敏; 岡本邦男; 藤原 季美子; 長谷川喜一; 金田裕靖; 田中薫; 武田真幸; 中川和彦
    第104回日本肺癌学会関西支部学術集会，大阪 2016年
  • インターナショナルシンポジウム8 Future direction of EGFR/HER family-targeted therapy 『Personalized Medicine in HER2-positive breast cancer』  [通常講演]
    Junji Tsurutani
    第14回日本臨床腫瘍学会学術集会，神戸 2016年
  • シンポジウム HER2陽性乳癌個別化治療の近未来  [通常講演]
    鶴谷純司
    第24回日本乳癌学会学術総会 2016年
  • ポスター 大学病院における早期からの緩和ケア・地域連携の実践 腫瘍内科と緩和気の融合の試み〜  [通常講演]
    吉田健史
    第21回日本緩和医療学会学術大会 2016年
  • ミニシンポジウム 当院における関節リウマチ患者の肺NTM症合併の検討  [通常講演]
    本多英弘; 吉野谷清和; 工藤慶太
    第56回日本呼吸器学会 2016年
  • ミニシンポジウム 非小細胞肺がんに対するラムシルマブとドセタキセルの併用療法：年齢別サブグループ解析  [通常講演]
    山田一彦; 高橋利明; 田中 薫; 中村 隆; 江夏総太郎; 田村友秀; 中川和彦
    第56回日本呼吸器学会 2016年
  • シンポジウム 肺癌診療におけるクリニカルシークエンス  [通常講演]
    武田真幸; 坂井和子; 中川和彦
    第56回日本呼吸器学会 2016年
  • イブニングセミナー 臨床医からのUP to date ALK陽性NSCLCの克服に向けて！病理・臨床・耐性研究の最前線  [通常講演]
    蔦 公治; 金田裕靖; 片山量平
    第56回日本呼吸器学会 2016年
  • Afatinib抵抗性の脳転移を有するEGFR変異陽性進行非小細胞肺がんに対して全脳照射後にErlotinibが長期奏効した一例  [通常講演]
    野長瀬祥兼; 渡邉諭美; 原谷浩司; 高濱隆幸; 武川直樹; 植田勲人; 田村孝雄; 中川和彦; 岡本邦男
    第103回日本肺癌学会関西支部学術集会 大阪 2016年
  • ポスター 扁平上皮癌への転化を来したEGFR遺伝子変異陽性肺腺癌の2例  [通常講演]
    原谷浩司; 林 秀敏; 西田諭美; 金田裕靖; 吉田健史; 武田真幸; 中川和彦
    第56回日本肺癌学会学術集会 横浜 2015年
  • ポスター KRAS変異陽性NSCLC対象のabemacichibとerlotinibの第?相比較試験  [通常講演]
    中川和彦; Jonathan Goldman; Peopei Shi; Martin Reck,Luis Paz-Ares; Andrew Koustenis
    第56回日本肺癌学会学術集会 横浜 2015年
  • ポスター ALK阻害剤による治療後に小細胞肺癌・扁平上皮癌への形質転換を認めたALK融合遺伝子陽性肺癌の1例  [通常講演]
    武川直樹; 中川和彦; 鶴谷純司; 清水俊雄; 武田真幸; 田中 薫; 岩朝 勤; 吉田健史; 林 秀敏; 谷?潤子; 高濱隆幸; 原谷浩司; 西田諭美
    第56回日本肺癌学会学術集会 横浜 2015年
  • ポスター 当院における非小細胞肺癌に対するre-biopsyの検討  [通常講演]
    田中 薫; 西田諭美; 原谷浩司; 野長瀬祥兼; 高濱隆幸; 吉田健史; 岩朝 勤; 林 秀敏; 武田真幸; 金田裕靖; 中川和彦
    第56回日本肺癌学会学術集会 横浜 2015年
  • ポスター Afatinib 抵抗性の脳転移を有するEGFR変異陽性進行非小細胞肺癌に対してErlotinibが長期奏効した一例  [通常講演]
    野長瀬祥兼; 岡本邦男; 西田諭美; 原谷浩司; 高濱隆幸; 武川直樹; 植田勲人; 田村孝雄; 中川和彦
    第56回日本肺癌学会学術集会 横浜 2015年
  • ポスター A Retrospective Analysis for 2000 Japanese patients with activating EGFR mutations−Real world evidence−（REAL2000）  [通常講演]
    熊谷 融; 井上 彰; 大江裕一郎; 今村文生; 中川和彦; 山本信之; 瀬戸貴司; 岡本 勇; 森田智視; 久保田亜紀; 福岡正博
    第56回日本肺癌学会学術集会 横浜 2015年
  • EGFR遺伝子変異陽性肺癌に対する血漿中cell free DNAを用いたT790M変異検出の臨床的有用性試験WJOG8014LTP  [通常講演]
    高濱隆幸; 坂井和子; 東 公一; 樋田豊明; 平野勝也; 新実彰男; 田中洋史; 海老則之; 澤 祥幸; 別所昭宏; 立原素子; 下川元嗣; 中川和彦; 中西洋一; 西尾和人
    第56回日本肺癌学会学術集会 横浜 2015年
  • ALK阻害剤既治療例を含むALK陽性肺がんに対するアレクチニブの安全性・有効性の最終解析(JP28927試験)  [通常講演]
    村上晴泰; 樋田豊明; 中川和彦; 瀬戸貴司; 里内美弥子; 西尾誠人; 堀田勝幸; 大江裕一郎; 武田晃司; 島田 忠; 田中 智宏; 田村友秀
    第56回日本肺癌学会学術集会 横浜 2015年
  • Clinical benefit of continued therapy with crizotinib beyond initial progression in ALK + NSCLC  [通常講演]
    金田裕靖; 武田真幸; 田中 薫; 吉田健史; 岩朝 勤; 岡本邦男; 高濱隆幸; 清水俊雄; 中川和彦
    第56回日本肺癌学会学術集会 横浜 2015年
  • Global Ph 2 study of ceritinib in ALK inhibitor-na?ve ALK+NSCLC（ASCEND−３）：Japanese subset results  [通常講演]
    Toyoaki Hida; Miyako Satouchi; Takashi Takashi Seto; Kazuhiko Nakagawa; Kota Tokushige; Hiroko Natori; Makoto Nishio
    第56回日本肺癌学会学術集会 横浜 2015年
  • 非小細胞肺癌におけるEGFR−TKI耐性に関わる分子ネットワークの解明  [通常講演]
    吉田健史; Zhang Guolin; Song Lanxi; Haura Eric B; Roche Joelle; Gemmill Robert; Drabkin Harry A; 浦本秀隆; 田中文啓; 岡本 勇; 中川和彦
    第56回日本肺癌学会学術集会 横浜 2015年
  • 高齢者進展型小細胞肺がんにおける臨床試験と実臨床の乖離-アンケート結果からの解析-  [通常講演]
    下川恒生; 三角祐生; 岡本浩明; 安宅信二; 田中洋史; 富澤由雄; 細見幸生; 酒井 洋; 後藤功一; 樋田豊明; 中川和彦; 今村文生; 高山浩一; 大江裕一郎
    第56回日本肺癌学会学術集会 横浜 2015年
  • 高齢者非扁平上皮がんに対するカルボプラチンとペメトレキセド併用療法の多施設第2相試験  [通常講演]
    金田裕靖; 田宮基裕; 中川和彦; 後藤功一; 葉 清隆; 岡本浩明; 下川恒生; 阿部哲也; 田中洋史; 多賀晴子; 武田晃司; 平島智徳; 安宅信二
    第56回日本肺癌学会学術集会 横浜 2015年
  • A randomized ｐhase ? of S-1/CDDP vs.VNR/CDDP with concurrent RT for LA-NSCLC:WJOG5008L  [通常講演]
    大柳文義; 小塚拓洋; 瀬戸貴司; 佐々木智成; 山中竹春; 國武直信; 清水淳市; 古平 毅; 武田真幸; 中松清志; 小野 哲; 原田英幸; 吉村成央; 堤 真一; 北島寛元; 片岡正明; 中川和彦; 西村恭昌; 中西洋一
    第56回日本肺癌学会学術集会 横浜 2015年
  • BEV/プラチナ療法増悪後のnon-SqNSCLCに対するDOC+BEVとDOCの無作為化第?相試験：WJOG5910L  [通常講演]
    林 秀敏; 武田真幸; 山中竹春; 瀬戸貴司; 岡田守人; 東 公一; 菅原俊一; 駄賀晴子; 平島智徳; 米阪仁雄; 浦田佳子; 村上晴泰; 齋藤春洋; 久保昭仁; 澤 祥幸; 宮原栄治; 野上尚之; 中川和彦; 中西洋一; 岡本 勇
    第56回日本肺癌学会学術集会 横浜 2015年
  • ワークショップ Oncogenic and drug-sensitive FGFR2 extracellular domain insertion mutations  [通常講演]
    谷?潤子; Dalia Ercan; Marzia Capellrtti; Michael Dodge; Chunxiao Xu; Magda Bahcall; Lynette Sholl; Peter Hammerman; Geoffrey Oxnard; Kwok-Kin Wong; 中川和彦; Pasi Janne
    第56回日本肺癌学会学術集会 横浜 2015年
  • ワークショップ EGFR遺伝子変異型非小細胞肺癌におけるアファチニブによるEGFR阻害剤への耐性克服治療について  [通常講演]
    米阪仁雄; 工藤慶太; 西田諭美; 高濱隆幸; 武田真幸; 金田裕靖; 中川和彦
    第56回日本肺癌学会学術集会 横浜 2015年
  • シンポジウム 非小細胞肺癌における受容体チロシンキナーゼ遺伝子変異の探索よ昨日解析・問題点  [通常講演]
    冨樫庸介; 水内 實; 林 秀敏; 小林祥久; 中川和彦; 光冨徹哉; 西尾和人
    第56回日本肺癌学会学術集会 横浜 2015年
  • プレナリーセッション 進行再発扁平上皮癌に対するネダプラチン+ドセタキセルとシスプラチン+ドセタキセルの無作為化第３相試験  [通常講演]
    坂 英雄; 宿谷威仁; 山中竹春; 平島智徳; 加藤晃史; 堀尾芳嗣; 安宅信二; 井上貴子; 大崎能伸; 前田忠士; 西 耕一; 澤 祥幸; 岡田守人; 藤本大智; 原田大志; 中川和彦; 中西洋一; 山本信之
    第56回日本肺癌学会学術集会 横浜 2015年
  • ワークショップ 高齢者NSCLCの予後因子としてのLungCancerSubscaleの有用性(JCOG0207,JCOG0803，WJOG4307L統合解析)  [通常講演]
    水谷友紀; 安藤昌彦; 塚田裕子; 阿部徹哉; 武田晃司; 横山 晶; 中村慎一郎; 中川和彦; 山本 昇; 大江裕一郎
    第56回日本肺癌学会学術集会 横浜 2015年
  • ワークショップ 日本人非小細胞肺癌に対する抗PD-１抗体Nivolumabの第?相試験  [通常講演]
    安宅信二; 西尾誠人; 樋田豊明; 中川和彦; 酒井 洋; 野上尚之; 高橋利明; 軒原 浩; 坂 英雄; 竹之山光広; 藤田史郎; 田中洋史; 武田晃司; 里内美弥子; 磯部 宏; 前門戸 任; 後藤功一; 平島智徳; 湊 浩一; 田村友秀
    第56回日本肺癌学会学術集会 横浜 2015年
  • 基調講演 転移性脳腫瘍に対する治療個別化のストラテジー  [通常講演]
    中川和彦
    第53回日本癌治療学会学術集会 京都 2015年
  • Phase ? studies of nivolumab in patients with advanced squamous or non-squamous non-small cell lung cancer  [通常講演]
    Naoyuki Nogami; Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshi Sakai; Shinji Atagi; Toshiaki Takahashi; Hiroshi Nokihara; Tomohide Tamura; 野上尚; 西尾誠人; 樋田豊明; 中川和彦; 酒井洋; 安宅信二; 高橋利明; 軒原浩; 田村友秀
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Study of predictive factor SRE in breast cancer patients during the treatment with zoledronic acid(乳癌骨転移患者におけるゾレドロン酸治療効果と臨床病理学的特徴の関連性についての検討)』  [通常講演]
    柳江正嗣; 鶴谷純司; 田根香織; 谷岡真樹; 藤本伸一郎; 藤原季美子; 山添譲; 千葉康敬; 高尾信太郎; 中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ポスター 前化学療法歴を有する切除不能・再発大腸癌に対するセカンドライン治療CPT-11 ±分子標的薬療法  [通常講演]
    Shinya Ueda; Tsutomu Sakiyama; Masaaki Terashima; Tomohiro Ozaki; Yusaku Akashi; Kazuhiko Nakagawa; 上田眞也; 崎山 勉; 寺嶋応顕; 尾崎智博; 明石雄策; 中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ポスター The safety and efficacy profiling of T-DM1 treatments of metastatic breast cancer patients. 当院における転移性乳癌に対するT-DM1 治療の効果と安全性の検討  [通常講演]
    Tsutomu Iwasa; Kazuhiko Nakagawa; Junji Tsurutani; Satomi Nishida; Yoshifumi Komoike; Yukihiko Hashimoto; Tatsuya Azumi; Wataru Shinzaki; 岩朝 勤; 中川和彦; 鶴谷純司; 西田諭美; 菰池佳史; 橋本彦; 安積達也; 新崎 亘
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ポスター Immune-related response kinetics in patient with melanoma receiving nivolumab, programmed cell death 1 (PD-1) inhibitor  [通常講演]
    Hiroyasu Kaneda; Satomi Nishida; Tsutomu Iwasa; Toshio Shimizu; Kazuya Fukuoka; Kazuhiko Nakagawa
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Docetaxel + ramucirumab (DR) versus docetaxel + placebo (D) as second-line treatment for advanced non-small cell lung cancer (NSCLC): A randomized, phase 2, double-blind, multicenter trial in Japan  [通常講演]
    Yukio Hosomi; Kiyotaka Yoh; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Kaoru Tanaka; Toyoaki Hida; Hiroshige Yoshioka; Terufumi Kato; Koji Takeda; Makoto Nishio; Hiroshi Sakai; Makoto Maemondo; Mitsuhiro Takenoyama; Hiroshi Nokihara; Masumi Tatsumi; Takashi Nakamura; Sotaro Enatsu; Tomohide Tamura; Kazuhiko Nakagawa
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Bevacizumab beyond disease progression in advanced non-squamous NSCLC (WJOG 5910L): a randomized phase?trial.  [通常講演]
    Takashi Seto; Masayuki Takeda; Hidetoshi Hayashi; Koichi Azuma; Morihito Okada; Shunichi Sugawara; Takeharu Yamanaka; Kazuhiko Nakagawa; Yoichi Nakanishi; Isamu Okamoto; 瀬戸貴司; 武田真幸; 林 秀敏; 東 公一; 岡田守人; 菅原俊一; 山中竹春; 中川和彦; 中西洋一
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Randomized phase ? study of nedaplatin+docetaxel vs cisplatin+docetaxel for advanced squamous cell lung cancer: WJOG5208L. 進行・再発肺扁平上皮癌に対するネダプラチン＋ドセタキセル療法とシスプラチンド＋ドセタキセル療 法の無作為化第?相比較試験  [通常講演]
    Haruko Daga; Takehito Shukuya; Takeharu Yamanaka; Takashi Seto; Koichi Goto; Hideo Saka; Shunichi Sugawara; Kazuhiko Nakagawa; Yoichi Nakanishi; Nobuyuki Yamamoto; 駄賀晴子; 宿谷威仁; 山中竹春; 瀬戸 貴司; 後藤功一; 坂 英雄; 菅原俊一; 中川和彦; 中西洋一; 山本信之
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • シンポジウム Safety of crizotinib in 892 Japanese ALK-positive advanced NSCLC patients: Interim report of postmarketing surveillance  [通常講演]
    Isamu Okamoto; Kazuhiko Nakagawa; Yuichiro Ohe; Naomi Ueno; Shigeo Banno; Yutaka Endo; Emiko Ohki; Akihiko Gemma; 岡本; 勇; 中川和彦; 大江裕一郎; 上野直美; 阪野茂生; 遠藤穣; 大木恵美子; 間昭彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ポスター 5-FU/ ドセタキセル/ ネダプラチン併用療法で長期にわたりCR が得られている進行食道癌の一例  [通常講演]
    Hiroto Ueda; Yoshikane Nonagase; Naoki Takegawa; Tatsuya Okuno; Shinichi Nishina; Shinya Ueda; Takao Tamura; Kazuhiko Nakagawa; 野長瀬祥兼; 武川直樹; 奥野達哉; 仁科慎一; 上田眞也; 田村孝雄; 中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Integrative algorithm to determine the metastatic carcinoma tissue of origin using next generation sequencing (NGS) 次世代シークエンサーを用いた原発不明癌に対する原発巣推定アルゴリズム  [通常講演]
    Hidetoshi Hayashi; Shuta Tomida; Yosuke Togashi; Kazuko Sakai; Yoshihiko Fujita; Junji Tsurutani; Issei Kurahashi; Takayasu Kurata; Kazuhiko Nakagawa; Kazuto Nishio; 林 秀敏; 冨田秀太; 冨樫庸介; 坂井和子; 藤田至彦; 鶴谷純司; 倉橋一成; 倉田宝保; 中川和彦; 西尾和人
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Pooled safety analysis of EGFR-TKI treatment for EGFR mutation-positive non-small cell lung cancer.  [通常講演]
    Masayuki Takeda; Isamu Okamoto; Kazuhiko Nakagawa; 岡本 勇; 中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Phase ?/? study of ASP8273 in patients with non-small-cell lung cancer (NSCLC) harboring EGFR activating mutations.  [通常講演]
    Toshio Shimizu; Hiroshi Nokihara; Haruyasu Murakami; Takashi Seto; Makoto Nishio; Koji Takeda; Akira Inoue; Katsuyuki Kiura; Koichi Azuma; Anne Keating; Andrew Krivoshik; Koichi Uegaki; Kentaro Takeda; Kanji Komatsu; Satoshi Morita; Masahiro Fukuoka; Kazuhiko Nakagawa; 清水俊雄; 軒原 浩; 村上晴泰; 瀬戸 貴司; 西尾 誠; 武田晃司; 井上 彰; 木浦勝行; 東 公一; Anne Keating; Andrew Krivoshik; 植垣 幸一; 武田健太朗; 小松完爾; 森田智視; 福岡正博; 中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Phase ? study of erlotinib + onartuzumab as first-line treatment for patients with MET-positive and EGFR-mutant NSCLC.（EGFR 遺伝子変異陽性及びMET 陽性の非小細胞肺癌を対象としたオナルツズマブと エルロチニブ併用 療法の第?相臨床試験）  [通常講演]
    Hiroshi Sakai; Kazuma Kishi; Takashi Seto; Toshiyuki Kozuki; Makoto Nishio; Fumio Imamura; Hiroshi Nokihara; Miyako,Satouchi; Takashi Tahata; Kazuhiko Nakagawa; 酒井洋; 岸 一馬; 瀬戸貴司; 上月稔幸; 西尾誠人; 今村文生; 軒原浩; 里内美弥子; 田畠崇史; 中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • インターナショナルセッション Updates on PFS and safety results of a Phase ?/? study (AF-001JP) of alectinib in ALK -rearranged advanced NSCLC.（ALK融合遺伝子陽性非小細胞肺癌を対象としたアレクチニブの第?/?相臨床試験（AF-001JP）におけるPFS並びに安全性情報の更新）  [通常講演]
    上月稔幸; 西尾誠人; 木浦勝行; 瀬戸貴司; 中川和彦; 前門戸任; 井上 彰; 樋田豊明; 田中智宏; 田村友秀
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • メディカルセミナー 乳癌診療ガイドライン2015年度版を日常診療にどう役立てるか？〜ホルモン受容体養成転移・再発乳癌におけるエベロリムスの位置づけ〜  [通常講演]
    鶴谷純司; 藤澤知巳
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ポスターディスカッション Woman in Oncology：Progress and Challenges （腫瘍学学会における女性会員の役割 海外学会や日本の他学会との相違）  [通常講演]
    鶴谷純司
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Joint Symposium Liquid biopsy could revolutionize cacer care （がん診療におけるリキッドバイオプシーの可能性）  [通常講演]
    鶴谷純司
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • Asia & Oceania Joint Symposium Current status in Japan (日本の現状)  [通常講演]
    中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ARCHER 1050：First-line dacomitinib vs gefitinib for advanced NSCLC in patients with EGFR activating mutation(s)  [通常講演]
    中川和彦
    第13回日本臨床腫瘍学会学術集会 札幌 2015年
  • ポスター掲示 原発性乳癌における乳房MRIの副病変評価の検討  [通常講演]
    安積達也; 久保田倫代; 濱田未佳; 新崎 亘; 藤島 成; 橋本幸彦; 乾 浩己; 北條敏也; 大和宗久; 西田諭美; 岩朝 勤; 鶴谷純司; 金森修一; 菰池佳史
    第23回日本乳癌学会学術総会 東京 2015年
  • ポスター掲示 ホルモン陽性転移・再発乳癌に対するフルベストラントの治療成績-実験例51例の後ろ向き検討-  [通常講演]
    菰池佳史; 久保田倫代; 濱田未佳; 新崎 亘; 安積達也; 橋本幸彦; 乾 浩己; 北條敏也; 西田諭美; 岩朝 勤; 鶴谷純司; 藤島 成; 大和宗久
    第23回日本乳癌学会学術総会 東京 2015年
  • ポスター討議 乳癌骨転移におけるゾレドロン酸治療に関する後ろ向きコホート研究  [通常講演]
    田根香織; 柳江正嗣; 鶴谷純司; 谷岡真樹; 藤本伸一郎; 藤原季美子; 山添 譲; 千葉康敬; 中川和彦; 菰池佳史; 高尾信太郎
    第23回日本乳癌学会学術総会 東京 2015年
  • ポスター討議 進行再発乳癌に対する早期レジメンとしてのErbulinの有効性・安全性の検討(SONG−BC01)  [通常講演]
    松並展輝; 阿部 元; 鶴谷純司; 岩朝 勤; 森島宏隆; 小田直文; 玉川孝治; 谷島裕之; 神垣俊二; 山村順; 稲治英生; 西 敏夫; 中野芳明; 萩野信夫; 山崎圭一; 菰池佳史; 手塚健志; 新田敏勝; 平井昭彦; 中川和彦
    第23回日本乳癌学会学術総会 東京 2015年
  • ポスター討議 当院におけるTDM-1使用状況に関して  [通常講演]
    岩朝勤; 西田諭美; 鶴谷純司; 中川和彦; 新崎 亘; 安積達也; 橋本幸彦; 菰池佳史
    第23回日本乳癌学会学術総会 東京 2015年
  • 一般セッション 乳癌術後薬物療法施行患者のQOL、副作用軽減、免疫指標に及ぼすLEMの効果に関する臨床研究  [通常講演]
    長島由紀子; 安積達也; 岩朝 勤; 鶴谷純司; 中川和彦; 前田訓子; 山本 滋; 岡 正朗
    第23回日本乳癌学会学術総会 東京 2015年
  • イブニングセミナー2 FNマネジメントのプラクティスギャップを埋める Bridging the gap of FN management between foreign countries and Japan  [通常講演]
    Louis Wing-Cheong Chow; 柏葉匡寛; 鶴谷純司
    第23回日本乳癌学会学術総会 東京 2015年
  • Alectinibによる治療後に小細胞肺癌・扁平上皮癌への形質転換を認めたALK融合遺伝子陽性肺癌の1例  [通常講演]
    高濱隆幸; 林 秀敏; 武川直樹; 植田勲人; 吉田健史; 岩朝 勤; 田中 薫; 武田真幸; 中川和彦
    第102回日本肺癌学会関西支部会学術集会 大阪 2015年
  • 肺がんにおける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定  [通常講演]
    谷?潤子; 武田真幸; 清水俊雄; 金田裕靖; 田中 薫; 岩朝 勤; 吉田健史; 高濱隆幸; 中川和彦; 坂井和子; 西尾和人
    第102回日本肺癌学会関西支部会学術集会 大阪 2015年
  • KRAS遺伝子変死陽性肺がんの臨床的特徴  [通常講演]
    林 秀敏; 武田真幸; 金田裕靖; 鶴谷純司; 中川和彦; 寺嶋雅人; 坂井和子; 西尾和人
    第102回日本肺癌学会関西支部会学術集会 大阪 2015年
  • 非詳細肺癌におけるEGFR−TKI耐性に関わる分子ネットワークの解明  [通常講演]
    吉田健史; 中川和彦
    第102回日本肺癌学会関西支部会学術集会 大阪 2015年
  • 扁平上皮癌への転化をj来したEGFR遺伝子変死陽性肺腺癌の2例  [通常講演]
    原谷浩司; 林 秀敏; 西田諭美; 金田裕靖; 吉田健史; 武田真幸; 中川和彦
    第102回日本肺癌学会関西支部会学術集会 大阪 2015年
  • 当科における非小細胞肺がんに対する re-biopsyの検討  [通常講演]
    田中 薫; 西田諭美; 原谷浩司; 野長瀬祥兼; 高濱隆幸; 吉田健史; 岩朝 勤; 林 秀敏; 武田真幸; 金田裕靖; 中川和彦
    第102回日本肺癌学会関西支部会学術集会 大阪 2015年
  • ALK陽性完全切除不能進行肺癌に対し化学療法および分子標的治療後にサルベージ手術を行った1例  [通常講演]
    阪口全宏; 須田健一; 岩崎拓也; 武本智樹; 富沢健二; 佐藤克明; 水内寛; 下治正樹; 小林祥久; 岡部崇記; 金田 裕靖; 中川和彦; 光冨徹哉
    第32回日本呼吸器外科学会 高松 2015年
  • ミニシンポジウム 肺がんにおける次世代シーケンサーを用いた変異解析に基づく分子標的薬適応決定  [通常講演]
    武田真幸; 坂井和子; 田中 薫; 吉田健史; 岩朝 勤; 高濱隆幸; 野長瀬祥兼; 岡部崇記; 林 秀敏; 岡本邦男; 金田裕靖; 清水俊雄; 西尾和人; 中川和彦
    第55回日本呼吸器学会学術講演会 東京 2015年
  • ミニシンポジウム 進展型小細胞肺がん(ED−SCLC)に対するCPT-11維持療法の忍容性試験  [通常講演]
    梅村茂樹; 細見幸生; 野上尚之; 西尾誠人; 山本昇; 中川和彦; 瀬戸貴司; 里内美弥子; 阿部徹哉; 近森研一; 野村尚吾; 後藤功一; 田村友秀; 大江裕一郎
    第55回日本呼吸器学会学術講演会 東京 2015年
  • ポスター EGFR遺伝子変異陽性非小細胞肺癌に対するerlotinibの初回治療における有用性の検討  [通常講演]
    西田諭美; 金田裕靖; 田中薫; 吉田健史; 岩朝勤; 工藤慶太; 高濱隆幸; 武田真幸; 清水俊雄; 中川和彦
    第122回日本内科学会講演会 京都 2015年
  • 再発進行乳癌におけるエリブリンとTS-1療法の検討  [通常講演]
    岩朝 勤; 西田諭美; 田中 薫; 工藤慶太; 吉田健史; 武田真幸; 金田裕靖; 清水俊雄; 鶴谷純司; 中川和彦
    第122回日本内科学会講演会 京都 2015年
  • 化学療法中に間質性肺炎増悪を来した肺癌患者転帰の後ろ向き検討  [通常講演]
    高濱隆幸; 金田裕靖; 田中 薫; 工藤慶太; 岩朝 勤; 吉田健史; 武田真幸; 清水俊雄; 鶴谷純司; 中川和彦
    第122回日本内科学会講演会 京都 2015年
  • がん疼痛治療におけるバイオマーカー探索  [通常講演]
    松岡弘道; 牧村ちひろ; 大塚正友; 酒井清裕; 阪本 亮; 小山敦子; 西尾和人; 中川和彦; 藤田至彦; 鶴谷純司
    第122回日本内科学会講演会 京都 2015年
  • 肺がんにおける次世代シーケンサーを用いた変死解析に基づく分子標的薬適応決定  [通常講演]
    武田真幸; 清水俊雄; 金田裕靖; 田中 薫; 岩朝 勤; 吉田健史; 高濱隆幸; 坂井和子; 西尾和人; 中川和彦
    第122回日本内科学会講演会 京都 2015年
  • リン酸化プロテオミクスを用いた非小細胞肺癌におけるEGFR-TKI耐性に関わる分子ネットワークの解析  [通常講演]
    吉田健史; Guolin Zhang; Matthew Smith; 岡部崇記; 岡本勇; Eric Haura; 中川和彦
    第122回日本内科学会講演会 京都 2015年
  • Pooled safety analysis of EGFR-TKI therapy in patients with EGFR-mutated non-small cell lung cancer  [通常講演]
    Masayuki Takeda; Isamu Omoto; Kazuhiko Nakagawa
    2014 ASCO Annual Meeting 2014年
  • Antitumor activity of alectinib(CH5424802/RO542802)for ALK-rearranged NSCLC with or without prior crizotinib treatment in bioequivalence study  [通常講演]
    Kazuhiko Nakagawa; Toyoaki Hida; Miyako Satouchi; Makoto Nishino; Katsuyuki Hotta; Haruyasy Murakami; Yuichiro Ohe; Koji Takeda; Masahiro Tatuno; Naoki Yoshikawa; Tomohiro Tanaka; Tomohide Tamura
    2014 ASCO Annual Meeting 2014年
  • P-816.喫煙によるニコチン曝露はEGFR遺伝子変異陽性肺癌においてEGFR-TKIの耐性因子である  [通常講演]
    林 秀敏; 冨樫 庸介; 岡本 邦男; 田中妙; 文田壮一; 新田亮多; 清川寛文; 坂本洋一; 寺嶋 雅人; Velasco Marco A de; 坂井 和子; 藤田 至彦; 冨田 秀太; 加藤元紀一; 中川 和彦; 西尾 和人
    第55回日本肺癌学会総会 2014年
  • PD-113.肺がん患者に対するマグネシウム補充によるシスプラチン関連腎障害の抑制効果の検討  [通常講演]
    木寺康裕; 川上尚人; 金田裕靖; 藤原季美子; 野村守弘; 千葉康敬; 西田升三; 山添譲; 鶴谷純司; 田村孝雄; 中川和彦
    第55回日本肺癌学会総会 2014年
  • 抗 HER3 抗体 Patritumab Patritumab による による Heregulin Heregulin 依存性 EGFR 阻害剤耐性の克服について  [通常講演]
    米阪仁雄
    第55回日本肺癌学会総会 2014年
  • EGFR 変異 NSCLC に於ける EGFR -TKI の tumor response, shrinkage pattern tumor response, shrinkage pattern tumor response, shrinkage pattern tumor response, shrinkage pattern tumor response, shrinkage pattern tumor response, shrinkage pattern tumor response, shri  [通常講演]
    武田 真幸; 岡本 勇; 中川 和彦
    第55回日本肺癌学会総会 2014年
  • ペメトレキセド、カルボプラチン投与後脳梗塞を発症した症例の検討  [通常講演]
    武田 真幸; 小林 岳彦; 丸毛 聡; 古下 義彦; 寺西 敬; 樋上 雄一; 加藤元一
    第55回日本肺癌学会総会 2014年
  • 肺癌に於ける次世代シーケンサを用いた変異解析基づく分子標的薬適応決  [通常講演]
    武田 真幸; 清水 俊雄; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆幸; 野 長瀬 祥兼; 岡部 崇記; 林 秀敏; 岡本 邦男; 坂井和子; 西尾和人; 中川和彦
    第55回日本肺癌学会総会 2014年
  • 切除不能局所進行肺扁平上皮癌に対する DE-766+CDDP+VNR+胸部放射線療法の無作為化第?相試験  [通常講演]
    田中 薫; 林 秀敏; 軒原 浩; 益田 典幸; 久保田 馨; 澤 祥幸; 高橋 利明; 野上 尚之; 高田 昇平; 早川 和重; 西西村 泰昌; 山本 信之; 田村友秀; 福岡 正博; 浅見 由美子; 井上 悟; 中川 和彦
    第55回日本肺癌学会学術集会 2014年
  • EGFR 遺伝子変異陽性非小細胞肺癌に対する 遺伝子変異陽性非小細胞肺癌に対する 遺伝子変異陽性非小細胞肺癌に対する erlotinib erlotinib の初回治療における有用 の  [通常講演]
    西田 諭美; 金田 裕靖; 工藤 慶太; 田中 薫; 吉田 健史; 岩朝 勤; 高濱 隆 幸; 武田 真幸; 清水 俊雄; 中川 和彦
    第55回日本肺癌学会総会 2014年
  • 日本人進行固形がん患者に対する 日本人進行固形がん患者に対する MK -34753475 （抗 PD -1抗体）の第 I相  [通常講演]
    清水 俊雄; 瀬戸 貴司; 平井 文彦; 竹中 朋祐; 鶴谷 純司; 金田 裕靖; 岩朝 勤; 川上 尚人; 野口 一夫; 嶋本 隆司; 中川 和彦
    第55回日本肺癌学会総会 2014年
  • 化学療法中に間質性肺炎増悪を来した癌患者転帰の後ろ向き検討  [通常講演]
    高濱 隆幸; 金田 裕靖; 田中 薫; 植田 勲人; 西田 諭美; 武川 直樹; 野長瀬 祥兼; 工藤 慶太; 岩朝 勤; 吉田 健史武田; 真幸; 清水 俊雄; 鶴谷 純司; 田村 孝雄; 中川 和彦
    第55回日本肺癌学会総会 2014年
  • P-338.副腎転移巣の破裂、出血により急激な全身状態悪化を来した原発性肺扁平上皮癌の一例  [通常講演]
    中田有紀; 高濱隆幸; 田中 薫; 植田勲人; 西田諭美; 武川直樹; 野長瀬祥兼; 工藤慶太; 岩朝 勤; 吉田健史; 武田真幸; 金田裕靖; 清水俊雄; 鶴谷純司; 田村孝雄; 中川和彦
    第55回日本肺癌学会総会 2014年
  • 新しい血管 新生阻害薬 新生阻害薬 Nintedanib (BIBF1120) Nintedanib (BIBF1120) Nintedanib (BIBF1120) の開発状況と最新情報 の開発状況と最新情報  [通常講演]
    金田裕靖
    第55回日本肺癌学会学術集会 2014年
  • EGFR -TKI 耐性の EGFR 変異陽性 NSCLC を対象とした を対象とした tivantinib (ARQ 197) tivantinib (ARQ 197) tivantinib (ARQ 197)tivantinib (ARQ 197) とエル ロチニブ併用の第 2相試験  [通常講演]
    金田 裕靖; 東 公一; 平島 智徳; 山本 信之; 高橋 利明; 西尾 誠人; 平田 泰三; 久保田 馨; 笠原 寿郎; 樋田 豊明; 吉岡 弘鎮; 鈴木 康平; 秋永士朗; 西尾和人; 光冨徹哉; 中川 和彦
    第55回日本肺癌学会 2014年
  • Phase I study of CO-1686、an irreversible mutant-selective inhibitor of EGFR mutations、in Japanese patients with T79M-positive NSCLC  [通常講演]
    金田裕靖; 清水俊雄; 樋田豊明; 村上晴泰; 軒原 浩; Jowell GO; Sarah Jqw-Tsai; Lindsey Rolfe; 中川和彦
    第55回日本肺癌学会 2014年
  • リン酸化プロテオミクスを用いた非小細胞肺癌におけるEGFR-TKI耐性に関わる分子ネットワークの解析  [通常講演]
    吉田健史; Guolin Zhang; Matthew; A. Smith、Alex; S. Lopez; Yun Bai; Jiannong Li; Bin Fang; John Koomen; Bhupendra Rawal; Kate J,Fisher; Ann; Y. Chen; 岡部崇記; 岡本 勇; 中川和彦; Eric B,Haura
    第55回日本肺癌学会 2014年
  • P-941.肺がん終末期呼吸困難の緩和に対する鎮静の検討と医療者の関わり  [通常講演]
    春木沙織; 山崎麻未; 中尾有花; 金田裕靖; 中川和彦
    第55回日本肺癌学会総会 2014年
  • O-111.高齢者LD-SCLCに対するシスプラチン分割投与+エトポシドと胸部加速過分割照射同時併用療法の第?相試験  [通常講演]
    岡本邦男; 岡本 勇; 武田真幸; 武田晃司; 中松清志; 小林真也; 林 秀敏; 西村恭昌; 中川和彦
    第55回日本肺癌学会総会 2014年
  • PD-90.新規ALK阻害剤であるアレクチニブをMET阻害剤との併用で効果が高まる  [通常講演]
    冨樫庸介; 林 秀敏; 寺嶋雅人; 坂井和子; 藤田至彦; 冨田秀太; 中川和彦; 西尾和人
    第55回日本肺癌学会総会 2014年
  • P-193.低酸素はALK融合遺伝子を有するH3122肺癌細胞株のALK阻害剤に対する耐性化を誘導する  [通常講演]
    冨樫庸介; 林 秀敏; 寺嶋雅人; 坂井和子; 藤田至彦; 冨田秀太; 中川和彦; 西尾和人
    第55回日本肺癌学会総会 2014年
  • 切除不能大腸癌に対するFOLFOX+bevacizumab（Bev）とFOLFIRI+Bev の第?相試験WJOG4407G  [通常講演]
    田村孝雄; 山崎健太郎; 奥野達哉; 仁科智裕; 大石達郎; 栗本拓也; 高山 哲治; 根来 裕二; 吉田 元樹; 杉山敏郎; 柴田義宏; 安藤昌彦; 森田 智視; 朴 成和; 兵頭一之介
    第52回日本癌治療学会学術集会 2014年
  • 新規分子標的治療開発状況  [通常講演]
    中川 和彦
    第52回日本癌治療学会学術集会 2014年
  • 抗がん薬化学療法における制吐療法を効果的に行うための多職種連携  [通常講演]
    中川 和彦
    第52回日本癌治療学会学術集会 2014年
  • 転移・再発乳癌患者における化学療法の現状と未来：日本発のエビデンス−SELECT BC  [通常講演]
    鶴谷 純司; 高島 勉; 原 文堅; 相良 吉昭; 渡辺 隆紀; 穂積 康夫; 井本 滋; 西村 令喜; 大橋 靖雄; 向井 博文
    第12回日本臨床腫瘍学会学術集会 2014年
  • First-line crizotinib vs. pemetrexed + cisplatin/carboplatin in Asian patients with advanced ALK+ NSCLC in PROFILE 1014  [通常講演]
    Kazuhiko Nakagawa; Dong-Wan Kim; Yi-Long Wu; Benjamin J. Solomon; Tarek Mekhai; Enriqueta Felip; Frederico; Cappuzzo,Fiona Blackhall; Tiziana Usari; Tony Mok
    第12回日本臨床腫瘍学会学術集会 2014年
  • EGFR遺伝子変異陽性患者におけるEGFR阻害剤の耐性後の投与期間についての検討  [通常講演]
    岡本 邦男; 林 秀敏; 高濱 隆幸; 文田 壮一; 田中 薫; 加藤 元一; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 当初高度リンパ節転移を疑われるも全身化学療法で手術転換が可能となった進行胃癌の1例  [通常講演]
    奥野 達哉; 池田 篤紀; 孝橋 道敬; 藤島 佳未; 鎮西 亮; 金光 聖哲; 今西 達也; 黒田 大介; 掛地 吉弘; 東 健
    第12回日本臨床腫瘍学会学術集会 2014年
  • 乳癌術後化学放射線療法中に二次性血液腫瘍を来した症例の検討  [通常講演]
    高濱 隆幸; 岩朝 勤; 鶴谷 純司; 新崎 亘; 安積 達也; 橋本 幸彦; 菰池 佳史; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 膵癌、大腸癌の重複癌に対してSOX-Bevacizumabが奏効した1例  [通常講演]
    高濱 隆幸; 野長瀬 祥兼; 崎山 勉; 川上 尚人; 仁科 慎一; 田村 孝雄; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 進行再発食道癌に対するドセタキセル、ネダプラチン、5-FUによる第一相試験  [通常講演]
    仁科 慎一; 上田 眞也; 野長瀬 祥兼; 岡部 崇記; 崎山 努; 川上 尚人; 田村 孝雄; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 肝機能障害を呈する胃癌肝転移患者に対しカペシタビンとシスプラチン併用療法が安全かつ効果的に投与で きた一例  [通常講演]
    野長瀬 祥兼; 崎山 勉; 濱 隆幸; 川上 尚人; 仁科 慎一; 田村 孝雄; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 非小細胞肺癌における抗HER3抗体PatritumabとErlotinib併用治療のBiomarkerであるHER3 Ligandのheregulin について  [通常講演]
    米阪 仁雄; 川上 尚人; 金田 裕靖; 岡本 勇; 廣谷 賢志; 西尾 和人; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 喫煙に伴うニコチン長期曝露によってEGFR遺伝子変異陽性肺癌はEGFR-TKIに耐性化を示す  [通常講演]
    林 秀敏; 冨樫 庸介; 岡本 邦男; 文田 壮一; 寺嶋 雅人; 坂井 和子; 藤田 至彦; 冨田 秀太; 中川 和彦; 西尾 和人
    第12回日本臨床腫瘍学会学術集会 2014年
  • EGFR変異NSCLCに於けるEGFR-TKI のtumor response, shrinkage patternによる生存の検討  [通常講演]
    武田 真幸; 岡本 勇; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • Clinical benefit of continued therapy with crizotinib beyond initial disease progression in advanced ALK positive NSCLC  [通常講演]
    金田 裕靖; 武田 真幸; 田中 薫; 吉田 健史; 岩朝 勤; 岡本 邦男; 川上 尚人; 高濱 隆幸; 清水 俊雄; 中川 和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • Tumor genomic profiling of NSCLC from the phase III trial of first-line S-1/CBDCA versus paclitaxel/CBDCA （WJOG6611LTR）  [通常講演]
    金田 裕靖; 岡本 勇; 坂井 和子; 森田 智視; 山 浩一; 富井 啓介; 前田 忠士; 中川 和彦; 中西 洋一; 西尾和人
    第12回日本臨床腫瘍学会学術集会 2014年
  • 進行・再発乳癌患者を対象としたEribulin/S-1併用療法の臨床第?相試験  [通常講演]
    岩朝 勤; 山 勉; 鶴谷純司; 田中 薫; 吉田健; 野長瀬祥兼; 藤阪保仁; 倉田宝保; 菰池佳史; 中川和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • EGFR陽性進行非小細胞肺癌に対する選択的サバイビン阻害剤YM155+エルロチニブ併用臨床第1相試験  [通常講演]
    清水俊雄; 岡本 勇; 西尾和人; 坂井和子; 會田秀巳; 橋井千昌; 青山幸司; 森下麻依子; 中川和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 日本における高齢化対策  [通常講演]
    中川和彦
    第12回日本臨床腫瘍学会学術集会 2014年
  • 肺癌診療の変貌ーゲフィチニブ登場から10年  [通常講演]
    中川和彦
    第31回日本脳腫瘍学会学術集会 2013年
  • エリブリンと各種乳癌治療薬との交又耐性の検討  [通常講演]
    鶴谷純司; 松岡弘道; 岡本邦男; 清水俊雄; 倉田宝保; 中川和彦; 藤島 成; 安積達也; 橋本幸彦; 菰池佳史
    第21回日本乳癌学術総会 2013年
  • 転移性乳癌患者におけるエリブリンの臨床効果と安全性プロファイル  [通常講演]
    﨑山 勉; 鶴谷純司; 谷﨑潤子; 松岡弘道; 岡本邦男; 清田秀美; 倉田宝保; 中川和彦
    第110回日本内科学会講演会 2013年
  • A phase I/Ib study of trametinib alone and with gemcitabine in Japanese patients  [通常講演]
    Shinichi Nishina; Junji Furuse; Takayasu Kurata; Akiyoshi Kasuga; Yasuhito Fujisaka; Hiroshi Kitamura; Toshio Shimizu; Atsuko Takasu; Wataru Okamoto; Daisuke Naruge; Fumio Nagashima; Kazuo Nagamatsu; Akihira Mukaiyama; Hideki Matsushita; Kazuhiko Nakagawa
    第51回日本癌治療学会学術集会 2013年
  • サバイビンを標的としたEGFRチロシンキナーゼ阻害剤に対する耐性克服  [通常講演]
    岡本 勇; 岡本邦男; 清水俊雄; 中川和彦; 九州大学病院呼吸器科; ARO; 近畿大学医学部腫瘍内科
    第17回日本がん分子標的治療学会学術集会 2013年
  • 個別化multiplexの体外診断薬承認に向けて  [通常講演]
    坂井和子; 冨田秀太; 光冨徹夜; 中川和彦; 西尾和人
    第17回日本がん分子標的治療学会学術集会 2013年
  • 『肺がん診療の変貌―ゲフィチニブ登場から10年』  [通常講演]
    中川和彦
    第31回日本脳腫瘍学会学術集会 2013年
  • 『Best of WCLC2013』  [通常講演]
    中川和彦
    第54回日本肺癌学会総会 2013年
  • 『進行胸腺癌に対するCarboplatin+Paclitaxel併用療法の臨床第２相試験(WJOG4207L)』  [通常講演]
    田中薫; 平井文彦; 山中竹春; 田口健一; 武田晃司; 駄賀晴子; 清水淳市; 小暮啓人; 木村達郎; 岩本康男; 小野 哲; 佐々木秀文; 福岡順也; 西山憲一; 瀬戸貴司; 一瀬幸人; 中川和彦; 中西洋一
    第54回日本肺癌学会総会 2013年
  • 『EGFR遺伝子変異もしくはALK転座陽性，局所進行非小細胞肺癌における放射線治療の治療成績』  [通常講演]
    林 秀敏; 岡本 勇; 木村英晴; 西村恭昌; 西尾和人; 中川和彦
    第54回日本肺癌学会総会 2013年
  • 『胃癌におけるMET amplification の発現頻度と臨床的意義』  [通常講演]
    川上尚人; 岡本 勇; 荒尾徳三; 岡本 渉; 松本一男; 谷口博一; 桑田季代子; 山口 永; 西尾和人; 中川和彦; 山田康秀
    第51回日本癌治療学会学術集会 2013年
  • A Phase I/Ib study of study of trametinib alone and with gemcitabine in Japanese patients』  [通常講演]
    NishinaShinichi; JunjiFuruse; TakayasuKurata; AkiyoshiKasuga; Yasuhito Fujisaka; HiroshiKitamura,ToshioShimizu; AtsukoTakasu; Wataru Okamoto; DaisukeNaruge; FumioNagashima; KazuoNagamastu; AkihiraMukaiyama; Hideki Mastushita; KazuhikoNakagawa
    第51回日本癌治療学会学術集会 2013年
  • 『我が国の肺癌臨床試験の国際競争力 』  [通常講演]
    中川和彦
    第51回日本癌治療学会総会 2013年
  • 『非小細胞肺癌2次治療における治療増悪後生存期間』  [通常講演]
    林秀敏; 岡本勇; 田栗正隆; 森田智視; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『Biomarker analysis of WJOG4107(A randomized phase ? trial of adjuvant chemotherapy with S-1 vs CDDP+S-1 in NSCLC)』  [通常講演]
    武田真幸; 光冨徹哉; 西尾和人; 岩本康男; 山中竹春; 吉岡弘鎮; 塚本修一; 小池輝明; 中川和彦; 中西洋一
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『Additional analysis of WJTOG0105 comparing second and third-generaion regimens with TRT in unresectable stage ? NSCLC』  [通常講演]
    金田裕靖; 里内美弥子; 千葉康敬; 山本信之; 西村恭昌; 藤阪保仁; 工藤新三; 樋田豊明; 安宅信二; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • HER２陽性進行再発胃癌に対するS-1+CDDP+Trastuzumab療法第?相試験(HERBIS-1)  [通常講演]
    仁科慎一; 田中淳二; 杉本直俊; 下川敏雄; 坂井大介; 黒川幸典; 小松嘉人; 高畑武功; 辻仲利政; 古河洋
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『ＥＧＦＲ，ＨＥＲ２及びＨＥＲ３阻害剤ＡＺＤ8931の第1相試験-進行固形癌患者対象の単剤投与及び進行再発乳癌患者対象のパクリタキセル-』  [通常講演]
    鶴谷純司; 倉田宝保; 藤阪保仁; 岡本渉; 林秀敏; 川上尚人; 辛栄成; 林暢哉; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『Phase I study of amatuximab in patients with advanced solid tumors.』  [通常講演]
    藤阪保仁; 倉田宝保; 田中薫; 工藤敏啓; 岡本邦男; 鶴谷純司; 金田裕靖; 北村智史; 並木雅幸; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『高齢者限局型小細胞肺癌に対するシスプラチン分割投与+エトポシドと胸部放射線加速過分割照射同時併用療法の第?相試験』  [通常講演]
    岡本邦男; 岡本勇; 田中薫; 金田裕靖; 岩朝勤; 武田真幸; 小林真也; 武田晃司; 西村恭昌; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『Crizotinibvs.pemetrexed or docetaxel in Japanese patients advanced ALK＋NSCLC：subanalysis of PROFILE1007』  [通常講演]
    中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『再発進行頭頸部癌に対するS-1顆粒とネダブラチン併用療法の臨床第１相試験』  [通常講演]
    田中薫; 林秀敏; 岡本勇; 上田眞也; 岡本邦男; 川上尚人; 仁科慎一; 武田真幸; 土井勝美; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『MET amplification as a potential therapeutic target in gastric cancer』  [通常講演]
    川上尚人; 岡本勇; 荒尾徳三; 岡本渉; 松本和子; 谷口弘和; 西尾和人; 中川和彦; 山田康秀
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『COMT Genotype and patients’recognition of pain reduction are predivtive makers for the response to morphine treatment』  [通常講演]
    松岡弘道; 荒尾徳三; 牧村ちひろ; 松本和子; 木村英晴; 今村ちよ; 谷川原祐介; 西尾和人; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『未承認薬を用いたグローバルオペレーション医師主導治験実施に関する施設インフラ体制確立の挑戦』  [通常講演]
    清水俊雄; 金田裕靖; 鶴谷純司; 岡本邦男; 田中薫; 大西理都子; 野村守弘; 曾田秀巳; 橋井千晶; 中川和彦
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『再発乳癌に対するエリブリン単剤での治療効果および悪性度・前治療との相関についての検討』  [通常講演]
    岩朝勤; 鶴谷純司; 松岡弘道; 岡本邦男; 清水俊雄; 倉田宝保; 中川和彦; 安積達也; 橋本幸彦; 菰池佳史
    第11回日本臨床腫瘍学会学術集会 2013年
  • 『Clinical significance of humen papillomavirus in orophryngeal cancer』  [通常講演]
    Hisato Kawakami; IsamuOkamoto; KyouichiTerao; KazukoSakai,SuzukiMinoru; KojiOno,KazutoNishio; YasumasaNIsimura; KatsumiDoi; KazuhikoNakagwa
    10．ASCO/JSMO Joint Symposium 第11回日本臨床腫瘍学会学術集会 2013年
  • 『エリブリンと各種乳癌治療薬との交叉耐性の検討』  [通常講演]
    鶴谷純司; 松岡弘道; 岡本邦男; 清水俊雄; 倉田宝保; 中川和彦; 藤島成; 安積達也; 橋本幸彦; 菰池佳史
    第21回日本乳癌学術総会 2013年
  • 『プレガバリン投与後の神経障害性疼痛へのデュロキセチンの可能性』  [通常講演]
    松岡弘道; 牧村ちひろ; 大塚正友; 阪本亮; 酒井清裕; 小山敦子; 中川和彦
    第18回日本緩和医療学会学術大会 2013年
  • 『進行・再発頭頚部扁平上皮癌に対するネダプラチン・S-1顆粒製剤の第?相臨床試験』  [通常講演]
    林 秀敏; 上田眞也; 田中 薫; 岡本 勇; 中川和彦
    第110回日本内科学会講演会 2013年
  • 『中枢気道狭窄に対する気道ステントの症状緩和とQOLに対する有用性の検討』  [通常講演]
    田中 薫; 宮?昌樹; 岡本邦男; 林 秀敏; 清田秀美; 上田眞也; 金田裕靖; 鶴谷純司; 岡本 勇; 中川和彦
    第110回日本内科学会講演会 2013年
  • 『進行再発食道癌に対するネダプラチンを用いた化学療法』  [通常講演]
    仁科慎一; 上田眞也; 岡本 渉; 川上尚人; 山 勉; 岡本邦男; 金田裕靖; 田中 薫; 吉田健史; 中川和彦
    第110回日本内科学会講演会 2013年
  • 『EML4−ALK陽性進行非小細胞肺癌における初回白金併用化学療法の治療効果の検討』  [通常講演]
    武田真幸; 岡本 勇; 坂井和子; 川上尚人; 西尾和人; 中川和彦
    第110回日本内科学会講演会 2013年
  • 『転移性乳がん患者におけるエリブリンの臨床効果と安全性プロファイル』  [通常講演]
    ??R?; C?ߒJ?; i; C; C; O?; M?j?C???c?G?; C?q?c???; C; ??a?F
    第110回日本内科学会講演会 2013年
  • プレガバリン投与後の神経障害性疼痛へのヂュロキセリンの可能性  [通常講演]
    松岡弘道; 牧村ちひろ; 大塚正友; 阪本亮; 酒井清裕; 小山敦子; 中川和彦
    第18回日本緩和医療学会学術大会 2013年
  • 当科におけるがん患者と主治医の軋轢の要因に関する調査と分析  [通常講演]
    鶴谷純司; 松岡弘道; 牧村ちひろ; 野長瀬祥兼; 岡本邦男; 田中 薫; 仁科慎一; 清水俊雄; 小山敦子; 中川和彦
    第26回日本サイコオンコロジー学会総会 2013年
  • 腫瘍内科医が受けるストレス度、満足度についての当科でのアンケート調査  [通常講演]
    野長瀬祥兼; 山 勉; 川上尚人; 松岡弘道; 田村孝雄; 小山敦子; 中川和彦
    第26回日本サイコオンコロジー学会総会 2013年
  • チームでの精神的サポートが効果的であった若年横紋筋肉腫の1例  [通常講演]
    田中 薫; 小山富美子; 内藤隆行; 濱田 傑; 安岡良文; 栗田隆志; 小山敦子; 中川和彦
    第26回日本サイコオンコロジー学会総会 2013年
  • エリブリンの治療効果における前治療歴、癌の悪性度との関連についての検討  [通常講演]
    崎山 勉
    第51 回 日本癌治療学会学術集会 2013年
  • クリゾチニブのre-challengeにより腫瘍縮小効果を認めたALK陽性肺がんの1例  [通常講演]
    田中 薫; 松岡弘道; 倉田宝保; 金田裕靖; 岡本 勇; 中川和彦
    第97回日本肺癌学会関西支部会，大阪 2013年
  • クリゾチニブによる放射線治療無効脳転移の著名な縮小が認められたALK陽性肺腺癌の１例  [通常講演]
    金田裕靖; 岡本 勇; 田中 薫; 吉田健史; 岩朝 勤; 岡本邦男; 山 勉; 清水俊雄; 藤阪保仁; 倉田宝保; 中川和彦
    第97回日本肺癌学会関西支部会，大阪 2013年
  • 嚢胞性脳転移を認めたALK陽性肺がんの2例  [通常講演]
    林 秀敏; 岡本 勇; 田中 薫; 谷?潤子; 中川和彦; 奥田武司; 加藤天美; 西村恭昌
    第97回日本肺癌学会関西支部会，大阪 2013年
  • What can WJOG and JCOG contribute to Japan-Taiwan phase I trials？  [通常講演]
    Nakagawa K
    The 2nd Japan-Taiwan Oncology Phase I Conference(JTOPIC),Taipei. 2013年
  • 進行・再発非小細胞肺がん患者を対象とした ｃ－MET阻害剤ARQ 197と EGFR阻害剤 Erlotinib の併用第Ⅰ相試験（ARQ197-003/005試験）  [通常講演]
    藤阪 保仁; 中川 和彦; 静岡県立がんセンター; 他, 他; 他, 他
    第10回日本臨床腫瘍学会学術集会 2012年10月 大阪 第10回日本臨床腫瘍学会学術集会
  • 血管破壊剤（VDA) オンブラリンの３週間隔投与時の日本人進行固形がん患者に対する第Ⅰ相臨床試験  [通常講演]
    倉田 宝保; 藤阪 保仁; 清田秀美; 林 秀敏; 田中 薫; 中川 和彦; 他; 他, 他; 静岡県立がんセンター
    第10回日本臨床腫瘍学会学術集会 2012年07月 大阪 第10回日本臨床腫瘍学会学術集会
  • エリブリン療法における用量調節の重要性について  [通常講演]
    鶴谷 純司; 牧村ちひろ; 松岡弘道; 中川 和彦
    第20回日本乳癌学会学術総会 2012年06月 熊本 第20回日本乳癌学会学術総会
  • 進行非小細胞肺癌におけるDｒiver oncogeneを標的とした個別化治療開発における課題と新たな試み  [通常講演]
    岡本 勇; 坂井和子; 西尾和人; 中川和彦
    第33回日本臨床薬理学会学術総会，沖縄 2012年
  • ALK融合遺伝子陽性肺癌に対する治療戦略 EML4-ALK陽性進行非小細胞肺癌における、初回白金併用化学療法の治療効果の検討  [通常講演]
    武田真幸; 岡本 勇; 坂井和子; 川上尚人; 西尾和人; 中川和彦
    第53回日本肺癌学会総会，岡山 2012年
  • 進行肺癌化学療法の最前線 進行非小細胞肺癌の臨床試験における試験治療増悪後の生存期間(post progression survival:PPS)の意義  [通常講演]
    林 秀敏; 岡本 勇; 田栗正隆; 森田智視; 中川和彦
    第53回日本肺癌学会総会，岡山 2012年
  • EML4-ALK陽性進行非小細胞肺癌における、初回白金併用化学療法の治療効果の検討  [通常講演]
    武田真幸; 岡本 勇; 坂井和子; 川上尚人; 西尾和人; 中川和彦
    第50回日本癌治療学会学術集会，横浜 2012年
  • EGFR遺伝子変異肺癌における1st EGFR-TKIによる有害事象後の2nd EGFR-TKIの意義  [通常講演]
    武田真幸; 岡本 勇; 鶴谷純司; 大磯直毅; 川田 暁; 中川和彦
    第50回日本癌治療学会学術集会，横浜 2012年
  • グローバルスタディの現状と未来 新薬グローバル開発試験の枠組 C)米国START Phase I Clinical Trials Program  [通常講演]
    清水俊雄; 倉田宝保; 藤阪保仁; 岡本 勇; 鶴谷純司; 金田裕靖; 田中 薫; 岡本邦男; 大西理都子; 張 智恵; 南 智美; 中川和彦
    第50回日本癌治療学会学術集会，横浜 2012年
  • がん底痛患者の抑うつと身体症状  [通常講演]
    牧村ちひろ; 松岡弘道; 鶴谷純司; 大塚正友; 小山敦子; 中川和彦
    第25回日本サイコオンコロジー学会総会，福岡 2012年
  • 患者自身の痕痛改善度予測が、定痛予後に与える影響について〜よくなると思う患者ほどよくなる〜  [通常講演]
    松岡弘道; 小山敦子; 牧村ちひろ; 大塚正友; 酒井清裕; 阪本 亮; 仁木 稔; 中川和彦
    第25回日本サイコオンコロジー学会総会，福岡 2012年
  • 医学生・研修医へのコミュ二ケーシヨン技術教育の試み  [通常講演]
    藤阪保仁; 小山富美子; 二宮ひとみ; 松岡弘道; 牧村ちひろ; 上田眞也; 金田裕靖; 鶴谷純司; 岡本勇; 倉田宝保; 宮崎彩子; 中川和彦
    第25回日本サイコオンコロジー学会総会，福岡 2012年
  • MET遺伝子増幅を有する胃癌に対するクリゾチニブの抗腫瘍効果  [通常講演]
    岡本 渉; 岡本 勇; 荒尾徳三; 坂井和子; 岡本邦男; 川上尚人; 金田裕靖; 仁科慎一; 鶴谷純司; 倉田宝保; 柳原五吉; 西尾和人; 中川和彦
    第71回日本癌学会学術総会，札幌 2012年
  • サバイビンを標的としたEGFRチロシンキナーゼ阻害剤の耐性克服  [通常講演]
    岡本邦男; 岡本 勇; 畑下恵里奈; 桑田季代子; 山口 永; 喜多 彩; 山中健太郎; 小野真弓; 中川和彦
    第71回日本癌学会学術総会，札幌 2012年
  • OCT４偽遺伝子であるPOU5F1Bの増幅は胃癌において予後不良因子である  [通常講演]
    林 秀敏; 荒尾徳三; 松本和子; 永井知行; 木村英晴; デベラスコ マルコ; 藤田至彦; 山田康秀; 中川和彦; 西尾和人
    第71回日本癌学会学術総会，札幌 2012年
  • ホームドクターと腫瘍内科の病診連携に関する報告；在宅看とりの現状と展望  [通常講演]
    新田 隆; 鶴谷純司; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 転移性乳癌患者におけるエリブリンの臨床効果と安全性プロファイル  [通常講演]
    谷崎潤子; 鶴谷純司; 松岡弘道; 清田秀美; 岡本邦男; 倉田宝保; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 進行非小細胞肺癌の臨床試験における試験治療増悪後の生存期間解析  [通常講演]
    林 秀敏; 岡本 勇; 田栗正隆; 森田智視; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 胃癌の第III相試験におけるprimary endpoint：OSとpostprogression survivalの関係について  [通常講演]
    川上尚人; 岡本 勇; 林 秀敏; 田栗 正隆; 森田智視; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • EGFR遺伝子変異陽性非小細胞肺癌患者におけるEGFR遺伝子特異抗体により検出されるEGFR遺伝子変異蛋白の発現と治療との関係  [通常講演]
    東 公一; 岡本 勇; 武田真幸; 桑野信彦; 小野真弓; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 大腸がん高発現遺伝子FOXQ1の機能解析  [通常講演]
    金田裕靖; 荒尾徳三; 田中 薫; 松本和子; 木村英晴; 永井智行; 酒井和子; 藤田 至彦; マルコ デベラスコ; 山田康秀; 鶴谷純司; 岡本 勇; 中川和彦; 西尾和人
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • OCT4偽遺伝子であるPOU5F1Bの増幅は胃がんにおいて予後不良因子である  [通常講演]
    林 秀敏; 荒尾徳三; 松本和子; 永井知行; 木村英晴; デベラスコ マルコ; 藤田至彦; 山田康秀; 中川 和彦; 西尾和人
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • モルヒネ治療効果を予測するバイオマーカーに関する探索的研究  [通常講演]
    牧村ちひろ; 荒尾徳三; 松岡弘道; 松本和子; 木村英晴; 今村知世; 谷川原祐介; 西尾和人; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • Activin AはTGF-βシグナルを介して血管内皮細胞増殖を抑制する。  [通常講演]
    金田裕靖; 荒尾徳三; 田中 薫; 松本和子; 木村英晴; 永井智行; 藤田至彦; マルコ デベラスコ; 山田康秀; 岡本 勇; 中川和彦; 西尾和人
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 消化器癌で高発現する遺伝子SRPX2は新規コンドロイチン硫酸プロテオグリカンである。  [通常講演]
    田中 薫; 荒尾徳三; 田村大介; 青松圭一; 古田一行; 松本和子; 金田裕靖; 工藤可苗; 藤田至彦; 木村英晴; 柳原五吉; 山田康秀; 岡本 勇; 中川和彦; 西尾和人
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 血管破壊剤（VDA）、オンブラブリンの3週間隔投与時の日本人進行固形がん患者に対する第１相臨床試験  [通常講演]
    倉田宝保; 村上晴泰; 藤阪保仁; 清田秀美; 林 秀敏; 田中 薫; 中川和彦; 小野澤祐輔; 渡邉純一郎; 山本信之; 青山剛和
    第10回日本臨床腫瘍学会学術集会，大阪 2012年
  • 進行・再発非小細胞肺がん患者を対象としたc-MET阻害剤ARQ 197とEGFR阻害剤Erlotinibの併用第１相試験 (ARQ 197-003/005試験)  [通常講演]
    藤阪保仁; 山本信之; 平島智徳; 武田晃司; 杉尾賢二; 里内美弥子; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪， 2012年
  • MassARRAYによるEML4-ALK検出系の構築  [通常講演]
    坂井和子; 岡本 勇; 竹澤 健; 平島智徳; 金田裕靖; 武田真幸; 松本和子; 木村英晴; 藤田至彦; 中川和彦; 荒尾徳三; 西尾和人
    第10回日本臨床腫瘍学会学術集会，大阪， 2012年
  • 日本のPhase?施設に求められるcapability（海外臨床第?相試験専門施設における経験より）  [通常講演]
    シンポジウム-我が国における第; 相試験の現状と問題点; 清水俊雄; 岡本 勇; 倉田宝保; 藤阪保仁; 鶴谷純司; 野村守弘; 南 智美; 阪口教奈子; 大西理都子; 張 智恵; 長谷祐子; 中川和彦
    第10回日本臨床腫瘍学会学術集会，大阪， 2012年
  • 腎不全患者に対するDocetaxel単剤による化学療法の薬物動態測定を用いた安全性評価  [通常講演]
    金田裕靖; 岡本 勇; 岡本邦男; 宮?昌樹; 田中 薫; 清田秀美; 谷?潤子; 山 勉; 藤阪保仁; 倉田宝保; 中川和彦
    第96回日本肺がん学会関西支部会，大阪 2012年
  • エリブリン療法における用量調節の重要性について  [通常講演]
    鶴谷純司; 牧村ちひろ; 松岡弘道; 中川和彦
    第20回日本乳癌学会学術総会，熊本 2012年
  • 心身両面からの全人的病態理解が治療に役立った術後乳がんの2症例  [通常講演]
    松岡弘道; 鶴谷純司; 牧村ちひろ; 小山敦子; 中川和彦
    第20回日本乳癌学会学術総会，熊本 2012年
  • OCT４偽遺伝子であるPOU5F1Bの胃がんでの増幅  [通常講演]
    林 秀敏; 荒尾徳三; 松本和子; 吉田修平; 藤田至彦; 加藤寛章; 永井知行; 木村英晴; 山田康秀; 中川和彦; 西尾和人
    第16回日本がん分子標的治療学会 2012年
  • EML4-ALK陽性肺癌におけるALK阻害剤とMEK阻害剤の併用効果の検討  [通常講演]
    谷?潤子; 岡本 勇; 竹澤 健; 東 公一; 西尾和人; 中川和彦
    第16回日本がん分子標的治療学会，北九州市 2012年
  • 中枢気道狭窄に対する気道ステントの症状緩和とQOLに対する有用性の検討  [通常講演]
    田中 薫; 宮?昌樹; 谷?潤子; 牧村ちひろ; 岡本邦男; 清田秀美; 林 秀敏; 松岡弘道; 上田眞也; 鶴谷純司; 中川和彦
    第17回日本緩和医療学会学術大会 2012年
  • がん性疼痛患者に対するオピオイド鎮痛緩和と心理尺度変化  [通常講演]
    牧村ちひろ; 松岡弘道; 鶴谷純司; 大塚正友; 小山敦子; 中川和彦
    第17回日本緩和医療学会学術大会 2012年
  • 進行非小細胞肺癌の再発憎悪による気道狭窄に対し、ステント留置後に化学療法を実施した一例  [通常講演]
    池田昌人; 米阪仁雄; 佃 博; 福岡正博; 宮?昌樹; 中川和彦
    第35回日本呼吸器内視鏡学会，東京 2012年
  • EGFR遺伝子変異性陽性小細胞肺癌患者におけるEGFR遺伝子特異抗体により検出されるEGFR遺伝子変異蛋白の発現と治療との関係  [通常講演]
    東 公一; 岡本 勇; 武田真幸; 山田一彦; 中川和彦; 星野友昭
    第52回日本呼吸器学会学術講演会，神戸 2012年
  • 抗悪性腫瘍薬の治験は安全か 相別SAE発生率の検討  [通常講演]
    清田秀美; 藤阪保仁; 川上尚人; 田中薫; 工藤敏啓; 鶴谷純司; 宮?昌樹; 岡本勇; 倉田宝保; 中川和彦
    第109回日本内科学会講演会 2012年
  • モルヒネ治療効果と血清中サイトカイン濃度との相関  [通常講演]
    牧村ちひろ; 松岡弘道; 荒尾徳三; 清田秀美; 武田真幸; 鶴谷純司; 大塚正友; 小山敦子; 西尾和人; 中川和彦
    第109回日本内科学会講演会 2012年
  • Current Status of S1 in management of lung cancer  [通常講演]
    Nakagawa K
    5th Asian Pacific Conference, (Hong Kong) 2012年
  • Indivualized therapy for lung cancer  [通常講演]
    Nakagawa K
    The 6th Chinese Symposium on Medical Oncology 2012年
  • The history and current state of cultivation of medical oncologists in Japan  [通常講演]
    CSMO; CACO Special Forum; The history; current state of clinical oncologist; training; Nakagawa K
    The 6th Chinese Symposium on Medical Oncology（Beijing） 2012年
  • Second-Line chemotherapy with S-1 after Cisplatin and Gemcitabine failure in patients with advanced biliary tract cancer.  [通常講演]
    Ueda S; Nakagawa K
    ESMO 14th World Congress on Gastrointestinal Cancer, Barcelona, Spain. 2012年
  • Chemotherapy with CPT-11 after gemcitabine failure in patients with advanced pancreatic cancer.  [通常講演]
    Kaneda H; Ueda S; Makimura C; Kiyota H; Oakmoto I; Tanaka K; Nishina S; Kudo T; Turutani J; Miyazaki M; FujisakaY; Okamoto W; Kirata T; Nakagawa K
    ESMO 14th World Congress on Gastrointestinal Cancer, Barcelona, Spain. 2012年
  • Differential roles of trans-phophorylated EGFR,HER2,HER3,and RET as heterodimerizoation partenrs of MET in lung cancer with MET amplification.  [通常講演]
    Tanizaki J; Okamoto I; Sakai K; Nakagawa K
    102rd American Association for Cancer Research Annual Meeting, 2012年
  • 原発不明癌に対するシスプラチンとTS-1の臨床第Ⅱ相試験  [通常講演]
    倉田 宝保; 津谷あす香; 岡本 勇; 上田 眞也; 福岡正博; 中川 和彦; 他, 他; 他, 他
    第９回日本臨床腫瘍学会学術集会 2011年07月 横浜 第９回日本臨床腫瘍学会学術集会
  • Results of a phase I dose escalation trial (WJOG3305) using accelerated hyperfractionated 3D-conformal radiation therapy (AHF-3DCRT) and concurrent chemotherapy for unresectable stage III Non-Small Cell Lung Cancer (NSCLC).  [通常講演]
    Tsujino K; 西村 恭昌; 西川 龍之; 中川 和彦; Tada T; Fukuda H; Kokubo M; Soejima T; Takada Y
    the 4th APLCC (Asia Pacific Lung Cancer Conference) 2010年12月 Seoul, Korea the 4th APLCC (Asia Pacific Lung Cancer Conference)
     
    非小細胞肺がんに対する加速過分割照射化学放射線療法の第I相臨床試験を報告した。
  • EGFR-TKI 獲得耐性肺癌に対する BIBW2992 とＴＳ標的薬剤の併用効果の検討  [通常講演]
    竹澤 健; 岡本 勇; 谷﨑 潤子; 西尾和人; 福岡正博; 中川 和彦
    第51回日本肺癌学会総会 2010年11月 広島 第51回日本肺癌学会総会
  • 進行肺腺癌を対象としたゲフィチニブ／S-1併用療法第１層臨床試験  [通常講演]
    清田 秀美; 岡本 勇; 田中 薫; 林 秀敏; 寺嶋応顕; 東 公一; 武田真幸; 米阪 仁雄; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦
    第51回日本肺癌学会総会 2010年11月 広島 第51回日本肺癌学会総会
  • EGFR-TKIｓ が無効であったＥＧＦＲ遺伝子変異陽性症例の検討  [通常講演]
    武田 真幸; 岡本 勇; 中川 和彦; 和泉市立病院
    第51回日本肺癌学会総会 2010年11月 広島 第51回日本肺癌学会総会
  • ゲフィチニブによる重篤な肺障害後 エルロチニブが耐容可能であった1例  [通常講演]
    武田 真幸; 岡本 勇; 牧村ちひろ; 中川 和彦; 和泉市立病院
    第51回日本肺癌学会総会 2010年11月 広島 第51回日本肺癌学会総会
  • 局所進行非小細胞肺癌に対する胸部放射線（ＴＲＴ）と同時併用のシスプラチン（Ｐ）+Ｓ－１（Ｓ）の第２相試験（ＷＪＯＧ３７０６）  [通常講演]
    宮﨑 昌樹; 中川 和彦; 西村恭昌
    第５１回日本肺癌学会総会 2010年11月 広島 第５１回日本肺癌学会総会
  • A phase I study of chemoradiotherapy with use of three-dimensional conformal radiotherapy (3D-CRT) and accelerated hyperfractionation (AHF) for unresectable non-small-cell lung cancer (NSCLC): WJOG3305.  [通常講演]
    Tada T; 西村 恭昌; 中川 和彦; Tsujino K; Fukuda H; Nishimura Y; Kokubo M; Negoro S; Kudoh S; Nakamura S; Nakanishi Y
    the 52nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology 2010年11月 San Diego, CA, USA the 52nd Annual Meeting of the American Society for Therapeutic Radiology and Oncology
     
    非小細胞肺がんに対する加速過分割照射同時化学放射線療法の臨床第I相試験結果を報告した。
  • EGFR-TKI 耐性Ｔ790M 肺癌に対するB IBW2992 とTS標的薬剤の効用効果  [通常講演]
    竹澤 健; 岡本 勇; 谷﨑 潤子; 福岡正博; 西尾和人; 中川 和彦
    第69回日本癌学会学術総会 2010年09月 大阪 第69回日本癌学会学術総会
  • 肺癌に対する抗体療法  [通常講演]
    中川 和彦
    第69回日本癌学会学術総会 2010年09月 大阪 第69回日本癌学会学術総会
  • Ｔ７９０ＭによるＥＧＦＲ-ＴＫＩ獲得耐性に対するＢＩＢＷ2992+Ｓ-１併用療法の分子生物学的検討  [通常講演]
    竹澤 健; 岡本 勇; 谷﨑 潤子; 中川 和彦; 福岡正博
    第92回日本肺癌学会関西支部会 2010年07月 大阪 第92回日本肺癌学会関西支部会
  • ソラフェニブは非小細胞肺癌株においてＫＲＡＳ野生型に対してはＢＲＡＦを ＫＲＡＳ変異型に対しては ＣＲＡＦを標的として  [通常講演]
    竹澤 健; 岡本 勇; 米阪 仁雄; 畑下恵理奈; 山田友紀; 福岡正博; 中川 和彦
    第14回日本がん分子標的治療学会学術集会 2010年07月 東京 第14回日本がん分子標的治療学会学術集会
  • 進行肺腺癌を対象としたゲフェチニブ／S-1 併用療法第１相臨床試験  [通常講演]
    清田 秀美; 岡本 勇; 谷﨑 潤子; 文田 壮一; 岡本 邦男; 牧村 ちひろ; 竹澤 健; 田中 薫; 林 秀敏; 岡本 渉; 寺嶋応顕; 東 公一; 金田裕靖; 武田真幸; 上田 眞也; 米阪 仁雄; 藤阪 保仁; 鶴谷 純司; 宮﨑 昌樹; 佐藤 太郎; 倉田 宝保; 中川 和彦
    第92回日本肺癌学会関西支部会 2010年07月 大阪 第92回日本肺癌学会関西支部会
  • パネルディスカッションⅣ 腫瘍学教育の現状と展望 『卒後教育の現状と問題点―腫瘍内科の立場から』  [通常講演]
    中川 和彦
    第42回日本医学教育学会 2010年07月 東京 第42回日本医学教育学会
  • Association of thymidylate synthase (TS) expression with response to S-1 plus carboplatin (CBDCA) in non-small cell lung cancer (NSCLC) patients (pts)  [通常講演]
    武田 真幸; 岡本 勇; 中川 和彦; 和泉市立病院
    46th A.S.C.O 2010年06月 U.S.A (Chicago) 46th A.S.C.O
  • ソラフェニブは肺癌細胞においてＫＲＡＳ野生型に対しては  [通常講演]
    竹澤 健; 岡本 勇; 田中 薫; 林 秀敏; 岡本 邦男; 米阪 仁雄; 福岡正博; 中川 和彦
    第8回日本臨床腫瘍学会総会 2010年03月 東京 第8回日本臨床腫瘍学会総会
  • ゾレドロン酸単剤で多臓器転移巣に対して抗腫瘍効果を認めた原発不明がんの一例  [通常講演]
    鶴谷 純司; 牧村ちひろ; 東 公一; 武田 真幸; 竹澤 健; 岡本 渉; 清田秀美; 林 秀敏; 田中 薫; 岡本邦男; 谷崎潤子; 岡本 勇; 西條長宏; 福岡正博; 中川 和彦
    第8回日本臨床腫瘍学会総会 2010年03月 東京 第8回日本臨床腫瘍学会総会
  • 教育セミナーBセッション「日本臨床腫瘍学会と専門医」  [通常講演]
    中川 和彦
    第8回日本臨床腫瘍学会 2010年03月 東京 第8回日本臨床腫瘍学会
  • ミートザエキスパート6 『癌科学療法の進歩と随伴する心血管合併症』  [通常講演]
    中川 和彦
    第74回日本循環器学会 2010年03月 京都 第74回日本循環器学会
  • シンポジウム「分子標的治療」  [通常講演]
    中川 和彦
    第４４回日本成人病学会学術大会 2010年01月 東京 第４４回日本成人病学会学術大会
  • 進行肺腺癌」を対象としたゲフィチニブ/S-1併用療法第Ⅰ相臨床試験  [通常講演]
    清田 秀美; 岡本 勇; 岡部崇記; 寺嶋応顕; 宮﨑 昌樹; 中川 和彦
    第50回日本肺癌学会総会 2009年11月 東京 第50回日本肺癌学会総会
  • がん薬物療法における最近の話題  [通常講演]
    中川 和彦
    第59回福岡がん化学療法研究会 2009年11月 福岡 第59回福岡がん化学療法研究会
  • IASLCWorkshop「Clinical trials for stageⅢ NSCLC」  [通常講演]
    中川 和彦
    第50回日本肺癌学会総会 2009年11月 東京 第50回日本肺癌学会総会
  • 肺癌薬物療法今、変革の時  [通常講演]
    中川 和彦
    第50回日本肺癌学会総会 2009年11月 東京 第50回日本肺癌学会総会
  • 肺癌細胞株におけるIGF-1R 阻害剤 ＣＰ-751,871の放射線増感効果の検討  [通常講演]
    岩朝 勤; 岡本 勇; 畑下恵理奈; 山田友紀; 福岡正博; 中川 和彦
    第68回日本癌学会学術総会 2009年10月 横浜 第68回日本癌学会学術総会
  • ソラフェニブはKRAS野生型非小細胞肺癌に対してはＢＲＡＦをＫＲＡＳ変異型非小細胞肺癌に対してはCRAFを標的にして抗腫瘍効果を示す  [通常講演]
    竹澤 健; 岡本 勇; 米阪 仁雄; 畑下恵理奈; 山田友紀; 福岡正博; 中川 和彦
    第68回日本癌学会学術総会 2009年10月 横浜 第68回日本癌学会学術総会
  • コメディカルセミナー「チーム医療の実践」  [通常講演]
    中川 和彦
    第47回癌治療学会総会 2009年10月 横浜 第47回癌治療学会総会
  • シンポジウム 国際共同治験の現状と変化～医師の立場から「肺癌」  [通常講演]
    中川 和彦
    第47回癌治療学会総会 2009年10月 横浜 第47回癌治療学会総会
  • MET遺伝子増幅を伴うゲフィチニブ獲得耐性非小細胞肺癌におけるSrc阻害剤の効果  [通常講演]
    岡本 勇; 吉田 健史; 福岡 正博; 西尾 和人; 中川 和彦
    第68回日本癌学会学術総会 2009年10月 横浜 第68回日本癌学会学術総会
  • A ｐｈａｓｅ Ⅲ、first-line trial of gefitinib versus cisplatin plus docetaxel for patients with advanced or recurrent non-small cell lung cancer (NSCLC) harboring activating mutation of the epidermal growthfactor receptor (EGFR)  [通常講演]
    鶴谷 純司; 岡本 勇; 福岡正博; 中川 和彦
    34th ESMO 2009年09月 Germany (Berlin ) 34th ESMO
  • がん分子標的薬の最新の話題  [通常講演]
    中川 和彦
    第28回京都放射線腫瘍研究会 2009年09月 京都 第28回京都放射線腫瘍研究会
  • Phase 1 study of sunitinib(SU) in combination with pemetrexed(Pem) in patients(pts) with advanced solid tumors(ST) 』  [通常講演]
    中川 和彦
    IASLC 13th World Conference on Lung Cancer 2009年08月 San Francisco IASLC 13th World Conference on Lung Cancer
  • 進行非小細胞肺癌の最新の治療戦略  [通常講演]
    中川 和彦
    第22回青森呼吸器研究会 2009年08月 青森 第22回青森呼吸器研究会
  • 肺癌生存期間延長の謎  [通常講演]
    中川 和彦
    福島県肺癌研究会 2009年07月 福島 福島県肺癌研究会
  • シンポジウム 『本邦における多施設共同研究の現状と課題―WJTOGからWJOGへ』  [通常講演]
    中川 和彦
    第49回日本呼吸器学会学術講演会 2009年06月 東京 第49回日本呼吸器学会学術講演会
  • Phase I Clinical and Biomarker Study of BIBF1120  [通常講演]
    岡本 勇; 金田 裕靖; 佐藤 太郎; 岡本 渉; 寺嶋 応顕; 荒尾 徳三; 西尾 和人; 中川 和彦; K. Konishi; R. Kaiser
    45th Annual Meeting of the American Society of Clinical Oncology 2009年06月 Orland, USA 45th Annual Meeting of the American Society of Clinical Oncology
  • シンポジウム『シグナル伝達阻害とトランスレーショナルリサーチ』  [通常講演]
    中川 和彦
    第7回日本臨床腫瘍学会学術集会 2009年03月 名古屋 第7回日本臨床腫瘍学会学術集会
  • EGFR-RAS  [通常講演]
    中川 和彦
    第7回日本臨床腫瘍学会 2009年03月 名古屋 第7回日本臨床腫瘍学会
  • EGFR-TKIs on Treatment in advanced NSCLC  [通常講演]
    中川 和彦
    International Congress on Anti-Cancer Treatment 2009年02月 International Congress on Anti-Cancer Treatment
  • EGFR－TKIの現状と将来展望  [通常講演]
    中川 和彦
    第2回日本海肺癌化学療法研究会 2009年02月 金沢市 第2回日本海肺癌化学療法研究会
  • Ｐｈａｓｅ Ｉ study of sunitinib(SU) in combination with pemetrexed(pem) in patients(pts) with advanced solid tumors(ST)  [通常講演]
    中川 和彦
    46th ASCO Annual Meeting 2009年 46th ASCO Annual Meeting
  • Phase III study of mitomycin/vindesine/cisplatin (MVP) vs. weekly irinotecan/carboplatin (IC) or weekly pacritaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (WJTOG0105): special ref  [通常講演]
    西村 恭昌; 中川 和彦; 福岡 正博; Tujino K; Satouchi M; Tanaka M; Kodaira T; Kokubo M; Fukuda H; Yamamoto N
    the 51st Annual Meeting of the American Society for Radiation Oncology 2009年 Chicago, Illinois, USA the 51st Annual Meeting of the American Society for Radiation Oncology
     
    非小細胞肺癌に対する化学放射線療法のランダム化比較試験(WJTOG0105)の結果を、放射線治療の観点から報告した。
  • 血液透析施行中の小細胞肺癌患者に対し化学療法を施行した1例  [通常講演]
    竹澤 健; 岡本 勇; 寺嶋応顕; 宮﨑 昌樹; 中川 和彦
    第72回日本呼吸器学会近畿地方会 2008年12月 大阪 第72回日本呼吸器学会近畿地方会
  • ランチョンセミナー 『肺癌化学療法の現状と展望』  [通常講演]
    中川 和彦
    日本呼吸器学会近畿地方会 2008年12月 日本呼吸器学会近畿地方会
  • 当院における肺門・縦隔病変に対するコンベックス走査式超音波気管支鏡ガイド生検の検討  [通常講演]
    宮﨑 昌樹; 文田壮一; 寺嶋応顕; 武田真幸; 清水俊雄; 市川靖子; 米阪仁雄; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡正博
    第７２回日本呼吸器学会第１０２回日本結核病学会近畿地方会 2008年12月 大阪 第７２回日本呼吸器学会第１０２回日本結核病学会近畿地方会
  • 呼吸器セミナー『非小細胞癌における分子標的薬の使い方』  [通常講演]
    中川 和彦
    第29回生涯教育講演会 2008年11月 第29回生涯教育講演会
  • ランチョンセミナー『進行非小細胞肺癌における新しい抗癌剤-TS-１を中心に-』  [通常講演]
    中川 和彦
    第49回日本肺癌学会総会 2008年11月 北九州市 第49回日本肺癌学会総会
  • 胃癌細胞におけるＩＭＰ-3 遺伝子の機能解析  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 工藤可苗; 金田裕靖; 藤田至彦; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 西尾和人
    第67回日本癌学会学術総会 2008年10月 名古屋 第67回日本癌学会学術総会
  • マツズマブはシスプラチンが誘導するＨＢ-ＥＧＦを介したＥＧＦＲシグナル伝達を抑制しシスプラチンの抗腫瘍効果を増強する  [通常講演]
    吉田 健史; 岡本 勇; 岩朝 勤; 福岡正博; 中川 和彦
    第67回日本癌学会学術総会 2008年10月 名古屋 第67回日本癌学会学術総会
  • 肺癌細胞株におけるYM155の放射線感受性増強作用の検討  [通常講演]
    岩朝 勤; 岡本 勇; 畑下恵理奈; 山田友紀; 福岡正博; 中川 和彦
    第67回日本癌学会学術総会 2008年10月 名古屋 第67回日本癌学会学術総会
  • パネリスト「がん分子標的薬の放射線感受性増強効果と今後の臨床開発」  [通常講演]
    中川 和彦
    第21回日本放射線腫瘍学会 2008年10月 第21回日本放射線腫瘍学会
  • ともに生きる会～がん治療の未来～  [通常講演]
    中川 和彦
    がん治療の未来を考えるシンポジウム 2008年10月 がん治療の未来を考えるシンポジウム
  • 肺癌化学療法の動向  [通常講演]
    中川 和彦
    第48回日本呼吸器学会学術講演会 2008年06月 第48回日本呼吸器学会学術講演会
  • ＩＭＰ-3 promotes cellular proliferation activity in gastric cancer  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 工藤可苗; 金田裕靖; 藤田至彦; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 西尾和人
    A.A.C.R 2008年04月 San Diego (U.S.A) A.A.C.R
  • Matuzumab and cetuximab activateb the epidermal growth factor receptor but fail to trigger downstream signaling by akt or erk  [通常講演]
    吉田 健史; 岡本 勇; 岡部崇記; 岩朝 勤; 佐藤 太郎; 西尾和人; 福岡正博; 中川 和彦
    A.A.C.R 2008年04月 San Diego (U.S.A) A.A.C.R
  • Radiosensitizing effect of YM155,a novel small molecule survivin suppressant, in non-small cell lung cancer cell lines  [通常講演]
    岩朝 勤; 岡本 勇; 佐藤 太郎; 福岡正博; 中川 和彦
    A.A.C.R 2008年04月 San Diego (U.S.A) A.A.C.R
  • 卒後教育プログラム  [通常講演]
    中川 和彦
    第96回日本泌尿器科学会総会 2008年04月 第96回日本泌尿器科学会総会
  • がん化学療法の現状と展望  [通常講演]
    中川 和彦
    第18回滋賀癌化学療法研究会 2008年02月 第18回滋賀癌化学療法研究会
  • 当院における肺門・縦隔病変に対するコンベックス走査式超音波気管支鏡ガイド下生検の検討  [通常講演]
    宮﨑 昌樹; 岡本邦男; 竹澤 健; 岡本 渉; 上田眞也; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡正博
    第８７回日本肺癌学会関西支部会 2008年02月 神戸 第８７回日本肺癌学会関西支部会
  • ワークショップ 「既治療小細胞肺癌に対するトポテカンとカルボプラチン併用の第I相試験（WJTOG0202）」  [通常講演]
    倉田 宝保; 佐藤 太郎; 中川 和彦; 福岡 正博; 菓子井達彦; 武田晃司; 坪井正博; 関順彦; 小林政彦
    日本肺癌学会総会 2008年 北九州市 日本肺癌学会総会
  • 大学病院における外来化学療法センターの運営  [通常講演]
    今野 元博; 奥野 清隆; 上嶋 一臣; 岡本 勇; 辰巳 陽一; 慎 玉姫; 藤原 季美子; 野村 守; 山添 譲; 渡部 洋; 中川 和彦; 塩﨑 均
    第46回日本癌治療学会総会 2008年 第46回日本癌治療学会総会
  • 血液透析施行中の小細胞肺癌患者に対し化学療法を施行した  [通常講演]
    竹澤 健; 岡本 勇; 岡本 邦男; 岡本 渉; 上田 眞也; 宮﨑 昌樹; 佐藤 太郎; 中川 和彦; 福岡正博
    第７０回日本呼吸器学会近畿地方会 2007年12月 京都 第７０回日本呼吸器学会近畿地方会
  • ヒト肺癌細胞株におけるＳ-1とゲフィチニブの併用効果の検討  [通常講演]
    岡部 崇記; 岡本 勇; 畑下恵理奈; 山田友紀; 佐藤 太郎; 田村研治; 福岡正博; 中川 和彦; 他機関; 他機関
    第４８回日本肺癌学会総会 2007年11月 名古屋 第４８回日本肺癌学会総会
  • 切除不能・再発成人悪性軟部腫瘍に対する ドキソルビシン＋イホマイド 併用療法の安全性  [通常講演]
    寺嶋 応顕; 岡本 勇; 宮﨑 昌樹; 岡本邦男; 竹澤 健; 岡本 渉; 上田 眞也; 森永 亮太郎; 佐藤 太郎; 福岡正博; 中川 和彦
    第４５回日本癌治療学会総会 2007年10月 京都 第４５回日本癌治療学会総会
  • 切除不能・進行膵癌５４例の検討  [通常講演]
    上田 眞也; 岡本 渉; 岡本邦男; 岡本 勇; 佐藤 太郎; 寺嶋 応顕; 森永 亮太郎; 宮﨑 昌樹; 福岡正博; 中川 和彦
    第４５回日本癌治療学会総会 2007年10月 京都 第４５回日本癌治療学会総会
  • Suppression of SRPX2 mRNA expression inhibits cellular growth and adhesion in gastric cancer cells  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 金田裕靖; Abe Y; 藤田至彦; 横手秀行; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 西尾和人
    66th Annual Meeting of the Japanese Cancer Association 2007年10月 横浜 66th Annual Meeting of the Japanese Cancer Association
  • Matuzumab and cetuximab activate the epidermal growth factor receptor but fail to trigger downstream signaling  [通常講演]
    吉田 健史; 岡本 勇; 岡部崇記; 岩朝 勤; 佐藤 太郎; 西尾和人; 福岡正博; 中川 和彦
    66th Annual Meeting of the Japanese Cancer Association 2007年10月 横浜 66th Annual Meeting of the Japanese Cancer Association
  • Synergistic effects of S-1 and gefitinib by modulating the metabolic enzymes of 5-fluorouracil in NSCLC cell lines  [通常講演]
    岡部 崇記; 岡本 勇; 畑下恵理奈; 山田友紀; 佐藤 太郎; 田村研治; 福岡正博; 中川 和彦; 他機関; 他機関
    66th Annual Meeting of the Japanese Cancer Association(第６６回日本癌学会学術総会) 2007年10月 横浜 66th Annual Meeting of the Japanese Cancer Association(第６６回日本癌学会学術総会)
  • The clinical development strategy for ixabepilone (BMS-247550)in patients with NSCLC  [通常講演]
    中川 和彦
    Asia-Pacific-Japan Lung Cancer Advisory Board 2007年10月 Seoul Asia-Pacific-Japan Lung Cancer Advisory Board
  • 合同シンポジウム｢がん化学療法のあり方｣  [通常講演]
    中川 和彦
    第45回日本癌治療学会総会 2007年10月 京都 第45回日本癌治療学会総会
  • 教育シンポジウム 『シグナル伝達系阻害剤』  [通常講演]
    中川 和彦
    第45回日本癌治療学会総会 2007年10月 京都 第45回日本癌治療学会総会
  • がん化学療法のあり方  [通常講演]
    中川 和彦
    第45回日本癌治療学会総会 2007年10月 第45回日本癌治療学会総会
  • Prognostic factors affecting survival on pretreated patients with locally advanced or metastatic non-small cell lung cancer  [通常講演]
    岡部 崇記; 田村研治; 中川 和彦; 福岡正博; 他機関; 静岡県立がんセンター; 他機関; 他機関; 他機関; 国立がんセンター
    The European Cancer Conference 2007年09月 Barcelona The European Cancer Conference
  • 非小細胞肺がんに対する臨床試験の最新治験  [通常講演]
    中川 和彦
    Korea-Japan Lung Cancer Medical Workshop 2007年09月 ソウル Korea-Japan Lung Cancer Medical Workshop
  • A Long-term Result by Hyperfractionated Radiotherapy with Concurrent Chemotherapy for Limited-stage Small Cell Lung Cancer (LD-SCLC): a Retrospective Analysis in a Single Institution.  [通常講演]
    柴田 徹; 小池 竜太; 中松 清志; 金森 修一; 大久保 充; 廣井 啓二; 西村 恭昌; 中川 和彦; 福岡 正博
    12th World Conference on Lung Cancer 2007年09月 Seoul, Korea 12th World Conference on Lung Cancer
     
    限局期小細胞肺癌に対する過分割照射の治療成績を報告した。 PE regimen併用でのMSTは28.6 monthsで 2/3/5/ year survival ratesは 51/32/24%であった。
  • EGFR抗体療法によるEGFR活性化と下流シグナル阻害  [通常講演]
    吉田 健史; 岡本 勇; 岡部崇記; 岩朝 勤; 佐藤 太郎; 西尾和人; 福岡正博; 中川 和彦
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会
  • 肺癌細胞株におけるYM155の放射線感受性増強作用の検討  [通常講演]
    岩朝 勤; 岡本 勇; 佐藤 太郎; 福岡正博; 中川 和彦
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会
  • 胃癌高発現遺伝子SRPX2の生物学的検討  [通常講演]
    田中 薫; 荒尾徳三; 前川麻里; 松本和子; 藤田至彦; 横手秀行; 柳原五吉; 山田康秀; 岡本 勇; 中川 和彦; 福岡正博; 西尾和人
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会
  • ヒト肺癌細胞株における S-1 とフィチニブの併用効果の検討  [通常講演]
    岡部 崇記; 岡本 勇; 佐藤 太郎; 田村研治; 福岡正博; 中川 和彦; 他機関; 他機関
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会
  • Manegement of Bone Metastases in Lung Cancer  [通常講演]
    中川 和彦
    Bisphosphonate International Symposium -New Strategy of Bisphosphonete in Lung Cancer 2007年07月 Bisphosphonate International Symposium -New Strategy of Bisphosphonete in Lung Cancer
  • YM155：Survivinを標的とした新しい分子標的薬  [通常講演]
    佐藤 太郎; 岡本 勇; 宮﨑 昌樹; 森永 亮太郎; 津谷あす香; 長谷川喜一; 寺嶋 応顕; 上田眞也; 福岡正博; 中川 和彦; 学外, 学外
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会
  • 本邦における血管新生阻害剤の臨床開発状況  [通常講演]
    岡本 勇; 中川 和彦
    第11回がん分子標的治療研究会総会 2007年07月 大阪 第11回がん分子標的治療研究会総会
  • Phase I study of YM155, a first-in-class surviving suppressant, in patients with advanced solid tumors in Japan  [通常講演]
    中川 和彦; 佐藤 太郎; 岡本 勇; 宮﨑 昌樹; 森永 亮太郎; 津谷 あす香; 長谷川 喜一; 寺嶋 応顕; 福岡 正博
    43th A.S.C.O. 2007年05月 43th A.S.C.O.
  • 非小細胞肺癌の術後補助化学療法 教育シンポジウムⅡ アジュバント化学療法の現状と課題  [通常講演]
    中川 和彦
    第5回日本臨床腫瘍学会 2007年03月 第5回日本臨床腫瘍学会
  • 肺腺癌加療中に同一部位に小細胞癌の発生を来たし EGFR遺伝子変異を認めた一例  [通常講演]
    文田 壮一; 森永亮太郎; 岡本 勇; 上田 眞也; 宮﨑 昌樹; 金田裕靖; 寺嶋応顕; 岡本 渉; 佃 博; 佐藤 太郎; 中川 和彦; 福岡正博
    第８５回日本肺癌学会関西支部会 2007年02月 大阪 第８５回日本肺癌学会関西支部会
  • 肺癌細胞株におけるＥＧＦＲ gene alteration, シグナル伝達と  [通常講演]
    岡部 崇記; 岡本 勇; 田村研治; 佐藤 太郎; 寺嶋 応顕; 吉田健史; 高田 實; 中川 和彦; 福岡正博
    第４７回日本肺癌学会総会 2006年12月 京都 第４７回日本肺癌学会総会
  • Pharmacokinetics and safety of escalating doses of darbepoetin alfa (KRN321) in cancer patients undergoing myelosuppressive chemotherapy.  [通常講演]
    山本 信之; 中川 和彦; 浅井 暁; 佐々木 康綱; 南 博信; 田村 友秀; 畠 清彦; 西條 長宏
    第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会 2006年12月 東京 第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会
  • Randomized phase II trial of irinotecan plus etoposide (IPE) every three weeks in patients with extensive disease small cell lung cancer (ED-SCLC)  [通常講演]
    武田 晃司; 中川 和彦; 関根 郁夫; 軒原 浩; 西脇 裕; 磯部 宏; 森 清志; 松井 薫; 西條 長宏; 田村 友秀
    第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会 2006年12月 東京 第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会
  • A phase I study of pemetrexed supplemented with folic acid (FA) and vitamin B12 (VB12) in Japanese patients with solid tumors.  [通常講演]
    中川 和彦; 福岡 正博; 工藤 新三; 根来 俊一; 松井 薫; 山本 信之
    第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会 2006年12月 東京 第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会
  • Differential constitutive activation of epidermal growth factor receptor(EGFR) in non-small-cell lung cancers bearing EGFR gene mutation and amplification  [通常講演]
    岡部 崇記; 中川 和彦; 岡本 勇; 佐藤 太郎; 福岡 正博; 医学部内科学教室; 医学部内科学教室; 近畿大学医学部奈良病院; 腫瘍内科; 独立行政法人国立病院機構近畿中央胸部疾患センター
    第3回国際化学療法学会癌治療総会第11回国際癌化学療法シンポジウム合同大会 2006年12月 東京都 第3回国際化学療法学会癌治療総会第11回国際癌化学療法シンポジウム合同大会
  • Phase I/II Trial of sequential chemoradiotherapy using a novel hypoxic cell radiosensitizer, doranidazole (PR-350), in patients (pts) with locally advanced non-small cell lung cancer (NSCLC)  [通常講演]
    西村 恭昌; 中川 和彦; 福岡 正博; Takeda K; Tanaka M; Kataoka M; Segawa Y; Tsujino K; Negoro S; Ariyoshi Y
    the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology 2006年11月 Philadelphia, PA, USA the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology
     
    非小細胞肺がんに対する低酸素細胞増感剤、ドラニダゾールの化学放射線療法における効果をI/II相試験で検討した。
  • 肺癌細胞株におけるＥＧＦＲ gene alteration, シグナル伝達とゲフィチニブ感受性との関連の検討  [通常講演]
    岡部 崇記; 岡本 勇; 田村研治; 寺嶋 応顕; 佐藤 太郎; 吉田健史; 高田 實; 中川 和彦; 福岡正博
    第６５回日本癌学会学術総会 2006年09月 横浜 第６５回日本癌学会学術総会
  • 肺癌細胞株におけるＥＧＦＲ gene alteration, シグナル伝達とゲフィチニブ感受性との関連の検討  [通常講演]
    岡部 崇記; 岡本 勇; 寺嶋 応顕; 佐藤 太郎; 田村研治; 高田 實; 中川 和彦; 福岡正博
    第１０回がん分子標的治療研究会総会 2006年06月 東京 第１０回がん分子標的治療研究会総会
  • Relationship between EGFR protein expression, EGFR gene amplification, EGFR gene mutations and gefitinib sensitivity in human non-small cell lung cancer cell lines  [通常講演]
    寺嶋 応顕; 岡本 勇; 田村研治; 岡部 崇記; 佐藤 太郎; 武田 真幸; 中川 和彦; 福岡正博
    97th American Association of Cancer Reserarch 2006年04月 U.S.A (Washington) 97th American Association of Cancer Reserarch
  • 進行胃癌に対するＴＳ-１とDocetaxel 併用療法に第１相試験  [通常講演]
    宮﨑 昌樹; 田村研治; 佐藤 太郎; 尾崎智博; 岡本 勇; 清水俊雄; 中川 和彦; 福岡 正博
    第４回日本臨床腫瘍学会総会 2006年03月 大阪 第４回日本臨床腫瘍学会総会
  • 進行非小細胞肺癌（ＮＳＣＬＣ）患者における骨転移、骨関連事象（ＳＲＥ）に関するretrospective study  [通常講演]
    津谷 あす香; 長谷川喜一; 森永亮太郎; 宮﨑 昌樹; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第８３回日本肺癌学会関西支部会 2006年02月 兵庫 第８３回日本肺癌学会関西支部会
  • 肺末梢腫瘤性病変に対するガイド－シス併用気管支内腔超音波断層法（ＥＢＵＳ-ＧＳ）の有効性の検討  [通常講演]
    長谷川 喜一; 野上 壽二; 宮﨑 昌樹; 岡部崇記; 寺嶋応顕; 津谷 あす香; 池田 昌人; 明石雄策; 森永亮太郎; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第８３回日本肺癌学会関西支部会 2006年02月 兵庫 第８３回日本肺癌学会関西支部会
  • EGFR遺伝子変異と遺伝子増幅を呈しゲフィチニブが有効であった肺扁平上皮癌の１例  [通常講演]
    森永 亮太郎; 岡本 勇; 宮﨑 昌樹; 長谷川喜一; 津谷あす香; 佐藤 太郎; 中川 和彦; 福岡 正博
    第８３回日本肺癌学会関西支部会 2006年02月 兵庫 第８３回日本肺癌学会関西支部会
  • 当院における肺門・縦隔病変に対するコンベックス走査式超音波気管支鏡ガイド下生検の使用経験  [通常講演]
    宮﨑 昌樹; 野上 壽二; 長谷川喜一; 森永 亮太郎; 津谷あす香; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第８３回日本肺癌学会関西支部会 2006年02月 兵庫 第８３回日本肺癌学会関西支部会
  • 進行大腸癌での内科と外科の接点：Oxaliplatin(L-OHP)+5+FU+1-LV併用療法（ＦＯＬＦＯＸ療法）の進行・再発大腸癌に対する有用性及び安全性のprofileを中心に  [通常講演]
    佐藤 太郎; 岡本 勇; 宮﨑 昌樹; 森永 亮太郎; 中川 和彦; 福岡 正博; 津谷あす香; 長谷川喜一; 清水俊雄; 田村研治; 尾崎智博
    第８４回日本消化器病学会近畿支部例会 2006年02月 兵庫 第８４回日本消化器病学会近畿支部例会
  • A randomized double-blind phase Ⅱa dose-finding study of ZD6474 in Japanese patients with NSCLC  [通常講演]
    中川 和彦; 福岡 正博; Kiura,K; Shinkai,T; Eguchi,K; Ohe,Y; Yamamoto,N; Tsuboi,M; Yokota,S; Jiang,H
    ASCO Annual Meeting 2006年 ASCO Annual Meeting
  • ZD6126の臨床第I相試験  [通常講演]
    倉田 宝保; 中川 和彦; 佐藤 太郎; 津谷 あす香; 田村友秀; 山本昇; 藤阪保仁; 堀池篤; 山田康秀
    日本臨床腫瘍学会総会 2006年 日本臨床腫瘍学会総会
  • Randomized phase II study of carboplatin and paclitaxel (CP) versus gemcitabine and vinorelbine (GV) in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): preliminary results of West Japan Thoracic Oncology Group 0004  [通常講演]
    倉田 宝保; 中川 和彦; 福岡 正博; Saito H; Kashii T; Takeda K; Iwamoto Y; Katakami N; Nakano T
    31st ESMO 2006年 31st ESMO
  • Dose intensive chemotherapy in advanced thymoma: report of Japan clinical oncology trials (JCOG9605 and 9606).  [通常講演]
    国頭 英夫; 中川 和彦; 田村 友秀; 福田 治彦; 武田 晃司; 西脇 裕; 片上 信之; 横山 晶; 野田 和正; 西條 長宏
    第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会 2006年 東京 第3回国際化学療法学会癌治療総会・第11回国際癌化学療法シンポジウム合同大会
  • 肺末梢腫瘤性病変に対するガイドシ－ス併用気管支内腔超音波断層法（ＥＢＵＳ-ＧＳ）の有効性の検討  [通常講演]
    長谷川 喜一; 野上 壽二; 宮﨑 昌樹; 岡部崇記; 寺嶋応顕; 津谷 あす香; 池田 昌人; 明石雄策; 森永亮太郎; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第７８回日本呼吸器内視鏡学会近畿支部会 2005年12月 大阪 第７８回日本呼吸器内視鏡学会近畿支部会
  • 進行非小細胞肺癌（ＮＳＣＬＣ）患者における骨転移、骨関連事象（ＳＲＥ）に関するretrospective study  [通常講演]
    津谷 あす香; 長谷川 喜一; 宮﨑 昌樹; 森永亮太郎; 岡本 勇; 佐藤 太郎; 野上 壽二; 中川 和彦; 福岡 正博; 田村研治; 倉田宝保
    第４６回日本肺癌学会総会 2005年11月 千葉 第４６回日本肺癌学会総会
  • 分子標的薬剤機能と臨床  [通常講演]
    中川 和彦
    第46回 日本肺癌学会総会 2005年11月 千葉 第46回 日本肺癌学会総会
  • 小細胞肺癌におけるゲフィチニブの効果とEGFR発現  [通常講演]
    岡本 勇; 福岡 正博; 中川 和彦; 宮﨑 昌樹
    第46回日本肺癌学会総会 2005年11月 千葉 第46回日本肺癌学会総会
  • 分子標的医療の展開-臨床の問題点とその克服 非小細胞肺癌に対するゲフィチニブの効果と耐性  [通常講演]
    中川 和彦
    第43回日本癌治療学会総会 2005年10月 名古屋 第43回日本癌治療学会総会
  • 当科における進行大腸癌に対するFOLFOX４の使用経験  [通常講演]
    佐藤 太郎; 岡本 勇; 宮﨑 昌樹; 野上 壽二; 森永 亮太郎; 中川 和彦; 福岡 正博; 長谷川喜一
    第83回日本消化器病学会近畿支部例会 2005年09月 大阪 第83回日本消化器病学会近畿支部例会
  • EGFR-TKIs:進行非小細胞肺癌における臨床的位置付け  [通常講演]
    中川 和彦
    第20回日本肺癌学会ワークショップ 2005年07月 札幌 第20回日本肺癌学会ワークショップ
  • 講演 新しい治療薬の話題 EGFR-TK  [通常講演]
    中川 和彦
    第6回臨床腫瘍夏期セミナー 2005年07月 東京 第6回臨床腫瘍夏期セミナー
  • 肺末梢腫瘤性病変に対するガイド－シス併用気管支内腔超音波断層法（ＥＢＵＳ）の有用性の検討  [通常講演]
    長谷川 喜一; 野上 壽二; 宮﨑 昌樹; 岡部崇記; 寺嶋応顕; 池田昌人; 明石雄策; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第７７回日本呼吸器内視鏡学会近畿支部会 2005年06月 京都 第７７回日本呼吸器内視鏡学会近畿支部会
  • 肺門・縦隔病変に対するコンベックス走査式超音波気管支鏡ガイド下生検の使用経験  [通常講演]
    宮﨑 昌樹; 野上 壽二; 長谷川喜一; 岡部崇記; 明石雄策; 池田昌人; 寺嶋応顕; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第７７回日本呼吸器内視鏡学会近畿支部会 2005年06月 京都 第７７回日本呼吸器内視鏡学会近畿支部会
  • 当科における電子スコ－プ（ＬＴＦ-240）を用いた局所麻痺下胸腔鏡の使用報告  [通常講演]
    宮﨑 昌樹; 野上 壽二; 寺嶋応顕; 岡部崇記; 明石雄策; 池田昌人; 尾崎智博; 津谷あす香; 佐藤 太郎; 岡本 勇; 中川 和彦; 福岡 正博
    第２８回日本呼吸器内視鏡学会総会 2005年06月 東京 第２８回日本呼吸器内視鏡学会総会
  • シンポジウム 分子メカニズムと分子標的治療  [通常講演]
    中川 和彦
    第45回 日本呼吸器学会学術講演会 2005年04月 千葉 第45回 日本呼吸器学会学術講演会
  • 講演 進行非小細胞肺癌の治療  [通常講演]
    中川 和彦
    第45回 日本呼吸器学会学術講演会 イブニングセミナー 2005年04月 東京 第45回 日本呼吸器学会学術講演会 イブニングセミナー
  • 肺癌 シグナル伝達阻害剤を含めた治療戦略  [通常講演]
    中川 和彦
    Tokyo Cancer Forum 2005 2005年04月 東京 Tokyo Cancer Forum 2005
  • 肺癌に対する塩酸アムルビシンと塩酸イリノテカン併用の臨床第Ⅰ相試験  [通常講演]
    宮﨑 昌樹; 倉田 宝保; 金田裕靖; 池田昌人; 津谷あす香; 米阪仁雄; 佐藤 太郎; 田村研治; 野上 壽二; 植島 久雄; 中川 和彦; 福岡 正博
    第４５回日本呼吸器学会総会 2005年04月 千葉 第４５回日本呼吸器学会総会
  • 肺癌化学療法の現状と展望 -TS-1を含めた新薬を中心として-  [通常講演]
    中川 和彦
    LCCS in 三河 2005年03月 愛知 LCCS in 三河
  • 肺癌に対する塩酸アムルビシンと塩酸イリノテカン併用の臨床第I相試験  [通常講演]
    宮﨑 昌樹; 倉田 宝保; 金田 裕靖; 池田 昌人; 津谷あす香; 米阪 仁雄; 佐藤 太郎; 田村 研治; 野上 壽二; 植島 久雄; 中川 和彦; 福岡 正博
    第3回日本臨床腫瘍学会総会 2005年03月 横浜 第3回日本臨床腫瘍学会総会
  • 分子標的治療の現状と問題点  [通常講演]
    中川 和彦
    第43回日本呼吸器学会総会 2005年03月 第43回日本呼吸器学会総会
     
    異例の速さで日本における承認を受け、大きな期待を荷った非小細胞肺癌治療薬であるEGFレセプターを標的としたゲフィチニブ（イレッサ）の臨床試験を中心に、肺癌領域における分子標的治療の現状と問題点を総括し、早期臨床試験の今後の方向性を検討する。
  • イレッサによる長期生存例の検討  [通常講演]
    尾崎 智博; 寺嶋 応顕; 明石 雄策; 池田 昌人; 津谷 あす香; 宮崎 昌樹; 佐藤 太郎; 田村 研治; 倉田 宝保; 野上 壽二; 中川 和彦; 福岡 正博
    第８１回日本肺癌学会関西支部会 2005年02月 大阪 第８１回日本肺癌学会関西支部会
  • 肺癌に対する塩酸アトルビシンと塩酸イリノテカン併用の臨床第Ｉ相試験  [通常講演]
    倉田 宝保; 宮﨑 昌樹; 池田 昌人; 津谷 あす香; 米阪 仁雄; 佐藤 太郎; 田村 研治; 野上 壽二; 中川 和彦; 福岡 正博; 金田 裕靖; 植島 久雄
    第８１回日本肺癌学会関西支部会 2005年02月 大阪 第８１回日本肺癌学会関西支部会
  • 当科におけるゲフィチニブによる肝障害の発生頻度とその対策  [通常講演]
    佐藤 太郎; 倉田 宝保; 野上 壽二; 田村 研治; 宮﨑 昌樹; 米阪 仁雄; 尾崎 智博; 池田 昌人; 金田 裕靖; 津谷 あす香; 寺嶋 応顕; 中川 和彦; 福岡 正博
    第45回日本肺癌学会総会 2004年10月 横浜 第45回日本肺癌学会総会
  • ＰＳ3（4）進行肺腺癌に対するゲフィチニブ（イレッサ）の臨床第Ⅱ相試験  [通常講演]
    倉田 宝保; 田村 研治; 野上 壽二; 佐藤 太郎; 宮﨑 昌樹; 津谷 あす香; 尾崎 智博; 金田 裕靖; 中川 和彦; 福岡 正博
    第４５回日本肺癌学会総会 2004年10月 横浜 第４５回日本肺癌学会総会
  • 進行非小細胞肺癌に対する他施設共同第Ⅲ相比較試験（ＦＡＣＳ研）の成績  [通常講演]
    倉田 宝保; 中川 和彦; 福岡 正博
    第４５回日本肺癌学会総会 2004年10月 横浜 第４５回日本肺癌学会総会
  • 進行胃癌に対するＴＳ-1とDocetaxel併用療法の第１相試験 -ポスタ-  [通常講演]
    佐藤 太郎; 田村 研治; 倉田 宝保; 野上 壽二; 宮﨑 昌樹; 米阪 仁雄; 中川 和彦; 福岡 正博
    第４２回日本癌治療学会総会 2004年10月 京都 第４２回日本癌治療学会総会
  • 肺癌に対する塩酸アムルビシンと塩酸イリノテカン併用の臨床第Ⅰ相試験  [通常講演]
    宮﨑 昌樹; 倉田 宝保; 金田 裕靖; 池田 昌人; 津谷 あす香; 米阪 仁雄; 佐藤 太郎; 田村 研治; 野上 壽二; 植島 久雄; 中川 和彦; 福岡 正博
    第４５回日本肺癌学会総会 2004年10月 横浜 第４５回日本肺癌学会総会
  • 再発進行非小細胞肺癌に対するゲフィチニブとCOX-2阻害剤の併用療法の第Ⅱ相試験  [通常講演]
    津谷 あす香; 田村 研治; 佐藤 太郎; 倉田 宝保; 野上 壽ニ; 中川 和彦; 植島 久雄; 小宮 武文; 福岡 正博
    第４５回日本肺癌学会総会 2004年10月 横浜 第４５回日本肺癌学会総会
  • 歯科治療器具による気管支異物の3症例  [通常講演]
    岩元 辰篤; 寺嶋 応顕; 池田 昌人; 津谷 あす香; 米阪 仁雄; 宮﨑 昌樹; 田村 研治; 倉田 宝保; 野上 壽二; 中川 和彦; 福岡 正博
    第75回日本呼吸器内視鏡学会近畿支部会 2004年09月 大阪 第75回日本呼吸器内視鏡学会近畿支部会
  • 局所麻酔下胸腔鏡検査にて確定診断の得られた悪性胸膜中皮腫症例の検討  [通常講演]
    津谷 あす香; 植島 久雄; 寺嶋 応顕; 金田 裕靖; 米阪 仁雄; 宮崎 昌樹; 倉田 宝保; 田村 研治; 野上 壽二; 中川 和彦; 福岡 正博
    第７８回日本肺癌学会関西支部会 2004年07月 大阪 第７８回日本肺癌学会関西支部会
  • 当院における極細経気管支鏡の使用経験  [通常講演]
    宮﨑 昌樹; 野上 壽二; 寺嶋 応顕; 金田 裕靖; 津谷 あす香; 池田 昌人; 米阪 仁雄; 佐藤 太郎; 田村 研治; 倉田 宝保; 中川 和彦; 福岡 正博
    第２７回日本呼吸器内視鏡学会総会 2004年06月 大阪 第２７回日本呼吸器内視鏡学会総会
  • Emerging data to better understanding in EGFR-TKI therapy’-Japanese Clinical Experience of Gefitinib  [通常講演]
    中川 和彦
    The Thai Society of Clinical Oncology Annual Meeting Symposium 2004年 The Thai Society of Clinical Oncology Annual Meeting Symposium
  • ゲフィチニブの奏効に関連する因子の検討  [通常講演]
    倉田 宝保; 金田 裕靖; 田村 研治; 野上 壽二; 中川 和彦; 福岡 正博
    日本呼吸器学会総会 2004年 日本呼吸器学会総会
  • 進行非小細胞肺癌に対するgemcitabine+CBDCA(CG)とgemcitabine+vinorelbine（GV）の無作為化比較試験―WJTOG0104  [通常講演]
    倉田 宝保; 中川 和彦; 福岡 正博; 山本信之; 杉浦孝彦; 高田佳木; 根来俊一; 松井薫; 菓子井達彦; 高田實; 中西洋一; 加藤晃史; 有吉寛
    日本臨床腫瘍学会 2004年 日本臨床腫瘍学会
  • 非小細胞肺癌に対するゲフィチニブの奏効に関連する因子の検討  [通常講演]
    倉田 宝保; 田村 研治; 佐藤 太郎; 金田 裕靖; 野上 壽二; 中川 和彦; 福岡 正博
    日本内科学会総会 2004年 日本内科学会総会
  • 進行非小細胞肺癌に対する Non-Platinum 併用化学療法後のsecond-line 化学療法についての検討  [通常講演]
    金田 裕靖; 米阪 仁雄; 倉田 宝保; 秋山 慶太; 築山正嗣; 宮﨑 昌樹; 田村研治; 植島 久雄; 野上 壽二; 中川 和彦; 福岡 正博; 山本信之; 浅井 暁
    第４４回日本肺癌学会総会 2003年11月 東京 第４４回日本肺癌学会総会
  • ゲフィチニブの奏効に関連する因子の検討  [通常講演]
    金田 裕靖; 田村研治; 明石雄策; 倉田 宝保; 中川 和彦; 福岡 正博
    第７８回日本肺癌学会関西支部会 2003年07月 大阪 第７８回日本肺癌学会関西支部会
  • ゲフィチニブとビノレルビン併用による抗腫瘍効果の検討  [通常講演]
    宮﨑 昌樹; 田村 研治; 中川 和彦; 福岡 正博
    第7回がん分子標的治療研究会 2003年06月 東京 第7回がん分子標的治療研究会
     
    ヒト肺癌株移植マウスモデルを用いてゲフィチニブとビノレルビン併用における抗腫瘍効果を検討した。またウェスタンブロット法を用いEGFRとErbB2の蛋白質発現レベルとリン酸化レベルを調べた。
  • 非小細胞肺癌におけるネダプラチンとゲムシタビン併用による臨床第I／II相試験  [通常講演]
    宮﨑 昌樹; 倉田 宝保; 植島 久雄; 野上 壽二; 田村 研治; 中川 和彦; 福岡 正博; 米阪 仁雄; 金田 裕靖; 山本 信之; 秋山 慶太
    第43回日本呼吸器学会総会 2003年03月 福岡 第43回日本呼吸器学会総会
     
    非小細胞肺癌に対するネダプラチンとゲムシタビンとの併用療法ｌにおける最大耐用量の推定、用量規制毒性および安全性の評価、推奨投与量の決定、抗腫瘍効果の判定を行った。現在の所、重篤な副作用なくdoseescalationを続行中である。
  • 癌治療における臨床試験－近畿大学における現状と問題－  [通常講演]
    中川 和彦
    第2回山口クリニカルオンコロジストセミナー 2003年03月 宇部 第2回山口クリニカルオンコロジストセミナー
     
    院内における臨床試験（治験を含む）を促進するために、近畿大学医学部として実施している治験管理センターの実際運用と近畿大学腫瘍内科における現状を報告した。CRCの必要性を訴えた。
  • 進行非小細胞肺癌に対するＮon-Platinum併用化学療法後のsecond-line化学療法についての検討  [通常講演]
    金田 裕靖; 米阪 仁雄; 倉田 宝保; 築山正嗣; 宮﨑 昌樹; 田村研治; 植島 久雄; 野上 壽二; 中川 和彦; 福岡 正博; 山本信之; 浅井 暁
    第７７回日本肺癌学会関西支部会 2003年02月 大阪 第７７回日本肺癌学会関西支部会
  • ゲフィチニブとビノレルビン併用による抗腫瘍効果の検討  [通常講演]
    宮﨑 昌樹; 田村 研治; 中川 和彦; 福岡 正博
    第1回日本臨床腫瘍学会 2003年02月 福岡 第1回日本臨床腫瘍学会
     
    ヒト肺癌株移植マウスモデルを用いてゲフィチニブとビノレルビンへ併用における抗腫瘍効果を検討した。またWesternblott法を用いEGFRとErbB2の蛋白質発現レベルとリン酸化レベルを調べた。
  • Symposium「Molecular Target Therapy on Non-small Cell Lung Cancer」  [通常講演]
    中川 和彦
    The 1st International Symposium on CNS Germ Cell Tumor 2003年 The 1st International Symposium on CNS Germ Cell Tumor
  • 歯科治療器具による気管支異物の2症例  [通常講演]
    岡部 崇記; 福岡 正博; 中川 和彦; 植島 久雄; 野上 壽二; 倉田 宝保; 田村 研治; 宮﨑 昌樹; 米阪 仁雄; 金田 裕靖; 寺嶋 応顕
    第72回日本気管支学会近畿地方会 2002年11月 大阪 第72回日本気管支学会近畿地方会
     
    当院における成人での気管支異物症例は11例であり、8例が義歯、歯であり、2例は歯科治療器具であった。2例とも右気管支であり、症例もなく鉗子により容易に取り除くことができた。治療器具は、気管を傷害することもあり早期に摘出することが必要である。
  • 進行非小細胞肺癌に対するNon-Platinum併用化学療法後のsecond-line化学療法についての検討  [通常講演]
    米阪 仁雄; 倉田 宝保; 宮﨑 昌樹; 田村 研治; 野上 壽二; 植島 久雄; 中川 和彦; 福岡 正博; 山本 信之; 浅井; 秋山 慶太
    第43回日本肺癌学会総会 2002年11月 福岡 第43回日本肺癌学会総会
     
    進行非小細胞肺癌で1st-line化学療法としてnon-platinum併用化学療法を受け、2nd-lineとしてプラチナ製剤と投与された18例について検討。毒性は耐用可能で、奏効率は17％と比較的良好であった。
  • 再発小細胞肺癌におけるweekly パクリタキセル投与の臨床第二相試験  [通常講演]
    宮﨑 昌樹; 倉田 宝保; 金田 裕靖; 米阪 仁雄; 田村 研治; 野上 壽二; 中川 和彦; 福岡 正博; 秋山 慶太
    第43回肺癌学会総会 2002年11月 福岡 第43回肺癌学会総会
     
    パクリタキセルは進展型小細胞肺癌に対して効果がある薬剤であるが、optimal doseおよびスケジュールは確立されておらず、weeklyに投与する臨床第2相試験を計画した。
  • 化学療法時の好中球減少に伴う感染症に対するcefezopranとmeropenemの有効性と安全性の検討  [通常講演]
    秋山 慶太; 倉田 宝保; 植島 久雄; 野上 壽二; 中川 和彦; 福岡 正博; 田村 研治; 宮﨑 昌樹; 米阪 仁雄; 金田 裕靖; 岡部 崇記
    第43回日本肺癌学会総会 2002年11月 福岡 第43回日本肺癌学会総会
     
    化学療法時の好中球減少に伴う感染症に対するcefezopranとmeropenemの有効性と安全性を比較検討した。結果、両群に有効性の差は認められなかった。
  • 非小細胞肺癌におけるネダプラチンとゲムシタビン併用による臨床第I/II相試験  [通常講演]
    倉田 宝保; 植島 久雄; 野上 壽二; 田村 研治; 宮﨑 昌樹; 米阪 仁雄; 金田 裕靖; 中川 和彦; 福岡 正博; 山本 信之
    第43回日本肺癌学会総会 2002年11月 福岡 第43回日本肺癌学会総会
     
    ネダプラチンは第2世代のプラチナ製剤で、非小細胞肺癌に有望とされている今回、その非小細胞肺癌に対しネダプラチンとゲムシタビンの併用第I相試験を行った。現在までのレベル3まで進み、毒性は軽微でレベル4を施行中である。
  • 非小細胞肺癌患者におけるシスプラチン、パクリタキセル、BNP7787併用第I相試験  [通常講演]
    植島 久雄; 中川 和彦; 福岡 正博; 根来 俊一; 松井 薫; 工藤 新三
    14th EORTC-NCI-AACR symposium 2002年11月 ドイツ 14th EORTC-NCI-AACR symposium
     
    シスプラチン、パクリタキセル併用化学療法を受けた非小細胞肺癌患者においてBNP7787を加えることにより、末梢神経障害の発生頻度は低下した。安全性には問題なく、化学療法の効果を減少させることもなかった。
  • 電子スコープ（LTF-240）を用いた局所麻酔下胸腔鏡検査  [通常講演]
    植島 久雄; 福岡 正博; 中川 和彦; 野上 壽二; 倉田 宝保; 田村 研治; 米阪 仁雄; 金田 裕靖
    第54回日本気管食道科学会 2002年11月 大阪 第54回日本気管食道科学会
     
    診断未確定の胸膜炎症例に対して内科医のみで、LTF-240を用いた局所麻酔下胸腔鏡検査を施行した。従来の胸腔鏡に比し、安全にかつ確実に確定診断が得られ、比較的低侵襲であり、有用な検査法と考えられた。
  • NSCLCにおける標的治療  [通常講演]
    中川 和彦
    IASLC Workshop of the current strategy for stage III-IV non-small cell lung cancer 2002年11月 福岡 IASLC Workshop of the current strategy for stage III-IV non-small cell lung cancer
     
    非小細胞肺癌に対する分子標的治療剤の現状について、特にZD1839について発表した。
  • 局所進行非小細胞肺癌のイリノテカンとカルボプラチンと胸部放射線併用における増量試験  [通常講演]
    金田 裕靖; 植島 久雄; 野上 壽二; 田村 研治; 倉田 宝保; 中川 和彦; 福岡 正博; 西村 恭昌; 明石 雄策
    27ｔｈ ESMO Congress 2002年10月 ニース 27ｔｈ ESMO Congress
     
    IIIb・IIIa期の非小細胞肺癌における標準的治療法はまだ確立されていないが、放射線化学療法の有効性が示唆されている。今回、新規抗癌剤を放射線の併用による増量試験を行い、安全性・有効性を評価した。
  • EGFR臨床試験－チロシンキナーゼ阻害剤－  [通常講演]
    中川 和彦
    17th Workshop on France-Japan Cooperative Cancer Research Program 2002年10月 フランス 17th Workshop on France-Japan Cooperative Cancer Research Program
     
    EGFレセプターの選択的阻害剤であるZD1839の前臨床試験及び臨床試験のデータを概説した。
  • 新分子標的治療の背景と原理～日本の経験と観点～  [通常講演]
    中川 和彦
    8th Central European Lung Cancer Conference European-Japanese Joint Symposium 2002年09月 オーストリア 8th Central European Lung Cancer Conference European-Japanese Joint Symposium
     
    分子標的薬剤に対する治療経験について発表した。特にEGFRに対するチロシンキナーゼ阻害剤イレッサの臨床試験について概説した。
  • 膵臓原発小細胞肺癌の１例  [通常講演]
    金田 裕靖; 野上 壽二; 宮﨑 昌樹; 田村研治; 倉田 宝保; 植島 久雄; 中川 和彦; 福岡 正博
    第７６回日本肺癌学会関西支部会 2002年08月 兵庫 第７６回日本肺癌学会関西支部会
  • CT透視下肺生検の有用性-これまでのCTガイド下肺生検と比較して-  [通常講演]
    寺嶋 応顕; 福岡 正博; 中川 和彦; 植島 久雄; 野上 壽二; 倉田 宝保; 田村 研治; 宮﨑 昌樹; 米阪 仁雄; 金田 裕靖; 明石 雄策; 秋山 慶太
    第76回日本肺癌学会関西支部会 2002年08月 神戸 第76回日本肺癌学会関西支部会
     
    平成9年6月から平成13年6月の間に行った非透視下症例103例、平成13年7月から平成14年6月の間に行った透視下症例25例について検査時間、正診率、合併症等をretrospectiveに比較し、CT透視下肺生検の有用性について検討した。
  • 膵臓原発小細胞癌の1例  [通常講演]
    野上 壽二; 金田 裕靖; 宮﨑 昌樹; 田村 研治; 倉田 宝保; 植島 久雄; 中川 和彦; 福岡 正博
    第167回日本内科学会近畿地方会 2002年06月 大阪 第167回日本内科学会近畿地方会
  • Ｒｉｓｋ ｆａｃｔｏｒｓ ｏｆ ｒａｄｉａｔｈｉｏｎ ｐｈｅｕｍｏｎｉｔｉｓ ｆｏｌｌｏｗｉｎｇ ｃｈｅｍｏｒａｄｉｏｔｈｅｒａｐｙ ｗｉｔｈ ＣＲＰ－11  [通常講演]
    佐藤 隆司; 田村 研治; 倉田 宝保; 植島 久雄; 野上 壽二; 中川 和彦; 福岡 正博
    第26回国際内科学会議 2002年05月 京都 第26回国際内科学会議
  • CRT-11を用いた放射線化学療法時における放射線肺臓炎の危険因子の検討  [通常講演]
    佐藤 隆司; 田村 研治; 植島 久雄; 野上 壽二; 倉田 宝保; 秋山 慶太; 中川 和彦; 福岡 正博
    The 38ｔｈ ＡＭＥＲＩＣＡＮ ＳＯＣＩＥＴＹ ＯＦ ＣＬＩＮＩＣＡＬ ＯＮＣＯＬＯＧＹ 2002年05月 オーランド The 38ｔｈ ＡＭＥＲＩＣＡＮ ＳＯＣＩＥＴＹ ＯＦ ＣＬＩＮＩＣＡＬ ＯＮＣＯＬＯＧＹ
     
    肺癌に対して放射線治療とＣＲＴ－11を含む（単剤または他剤との併用）化学療法との同時併用療法を行った症例における放射線肺臓炎を来す危険因子を多変量解析で行った。結果は、ＣＲＴ－11の投与量25㎎/㎡以上と総投与量に関連することを報告した。
  • 電子スコープ（LTF240）を用いた局所麻酔下胸腔鏡検査の使用経験  [通常講演]
    植島 久雄; 倉田 宝保; 野上 壽二; 中川 和彦; 福岡 正博; 田村 研治; 小宮 武文; 宮﨑 昌樹; 山本 信之; 浅
    第25回日本気管支学会総会 2002年05月 札幌 第25回日本気管支学会総会
     
    確定診断の困難な胸膜炎症例に対して、新しく開発された電子スコープLTF240を用いて局所麻酔下に胸腔鏡検査を施行した。スコープは操作性に優れたものであり、全症例において確定診断がなされ、安全性にも問題がなかった。
  • 放射線肺臓炎を誘発するＣＲＴ－11の投与量に関する検討  [通常講演]
    佐藤 隆司; 田村 研治; 植島 久雄; 野上 壽二; 倉田 宝保; 秋山 慶太; 中川 和彦; 福岡 正博
    第42回日本呼吸器学会総会 2002年04月 仙台 第42回日本呼吸器学会総会
  • 高齢者ＥＤ－ＳＣＬＣの再発例に対して、トポテカン単剤化学療法が安全に施行できた症例  [通常講演]
    北口 佐也子; 田村 研治; 倉田 宝保; 植島 久雄; 野上 壽二; 中川 和彦; 福岡 正博
    第75回日本肺癌学会関西支部会 2002年02月 大阪 第75回日本肺癌学会関西支部会
  • Clinical evaluation of a selective EGFR tyrosin kinase inhibitor,Iressa,Experience and perspectives in Japan  [通常講演]
    中川 和彦
    Irland Cancer Care Meetin 2002年 Irland Irland Cancer Care Meetin
  • Phase III trial with docetaxel in advanced-NSCLC.  [通常講演]
    中川 和彦
    IASLC Workshop of the current strategy for stage III-IV non-small cell lung cancer 2002年 福岡 IASLC Workshop of the current strategy for stage III-IV non-small cell lung cancer
  • EGFR tyrosine kinase inhibitors: ZD1839 and ZD6474  [通常講演]
    中川 和彦
    The 7th International Symposium on Cancer Chemotherapy. 2002年 東京 The 7th International Symposium on Cancer Chemotherapy.
  • Symposium「EGFR tyrosine kinase inhibitors: Novel therapy in lung cancer」  [通常講演]
    中川 和彦
    Cancer Care Ireland 2002年 Belfast, Ireland Cancer Care Ireland
  • Clinical evaluation of a EGFR selective tyrosine kinase inhibitor, ZD1839 (Iressa-).  [通常講演]
    中川 和彦
    18th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium 2002年 名古屋 18th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium
  • Gene expression monitoring with cDNA array revealed the major biological targets of farnesyl transferase (FT) inhibitor, R115777 (ZarnestraTM), in a phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study.  [通常講演]
    中川 和彦; 西尾 和人; 福岡 正博; Yamamoto N; Koizumi F; Ohashi Y; d D. W; Ito H; Kobayashi G
    American Society of Clinical Oncology 2002年 Orland American Society of Clinical Oncology
  • Symposium「Background and rationale of new molecular targeted therapies-Japanese experience and point of view.」  [通常講演]
    中川 和彦
    8th Central European Lung Cancer Conference European-Japanese Joint Symposium 2002年 Austria 8th Central European Lung Cancer Conference European-Japanese Joint Symposium
  • workshop「Clinical evaluation of a EGFR selective tyrosine kinase inhibitor, ZD1839 (Iressa?).」  [通常講演]
    中川 和彦
    17th Workshop on France-Japan Cooperative Cancer Research Program 2002年 フランス 17th Workshop on France-Japan Cooperative Cancer Research Program
  • Symposium 「Is concurrent chemoradiotherapy superior to sequential chemoradiotherapy.」  [通常講演]
    中川 和彦
    Cross Chemoradiation in NSCLC 2002年 ミラノ Cross Chemoradiation in NSCLC
  • 既治療無効小細胞肺癌に対するパクリタキセル毎週投与の第II相試験  [通常講演]
    倉田 宝保; 鶴谷 純司; 田村 研治; 中川 和彦; 福岡 正博; 山本信之; 梁尚志; 高田実; 工藤新三; 河原正明
    日本内科学会総会 2002年 日本内科学会総会
  • Phase II study of weekly paclitaxel for relapsed small cell lung cancer.  [通常講演]
    倉田 宝保; 鶴谷 純司; 田村 研治; 中川 和彦; 福岡 正博; Yamamoto N Tamura; K; Takada M Kudoh; S Kawahara M
    ASCO 2002年 ASCO
  • 非小細胞肺癌におけるネダプラチンとゲムシタビン併用による臨床第I/II相試験  [通常講演]
    倉田 宝保; 山本信之; 植島 久雄; 野上 壽二; 田村 研治; 秋山 慶太; 宮﨑 昌樹; 米阪 仁雄; 金田 裕靖; 中川 和彦; 福岡 正博; 築山正嗣
    日本肺癌学会 2002年 日本肺癌学会
  • 放射腺肺臓炎を誘発するＣＲＴ－11の投与量に関する検討  [通常講演]
    佐藤 隆司; 田村 研治; 倉田 宝保; 植島 久雄; 野上 壽二; 中川 和彦; 福岡 正博
    第75回日本肺癌学会関西支部会 2002年 大阪 第75回日本肺癌学会関西支部会
  • 各計算法によるカルボプラチン投与量の差についての検討  [通常講演]
    金田 裕靖; 山本信之; 浅井 暁; 植島 久雄; 野上 壽二; 倉田 宝保; 田村研治; 米阪 仁雄; 秋山 慶太; 中川 和彦; 福岡 正博
    第４２回日本肺癌学会総会 2001年11月 大阪 第４２回日本肺癌学会総会
  • 検診ＣＴで発見された診断困難な陰影を呈し、ＣＴにおける経過が追えた微小肺腺癌の一例  [通常講演]
    上田 朋子; 明石雄策; 大森 隆; 金田 裕靖; 佐藤 隆司; 倉田 宝保; 中川 和彦; 東田 有智; 福岡 正博; 原 聡
    第42回日本肺癌学会総会 2001年11月 大阪 第42回日本肺癌学会総会
  • 未治療限局型小細胞肺癌に対する化学療法+放射線療法+外科療法によるtrimadality therapy のpilot study  [通常講演]
    原 聡; 廣畑 健; 南 憲司; 大塚 浩史; 塩﨑 均; 森山 あづさ; 植島 久雄; 中川 和彦; 福岡 正博; 西村 恭昌
    第42回日本肺癌学会 2001年11月 大阪 第42回日本肺癌学会
     
    未治療限局型小細胞肺癌に対して化学療法+放射線療法+外科療法によるtrimadality therapy のを施行したpilot studyの治療成績を報告した。
  • Pharmacokinetic / pharmacodynamic study of weekly cisplatin plus docetaxel  [通常講演]
    清水 俊雄; 福岡 正博; 中川 和彦; 池田 昌人; 梁; 尚志; 高田 実; 山本 信之
    第42回肺癌学会総会 2001年11月 大阪市 第42回肺癌学会総会
     
    Pharmacokinetic / pharmacodynamic study of weekly cisplatin plus docetaxel
  • 標準的治療のない癌患者に対するシスプラチンとWeeklyパクリタキセルにおける臨床第１相試験  [通常講演]
    宮﨑 昌樹; 野上 壽二; 明石 雄策; 中川 和彦; 福岡 正博
    第４２回日本肺癌学会総会 2001年11月 大阪 第４２回日本肺癌学会総会
  • 前治療無効及び再発進行肺癌に対するsecond lineCBDCA+ｗｅｅｋｌｙ Paclitaxelのphasel試験  [通常講演]
    野上 壽二; 宮﨑 昌樹; 明石 雄策; 中川 和彦; 福岡 正博
    第42回日本肺癌学会総会 2001年11月 大阪 第42回日本肺癌学会総会
  • 未治療進行非小細胞肺癌に対するGemcitabine+Vinorelbineの第1相試験（ＷＪＴＯＧ9908）  [通常講演]
    野上 壽二; 中川 和彦; 福岡 正博
    第42回日本肺癌学会総会 2001年11月 大阪 第42回日本肺癌学会総会
  • 固形癌に対するタキソール、ゲムシタビン、ビノレルビン併用化学療法の併用第一相試験  [通常講演]
    植島 久雄; 森山 あづさ; 田村 研治; 倉田 宝保; 小宮 武文; 中川 和彦; 福岡 正博; 浅井 暁; 山本
    第42回日本肺癌学会総会 2001年11月 大阪 第42回日本肺癌学会総会
     
    固形癌に対するタキソール、ゲムシタビン、ビノレルビン併用化学療法での最大耐用量はそれぞれ1000/25/60mg/m/weekであり用量制限毒性は発熱性好中球減少症であった。
  • 切除不能局所進行型非小細胞肺癌に対するweekly CPT-11 + CBDCA + concurrent thoracic radiotherapy のpilot study  [通常講演]
    植島 久雄; 福岡 正博; 中川 和彦; 野上 壽二; 西村 恭昌; 森山 あづさ; 小宮 武文; 山本 信之
    第60回日本癌学会 2001年09月 横浜 第60回日本癌学会
     
    切除不能III期非小細胞肺癌に対し、塩酸イリノテカン及びカルボプラチンの毎週投与と60Gyの放射線併用療法について効果、安全性を報告した。奏効率は83％で、重篤な副作用はなく、有用と考えられた。
  • 検診ＣＴで発見された診断困難な陰影を呈し、Ｃｔにおける経過が追えた微小肺腺癌  [通常講演]
    山藤 緑; 倉田 宝保; 秋山 慶太; 森山 あづさ; 田村 研治; 小宮 武文; 植島 久雄; 中川 和彦; 福岡 正博; 白石 治; 原 聡
    第74回日本肺癌学会関西支部会 2001年07月 京都 第74回日本肺癌学会関西支部会
  • カルバート式を用いたCarboplatin のクリアランス計算における蓄尿法とCockcroft法、Jellife法の比較  [通常講演]
    山本 信之; 福岡 正博; 中川 和彦
    第57回日本呼吸器学会近畿地方会 2001年07月 大阪 第57回日本呼吸器学会近畿地方会
     
    カルボプラチンの投与量を計算するためのそれぞれの式の差を検討した。
  • 肺癌化学療法における新戦略と支持療法  [通常講演]
    中川 和彦
    5th International Conference of the Asian Clinical Oncology Society Granocyte Satellite Symposium 2001年04月 台湾 5th International Conference of the Asian Clinical Oncology Society Granocyte Satellite Symposium
  • 局所進行型非小細胞肺がんに対するweekly taxotere + cisplatinと胸部放射線の同時併用第I相試験  [通常講演]
    山本 信之; 福岡 正博; 中川 和彦; 植島 久雄; 小宮 武文
    第98回日本内科学会総会 2001年04月 横浜 第98回日本内科学会総会
     
    StageIII A/B期の非小細胞肺がんに対するタキソテア+シスプラチンと胸部放射線の同時併用療法における抗がん剤の至適投与法について発表した。
  • Induction of MRP5/SMRP m RNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin.  [通常講演]
    鶴谷 純也; 西尾 和人; 吉田 誠; 畑下恵理奈; 小宮 武文; 中川 和彦; 福岡 正博; Akutagawa; S. Koh; Y. Saijo, N; Suzuki, T
    AACR Annual Meeting 2001年03月 New Orleans LA. AACR Annual Meeting
  • 新世紀を迎えた肺癌治療の展開  [通常講演]
    小宮 武文; 福岡 正博; 中川 和彦
    日本呼吸器学会総会 2001年03月 東京都 日本呼吸器学会総会
     
    新世紀を迎えた肺癌治療の展開 (6) 癌分子標的治療の現状と展望
  • Farnesy1 transferase inhibitor (FTI): R115777.  [通常講演]
    中川 和彦
    The 6th International Symposium on Cancer Chemotherapy 2001年 東京 The 6th International Symposium on Cancer Chemotherapy
  • A phase Ⅰ, pharmacokinetic (PK) and pharmacodynamic (PD) study of the farnesyl transferase inhibitor (FTI) R115777 in Japanese patients with advanced non-hematological malignancies  [通常講演]
    中川 和彦; 西尾 和人; 福岡 正博; Yanmamoto N; Ohashi Y; End D; Bol K; Ito H
    American Society of Clinical Oncology, 2001年 San Francisco American Society of Clinical Oncology,
  • Phase I and pharmacokinetic study of CPT-11 and Taxol in patients with lung cancer.  [通常講演]
    倉田 宝保; 米阪 仁雄; 秋山 慶太; 田村 研治; 植島 久雄; 中川 和彦; 福岡 正博; 浅井暁 山本信之
    日本癌治療学会 2001年 日本癌治療学会
  • Phase I and pharmacokinetic study of CPT-11 and Taxol in patients with lung cancer.  [通常講演]
    倉田 宝保; 米阪 仁雄; 田村 研治; 秋山 慶太; 植島 久雄; 中川 和彦; 福岡 正博; 浅井暁 山本信之
    日本肺癌学会 2001年 日本肺癌学会
  • A phase I, pharmacokinetic (PK) and pharmacodynamic (PD) study of the farnesyl transferase inhibitor (FTI) R115777 in Japanese patients with advanced non-hematological malignancies.  [通常講演]
    中川 和彦; 西尾 和人; 山本信之; 福岡 正博; Ohashi, Y; End; D. Bol; K. Ito, H
    2001 American Society Clinical Oncology meeting A317, 2001. 2001年 2001 American Society Clinical Oncology meeting A317, 2001.
  • 非小細胞肺癌脳転移症例に対するＲａｄｉｏｓｕｒｇｅｒｙの有用性の検討  [通常講演]
    上田 朋子; 清水 俊雄; 森 富美子; 金田 裕靖; 森田 泰慶; 葛本 佳正; 中川 和彦; 福岡 正博
    第73回日本肺癌学会関西支部会 2001年01月 大阪 第73回日本肺癌学会関西支部会
  • 前治療無効及び再発進行肺癌に対するsecond line CBDCA+weekly Paclitaxelの phase Ｉ試験  [通常講演]
    野上 壽二; 中川 和彦; 福岡 正博
    第７３回日本肺癌学会関西支部会 2001年01月 大阪 第７３回日本肺癌学会関西支部会
  • 太陽原発神経内分泌腫瘍の1例  [通常講演]
    尾崎 智博; 福岡 正博; 森山 あづさ; 小宮 武文; 植島 久雄; 中川 和彦; 東田 有智
    第56回日本呼吸器学会近畿地方会 2000年12月 京都 第56回日本呼吸器学会近畿地方会
     
    表在及び縦隔リンパ節腫張、皮下及び骨転移、大腫腫瘍を認めた70際の男性で、最終診断は非常に稀である大腫原発神経内分泌腫瘍、また化学療法が奏効し、PS4から1に改善した症例を経験
  • 再発進行癌に対するsecond-line weekly docetaxel のphase I/II study  [通常講演]
    清水 俊雄; 福岡 正博; 中川 和彦; 梁 尚志; 高田; 山本 信之
    第41回肺癌学会総会 2000年11月 東京 第41回肺癌学会総会
     
    再発進行癌に対するsecond-line weekly docetaxel のphase I/II study
  • 局所進行型非小細胞肺がんに対するＷeekly Taxotere(TXT)+Cisplatin(CDDP)と胸部放射線の同時併用療法の第１相試験  [通常講演]
    野上 壽二; 中川 和彦; 植島 久雄; 森山あづさ; 福岡 正博
    第４１回日本肺癌学会総会 2000年11月 東京 第４１回日本肺癌学会総会
  • 再発しない前治療無効小細胞肺癌に対する塩酸イリノテカンとドキソルビシン併用第II相試験  [通常講演]
    植島 久雄; 福岡 正博; 小宮 武文; 中川 和彦; 森山 あづさ; 山本 信之; 根来 俊一; 瀧藤 伸英; 武田 晃司
    第41回日本肺癌学会総会 2000年11月 東京 第41回日本肺癌学会総会
     
    再発および前治療無効小細胞肺癌に対し、本治療施行した。29例中14例に効果を認め、奏効率は48％、中間生存期間は6.5ヶ月で有った、毒性は治療関連死を1例認めたが、他の症例では耐用可能なものであった。
  • 固形癌患者に対するZD1839（Iressa）の間欠投与時の臨床第I相試験  [通常講演]
    山本 信之; 福岡 正博; 中川 和彦; 根来 俊一
    第41回日本肺癌学会総会 2000年11月 東京 第41回日本肺癌学会総会
     
    新規抗癌剤であるZD1839の第I相試験の結果を報告した。
  • Selenium Detector Radiographyにおける小型肺腫瘤影の検出  [通常講演]
    清水 俊雄; 福岡 正博; 中川 和彦; 山上 冨美子; 野; 朋子; 葛本 佳正; 粟井 和夫; 堀
    第38回日本癌治療学会総会 2000年10月 仙台市 第38回日本癌治療学会総会
     
    Selenium Detector Radiographyにおける小型肺腫瘤影の検出
  • 再発、治療抵抗性小細胞肺癌に対するWeekly Taxol の治療効果の検討  [通常講演]
    秋山 慶太; 福岡 正博; 中川 和彦; 植島 久雄; 小宮 武文; 森山 あづさ; 山本 信之
    第59回日本癌学会総会 2000年10月 横浜 第59回日本癌学会総会
     
    再発ないし前治療無効の小細胞肺癌に対するPaclitaxel Weekly 化学療法の抗腫瘍効果と安全性を検討し報告した。
  • 局所進行非小細胞肺癌に対するWeekly Taxotere (TXT) + Cisplatin （CDDP) と胸部放射線療法の第I相試験  [通常講演]
    森山 あづさ; 福岡 正博; 小宮 武文; 中川 和彦; 山本 信之
    European society medical oncology congress2000 2000年10月 ハンブルク European society medical oncology congress2000
     
    局所進行型非小細胞肺癌患者におけるTXT、CDDPの毎週投与（6回）と胸部放射線治療の併用療法における抗癌剤の最大耐用量（MTD)、推奨投与量（RD）、用量制限毒制（DLT)の決定と奏効率、生存期間の観察を行った。
  • 未治療限局型小細胞肺癌に対するTrimodality Therapy の Pilot Study  [通常講演]
    森山 あづさ; 福岡 正博; 植島 久雄; 中川 和彦; 原 聡; 西村 恭昌; 山本 信之
    第38回日本癌治療学会総会 2000年10月 仙台 第38回日本癌治療学会総会
     
    限局型小細胞肺癌に対し、PE（CDDP、VP-16）併用化学療法とAHF法による同時放射線療法を行いさらに外科的治療を加えたTrimodality Therapy を9例に対して行った。本治療法の安全性及び生存について報告する。
  • 固形癌患者に対するZD1839（Iressa） 間欠投与の臨床第I相試験  [通常講演]
    植島 久雄; 福岡 正博; 中川 和彦; 田村 友秀; 工藤 新三; 吉村 成央; 根来 俊一; 武田 晃司
    第25回ESMO（ヨーロッパ臨床腫瘍学会） 2000年10月 ハンブルグ 第25回ESMO（ヨーロッパ臨床腫瘍学会）
     
    肺癌を中心として固形癌患者にZD1839の間欠投与第I相試験を施行した。非小細胞肺癌にて4例の奏効例を認め、毒性は皮膚症状、消化器症状を認めるが、血液毒性はほとんどなく、重篤な毒性は認められなかった。
  • 進行非小細胞肺癌に対するドセタキセル＋シスプラチンとCPT-11＋シスプラチンの無作為化第II相試験  [通常講演]
    山本 信之; 福岡 正博; 中川 和彦; 根来 俊一
    25th Cogress of the European Society for Medical Oncology 2000年10月 ハンブルク 25th Cogress of the European Society for Medical Oncology
     
    West Japan Thoracic oncology group (WJTOG) で行った進展型非小細胞肺癌を対象としたドセタキセル＋シスプラチンとドセタキセル＋CPT-11の無作為化第II相試験の結果を報告した。
  • 分子標的薬剤の臨床開発  [通常講演]
    福岡 正博; 中川 和彦
    第59回日本癌学会総会 2000年10月 横浜 第59回日本癌学会総会
     
    最近臨床試験に導入された分子標的治療薬として、MMP阻害剤、EGFR阻害剤、VEGFR阻害剤、Farnesy1 Transferace阻害剤、Cycline-dependent阻害剤などについて効果、毒性、今後の展望について述べた。
  • 新規抗がん剤ritterazine B  [通常講演]
    小宮 武文; 福岡 正博; 中川 和彦; 鶴谷 純司; 吉田 誠; 植島 久雄; 山本 信之
    2000年07月 
    新規抗がん剤ritterazine B
  • 非小細胞肺癌脳転移例に対するCDDP+CPT-11併用化学療法、同時全脳照射のPilot Study  [通常講演]
    森山 あづさ; 福岡 正博; 植島 久雄; 小宮 武文; 中川 和彦; 山本 信之; 秋山 慶太; 浅井 暁
    第55回日本呼吸器学会地方会 2000年07月 奈良 第55回日本呼吸器学会地方会
     
    6例の神経症状を有する非小細胞肺癌脳転移例に対してCDDP+CPT-11併用化学療法を2コース施行し、同時に全脳照射を加えるPilot Study を行った。副作用、治療反応ならびに治療のfeasiobilityについて報告する。
  • 癌抑制遺伝子TSG101の肺癌における遺伝子異常  [通常講演]
    植島 久雄; 福岡 正博; 小宮 武文; 中川 和彦; 根来 俊一; 多田 弘人
    第72回日本肺癌学会関西支部会 2000年07月 大阪 第72回日本肺癌学会関西支部会
     
    新しい癌抑制遺伝子であるTSG101の肺癌における異常について検索した。37手術検体中21検体、8細胞株中6細胞株において正常の長さのDNAフラグメントとともにそれより短い欠夫を伴ったDNAフラグメントをRT-PCRにて認めた。
  • 小細胞肺癌脳転移例に対する全身化学療法の検討  [通常講演]
    秋山 慶太; 福岡 正博; 中川 和彦; 山本 信之
    第161回日本内科学会近畿地方会 2000年06月 和歌山 第161回日本内科学会近畿地方会
     
    小細胞肺癌において脳転移に化学療法が有効であるとされており全身化学療法が行われる。今回1997年1月～2000年3月までに当科に入院した小細胞肺癌脳転移例について抗癌剤の効果、予後、再発形式などを検討した。
  • 気管、肺転移を認めた食道原発のMalignant melanoma の1例  [通常講演]
    森山 あづさ; 福岡 正博; 中川 和彦; 小宮 武文; 植島 久雄; 山本 信之
    第23回日本気管支学会総会 2000年06月 横浜 第23回日本気管支学会総会
     
    2年前食道原発の悪性黒色腫に対し食道全摘術を受けた64歳男性に対し気管、肺転移を認めたためDAC-Tam化学療法を1コース行うも再増悪した。軌道確保目的でDumon型ステント挿入後、放射線照射を行い奏効した症例報告
  • NON-プラチナムトリプレットレジメンの第I相試験  [通常講演]
    山本 信之; 福岡 正博; 森山 あづさ; 小宮 武文; 植島 久雄; 中川 和彦; 浅井 暁; 秋山 慶太
    第14回進行肺癌治療懇話会 2000年06月 東京 第14回進行肺癌治療懇話会
     
    プラチナ製剤を含まない3剤の抗がん剤（ビノレルビン＋ジェミシタビン＋パクリタキセル）の第I相試験について報告した。
  • 高齢者非小細胞肺癌に対するドセタキセルの第II相試験  [通常講演]
    吉村 成央; 福岡 正博; 中川 和彦; 工藤 新三; 根来 俊一; 瀧藤 伸英
    36th Annual Meeting of the American Society of Clinical Oncology 2000年05月 New Orleans, Luisiana 36th Annual Meeting of the American Society of Clinical Oncology
     
    70才以上の高齢者非小細胞肺癌患者30例を対象にドセタキセル60mg/cm23週毎に投与し、17.9%の奏効率、1年生存率48％の成績を報告した。
  • シスプラチンとドセタキセル2剤併用週1回投与の第I相試験  [通常講演]
    梁 尚志; 福岡 正博; 中川 和彦; 高田 實; 山本 信之
    36th Annual Meeting of the American Society 2000年05月 36th Annual Meeting of the American Society
     
    IIIB、IV期の非小細胞肺癌を対象としドセタキセルとシスプラチン2剤の週1回投与による第I相試験を行い、シスプラチン25mg/m2とドセタキセル45mg/m2が最大耐量であることを報告した。
  • 進行非小細胞肺癌に対するドセタキセル＋シスプラチンとＣＰＴ－１１＋シスプラチンの比較第ＩＩ相試験  [通常講演]
    武田 晃司; 福岡 正博; 中川 和彦; 山本 信之; 根来 俊一; 松井 薫; 河原 正明; 高田 佳木; 有吉 寛
    36th Annual Meeting of the American Society of Clinical Oncology 2000年05月 New orleans, Luisiana 36th Annual Meeting of the American Society of Clinical Oncology
     
    西日本肺癌治療共同研究グループ（ＷＪＴＯＧ）で行ったIIIB、IV期の非小細胞肺癌を対象としたドセタキセル＋シスプラチンとイリノテカン＋ドセタキセルの無作為化比較第II相試験の結果を報告した。奏効率、生存期間に差を認めなかった。
  • 未治療限局型小細胞肺癌に対するTrimodality の pilot Study  [通常講演]
    森山 あづさ; 福岡 正博; 中川 和彦; 原 聡; 西村 恭昌; 山本 信之; 浅井 暁; 武田 晃司; 根来 俊一; 多田 弘人
    第40回日本呼吸器学会総会 2000年03月 広島 第40回日本呼吸器学会総会
     
    限局型小細胞肺癌に対しPE併用化学療法とAHF法による同時放射線療法を行い、さらに外科的治療を加えるTrimodality therapy を9症例に対して行った。本治療法の安全性、病理学的所見について報告した。
  • 非小細胞肺がんに関するWeekly Cisplatin + Docetaxel concurrent thoracic radiotherapy の第I/II相試験  [通常講演]
    山本 信之; 福岡 正博; 中川 和彦; 西村 恭昌; 中松 清志
    第9回京都放射線腫瘍研究会 2000年01月 京都 第9回京都放射線腫瘍研究会
     
    切除不能III期非小細胞肺がんに対して化学療法（シスプラチン＋ドセタキセル）と胸部放射線との同時併用療法の用量設定試験を行ったので、その結果を発表した。
  • 高齢者限局型非小細胞肺癌(NSCLC)に対する少量カルボプラチン(CBDCA)連日投与と同時胸部放射線療法におけるCDBCAのAUC escalation study  [通常講演]
    家田 泰浩; 山本信之; 吉田 誠; 小宮 武文; 野上 壽二; 中川 和彦; 西村 恭昌; 福岡 正博; 山田政司; 工藤
    第４０回日本肺癌学会総会 1999年10月 札幌 第４０回日本肺癌学会総会
     
    CBDCAの投与量を， Calvert 式より総投与量を算出し，それを25分割し1回投与量とした，高齢者非小細胞肺癌（Non-Small Cell Lung Cancer：NSCLC）に対する少量Carboplatin(CBDCA)連日投与と胸部放射線療法(TRT)の治療方法は，高齢者NSCLCに対して，毒性を予測・制御でき，安全でかつ，治療効果を高めることが期待できると考えらる．
  • 高齢者限局型非小細胞肺癌に対する少量カルボプラチン連日投与と同時放射線療法におけるカルボプラチンのＡＵＣescalation study  [通常講演]
    家田 泰浩; 山本信之; 吉田 誠; 野上 壽二; 小宮 武文; 中川 和彦; 西村 恭昌; 福岡 正博; 山田政司; 工藤
    35th ASCO 1999年05月 アトランタ 35th ASCO
  • 高齢者限局型非小細胞肺癌(NSCLC)に対する少量カルボプラチン(CBDCA)連日投与と同時胸部放射線療法におけるCDBCAのAUC escalation study  [通常講演]
    家田 泰浩; 山本信之; 吉田 誠; 小宮 武文; 野上 壽二; 中川 和彦; 西村 恭昌; 福岡 正博; 山田政司; 工藤
    第３９回日本呼吸器学会総会 1999年03月 横浜 第３９回日本呼吸器学会総会
     
    CBDCAの投与量を， Calvert 式より総投与量を算出し，それを25分割し1回投与量とした，高齢者非小細胞肺癌（Non-Small Cell Lung Cancer：NSCLC）に対する少量Carboplatin(CBDCA)連日投与と胸部放射線療法(TRT)の治療方法は，高齢者NSCLCに対して，毒性を予測・制御でき，安全でかつ，治療効果を高めることが期待できると考えらる．
  • プラチナ製剤または塩酸イリノテカンを含む非小細胞肺癌既化学療法に対するDocetaxelのPilot study  [通常講演]
    家田 泰浩; 山本信之; 吉田 誠; 野上 壽二; 中川 和彦; 福岡 正博
    第４６回日本化学療法学会総会 1998年06月 和歌山 第４６回日本化学療法学会総会
  • 高齢者切除不能非小細胞肺癌に対する、胸部放射線療法と少量carboplatinのdose finding study  [通常講演]
    家田 泰浩; 山本信之; 吉田 誠; 川合右展; 中川 和彦; 東田 有智; 福岡 正博
    第３８回日本肺癌学会総会 1997年11月 仙台 第３８回日本肺癌学会総会
     
    CBDCAの投与量を， Calvert 式より総投与量を算出し，それを25分割し1回投与量とした，高齢者非小細胞肺癌（Non-Small Cell Lung Cancer：NSCLC）に対する少量Carboplatin(CBDCA)連日投与と胸部放射線療法(TRT)の治療方法は，高齢者NSCLCに対して，毒性を予測・制御でき，安全でかつ，治療効果を高めることが期待できると考えらる．
  • Updated Results of Phase 1 Study of DS-820a in HER2-Expressing or-Mutated Advanced Non-Small- Cell Lung Cancer.  [通常講演]
    Junji Tsurutani; Haesong Park; Toshihiko Doi; Shanu Modi; Shunji Takahashi; Kazuhiko Nakagawa; Ian E. Krop; Saiama N. Waqar; Kiyotake Yoh; Bob T. Li; Shinishiro Taira; Takahiro Jikoh; Jameet Singh
    IASLC 19th World Conference on Lung Cancer, Tront, Canada
  • Clinical Characteristics of Non-Small Cell Lung Cancer Harboring Mutations in Exon 20 Of EGFR or HER2.  [通常講演]
    Masayuki Takeda; Kazuko Sakai; Hidetoshi Hayashi; Kaoru Tnaka; Jinko Tanizaki; Takayuki Takahama; Koji Haratani; Kazuto Nishio; Kazuhiko Nakagawa
    IASLC 19th World Conference on Lung Cancer, Tront, Canada
  • Dacomitinib (daco) versus gefitinib (gef) for first-line treatment of advanced NSCLC (ARCHER 1050):Final overall survival (OS) analysis.  [通常講演]
    Tony Mok; ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Min Young Lee; Rolf Gerhard Linke; Rafael Rosell; Jesus Corral Jaime; Maria Rita Migliorino; Adam Pluzanski; Eric I Sbar; Tao Wang; Jane; Liang White; Yi-Long Wu
    American Society of Clinical Oncology Annual Meeting, Chicago IL, U.S.A.
  • Poster Session Relationship between checkpoint molecule B7-H3 and refractoriness to anti-PD-1 therapy in non-small cell lung  [通常講演]
    Kimio Yonesaka; Keita Kudoh; Shiki Takamura; Hitomi Sakai; Ryoji Kato; Koji Haratani; Takayuki Takahama; Kaoru Tanaka; Hidetoshi Hayashi; Hiroyuki Kaneda; Masayuki Takeda; Osamu Maenishi; Michiko Yamato; Masaaki Miyazawa; Kazuto Nishio; Kazuhiko Nakagawa
    American Society of Clinical Oncology Annual Meeting, Chicago IL, U.S.A.
  • Dacomitinib Versus Gefitinib for the First-Line Treatment of Advanced EGFR＋NSCLC in Japanese Patients (ARCHER 1050).  [通常講演]
    Kazuhiko Nakagawa; F Ohyanagi; Terufumi Kato; T Takahashi; H Kaneda; N Nogami; Seiji Niho; N Yamamoto; Y Fujita; H Zhang; E I Sbar; T Wang; R Linke; F Tsuji; Tony SK Mok
    IASLC and 18th World Conference on Lung Cancer 2017
  • Randomised Phase 1b/3 Study of Erlotinib ＋ Ramucirumab in Untreated EGFR Mutation-Positive Stage IV NSCLC：Phase 1b Outcomes.  [通常講演]
    Kazuhiko Nakagawa; Edward Brian Garon; Luis Paz-Ares; S. Ponce; J Corral Jaime; O. Juan Vidal; Ernest Nadal; K Kiura; Keunchil Park; R.C.Widau; E. Alexandris; S He; P Lee; Martin Reck
    IASLC and 18th World Conference on Lung Cancer 2017
  • Symptom Impact of First-Line Dacoimitinib versus Gefitinib in EGFR-Positive NSCLC:Results from a Randomised Phase 3 Study.  [通常講演]
    Rickard Sandin; M.R.Migliorino; Tony SK Mok; Yi-Long Wu; X Zhou; K.H.Lee; Kazuhiko Nakagawa; Seiji Niho; F Tsuji; R. Linke; Rafael Rosell; J. Corral; A Pluzanski; E..I. Sbar; A. Reisman; T Wang; J.L.White; Ying Cheng
    IASLC and 18th World Conference on Lung Cancer 2017
  • Underrepresentation of Elderlu Patients with SD-SCLC as Clinical Trial Candidates(JCOG1201/TORG1528).  [通常講演]
    Yuki Misumi; Tsuneo Shimokawa; Hiroaki Okamoto; Shinji Atagi; H Tnaka; Koichi Goto; Kazuhiko Nakagawa; T Hida; Nobuyuki Yamamoto; Y Hosomi; Terufumi Kato; Isamu Okamoto; Yuichiro Ohe
    IASLC and 18th World Conference on Lung Cancer 2017
  • A Checkpoint Molecule B7-H3 as a Novel Immune Therapy Target for Non-Small Cell Lung Cancer(NSCLC.)  [通常講演]
    Kimio Yonesaka; K Kudoh; S Takamura; H Sakai; R Kato; K Haratani; T Takahama; K Tanaka; Hidetoshi Hayashi; H Kaneda; M Takeda; O Maenishi; M Yamato; M Miyazawa; Kazuto Nishio; Kazuhiko Nakagawa
    IASLC and 18th World Conference on Lung Cancer 2017
  • Clinical Activity of ASP8273 in Asian Non-Small Cell Lung Cancer Patients with EGFR Activating and T790M Mutations.  [通常講演]
    Keuntil Park; K Azuma; C Tsai; Takeshi Seto; H Nokihara; James Yang; Sang-We Kim; H Murakami; Makoto Nshio; K Kiura; A Inoue; K Takeda; Jin-Hyoung Kang; hidetoshi Hayashi; T Nakagawa; Y Kaneko; R Akazawa; M Shimazaki; S Morita; M Fukuoka; Kazuhiko Nakagawa
    IASLC and 18th World Conference on Lung Cancer 2017
  • T790M-Selective EGFR-TKI Combined with Dasatinib as an Optimal Strategy for Overcoming EGFR-TKI Resistance in T790M-positive NSCLC.  [通常講演]
    Takeshi Yoshida; S.Wtanabe; H Kawakami; N Takegawa; Junko Tanizaki; Hidetoshi Hayashi; M Takeda; Kimio Yonesaka; J Tsurutani; Kazuhiko Nakagawa
    IASLC and 18th World Conference on Lung Cancer 2017
  • Peripheral Blood Biomarkrs Associated with Clinical Outcome in Non-Small Cell Lung Cancer Ptients Treated with Nivolumab.  [通常講演]
    Junko Tanizaki; K Haratani; Hidetoshi Hayashi; Y Chiba; Kimio Yonesaka; K Kudo; H Kaneda; Y Hasegawa; K Tanaka; M Takeda; Kazuhiko Nakagawa
    IASLC and 18th World Conference on Lung Cancer 2017
  • Updated Results of Phase II, Liquid Biopsy Study in EGFR Mutated NSCLC Patients Treated with Afatinib(WJOG8114LTR).  [通常講演]
    Hidetoshi Hayashi; H; Akamatsu, Y Koh; S Morita、Daichi Fujmoto; Isamu Okamoto; A.Bessho; K Azuma; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    IASLC and 18th World Conference on Lung Cancer 2017
  • Phase I/II study of intermitted Erlotinib in Combination with Docetaxel in Patients with Recurrent NSCLC with Wild-Type EGFR:WJOG4708L  [通常講演]
    Tatsuo Kimura; Tomoya Kawaguchi; S Kudoh; Y Chiba; H Yoshioka; K; Watanabe; T Kijima; Y Kogure; T Oguri; Naruo Yoshimura; T Niwa; T Kasai; Hidetoshi Hayashi; A Ono; H Tanaka; S Yano; S Nakamura; Nobuyuki Yamamoto; Yoichi Nakanishi; Kazuhiko Nakagawa
    IASLC and 18th World Conference on Lung Cancer 2017
  • Final Results of Phase I/II study (AF-001JP) of Alectinib, a Selective CNS-Active ALK Inhibtor, In ALK＋NSCLC Patients.  [通常講演]
    Makoto Nishio; K. Kiura; Takashi Srto; Kazuhiko Nakagawa; M.Maemondo; A. Inoue; T.Hida; H Yoshioka; M.Harada; Yuishiro Ohe; N. nogami; H Murakami; K Takeuchi; S Inamura; H Kuriki; T Shimada
    IASLC and 18th World Conference on Lung Cancer 2017
  • First-Line Dacomitinib versus Gefitinib in Advanced Non-small-cell Lung Cancer with EGFR mutation Subgroups  [通常講演]
    Yi-Long wu; Ying Cheng; X. Zhou; K.H Lee; Kazuhiko Nakagawa; Siji Niho; F Tsuji; Rafael Rosell; J Corral; M.R.Migliorino A; Pluzanski R. Like; E. I; Sbar. T; Wng H; Zhang Tony; SK Mok
    IASLC and 18th World Conference on Lung Cancer 2017
  • A Phase II Study of Nivolumab:A Multicenter, Open-Label, Single Arm Study in Malignant Pleural Mesothelioma  [通常講演]
    Yasushi Goto; Morishito Okada; T Kijima; K Aoe; Terufumi Kato; N Fujimot; Kazuhiko Nakagawa; Y Tekada; T Hida; K Kanai; F Imamura; S Oisumi; T Takahashi; M Takenoyama; H.Tanaka.Yuishiro Ohe
    IASLC and 18th World Conference on Lung Cancer 2017
  • Alectinib First  [通常講演]
    Kazuhiko Nakagawa
    IASLC and 18th World Conference on Lung Cancer 2017
  • Breakfast Symposium Systemic therapy for breast cancer: from Tegafur/uracil(UFT) to Tegafur/Gimeracil/Oteracil potassium (TS-1)  [通常講演]
    Junji Tsurutani
    2017 Taipei International Breast Cancer Symposium 台北
  • ポスター Safety and clinical activity of DS-6051b, a ROS1/TRK inhibitor, in Japanese patients with NSCLC harboring ROS1 fusion gene.  [通常講演]
    M. Takeda; T. Seto; Y. Fujiwara; N.Yamamoto; K.Nosaki; R. Toyozawa; C.Abe,R.Shiga; K.Nakamaru; K.Nakagawa
    The European Society of Medical Oncology, Madrid, Spain.
  • ポスター Updated results of phase 1 tudy of DS-8201a in patients with HER2[expressing non-breast,non-gastric malignacies.  [通常講演]
    J.Tsurutani; T. Doi; H. Iwata; S. Takahashi; S. Modi; K.Tamura; K. Shitara; H.Taniguchi; S.Tiara; B. Li; A.Shimoura; Y.Sato; K. Akiyama; Y.Fijisaki; C.Lee; A. Yver; K. Nakagawa
    The European Society of Medical Oncology, Madrid, Spain.
  • Single agent activity of DS-801a, a HER2-taegeting antibody-drug conjugate, in heavily pretreated HER2 expressing solid tumors  [通常講演]
    Toshihiko Doi; Hiroji Iwata; Junji Tsrutani; Shunji Takahashi; Haeseong Park,Charles H.Redfen; Kohei Shitara; Chikako Shimizu; Hiroya Taniguchi; Tsutomu Iwasa; Shinishiro Taira; Albert C.Lockhart Jennifer; M. fisher; Takahiro Jikoh; Yoshihiko Fujisaki; Caleb C.Lee; Antonie Yver; Kenji Tamura
    American Society of Clinical Oncology 2017
  • Updated efficacy and safety of the J-alex study compareing alectinib (ALC) with crizotinib (CRZ) in ALK-inhibitor na?ve ALK fusion positive non-small cell lung cancer (ALK＋NSCLC).  [通常講演]
    Yuichi Takiguchi; Toyoaki Hida; Hiroshi Nokihara; Masaaki Kondo; Young Hak Kim; Koichi Azuma; Takeshi Seto; Makoto Nishio; Hiroshige Yoshioka; Fumio Imamura; Katsuyuki Hotta; Satoshi Watanabe; Koichi Goto; Kazuhiko Nakagawa; Tetsuya; Mitsudomi Nobuyuki Yamamoto; Hiroshi Kuriki; Naohito Inagaki; Tomohiro Tanaka; Tomohide Tamura
    American Society of Clinical Oncology 2017
  • Randmized trial of thoracic radiotherapy with or without concurrent daily low-dose carboplatin in elderly patients with locally advanced non-small cell ling cancer(NSCLC):Long-term follow-up of Japan Clinical Oncology Group (JCOG) study JCOG0301.  [通常講演]
    Shinji Atagi; Junki Mizusawa; Satouchi Ishikura; Toshiaki Takahashi; Hiroki Okamoto; Hiroshi Tanaka; Koichi Goto; Kazuhiko Nakagawa; Masao Harada; Yuichiro Takeda; Naoyuki Nogami; Yuka Fujita; Takashi Kasai; Kazima Kishi; Toshiyuki Sawa; Koji Takeda; Keisuke Tomii; Miyako Satouchi; Takashi Sto; Yuichiro Ohe
    American Society of Clinical Oncology 2017
  • Dacomitinib Versus Gefitinib for the First-Line Treatment of Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer(ARCHER 1050):A Randmised,Open-Label Phase III Trial.  [通常講演]
    Tony Mok; Ying Cheng; Xiangdong Zhou; Ki Hyeong Lee; Kazuhiko Nakagawa; Seiji Niho; Fumito Tsuji; Rafael Rosell; Jesus Corral jaime; Maria Rita Migliorino; Adam Pluzanski; Rofl Gerhard Linke,Eric Sbar; Tao Wang; Yi-Long Wu
    American Society of Clinical Oncology 2017
  • Tolerability and antitumor activity of ASP8273 in TKI-na?ve Japanese subjects with EGFR mutation-positive non small cell lung cancer.  [通常講演]
    Shunichi Sugawara; Koichi Azuma; Makoto Nishio; Hidetoshi Hayashi; Kastuyuki Kiura; Miyako Satouchi; Toyoaki Hida; Atsushi Nakamura; Yasuo Iwamoto; Akira Inoue; Koji Takeda; Satoshi Ikeda; Tomoki Nakagawa; Seitaro Asahina; Kanji Komatsu; Satoshi Morita; Masahiro Fukuoka; Nakagawa Kazuhiko
    American Society of Clinical Oncology 2017
  • Novolmab-induced interstitial lung Diases(ILD)in Japanaese Patients with non-small cell lung cancer:A study on risks factors using interim results of post-marketing all-case surveillance.  [通常講演]
    Hirotsugu Kenmotsu; Fumikazu Sakai; Terufumi Kato; Masahiro Kusumoto; Tomohisa Baba; Kazuyoshi Kuwano; Akihiko Gemmma; Kazuhiko Nakagawa; Yoichi Nakanishi; Nobuyuki Yamamoto; Yoshihiko Ito; Yasuhiro Tahara; Yuichiro Ohe
    American Society of Clinical Oncology 2017
  • Predictive impact of complete molecular response in plasma:Phase II liquid biopsy study in EGFR mutated NSCLC patients treated with afatinib(WJOG8114LTR)  [通常講演]
    Kohei Otsubo; Hiroaki Akamatsu; Yasuhiro Koh; Satomi Morita; Daichi Fujimoto; Akihiro Bessho; Koichi Azuma; Kazuhiko Nakagawa; Nobuyuki Yamamoto
    American Society of Clinical Oncology 2017
  • Cancer Immunotherapy Combination: Colon cancer  [通常講演]
    Kawakami Hisato
    6th Japan-Taiwan Oncology Phase I Conference
  • Cancer Immunotherapy Combination: Non-small cell lung cancer  [通常講演]
    Hidetoshi Hayashi
    6th Japan-Taiwan Oncology Phase I Conference
  • NRP2b, a unique isoform of NRP2, promotes aggressive lung cancer phenotypes.  [通常講演]
    Anastasios Dimou; Patrick Nasarre; Joyce Nair-Menon; Takeshi Yoshida; Eric Haura; Monica Gooz; Kent Armeson,Robert Gemmill Harry Drabkin
    American Association for Cancer Research 2017
  • Targeting CDK1 and MEK/ REK overcome mutant BRAF-mediated apoptosis resistance in human colorectal cells.  [通常講演]
    Hisato Kawakami; Shengbing Huang; Frank A.Sinicrope
    American Association for Cancer Research 2017
  • DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, abrogates the resistance to T-DM1 in HER2-positive gastric cancer: a preclinical syudy.  [通常講演]
    Yoshikane Nonagase; Noki Takegawa; Kimio Yonesaka; Kazuko Sakai; Yusuke Ogitani; Junji Tsurutani; Kazuto Nishio; Kazuhiko Nakagawa
    American Association for Cancer Research 2017
  • U3-1402, a novel HER3-targeting ADC, and a novel DNA topoisomerase I inhibittor inhibit the growth of non-small cell lung cancer with EGFR mutation.  [通常講演]
    Kimio Yonesaka; Koji Haratani; kenji Hirotani; Kasuhiko Nakagawa
    American Association for Cancer Research 2017
  • Poster 『Clinical Outcome of Node-Negative Oligometastatic Non-small Cell Lung Cancer』  [通常講演]
    Takeda Masayuki; Kazuhiko Nakagawa
  • Oral Abstract Session 『Randomized Phase 1b/3 Study of Erlotinib plus Ramucirumab in First-Line EGFR Mut+Stage IV NSCLC: Phase 1b Safety Results』  [通常講演]
    Kazuhiko Nakagawa
  • Biomarker analysis of S-1 in SELECT-BC:A randmized phase III study of taxane versus S-1 as the first-line chemotherapy for metastasis breast cancer(SERECT-BC EURECA).  [通常講演]
    Hara F; Mukai H; Ohsumi S; Yotsumoto D; Takashima T; Hozumi Y; Watanabe T; Siato T; Wtanabe K; Tsurutani J; Toyoma T; Akabane H; Nishimura R; Taira N; Uemura Y; Ohashi Y
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL ,
  • The Nationwide Cancer Genome Screening Project in Japan, SCRUM-Japan (GI-SCREEN):MSI-status and cancer-related genome alterations in sdvaced colorectal cancer(CRC)-GI-SCREEN 2013-01-CRC sub-study  [通常講演]
    Kajiwara T; Shitara K; Denda T; Yuki S; Tamura T; Kawasaki K; Shinozaki E; Eguchi T; Nakajima; Kato K; Akagi K; Esaki T; Okano N; Kudo T; Kadowaki S; Ebi H; Yamamoto Y; Fujii S; Doi T; Ohtsu A; Yoshino T
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL ,
  • The Nationwide Cancer Genome Screening Project in Japan, SCRUM-Japan GI-SCREEN:Efficient identification of cancer genome alterations in advanced colorectal cancer.  [通常講演]
    Kato T; Okamoto W; Hamaguchi T; Hara H; Taniguchi H; Mizukami T; Denda T; Moriwaki T; Esaki T; Yuki S; Oki E; Kajiwara T; Kudo T; Naruge D; Tamura T; Fujii S; Doi T; Ohtsu A; Shitara K; Yoshino T
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL ,
  • Alectinib (ALC) versus crizotinib（CRZ）in AKL-inhibitor na?ve ALK-positive non-small cell lung cancer (ALK+NSCLC)：Primary results from the J-ALEX study  [通常講演]
    Nokihara H; Hida T; Kondo M; Kim H Y; Azuma K; Seto T; Takiguchi Y; Nishio M; Yoshioka H; Imamura F; HOtta K; Watanabe S; Goto K; Nakagawa K; Mitsudomi T; Yamamoto N; Kuriki H; Asabe R
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL ,
  • Phase I/II study of nab-paclitaxel(nab-P) with cisplatin(C) and thoracic radiation(TRT) in patients with locally advanced NSCLC:Safety results of phase I part.  [通常講演]
    Hayashi H; Ogura M; Niwa T; Ikeo S; Yokoi T; Torii Y; Okamoto K; Tamura Y; Tanaka K; Fujisaka Y; Goto I; Kaneda H; Kurata T; Yoshioka H; Nakagawa K
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Overall survival(OS) of EGFR mutation-positive non-small cell lung cancer(NSCLC)patients:Real-world treatment patterns of 1,660 Japanese patients(pts).  [通常講演]
    Yoshida K; Inoue A; Sugawara S; Murakami S; Saka H; Morita S; Kim H, Y; Imamura F; Takeda K; Nakagawa K; Takeda M; Atagi S; Hasegawa Y; Yamamoto N; Katakami N; Yoshioka H; Iwamoto Y; Okamoto I; Seto T; Ohe Y
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Soluble heregulin, HER3 ligand, to predict the efficacy of anti-HER3 antibody partitumab combination with erlotinib in randomized phase II study ,HERALD, for non-small cell lung cancer  [通常講演]
    Yonesaka K; Hirotani K; Pawel V J; Dediu M; Chen S; Copigneaux C; Nakagawa K
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Phase I study of YM155, selective surviving suppressant in combination with elrotinib in patients with EGFR-mutant advanced non-small cell lung cancer.  [通常講演]
    Shimizu T; Nishio K; Sakai K; Hayashi H; Okamoto K; Takeda M; Iwasa T; Tanaka K; Aoyama K; Morishita M; Nakagawa K
    52nd Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • The Impact on overall survival (OS) of first-line gefitinib (G) and erlotinib (E) and of clinical factors in advanced non-small cell lung ancer (NSCLC) with activating epidermal growth factor receptor mutations (EGFR mut) based on meta-analysis of 1,231 p  [通常講演]
    Chee Lee, Lucy Claire Davies; Yi-Long Wu; Tetsuya Mitsudomi; Akira Inoue; Rafael Rosell; Caicum Zhou; Kazuhiko Nakagawa; Sumitra Throngprasert; Masahiro Fukuoka; Richard J Gralla; Val Gebski; Tony Mok; James Chih-Hsin Yang
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Final overall survival results of a randomized phase III trial comparing weekly docetaxel plus cisplatin(DP) with 3-weekly docetaxel (D) monotherapy in elderly patients(pts) with advanced non-small-cell lung cancer(NSCLC):intergroup trial JCOG0803/WJOG430  [通常講演]
    Koji Takeda; Tetsuya Abe; Yuichiro Ohe; Shinzoh Kudoh; Yukio Ichinose; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Koichi Minato; Toshiyuki Sawa; Yasuo Iwamoto; Hideo Saka; Junki Mizusawa; Tomonori Mizutani; Shinichiro Nakamura; Masahiko Ando; Akira Yokoyama; Kazuhiko Nakagawa; Nagahiro Saijo; Tomohide Tamura
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • The Impact on overall survival (OS) of first-line gefitinib (G) and erlotinib (E) and of clinical factors in advanced non-small cell lung ancer (NSCLC) with activating epidermal growth factor receptor mutations (EGFR mut) based on meta-analysis of 1,231 p  [通常講演]
    Chee Lee, Lucy Claire Davies; Yi-Long Wu; Tetsuya Mitsudomi; Akira Inoue; Rafael Rosell; Caicum Zhou; Kazuhiko Nakagawa; Sumitra Throngprasert; Masahiro Fukuoka; Richard J Gralla; Val Gebski; Tony Mok; James Chih-Hsin Yang
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Final overall survival results of a randomized phase III trial comparing weekly docetaxel plus cisplatin(DP) with 3-weekly docetaxel (D) monotherapy in elderly patients(pts) with advanced non-small-cell lung cancer(NSCLC):intergroup trial JCOG0803/WJOG430  [通常講演]
    Koji Takeda; Tetsuya Abe; Yuichiro Ohe; Shinzoh Kudoh; Yukio Ichinose; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Koichi Minato; Toshiyuki Sawa; Yasuo Iwamoto; Hideo Saka; Junki Mizusawa; Tomonori Mizutani; Shinichiro Nakamura; Masahiko Ando; Akira Yokoyama; Kazuhiko Nakagawa; Nagahiro Saijo; Tomohide Tamura
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Phase I study of S-trans, trans-famestylthiosalicylic (saliraslb), a noveloral RAS inhibitor in Japanese patients with advanced solid tumors.  [通常講演]
    T. Shimizu; N. Okano; T. Kurata; D. Naruge; Y. Fujisaka; H. Kitamura; F. Nagashima; K. Nakagawa; J. Furuse
    ESMO ASIA 2015, Singapore
  • Long-term treatment with nintedanib of NSCLC associated with CCDC6-RET rearrangement  [通常講演]
    M. Takeda; K. Sakai; K. Okamoto; H. Hayashi; K. Tanaka; T. Shimizu; K. Nishio; K. Nakagawa
    ESMO ASIA 2015, Singapore
  • ALK management and resistance  [通常講演]
    K. Nakagawa
    ESMO ASIA 2015, Singapore
  • Immunotherapy/ Anti-Agiogenesis : Current trials in Japan  [通常講演]
    K. Nakagawa
    2nd Expert Panel Dresden
  • Poster Clinical Applications of Next Generation Sequencing on Therapeutic Decision-Making in Lung Cancer (ID 1007)  [通常講演]
    M. Takeda; K. Sakai; M. Terashima; H. Kaneda; H. Hayashi; K. Tanaka; T. Iwasa; T. Yoshida; T. Takahama; K. Nishio; K. Nakagawa
    16th World Conference on lung cancer.(IASLC) Denver
  • Poster An Open-Label, Multicenter, Phase 1b/2 Study to Evaluate Necitumumab in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced (Stage IV) Squamous Non-Small Cell Lung Cancer (NSCLC)  [通常講演]
    T. Tamura; M. Nishio; N. Yamamoto; Y. Ohe; K. Wolff; M. Tsujimoto; S. Enatsu; K. Nakagawa
    16th World Conference on lung cancer.(IASLC) Denver
  • Poster Updated Data from JP28927 Study of Alectinib in ALK+ NSCLC Patients with or without History of ALK Inhibitor Treatment (ID 346)  [通常講演]
    K. Hotta; T. Hida; K. Nakagawa; T. Seto; M. Satouchi; M. Nishio; H. Murakami; Y. Ohe; K. Takeda; T. Yoshimoto; T. Tanaka; T. Tamura
    16th World Conference on lung cancer.(IASLC) Denver
  • Poster Multicenter, Randomized, Double-Blind Study of Erlotinib plus Ramucirumab or Placebo in Patients with EGFR Mutation-Positive Metastatic NSCLC (ID 1560)  [通常講演]
    E.B. Garon; M. Reck; O.J. Vidal; E. Nadal; P. Lee; R. Dalal; J. Liu; S. He; J. Treat; K. Nakagawa
    16th World Conference on lung cancer.(IASLC) Denver
  • MINI A Randomized Phase II Study of S-1 and Cisplatin vs Vinorelbine and Cisplatin with Concurrent Radiotherapy for Locally Advanced NSCLC: WJOG5008L(ID 544)  [通常講演]
    J. Shimizu; T. Kodaira; T. Seto; T. Sasaki; T. Yamanaka; N. Kunitake; F. Ohyanagi; T. Kozuka; M. Takeda; K. Nakamatsu; T. Takahashi; H. Harada; N. Yoshimura; S. Tsutsumi; H. Kitajima; M. Kataoka; K. Nakagawa; Y. Nishimura; Y. Nakanishi
    16th World Conference on lung cancer.(IASLC) Denver
  • ORAL Biomarkers for Efficacy in JO25567 Study Evaluating Erlotinib plus Bevacizumab versus Erlotinib in Advanced NSCLC with EGFR Mutation (ID 306)  [通常講演]
    S. Atagi; M. Nishio; K. Goto; Y. Hosomi; T. Seto; T. Hida; K. Nakagawa; H. Yoshioka; N. Nogami; M. Maemondo; S. Nagase; I. Okamoto; N. Yamamoto; T. Yamanaka; Y. Igawa; K. Tajima; M. Fukuoka; K. Nishio; N. Yamamoto
    16th World Conference on lung cancer.(IASLC) Denver
  • ORAL Randomized Trial of Gefitinib with and without Pemetrexed as First-Line Therapy in East-Asian Patients with Advanced NS NSCLC with EGFR Mutations (ID 1319)  [通常講演]
    Y. Cheng; H. Murakami; P. Yang; J. He; K. Nakagawa; J.H. Kang; J. Kim; T. Puri; M. Orlando; X. Wang; S. Enatsu; J.C. Yang
    16th World Conference on lung cancer.(IASLC) Denver
  • ORAL Retrospective Analysis of ctDNA EGFR Mutations in the Phase III, Randomized IMPRESS Study  [通常講演]
    S. Kim; Y. Wu; K. Nakagawa; J.-. Yang; M. Ahn; J. Wang; J.C. Yang; Y.-. Lu; S. Atagi; S. Ponce; J. Soria; T. Mok; X. Shi; R. Taylor; H. Jiang; K. Thress
    16th World Conference on lung cancer.(IASLC) Denver
  • ORAL Randomized Phase III Study of Nedaplatin plus Docetaxel versus Cisplatin plus Docetaxel for Advanced Squamous Cell Lung Cancer (WJOG5208L)  [通常講演]
    T. Seto; T. Shukuya; T. Yamanaka; T. Hirashima; T. Kato; Y. Horio; S. Atagi; T. Inoue; Y. Ohsaki; T. Maeda; K. Nishi; T. Sawa; M. Okada; D. Fujimoto; T. Harada; K. Nakagawa; Y. Nakanishi; N. Yamamoto
    16th World Conference on lung cancer.(IASLC) Denver
  • Mini Phase II Studies of Nivolumab in Patients with Advanced Squamous (SQ) or Non-Squamous (NSQ) Non-Small-Cell Lung Cancer (NSCLC) (ID 1329)  [通常講演]
    K. Nakagawa; M. Nishio; T. Hida; H. Sakai; N. Nogami; S. Atagi; T. Takahashi; H. Nokihara; H. Saka; M. Takenoyama; S. Fujita; H. Tanaka; K. Takeda; M. Satouchi; H. Isobe; M. Maemondo; K. Goto; T. Hirashima; K. Minato; T. Tamura
    16th World Conference on lung cancer.(IASLC), Denver
  • The expression level of HER3 ligand heregulin mRNA as a predictive biomarker for anti-HER3 antibody patritumab conbined erlotinib in non-mall sell lung cancer  [通常講演]
    Kimio Yonesaka; Hisato Kawakami; Hiroyasu Kaneda; Isamu Okamoto; Kenji Hirotani; Kazuto Nishio; Kazuhiko Nakagawa
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Bevacizumab beyond disease progression after first-line treatment with bevacizumab plus chemotherapy inadvanced nonsquamous non-small cell lung cancer (WJOG5910L):An open-label, randomized, phase II trial.  [通常講演]
    Masayuki Takeda; Takashi Seto; Hidetoshi Hayashi; Morihito Okada; Koichi Azuma; Shunichi Sugawara; Haruko Daga; Tomonori Hirashima; Kimio Yonesaka; Yoshiko Urata; Haruyasu Murakami; Garuhiro Saito; Akihito Kudo; Toshiyuki Sawa; Eiji Miyahara; Naoyuiki Nogami; Takeharu Yamanaka; Youichi Nakanishi; Kazuhiko Nakagawa; Isamu Okamoto; West Japan; Oncology Group
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Phase II studies of nivolumab (anti-PD-1,BMS-936558) in patients with advanced squamous (sq) or nonsquamous (non-sq) non-small cell lung cancer (NSCLC)  [通常講演]
    Makoto Nishio; Toyoaki Hida; Kazuhiko Nakagawa; Hiroshi Sakai; Naoyuki Nogami; Shinji Atagi; Toshiaki Takahashi; Hiroshi Nokihara; Hdeo Saka; Mitsuhiro Takenoyama; Shiro Fujita; Hiroshi Tanaka; Koji Takeda; Miyako Satouchi; Hirsohi Isobe; Makoto Maemondo; Koishi Goto; Tomonori Hirashima; Koichi Minato; Tomohide Tamura
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • The Impact on overall survival (OS) of first-line gefitinib (G) and erlotinib (E) and of clinical factors in advanced non-small cell lung ancer (NSCLC) with activating epidermal growth factor receptor mutations (EGFR mut) based on meta-analysis of 1,231 p  [通常講演]
    Chee Lee, Lucy Claire Davies; Yi-Long Wu; Tetsuya Mitsudomi; Akira Inoue; Rafael Rosell; Caicum Zhou; Kazuhiko Nakagawa; Sumitra Throngprasert; Masahiro Fukuoka; Richard J Gralla; Val Gebski; Tony Mok; James Chih-Hsin Yang
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Docetaxel + ramucirumab (DR) versus docetaxel + placebo (D) as second-line treatment for advanced non-small-cell-lung cancer (NSCLC): A randomized, phase II, double-blind, multicenter trial in Japan.  [通常講演]
    Yukio Hosomi; Kiyotaka Yoh; Kazuo Kasahara; Kazuhiko Yamada; Toshiaki Takahashi; Kaoru Tanaka; Toyoaki Hida; Hiroshige Yoshioka; Terufumi Kato; Koji Takeda; Makoto Nishio; Hiroshi Sakai; Makoto Maemondo; Mitsuhiro Takenoyama; Hiroshi Nokihara; Masumi Tatsumi; Takashi Nakamura; Sotaro Enatsu; Tomohide Tamura; Kazuhiko Nakagawa
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • ASP8273, a mutant-selective irreversible EGFR inhibitor in patients (pts) with NSCLCharboring EGFR activating mutations: Preliminary results of first-in-human phase I study in Japan.  [通常講演]
    Yasushi Goto; Hiroshi Nokihara; Haruyasu Murakami; Toshio Shimizu; Takashi Seto; Andrew P. Krivoshik; Anne Therese Keating; Koichi Uegaki; Kentaro Takeda; Kanji Komatsu; Stoshi Morita; Masahiro Fukuoka; Kazuhiko Nakagawa
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Transcriptional expression of Bcl-2 as predictive of response to neoaduvant chemotherapy with trastuzumab in HER2-positive ER-positive breast cancer patients.  [通常講演]
    Maki Tanioka; Kazuko Sakai; Tamotsu Sudo; Toshiko Sakuma; Kouichi Hirokaga; Shintaro Takao; Hironobu Shunichi Negoro; Kazuhiko Nakagawa; Kazuto Nishio
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • 『A randomized phase II study of TS-1 plus cisplatin versus vinorelbine plus cisplatin with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer(LA-NSCLC):WJOG5008L  [通常講演]
    Takashi Seto; Tomonari Sasaki; Takeharu Yamanaka; Naonobu Kunitake; Junichi Shimizu; Takeshi Kodaira; Makoto Nishio; Takuyo Kozuka; Toshiaki Takahashi; Hideyuki Harada; Naruo Yasumasa; Shinichi Tsutsumi; Hiromoto Kitajima; Masaaki Kataoka; Kazuhiko Nakagawa; Yasumasa Nishimura; Youichi Nakanishi
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Randomized phase III study of nedaplatin (N) plus docetaxel (D) versus cisplatin (C) plus D for advanced or relapsed squamous cell carcinoma of the lung (SqLC):WJOG5208L.  [通常講演]
    Takehito Shukuya; Takeharu Yamanaka; Takashi Seto; Haruko Daga; Koichi Goto; Hideo Saka; Shunichi Sugawara; Toshiaki Takahashi; Soichiro Yokota; Hiroyasu Kaneda; Tomoya Kawaguchi; Seisuke Nagase; Tetsuya Oguri; Yasuo Iwamoto; Takashi Nishimura; Yoshihiro Hattori; Kazuhiko Nakagawa; Youichi Nakanishi; Nobuyuki Yamamoto
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • A phase I/II study with a CNS-penetant, selective ALK inhibitor alectinib in ALK-rearranged non-small cell lung cancer(ALK+NSCLC)patients（ｐｔｓ）：Updates on progression free survival (PFS) and safety results from AF-001JP  [通常講演]
    Yuichiro Ohe; Makoto Nishio; Katsuyuki Kiura; Takashi Seto; Kazuhiko Nakagawa; Makoto Maemonndo; Akira Inoue; Toyoaki Hida; Hiroshige Yoshioka; Hiroshi Kuriki; Tomohiro Tanaka; Tomohide Tamura
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Final overall survival results of a randomized phase III trial comparing weekly docetaxel plus cisplatin(DP) with 3-weekly docetaxel (D) monotherapy in elderly patients(pts) with advanced non-small-cell lung cancer(NSCLC):intergroup trial JCOG0803/WJOG430  [通常講演]
    Koji Takeda; Tetsuya Abe; Yuichiro Ohe; Shinzoh Kudoh; Yukio Ichinose; Hiroaki Okamoto; Nobuyuki Yamamoto; Hiroshige Yoshioka; Koichi Minato; Toshiyuki Sawa; Yasuo Iwamoto; Hideo Saka; Junki Mizusawa; Tomonori Mizutani; Shinichiro Nakamura; Masahiko Ando; Akira Yokoyama; Kazuhiko Nakagawa; Nagahiro Saijo; Tomohide Tamura
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • Poster Speaker Antitumor activity of alectinib (CH5424802/RO5424802) for ALK-rearrangedNSCLC with or without prior crizotinib treatment in bioequivalence study  [通常講演]
    Kazuhiko Nakagawa
    51st Annual Meeting of American Society Of Clinical Oncology, U.S.A, Chicago, IL
  • 『Pro. vs. Con.EGFR-TKIs』.  [通常講演]
    Kazuhiko Nakagawa
    15th World Lung Conference on Lung Cancer, Sydney
  • A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: Updated safety and efficacy results from AF-001JP  [通常講演]
    KazuhikoNakagawa,KatsuyukiKiura; Makoto Nishio; Takashi Seto; Makoto Maemondo; Akira Inoue; ToyoakiHida; Nobuyuki Yamamoto; Hiroshige Yoshioka; Masao Harada; Yuichiro Ohe; NaoyukiNogami; Kengo Takeuchi; Tadashi Shimada; Tomohiro Tanaka; Tomohide Tamura
    49th American Society of Clinical Oncology, Chicago,
  • Molcular networks of the EGFR-TKI resistant lung cancer ?How to apply new technologies to bench-to-bed research-  [通常講演]
    English Oral Sessions; Takeshi Yoshida; Guolin Zhang; Yun Bai; Bin Fang; Bhupendra Rawal; Kate J Fisher; Ann Chen; Takafumi Okabe; Isamu Okamoto; Kazuhiko Nakagawa; Eric B Haura
    The 71st Annual Meeting of the Japanese Cancer Association,
  • MET遺伝子増幅陽性胃癌に対するMETチロシンキナーゼ阻害剤クリゾチニブの抗腫瘍効果  [通常講演]
    岡本 渉; 岡本 勇; 荒尾徳三; 仁科慎一; 上田眞也; 川上尚人; 柳原五吉; 倉田宝保; 西尾和人; 中川 和彦
    第10回日本臨床腫瘍学会学術集会，大阪
  • Roles of BIM induction and survivin down-regulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification.  [通常講演]
    International Session; Breast Cancer Translational Study; Junko Tanizaki; Isamu Okamoto; Soichi Fumita; Wataru Okamoto; Kazuhiko Nakagawa
    10th Annual Meeting Japanese Society of Medical Oncology. Osaka,

MISC

産業財産権

  • PCT/JP2010/053795:非小細胞肺癌に対する化学療法の治療効果予測方法  2010年03月
    中川 和彦, 萩本啓文

受賞

  • 1997年 米国臨床腫瘍学会トラベルアワード(ASCO)
  • 1996年 米国癌学会トラベルアワード(AACR)
  • 1988年 米国臨床腫瘍学会トラベルアワード(ASCO)

共同研究・競争的資金等の研究課題

  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 鶴谷 純司; 中川 和彦; 米阪 仁雄
     
    HER2遺伝子増幅を有する乳癌細胞株、胃癌細胞株にヘレギュリンを接触するとラパチニブ、トラスツズマブに対する薬剤感受性が低下したが、T-DM1では低下しなかった。SKBR3、N87にヘレギュリン遺伝子を導入し、ラパチニブとトラスツズマブに感受性が低下したが、T-DM1では低下しなかった。N87ヘレギュリン導入株をマウスに移植し、ラパチニブ、トラスツズマブでは感受性低下が認められたが、T-DM1では変化が認められなった。トラスツズマブに耐性となったHER2陽性乳癌、胃癌患者の治療後癌組織のヘレギュリン発現が増加していた。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 岡本 渉; 中川 和彦; 西尾 和人; 岡本 勇; 荒尾 徳三; 川上 尚人
     
    MET遺伝子増幅をもつ胃癌細胞は、METチロシンキナーゼ阻害剤（MET阻害剤）の暴露により、アポトーシスをおこすことで著明な抗腫瘍効果を示す。本研究は、MET阻害剤により引き起こされるアポトーシスの分子メカニズムを明らかにした。また、患者検体から得られた組織標本を用いて、日本人の胃癌におけるMET遺伝子増幅の頻度や予後などの疫学情報を明らかにした。さらに、MET阻害剤が臨床応用された後に問題となることが想定される、薬剤耐性のメカニズムを解析するために重要なMET阻害剤耐性の胃癌細胞株を樹立した。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 岡本 勇; 中川 和彦; 西尾 和人; 坂井 和子
     
    本研究ではMassARRAYシステムを用いて、200例の進行非小細胞肺癌症例のパラフィン包埋組織よりEML4-ALK融合遺伝子の検出を試み、全例が測定可能であり、うち18例(9.0%)にEML4-ALK融合遺伝子を検出することに成功した。プラチナ併用化学療法の効果はALK転座陽性例、EGFR遺伝子変異陽性例、野生型、いずれも大きな差は見いだされなかった。 さらにMassARRAYを用いて26遺伝子変異をマルチプレックスに解析し気管支鏡で得られた90％以上の検体で解析が可能であり、微小検体が遺伝子診断に使用できることが示された。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2011年 -2013年 
    代表者 : 岡本 邦男; 中川 和彦; 岡本 勇
     
    ＥＧＦＲチロシンキナーゼ阻害剤によるアポトーシスにおいてｻﾊﾞｲﾋﾞﾝの発現低下が重要な役割を果たしていることをin vitro、in vivoにおいて証明した。そしてEGFR阻害剤に耐性を示すEGFR遺伝子変異陽性非小細胞肺癌株に対し、EGFR阻害剤であるエルロチニブとサバイビン阻害剤であるYM155の併用を行うことでその耐性を克服し、これらの細胞にアポトーシスを生じさせることができることをin vitro、in vivoにおいて証明した。 これらの成果をもとにエルロチニブとYM155の併用療法がEGFR阻害剤の耐性を克服できる可能性を示した論文として海外雑誌に報告した。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2011年 -2011年 
    代表者 : 宮崎 昌樹; 中川 和彦; 岡本 勇
     
    1)EML4-ALK陽性細胞において活性化される分子の同定 レトロウイルスを用いた手法でNIH3T3細胞にEML4-ALKを恒常的に発現する細胞株(3T3/EML4-ALK)を樹立した。3T3/EML4-ALKはin vitro, in vivo共に強いtransforming活性を示した。ウエスタンブロット法を用いた下流シグナル解析において、親株と比べMAPキナーゼシグナル経路とSTAT3シグナル経路が強く活性化されており、こらら2つの下流シグナルがEML4-ALKによる増殖シグナルの担い手であることが示された。 2)ALKキナーゼ阻害剤によるEML4-ALK陽性細胞のアポトーシス誘導に関わるアポトーシス実行因子の探索 3T3/EML4-ALKをはじめとするEML4-ALK陽性細胞はALK阻害剤によりアポトーシスが誘導されるが、この際にMAPキナーゼシグナル抑制に伴いpro-apoptotic蛋白であるBIMの発現誘導が、またSTAT3シグナル抑制に伴いanti-apoptoticシグナルであるサバイビンの抑制が関与することを見出した。これらEML4-ALKの下流シグナル及びアポトーシス関連蛋白質の同定は、今後のALK阻害剤の臨床開発に有用である。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2009年 -2011年 
    代表者 : 岡本 勇; 中川 和彦; 西尾 和人
     
    臨床上喫緊の課題であるEGFR遺伝子変異陽性非小細胞肺癌患者における、EGFR)チロシンキナーゼ阻害剤(EGFR-TKIs)に対する獲得耐性の克服を目指し、第2世代EGFR-TKIsであるBIBW2992とTSを標的とする抗癌剤(S-1あるいはペメトレキセド)との相乗効果及び、EGFR-TKIとサバイビン抑制剤のYM155の併用が有用であることを示した前臨床データを得た。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2005年 -2007年 
    代表者 : 佐藤 太郎; 中川 和彦; 福岡 正博; 田村 研治; 津谷 あす香
     
    非小細胞肺癌の既治療例でEGFR阻害剤であるゲフィチニブが有効である事、非小細胞肺癌ではCOX-2の発現が高く予後に関連している事、一部の抗癌剤との併用で抗腫瘍効果の増強が報告されている事、EGFRとCOX-2には関連性があることを背景として、EGFR阻害剤であるゲフィチニブとGOX-2阻害剤であるメロキシカムとの併用により相加・相乗効果が期待できると考え第II相試験を行っている。【目標】再発非小細胞肺癌に対するゲフィチニブ/メロキシカム併用療法の奏効率と安全性の検討を行う。【対象】組織診で確定診断が得られている非小細胞肺癌患者(PS:0-2、前治療2レジメン以下、測定可能病変有)【方法】ゲフィチニブ250mg/メロキシカム10mgをday1より1日1回内服とし、PD(増悪)まで継続した。【現時点までの成果】2008年2月までに23例が登録された患者背景は以下の通りである。年齢中央値68歳、男/女:10/13、組織型:腺癌/扁平上皮癌/非小細胞肺癌:18/3/2、PS(performance status)0/1/2:3/18/2、病期;III/IV:5/18、MST(生存期間中央値):210日であった。奏効率、毒性、臨床組織検体におけるEGFR、リン酸化 EGFR、COX-2の発現量等の免疫組織学的検討、血清中のCOX-2、PGE2・PGl2等プロスタグランジン類の検討を施行を行ったが、有意な相関は見出されなかった。
  • 日本学術振興会：科学研究費助成事業
    研究期間 : 2004年 -2006年 
    代表者 : 福岡 正博; 田村 研治; 樋田 豊明; 中川 和彦; 倉田 宝保; 有吉 寛
     
    本研究では、IIIB/IV期進行非小細胞肺癌を対象とし、標準的治療であるプラチナを含む2剤併用化学療法単独群とその後にゲフィチニブを維持療法として投与する群を比較する多施設共同無作為化試験を行い、それに付随してトランスレーショナル・リサーチ(TR)を実施することとした。TRの内容はゲフィチニブ投与症例において、腫瘍組織でのヒト上皮成長因子受容体I、II(EGFR、HER2)、そのリン酸化レベル(pEGFR、pHER2)、及びインスリン類似成長因子1受容体(IGF-IR)の免疫組織染色による発現量の解析、EGFRの遺伝子変異を検索し奏効度、無再発生存(TTP)との相関を検討した。組織型、病期、性、化学療法の内容、PS、施設を動的割付因子として化学療法群(A群)と化学療法後のゲフィチニブ維持療法群(B群)に割り付け600例を集積することとした。A群は化学療法を最低3サイクル以上、最大6サイクルまで投与しPDになるまで後治療を加えない。B群は化学療法を3サイクル施行後、有効および不変症例に対し、ゲフィチニブ250mg/日をPDになるまで投与した。本試験は、平成15年3月より平成17年5月に604例が集積され、解析対象例は577例(A群287例、B群290例)であった。TR試験にはゲフィチニブ維持療法群から103例の腫瘍検体が登録され、女性58%、腺癌83%、非喫煙者55%、98例が評価可能症例であった。解析の結果では、41例(42%)にEGFRの遺伝子変異が見られ14例がエクソン19の欠失、27例がエクソン21の点突然変異であった。遺伝子変異のある症例とない症例の有効率は62%と26%(p=0.002)、TTPは10.1ヶ月と5.1ヶ月(HR0/64;P=0.048)で有意な差が認められた。pEGFRの発現およびpHER2の発現度はEGFRの遺伝子変異の頻度と相関していた。以上よりpEGFRの発現度からEGFRの遺伝子変異、そして有効性を予測できると結論した。
  • 肺癌化学療法の確立
  • 新しい抗癌剤の臨床開発
  • Establishment of Lung cancer chemotherapy
  • Clinical developement of new anti-cancer drugs

委員歴

  • 2015年04月 - 現在   西日本胸部臨床腫瘍臨床研究機構(WJTOG)   理事長   西日本胸部臨床腫瘍臨床研究機構(WJTOG)
  • 2009年01月 - 現在   日本臨床薬理学会   指導医
  • 2006年05月 - 現在   日本呼吸器学会   代議員   日本呼吸器学会
  • 2004年04月 - 現在   日本臨床腫瘍学会   協議員、副理事長(2013年～2019年)、理事(2008年～2022年)、暫定指導医(2004年～2019)、学術企画委員会(2013年～2022年)   日本臨床腫瘍学会
  • 2000年10月 - 現在   日本肺癌学会   理事(2006年～)、評議員及び財務委員(2014年～)   日本肺癌学会
  • 日本内科学会   近畿支部・評議員   日本内科学会

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