TAKAHAMA Takayuki

    Department of Medicine Lecturer in Medical School
Last Updated :2024/04/25

Researcher Information

Degree

  • M.D., Ph. D.(2018/03 Kindai University)

J-Global ID

Research Areas

  • Life sciences / Tumor diagnostics and therapeutics

Academic & Professional Experience

  • 2022/04 - Today  Kindai UniversityKindai University Hospotal
  • 2021/04 - 2022/03  Kindai UniversityDepartment of medical oncology
  • 2020/04 - 2021/03  Kindai UniversityNara Hospital Kindai University
  • 2019/04 - 2020/03  Kindai UniversityNara Hospital Kindai University
  • 2015/04 - 2019/03  Kindai UniversityFaculty of Medicine
  • 2013/04 - 2015/03  Kindai UniversityKindai University Hospotal
  • 2012/04 - 2013/03  Kagawa University内分泌代謝血液免疫呼吸器内科学
  • 2011/04 - 2012/03  Kagawa prefectural central hospitalRespiratory medicine
  • 2009/04 - 2011/03  Kagawa prefectural central hospital

Education

  • 2015/04 - 2018/03  Kindai University  Faculty of Medicine  大学院医学研究科
  • 2003/04 - 2009/03  Kagawa University  Faculty of Medicine  School of Medicine

Association Memberships

  • THE JAPANESE ASSOCIATION FOR MOLECULAR TARGET THERAPY OF CANCER   THE JAPAN SOCIETY FOR RESPIRATORY ENDOSCOPY   THE JAPANESE ASSOCIATION FOR INFECTIOUS DISEASES   THE JAPAN LUNG CANCER SOCIETY   THE JAPANESE RESPIRATORY SOCIETY   THE JAPANESE CANCER ASSOCIATION   日本臨床腫瘍学会   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   

Published Papers

  • 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 American Society for Clinical Investigation 134 (7) 2024/04 
    BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.
  • Daisuke Hazama; Kenji Nakahama; Hiroaki Kodama; Akito Miyazaki; Koichi Azuma; Yosuke Kawashima; Yuki Sato; Kentaro Ito; Yoshimasa Shiraishi; Keita Miura; Takayuki Takahama; Satoshi Oizumi; Yoshinobu Namba; Satoshi Ikeda; Hiroshige Yoshioka; Asuka Tsuya; Yuichiro Yasuda; Yoshiki Negi; Ayako Hara; Michihito Toda; Motoko Tachihara
    JTO clinical and research reports 5 (1) 100613 - 100613 2024/01 
    INTRODUCTION: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer associated with poor prognosis and resistance to conventional chemotherapy. Immune checkpoint inhibitors (ICIs), alone or in combination with chemotherapy, were found to have clinical benefits in PSC in recent studies. Nevertheless, because these studies included a small number of patients owing to disease rarity, larger studies are needed to evaluate the effectiveness and safety of ICI-based therapy for PSC. METHODS: This multicenter retrospective study evaluated patients with ICI-naive advanced or metastatic PSC who were treated with ICI-based therapy at 25 hospitals in Japan. RESULTS: A total of 124 patients were evaluated. The overall response rate, median progression-free survival (PFS), and median overall survival (OS) were 59.0%, 10.5 months, and 32.8 months, respectively. The PFS and OS rates at 24 months were 35.3% and 51.5%, respectively. Programmed death-ligand 1 expression, concomitant chemotherapy, and the treatment line were not significantly associated with PFS or OS. Immune-related adverse events (irAEs) were observed in 70 patients (56.5%), including 30 (24.2%) with grade 3 to 5 events. Patients with mild irAEs (grades 1-2) had longer PFS and OS than did those with severe (grades 3-5) or no irAEs. In a multivariate analysis, any-grade irAEs and the absence of liver metastases were independently associated with PFS, whereas any-grade irAEs and Eastern Cooperative Oncology Group performance status less than or equal to 1 were independently associated with OS. CONCLUSIONS: ICI-based therapy was found to have promising effectiveness in patients with advanced or metastatic PSC, regardless of programmed death-ligand 1 expression, concomitant chemotherapy, or treatment line.
  • 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  2023/12 [Refereed]
     
    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.
  • Yasushi Goto; Hirotsugu Kenmotsu; Motohiro Tamiya; Shuji Murakami; Takayasu Kurata; Noriko Yanagitani; Hirokazu Taniguchi; Shoichi Kuyama; Junichi Shimizu; Toshihide Yokoyama; Naoko Shimada; Tadashi Maeda; Akihiro Tamiya; Ayumi Uchiyama; Kazuyoshi Imaizumi; Takayuki Takahama; Terufumi Kato; Hidetoshi Hayashi; Naoko Shiraiwa; Shigeyuki Toyoizumi; Hironori Kikkawa; Despina Thomaidou; Makoto Nishio
    JTO Clinical and Research Reports Elsevier BV 4 (5) 100508 - 100508 2666-3643 2023/05 
    INTRODUCTION: Lorlatinib is an ALK tyrosine kinase inhibitor approved in Japan for the treatment of advanced ALK+ NSCLC. There has been little evidence about lorlatinib efficacy after first-line (1L) alectinib in clinical practice in Japan. METHODS: We retrospectively analyzed patients with advanced ALK+ NSCLC previously treated with 1L alectinib at multiple sites in Japan. Primary objectives were to collect patient demographics at baseline and estimate time to treatment failure (TTF) with second-line (2L) or third-line (3L) or later line (≥3L) lorlatinib treatment. Secondary objectives included objective response rate (ORR) with lorlatinib, reason for discontinuation and time to last treatment failure with lorlatinib, TTF and ORR of alectinib, and combined TTF. RESULTS: Among the 51 patients included in the study, 29 (56.9%) received 2L and 22 (43.1%) received ≥3L lorlatinib treatment. At lorlatinib initiation, brain metastases were reported in 25 patients (49.0%), and 32 (62.7%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Median TTF with lorlatinib was 11.1 months (95% confidence interval [CI]: 4.6-13.8) in any line, 10.8 months (95% CI: 3.9-13.8) in 2L, and 11.5 months (95% CI: 2.9-not reached) in ≥3L. Median TTF was 11.5 months (95% CI: 3.9-not reached) in patients with brain metastases at lorlatinib initiation and 9.9 months (95% CI: 4.3-13.8) in patients without brain metastases. ORR was 35.7% with any-line lorlatinib treatment. CONCLUSIONS: Patient characteristics and efficacy were comparable with previous reports when lorlatinib was given after 1L alectinib in patients with ALK+ NSCLC.
  • Yasuo Otsuka; Yoriaki Komeda; Masayuki Takeda; Takayuki Takahama; Masashi Kono; Mamoru Takenaka; Satoru Hagiwara; Naoshi Nishida; Hiroshi Kashida; Masatoshi Kudo
    Case Reports in Medicine Hindawi Limited 2023 1 - 4 1687-9627 2023/02 
    A 76-year-old woman presented with lower abdominal pain and nausea and was referred to the gastroenterology department in our institution. Previous contrast-enhanced computed tomography (CE-CT) for follow-up after breast cancer surgery had indicated a soft tissue mass below the right diaphragm, which was considered a benign change. CE-CT performed at the first visit to our department revealed further thickening of the soft tissue mass with extension to the liver surface. In addition, ascites and nodules were observed in the abdominal cavity. Histopathological examination of a biopsy specimen revealed peritoneal invasion of atypical epithelioid cells with trabecular and glandular patterns. The tumor cells were positive for AE1/AE2, calretinin, WT-1, D2-40, HEG1, EMA, BAP1, and MTAP and negative for carcinoembryonic antigen, MOC-31, Ber-Ep4, ER, PgR, TTF-1, claudin 4, and desmin. A diagnosis of epithelioid mesothelioma was made. The patient received chemotherapy with cisplatin (75 mg/m2) and pemetrexed (500 mg/m2). After six courses of combined chemotherapy, pemetrexed was administered as a single agent. At the time of writing this report, she was undergoing over the 30th course of chemotherapy without any significant side effects. Diffuse malignant peritoneal mesothelioma is a rare, fatal, and progressive disease. Our patient achieved long-term survival of more than 5 years with maintenance therapy using single-agent pemetrexed.
  • Fujita, Y.; Matsuoka, H.; Chiba, Y.; Tsurutani, J.; Yoshida, T.; Sakai, K.; Nakura, M.; Sakamoto, R.; Makimura, C.; Ohtake, Y.; Tanaka, K.; Hayashi, H.; Takeda, M.; Okuno, T.; Takegawa, N.; Haratani, K.; Takahama, T.; Tanizaki, J.; Koyama, A.; Nishio, K.; Nakagawa, K.
    Oncology Letters 26 (2) 355 - 355 1792-1082 2023 
    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.
  • 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 2023/01 
    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.
  • Tsukamoto, S.; Takahama, T.; Mavrogenis, A.F.; Tanaka, Y.; Tanaka, Y.; Errani, C.
    Musculoskeletal Surgery 107 (1) 2035-5114 2023
  • 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 (NPO)日本肺癌学会 62 (6) 491 - 491 0386-9628 2022/11
  • 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 (NPO)日本肺癌学会 62 (5) 439 - 439 0386-9628 2022/10
  • 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 (NPO)日本肺癌学会 62 (5) 439 - 439 0386-9628 2022/10
  • 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 2022/08 
    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.
  • 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 近畿大学医学会 47 (1-2) 19 - 25 0385-8367 2022/06 
    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)
  • Daichi Fujimoto; Satoru Miura; Kenichi Yoshimura; Kazushige Wakuda; Yuko Oya; Koji Haratani; Shoichi Itoh; Takehiro Uemura; Ryotaro Morinaga; Takayuki Takahama; Kazuhisa Nakashima; Motoko Tachihara; Go Saito; Junko Tanizaki; Kohei Otsubo; Satoshi Ikeda; Hirotaka Matsumoto; Satoshi Hara; Akito Hata; Takeshi Masuda; Nobuyuki Yamamoto
    JTO clinical and research reports 3 (2) 100265 - 100265 2666-3643 2022/02 
    Introduction: The real-world effectiveness of combination treatment with cytotoxic chemotherapy and programmed cell death protein-1 or programmed death-ligand 1 inhibitor for NSCLC, especially for the elderly (aged ≥75 y) or those with poor performance status (≥2), has not been fully elucidated. We investigated the real-world effectiveness and safety of this combination therapy in these populations. Methods: This multicenter retrospective study evaluated patients who are chemo-naïve with advanced NSCLC who received a combination of platinum, pemetrexed, and pembrolizumab between December 2018 and June 2019. This was an updated prespecified secondary analysis with the primary objective of investigating the safety and effectiveness in this cohort. Results: Overall, 299 patients were included. Multivariate analysis identified performance status (0-1) and programmed death-ligand 1 tumor proportion score (≥50%) as significant independent predictors of progression-free survival (p = 0.007, and p = 0.003, respectively). The incidence of severe adverse events (AEs) was higher in the elderly and those with poor performance status than in their younger and good performance status counterparts. A total of 71 patients developed AEs that led to treatment discontinuation, and AE-related treatment discontinuation occurred at a significantly higher rate in older patients (median [range]) (70 [46-82] y) than in younger patients (68 [31-84] y) (p <0.001). Conclusions: Combination treatment with pembrolizumab plus chemotherapy had low real-world effectiveness for poor performance status patients. Severe AEs occurred at a higher rate in the elderly and poor performance status patients, and the AE-related treatment discontinuation rate increased with age. Physicians should be cautious about using this regimen, especially in the elderly and poor performance status patients.
  • Takahiro Kimura; Takayuki Takahama; Tomoko Wakasa; Shiori Adachi; Yusaku Akashi; Takao Tamura; Katsunari Yane
    Molecular and clinical oncology 16 (1) 2 - 2 2022/01 
    Immune checkpoint inhibitors (ICIs) have markedly changed the treatment landscape for melanoma; however, their efficacy and applications are currently limited and medical requirements remain unmet. The present case study reports on a 85-year-old female patient who visited our outpatient clinic with a 1-month history of a buccal mucosa mass and was diagnosed with locally advanced mucosal melanoma of the head and neck. The patient's tumor progressed right after the administration of nivolumab, compromising oral intake. Palliative debulking surgery was performed. Subsequently, the other part of the melanoma on the hard palate slightly decreased in size without forming new lesions for more than one year after surgery. The present case exemplifies that tumor volume reduction surgery may increase the response to ICI and may prolong the duration of response. This combination therapy may be more effective in patients whose tumors increase in size after administration of ICIs or whose tumor is already large at the beginning of treatment. The combination of ICIs and debulking surgery may become an important treatment option in the future for locally advanced mucosal melanoma.
  • Yoshinori Imamura; Kaoru Tanaka; Naomi Kiyota; Hidetoshi Hayashi; Ichiro Ota; Akihito Arai; Shigemichi Iwae; Shujiro Minami; Katsunari Yane; Tomoko Yamazaki; Yoshiaki Nagatani; Masanori Toyoda; Takayuki Takahama; Kazuko Sakai; Kazuto Nishio; Naoki Otsuki; Ken-ichi Nibu; Hironobu Minami
    Medical Oncology Springer Science and Business Media LLC 38 (11) 128 - 128 1357-0560 2021/11 
    The clinical utility of systemic therapy and genomic profiling in non-squamous-cell head and neck cancer (NSCHNC) has not been fully elucidated. This phase II trial evaluated the efficacy and safety of docetaxel and cisplatin combination in the first-line setting. Eligibility criteria were recurrent and/or metastatic NSCHNC; progressive disease within the last 6 months; no prior systemic therapy; and ECOG performance status of 0-1. Patients received docetaxel (75 mg/m2 on day 1) and cisplatin (75 mg/m2 on day 1), repeated every 21 days for 6 cycles. The primary endpoint was confirmed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events. Next-generation sequencing (NGS) was performed using the Ion AmpliSeq Cancer Hotspot Panel v2. Twenty-three patients were enrolled from November 2012 to October 2016, of whom 8 were male. Median age was 57 years. Ninety-six percent of cases were metastatic. Among 22 evaluable patients, confirmed ORR was 45% (95% confidential interval 24-68%). With a median follow-up period of 18.8 months, median PFS and OS were 6.7 and 20.1 months, respectively. Grade 3/4 adverse events included febrile neutropenia (39%) and anemia (22%). No treatment-related deaths were observed. NGS analysis revealed potential treatment targets, including ERBB2, KIT, and ALK. The docetaxel and cisplatin combination regimen can be considered a new treatment option in recurrent and/or metastatic NSCHNC, although primary prophylaxis for febrile neutropenia should be considered. Diverse genomic alterations may lead novel treatment options.This trial was registered with the UMIN Clinical Trials Registry as UMIN000008333 on [September 1st, 2012].
  • 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 Frontiers Media {SA} 11 763468 - 763468 2234-943X 2021/10 
    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.
  • T. Takahama; H. Shimizu; H. Kaneda; H. Horinouchi; K. Watanabe; T. Yoshida; K. Hasegawa; K. Onishi; K. Yoshimura; T. Sawa; A. Gemma
    Journal of Thoracic Oncology Elsevier BV 16 (10) S1133 - S1133 1556-0864 2021/10
  • 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 (NPO)日本肺癌学会 61 (6) 649 - 649 0386-9628 2021/10
  • 高濱 隆幸; 清水 秀文; 堀之内 秀仁; 吉田 健史; 渡邊 清高; 金田 裕靖; 長谷川 一男; 大西 幸次; 吉村 健一; 澤 祥幸; 弦間 昭彦
    肺癌 (NPO)日本肺癌学会 61 (6) 586 - 586 0386-9628 2021/10
  • 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 (NPO)日本肺癌学会 61 (6) 499 - 499 0386-9628 2021/10
  • 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 1341-9625 2021/09 
    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.
  • Esuteru Hirokawa; Satomi Watanabe; Kazuko Sakai; Masayuki Takeda; Chihiro Sato; Takayuki Takahama; Kazuto Nishio; Kazuhiko Nakagawa
    Thoracic cancer 12 (16) 2283 - 2287 1759-7706 2021/08 
    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.
  • Hidefumi Shimizu; Takayuki Takahama; Hiroyasu Kaneda; Hidehito Horinouchi; Takeshi Yoshida; Kiyotaka Watanabe; Kazuo Hasegawa; Kouji Onishi; Kenichi Yoshimura; Toshiyuki Sawa; Akihiko Gemma
    Annals of Oncology Elsevier BV 32 S306 - S306 0923-7534 2021/07
  • 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 1574-0153 2021 
    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.
  • 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 Wiley 15 (1) 126 - 137 1574-7891 2021/01 
    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).
  • 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 - e596 1083-7159 2020/12 
    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.
  • 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 (NPO)日本肺癌学会 60 (2) 148 - 148 0386-9628 2020/04
  • Kurosaki, T.; Kawakami, H.; Mitani, S.; Kawabata, R.; Takahama, T.; Nonagase, Y.; Fumita, S.; Ozaki, T.; Chiba, Y.; Tamura, T.; Nakagawa, K.
    In vivo (Athens, Greece) Anticancer Research USA Inc. 34 (4) 1921 - 1929 0258-851X 2020 [Refereed]
     
    Background/Aim: This study aimed to seek clinical biomarkers of nivolumab monotherapy for advanced gastric cancer (AGC) of which efficacy is limited. We focused on Glasgow Prognostic Score (GPS), which reflects systemic inflammatory and nutritional status as well as disease control by chemotherapy immediately before nivolumab (DCBC). Patients and Methods: AGC patients with measurable lesions who were treated with nivolumab in the third- or later-line were included. DCBC was defined as a best overall response of complete response (CR), partial response, stable disease, or non-CR/non-progressive disease achieved by chemotherapy immediately before nivolumab. Results: Eighty patients were analyzed. Among the various clinical factors, multivariable analysis revealed that a GPS of 2 was significantly associated with a shorter overall survival and DCBC was significantly associated with a longer progression-free survival. Conclusion: We present the potential of GPS and DCBC as efficient biomarkers of nivolumab for AGC, that warrants further evaluation.
  • 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 0169-5002 2020/01 [Refereed]
     
    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.
  • 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 Wiley 126 (9) 1940 - 1948 0008-543X 2020/01 [Refereed]
     
    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.
  • 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 2019/12 [Refereed]
     
    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.
  • 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 - e592 1526-8209 2019/10 [Refereed]
  • 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 2019/09 [Refereed]
     
    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.
  • 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 2019/08 [Refereed]
     
    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.
  • Masayuki Takeda; Kazuko Sakai; Takayuki Takahama; Kazuya Fukuoka; Kazuhiko Nakagawa; Kazuto Nishio
    Cancers 11 (6) 2019/05 [Refereed]
     
    : 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.
  • 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 1556-0864 2019/03 [Refereed]
  • 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 1083-7159 2019/02 [Refereed]
     
    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.
  • Fujita Etsuo; Ohya Daichi; Kitamura Yousuke; Yamamura Risa; Ishikawa Kana; Sagimori Miki; Ohta Fuminori; Kiyoi Megumi; Kawabata Yoshitaka; Hashimoto Tadayuki; Aoki Tatsuya; Kayama Yuta; Mukai Yosuke; Nakamura Ryo; Yabuuchi Toshinobu; Furuta Katsuyuki; Hikimoto Shigetoshi; Takahata Masahiro; Sougawa Hiromichi; Kobayashi Katsunobu; Hoshiya Hironobu; Nakachi Kenichiro; Ikejima Miwa; Furukawa Kenichi; Kawahara Masaaki; Takahama Takayuki; Nishikawa Yusaku; Tohda Yuji; Shimada Kousuke; Yamamoto Katsuhiro
    日本臨床生理学会雑誌 日本臨床生理学会 48 (3) 127 - 133 0286-7052 2018/08 
    肺癌の診断に気管支肺胞洗浄液(BAL)のサイトケラチンフラグメント(CYFRA)を使用できるか検討するため、患者39名(男31名、女8名、平均年齢73.2±1.6歳)のBALにおけるCYFRA濃度を測定した。全員のBALのCYFRA値は49.4±21.8ng/mLで、そのうち悪性と診断された患者27名の値は38.0±12.9ng/mL、良性病変の患者12名の値は75.0±66.0ng/mLで、有意差は認めなかった。一方、血清中のCYFRA値は、全員、悪性、良性の患者でそれぞれ、4.5±0.8ng/mL、5.5±1.1ng/mL、2.3±0.6ng/mLであった。BALのCYFRAの平均値は悪性の症例よりも良性の症例で高く、血清CYFRA値では悪性の症例のほうが高い傾向がみられた。
  • 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 : an official journal of the American Association for Cancer Research American Association for Cancer Research Inc. 24 (11) 2653 - 2664 1557-3265 2018/06 [Refereed]
     
    Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8+ tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry.Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8+ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8+ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8+ TILs and recovery of effector function. CD8+ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8+ T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction.Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8+-T-cell-mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3-expressing NSCLCs. Clin Cancer Res; 24(11); 2653-64. ©2018 AACR.
  • Takahama, T.; Sakai, K.; Nakagawa, K.; Nishio, K.
    Annals of Oncology 29 2018
  • 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 [Refereed]
  • Fujita Etsuo; Shojima Kensaku; Nishimura Hideko; Hattori Maiko; Takahata Masahiro; Sougawa Hiromichi; Kobayashi Katsunobu; Hoshiaya Hironobu; Ohta Fuminori; Kiyoi Megumi; Nakai Takeo; Tsunoi Kazuyuki; Sakanaka Keiichiro; Tanaka Akio; Deguchi Yoko; Horiuchi Yuko; Iwahashi Naoyuki; Furukawa Kenichi; Hirabayashi Yasuo; Inagaki Takashi; Kawahara Masaaki; Takahama Takayuki; Nakanishi Yuya; Nishikawa Yusaku; Tohda Yuji; Shimada Kousuke; Yamamoto Katsuhiro
    日本臨床生理学会雑誌 日本臨床生理学会 47 (2) 105 - 111 0286-7052 2017/05 
    BAL中のSCCを測定して肺癌の診断を行い、血清SCC測定結果と比較した。肺癌の疑いのある患者68名(男48名、女20名、平均71.4名)に、PETとGaシンチグラフィーを行い、経気管支鏡肺生検、経気管支鏡生検またはBALを含む組織検査または細胞診を行った。肺癌患者ではBAL中のSCC抗原マーカー(435.5±61.1ng/mL)は、良性病変(354.2±86.9ng/mL)よりもわずかに高値を示した。血清のSCC抗原マーカー(3.3±0.9ng/mL)も良性病変(1.3±0.1ng/mL)よりもわずかに高値を示した。以上より、この測定値を他の放射線画像診断と併用すると、肺癌の診断の信頼性が高くなると考えられた。
  • 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 IMPACT JOURNALS LLC 7 (51) 84860 - 84871 1949-2553 2016/12 [Refereed]
     
    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.
  • 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 IMPACT JOURNALS LLC 7 (36) 58492 - 58499 1949-2553 2016/09 [Refereed]
     
    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.
  • 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 SPRINGER 34 (3) 394 - 6 0167-6997 2016/06 [Refereed]
     
    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.
  • 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 OXFORD UNIV PRESS 26 (12) 2477 - 2482 0923-7534 2015/12 
    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.
  • 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 IMPACT JOURNALS LLC 6 (32) 33602 - 11 1949-2553 2015/10 [Refereed]
     
    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.
  • Takayuki Takahama; Masayuki Takeda; Shinichi Nishina; Kazuhiko Nakagawa
    BMC research notes BioMed Central Ltd. 8 (1) 100 - 100 1756-0500 2015/03 [Refereed]
     
    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.
  • Naoki Watanabe; Tomoya Ishii; Takayuki Takahama; Akira Tadokoro; Nobuhiro Kanaji; Hiroaki Dobashi; Shuji Bandoh
    Internal medicine (Tokyo, Japan) JAPAN SOC INTERNAL MEDICINE 53 (23) 2711 - 5 0918-2918 2014 [Refereed]
     
    A 55-year-old woman was admitted for an evaluation of a mediastinal mass, bilateral cervical lymphadenopathy and a left breast tumor. Although pathology revealed a diagnosis of breast cancer, the cervical lymph nodes differed from the breast lesion. An anaplastic lymphoma kinase (ALK) gene analysis revealed ALK rearrangement in the cervical lymph nodes only, which were therefore diagnosed as reflective of metastasis of lung adenocarcinoma. The mediastinal tumor was also diagnosed as an ALK-positive lung adenocarcinoma based on its therapeutic response. ALK gene analyses can be used to identify primary lesions in patients with cancers of unknown primary sites.
  • Nobuhiro Kanaji; Yoshio Kushida; Shuji Bandoh; Tomoya Ishii; Reiji Haba; Akira Tadokoro; Naoki Watanabe; Takayuki Takahama; Nobuyuki Kita; Hiroaki Dobashi; Takuya Matsunaga
    American Journal of Case Reports 14 543 - 547 1941-5923 2013/12 [Refereed]
     
    Objective: Background:Rare disease Membranous glomerulonephritis can occur secondarily from infectious diseases. There are no reports describing membranous glomerulonephritis caused by non-tuberculous mycobacterium infection. However, several cases with membranous glomerulonephritis due to Mycobacterium tuberculosis have been reported. Mycobacterium shimoidei is an uncommon pathogen, and less than 20 cases with this species have been reported. A therapeutic regimen for this infection has not been established yet. Case Report: An 83-year-old Japanese man presented with productive cough for 6 months. Computed tomography scan showed multiple cavities in the bilateral pulmonary felds. Acid-fast bacilli were evident in his sputum by Ziehl-Neelsen staining (Gafky 3). PCR amplifcations for Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium intracellulare were all negative. Finally, Mycobacterium shimoidei was identifed by rpoB sequencing and 16S rRNA sequencing. Urine examination showed a sub-nephrotic range of proteinuria and histology of the kidney showed membranous glomerulonephritis. Antimycobacterial treatment with clarithromycin, rifampicin, and ethambutol dramatically improved not only the pulmonary disease, but also the proteinuria. Conclusions: To the best of our knowledge, the presented case is the frst report showing non-tuberculous mycobacteriuminduced secondary membranous glomerulonephritis. A combination with clarithromycin, ethambutol, and rifampicin might be efective for treatment of Mycobacterium shimoidei infection. © Am J Case Rep.
  • Nobuhiro Kanaji; Yoshio Kushida; Shuji Bandoh; Tomoya Ishii; Reiji Haba; Akira Tadokoro; Naoki Watanabe; Takayuki Takahama; Nobuyuki Kita; Hiroaki Dobashi; Takuya Matsunaga
    The American journal of case reports 14 543 - 7 1941-5923 2013 [Refereed]
     
    PATIENT: Male, 83 FINAL DIAGNOSIS: Membranous glomerulonephritis Symptoms: Producting cough Medication: - Clinical Procedure: - Specialty: Nephrology. OBJECTIVE: Rare disease. BACKGROUND: Membranous glomerulonephritis can occur secondarily from infectious diseases. There are no reports describing membranous glomerulonephritis caused by non-tuberculous mycobacterium infection. However, several cases with membranous glomerulonephritis due to Mycobacterium tuberculosis have been reported. Mycobacterium shimoidei is an uncommon pathogen, and less than 20 cases with this species have been reported. A therapeutic regimen for this infection has not been established yet. CASE REPORT: An 83-year-old Japanese man presented with productive cough for 6 months. Computed tomography scan showed multiple cavities in the bilateral pulmonary fields. Acid-fast bacilli were evident in his sputum by Ziehl-Neelsen staining (Gaffky 3). PCR amplifications for Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium intracellulare were all negative. Finally, Mycobacterium shimoidei was identified by rpoB sequencing and 16S rRNA sequencing. Urine examination showed a sub-nephrotic range of proteinuria and histology of the kidney showed membranous glomerulonephritis. Antimycobacterial treatment with clarithromycin, rifampicin, and ethambutol dramatically improved not only the pulmonary disease, but also the proteinuria. CONCLUSIONS: To the best of our knowledge, the presented case is the first report showing non-tuberculous mycobacterium-induced secondary membranous glomerulonephritis. A combination with clarithromycin, ethambutol, and rifampicin might be effective for treatment of Mycobacterium shimoidei infection.
  • Akira Tadokoro; Tomoya Ishii; Takayuki Takahama; Naoki Watanabe; Koshiro Takano; Nobuhiro Kanaji; Osamu Imataki; Hiroaki Dobashi; Shuji Bandoh; Takuya Matsunaga
    Internal medicine (Tokyo, Japan) JAPAN SOC INTERNAL MEDICINE 52 (17) 1953 - 6 0918-2918 2013 [Refereed]
     
    Focal segmental glomerulosclerosis (FSGS) is extremely rare among paraneoplastic nephrotic syndromes. We herein report a case of lung adenocarcinoma with nephrotic syndrome caused by paraneoplastic FSGS. A 68-year-old man visited our hospital for an evaluation of a right hilar mass on chest radiography and supraclavicular lymphadenopathy. Because an aspiration biopsy of the supraclavicular lymph node revealed adenocarcinoma, the patient was diagnosed with lung adenocarcinoma. He also had nephrotic syndrome, and the pathological findings of the renal biopsy demonstrated FSGS. Standard-dose carboplatin-containing chemotherapy led to a partial response for lung cancer and improved the patient's nephrotic syndrome without causing any adverse renal effects.
  • Nobuhiro Kanaji; Shuji Bandoh; Tomoya Ishii; Akira Tadokoro; Naoki Watanabe; Takayuki Takahama; Reiji Haba; Osamu Imataki; Hiroaki Dobashi; Takuya Matsunaga
    LUNG CANCER ELSEVIER IRELAND LTD 77 (2) 293 - 298 0169-5002 2012/08 [Refereed]
     
    The presence of fusion genes between the anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) genes is useful for determining appropriate molecular-targeted therapies in patients with non-small cell lung cancer (NSCLC). The diagnosis of NSCLC is often judged from transbronchial cytological specimens. The efficacy of RT-PCR for detection of EML4-ALK fusion genes in transbronchial cytological specimens has not been studied. Here, we evaluated the detection rate of EML4-ALK fusion genes in transbronchial cytological specimens positive for NSCLC by immediate cytology during bronchoscopic examination. Various numbers of H2228 cells carrying EML4-ALK variant 3 were combined with 1 x 10(6) wild-type WBCs. The RNA was extracted and the sensitivity of detection of the EML4-ALK fusion gene was determined using a nested RT-PCR. A total of 161 cell samples, from cases without available tissue samples, obtained by bronchoscopic examinations utilized for immediate cytology in patients with NSCLC were subsequently analyzed for EML4-ALK fusion genes using a nested multiplex RT-PCR. EML4-ALK variant 3 was detected in a small number of H2228 cells (10 cells), even in the presence of 1 x 106 WBCs (sensitivity: 0.001%). In the patient cytological samples, EML4-ALK fusion genes were detected in five of 161 NSCLCs (3.1%) and four of 88 adenocarcinomas (4.5%). Sequencing confirmed that these samples included three variant 1 genes, one variant 2 gene and one variant 3 gene. Using the same cytological samples, EGFR mutations were detected in 39 of 161 NSCLCs (24.2%) and 36 of 88 adenocarcinomas (40.9%). There was no case in which both EML4-ALK fusion and EGFR mutation were simultaneously detected. Rapid diagnosis during bronchoscopy utilizing immediate cytology contributed to the selection of the best samples for genetic analysis. EML4-ALK fusion genes as well as EGFR mutations were successfully detected in a small number of cancer cells from transbronchial cytological specimens using a nested multiplex RT-PCR. Our present strategy can be integrated into the clinical process without additional invasive examination of patients. In the era of molecular-targeted treatments for NSCLC, the combination of rapid diagnosis during bronchoscopic examination and stocking samples as cDNA could further correspond to genetic analyses of accumulating driver genes in NSCLC. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

MISC

Awards & Honors

  • 2020/09 Nara medical association Nara medical association Young Researcher's Award
  • 2017/05 West Japan Oncology Group Ariyoshi/Fukuoka Prize

Research Grants & Projects

  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2022/04 -2026/03 
    Author : 北島 一宏; 山門 亨一郎; 甲斐田 勇人; 大崎 洋充; 渡部 直史; 木島 貴志; 南 俊行; 高濱 隆幸
  • Japan Society for the Promotion of Science:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2019/04 -2022/03 
    Author : HAYASHI Hidetoshi
     
    After approval of the research protocol by the institutional review board at multiple institutions, including Kinki University, registration of cases and collection of clinical information were conducted at each institution, and a total of 125 cases were registered from four institutions. Tumor tissue samples (FFPE) obtained by biopsy or surgery were collected from 90 of the registered cases, and RNA/DNA was extracted at our institution, and tumor immunity-related gene expression was evaluated using nCounter, PanCancer, and IO360 Panel. Part of the analysis is still in progress, and the final analysis is expected to include 60 patients. We found that response to combination therapy with immune checkpoint inhibitors and chemotherapy correlated with PD-L1 expression and some immune-related gene expression.

Committee Membership

  • 2024/02 - Today   The Japanese society of medical oncology   Specialist committee
  • 2023/12 - Today   International Association for the Study of Lung Cancer   The Global Multidisciplinary Practice Standards Committee (GMPSC)
  • 2023/05 - Today   West Japan Oncology Group   Education and Public Relations Committee
  • 2022/04 - Today   The Japanese Respiratory Society   Adult Pneumonia Practice Guideline 2022 Preparation Committee Member of the Systematic Review Committee
  • 2019/07 - Today   Japanese Lung Cancer Society   Guidelines Review Committee Subcommittee on Guidelines for Patients
  • 2022/03 -2024/02   Japan Society of Medical Oncology   Member of the Supervisory Medical Examination Section
  • 2017/07 -2023/03   Ministry of Health, Labour and Welfare Commissioned Project for Training of Personnel Engaged in Genomic Medicine for Cancer Genomic Medicine Worker Training Committee


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