詳細

下治　正樹 （シモジ　マサキ）

  • 医学科　医学部講師
Last Updated :2024/04/25

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

    肺癌の治療。特に外科治療を専門としています。

研究者情報

学位

  • 医学（2018年03月）

ホームページURL

J-Global ID

現在の研究分野（キーワード）

    肺癌の治療。特に外科治療を専門としています。

研究分野

  • ライフサイエンス / 呼吸器外科学

研究活動情報

論文

  • Akira Hamada; Kenichi Suda; Masaya Nishino; Keiko Obata; Hana Oiki; Tomoyo Fukami; Shota Fukuda; Toshio Fujino; Shuta Ohara; Takamasa Koga; Masato Chiba; Masaki Shimoji; Masaoki Ito; Toshiki Takemoto; Junichi Soh; Yasuhiro Tsutani; Tetsuya Mitsudomi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2023年09月 
    INTRODUCTION: Approximately 10% of mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR-tyrosine kinase inhibitors (TKIs). Several novel EGFR-TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the US FDA. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR-TKIs of earlier generations. METHODS: We chronically exposed Ba/F3 cells transduced with five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations. RESULTS: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib showed good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR-TKIs, except for erlotinib, which was active for insFQEA with C797S. CONCLUSIONS: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M.
  • 画像上cN3が疑われるも病理学的にcN0であった非小細胞肺がんの2症例
    岡本 鴻児; 須田 健一; 小原 秀太; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 津谷 康大
    肺癌 63 3 255 - 255 (NPO)日本肺癌学会 2023年06月
  • 原発性肺癌切除例における人工知能解析プログラムを用いた腫瘍体積増大速度の臨床的意義
    福田 祥大; 宗 淳一; 小原 秀太; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 津谷 康大
    日本呼吸器外科学会雑誌 37 3 O51 - 4 (一社)日本呼吸器外科学会 2023年06月
  • Uniportal VATS区域切除の実際 難点と克服法を動画から
    千葉 眞人; 福田 祥大; 小原 秀太; 濱田 顕; 下治 正樹; 武本 智樹; 須田 健一; 宗 淳一; 光冨 徹哉; 津谷 康大
    日本呼吸器外科学会雑誌 37 3 O60 - 1 (一社)日本呼吸器外科学会 2023年06月
  • 多発肺転移をきたした子宮筋腫の2症例
    永山 孝郁; 須田 健一; 小原 秀太; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 津谷 康大
    日本呼吸器外科学会雑誌 37 3 P11 - 6 (一社)日本呼吸器外科学会 2023年06月
  • 呼吸器外科領域でのロボット支援下手術の克服すべき課題と手技の工夫 局所進行肺癌に対する術前化学放射線療法後ロボット支援下胸腔鏡手術の可能性
    宗 淳一; 下治 正樹; 武本 智樹; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 須田 健一; 津谷 康大
    日本外科学会定期学術集会抄録集 123回 WS - 6 (一社)日本外科学会 2023年04月
  • PD-L1高発現非小細胞肺癌における術前血清フィブリノゲン値の臨床的意義
    小原 秀太; 須田 健一; 福田 祥大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉; 津谷 康大
    日本外科学会定期学術集会抄録集 123回 SF - 3 (一社)日本外科学会 2023年04月
  • 肺癌術後の経時的ctDNA測定が病勢予測に有用であった1例
    櫻井 真倫; 小原 秀太; 須田 健一; 福田 祥大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 津谷 康大; 光冨 徹哉
    肺癌 62 5 439 - 439 (NPO)日本肺癌学会 2022年10月
  • Toshio Fujino; Kenichi Suda; Takamasa Koga; Akira Hamada; Shuta Ohara; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
    Journal of hematology & oncology 15 1 79 - 79 2022年06月 
    BACKGROUND: Capmatinib and tepotinib are guideline-recommended front-line treatments for non-small-cell lung cancer (NSCLC) patients with MET exon 14 skipping mutations (METex14). However, the emergence of acquired resistance to capmatinib/tepotinib is almost inevitable partially due to D1228X or Y1230X secondary mutations of the MET. In this study, we explored agents that are active against both D1228X and Y1230X MET to propose an ideal sequential treatment after capmatinib/tepotinib treatment failure in NSCLC patients with METex14. METHODS: The inhibitory effects of 300 drugs, including 33 MET-TKIs, were screened in Ba/F3 cells carrying METex14 plus MET D1228A/Y secondary mutations. The screen revealed four-candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). Therefore, we performed further growth inhibitory assays using these four MET-TKIs plus cabozantinib and merestinib in Ba/F3 cells carrying MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations. We also performed analyses using Hs746t cell models carrying METex14 (with mutant allele amplification) with/without D1228X or Y1230X in vitro and in vivo to confirm the findings. Furthermore, molecular dynamics (MD) simulations were carried out to examine differences in binding between type II MET-TKIs. RESULTS: All 6 type II MET-TKIs were active against Y1230X secondary mutations. However, among these 6 agents, only foretinib showed potent activity against D1228X secondary mutations of the MET in the Ba/F3 cell and Hs746t in vitro model and Hs746t in vivo model, and CEP-40783 and altiratinib demonstrated some activity. MD analysis suggested that the long tail of foretinib plays an important role in binding D1228X MET through interaction with a residue at the solvent front (G1163). Tertiary G1163X mutations, together with L1195F/I and F1200I/L, occurred as acquired resistance mechanisms to the second-line treatment foretinib in Ba/F3 cell models. CONCLUSIONS: The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230.
  • 肺癌周術期治療:最新の話題と今後の展開 肺癌術後におけるcirculating tumor DNA検出の意義
    小原 秀太; 須田 健一; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
    日本呼吸器外科学会雑誌 36 Suppl. WS2 - 6 (一社)日本呼吸器外科学会 2022年05月
  • COVID-19 pandemicが外科切除の対象となる肺がん患者に与えた影響
    須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
    日本呼吸器外科学会雑誌 36 Suppl. O66 - 2 (一社)日本呼吸器外科学会 2022年05月
  • Uniportal VATS気管支形成術の経験と導入における工夫
    千葉 眞人; 宗 淳一; 小原 秀太; 藤野 智大; 濱田 顕; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
    日本呼吸器外科学会雑誌 36 Suppl. O87 - 6 (一社)日本呼吸器外科学会 2022年05月
  • 縦隔リンパ節郭清を伴う肺葉切除におけるロボット支援手術の特徴と可能性 ハイブリッド・単孔式と比較して
    宗 淳一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉
    日本呼吸器外科学会雑誌 36 Suppl. O94 - 3 (一社)日本呼吸器外科学会 2022年05月
  • 当院における肺癌根治切除後の乳び胸合併症例の検討
    武本 智樹; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉
    日本呼吸器外科学会雑誌 36 Suppl. O101 - 1 (一社)日本呼吸器外科学会 2022年05月
  • 肺癌周術期合併症と糖尿病との関連
    下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉
    日本呼吸器外科学会雑誌 36 Suppl. O106 - 6 (一社)日本呼吸器外科学会 2022年05月
  • Akira Hamada; Kenichi Suda; Toshio Fujino; Masaya Nishino; Shuta Ohara; Takamasa Koga; Takanobu Kabasawa; Masato Chiba; Masaki Shimoji; Makoto Endoh; Toshiki Takemoto; Junichi Soh; Naoki Yanagawa; Satoshi Shiono; Tetsuya Mitsudomi
    JTO clinical and research reports 3 5 100321 - 100321 2022年05月 
    Introduction: Recent studies have suggested that including presence or absence of ground-glass opacity (GGO) may improve the tumor descriptor (T descriptor) classification in clinical stage I NSCLC. In this study, we analyzed prognostic implications of presence or absence of GGO, size of the solid component, and predominant histology to identify the true prognostic determinant for early-stage NSCLC. Methods: We retrospectively examined 384 patients with clinical stage I NSCLC (solid: 242, part solid: 142) who underwent complete resection between 2009 and 2013. Results: Survival curves of the whole cohort revealed good separation using the current TNM classification. Nevertheless, the part-solid group had a favorable prognosis irrespective of solid component size. Conversely, patients in the solid tumor group with tumors between 3 and 4 cm had a worse prognosis than patients whose tumors were less than or equal to 3 cm. Thus, we propose the following novel T descriptor classification: IA, part-solid tumors; IB, solid tumors less than or equal to 3 cm; and IC, solid tumors between 3 and 4 cm. This novel classification system stratified patient prognosis better than the current classification. On pathologic evaluation, the part-solid group always had better prognoses than the solid group in each subgroup divided by pathologic grade. Conclusions: These results suggest that presence of GGO is the true prognostic determinant of stage I NSCLC, irrespective of the size of the solid component. Our novel T descriptor classification system could more accurately predict prognoses of clinical stage I NSCLC cases.
  • Kenichi Suda; Shuta Ohara; Toshio Fujino; Akira Hamada; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
    Clinical lung cancer 23 1 e60-e68  2022年01月 
    BACKGROUND: The differential diagnosis of a solitary solid-type lung nodule is diverse. 18F-fluorodeoxyglucose positron emission tomography (PET) has a high sensitivity in the diagnosis of solid-type lung cancers; however, PET-negative, solid-type lung cancers are rarely observed. In this study, we analyzed the clinical/genetic features and prognosis of PET-negative, solid-type lung cancers. PATIENTS AND METHODS: Between January 2007 and February 2020, 709 patients with solid-type lung cancers (tumor size ≥2.0 cm) underwent pulmonary resection. Clinical, genetic, and prognostic features were evaluated in 27 patients (3.8%) with tumors showing negative PET results defined as SUVmax <2.0. RESULTS: All 27 patients had lung adenocarcinoma; 23 had invasive adenocarcinomas and 4 had invasive mucinous adenocarcinomas. The PET-negative group showed high frequencies of females and never-smokers. Recurrence-free survival was significantly better in the PET-negative group compared with PET-positive counterparts extracted using propensity score matching from patients who underwent pulmonary resection during the same period (P = .0052). Furthermore, 83% of PET-negative, solid-type invasive lung adenocarcinoma patients harbored EGFR mutation, which was significantly higher than that of PET-positive, solid-type invasive lung adenocarcinoma patients (38%, n = 225) who received EGFR mutation testing in our cohort (P < .0001). PET-negative, solid-type lung adenocarcinoma patients with EGFR mutations had significantly better recurrence-free survival compared with PET-positive, solid-type lung adenocarcinoma patients with EGFR mutations extracted using propensity score matching (P = .0030). CONCLUSION: PET-negative, solid-type lung cancers are characterized with a high incidence of EGFR mutation and a better prognosis compared with PET-positive, solid-type lung cancer.
  • Akira Hamada; Kenichi Suda; Takamasa Koga; Toshio Fujino; Masaya Nishino; Shuta Ohara; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuro Uchida; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 162 79 - 85 2021年12月 
    OBJECTIVES: The LUX-Lung 8 randomized trial (LL8) demonstrated a prolonged progression-free survival (PFS) in patients with metastatic squamous cell carcinoma (SCC) of the lung after treatment with afatinib compared with erlotinib. A secondary analysis of the LL8 reported that the presence of rare HER2/HER4 mutations may be partly responsible for this result. Patients with HER2 (hazard ratio [HR] 0.06/p-value 0.02) or HER4 (HR 0.21/p-value unreported) mutations had longer PFS after treatment with afatinib. However, the biological function of these mutations is unclear. MATERIALS AND METHODS: Ten HER2 and 13 HER4 point mutations that were detected in the secondary analysis were transduced into the mouse pro-B cell line (Ba/F3) to determine changes in interleukin-3 (IL-3) dependence and sensitivity to six EGFR or pan-HER tyrosine kinase inhibitors (TKIs), including afatinib and erlotinib. The efficacy of the six TKIs was compared using a sensitivity index, defined as the 50% inhibitory concentration divided by trough concentration of each drug at clinically recommended doses. RESULTS: Seven out of 10 Ba/F3 clones expressing HER2 mutations and all 13 Ba/F3 clones expressing HER4 mutations did not grow in the absence of IL-3, indicating these mutations were non-oncogenic. Three Ba/F3 clones expressing the HER2 mutations E395K, G815R, or R929W acquired IL-3-independent growth. The sensitivity indices for afatinib were ≤ one-fifth of those for erlotinib in all three lines. Other second/third-generation (2G/3G) TKIs showed high efficacy against clones expressing these HER2 mutations. CONCLUSIONS: The majority of HER2/4 mutations detected in lung SCC from LL8 were not oncogenic in the Ba/F3 models, suggesting that the presence of HER2/4 mutations were not responsible for the superior outcomes of afatinib in the LL8 study. However, SCC of the lung in some patients may be driven by rare HER2 mutations, and these patients may benefit from 2G/3G pan-HER-TKI treatment.
  • Toshiki Takemoto; Junichi Soh; Shuta Ohara; Toshio Fujino; Takamasa Koga; Masaya Nishino; Akira Hamada; Masato Chiba; Masaki Shimoji; Kenichi Suda; Kenji Tomizawa; Tetsuya Mitsudomi
    Surgery today 51 9 1480 - 1487 2021年09月 
    PURPOSE: Few studies have so far focused on the preoperative presence of venous thromboembolism (VTE) in lung cancer patients undergoing surgery. In this study, we investigated the prevalence and risk factors for preoperative deep venous thrombosis (DVT) in patients scheduled to undergo lung cancer surgery. METHODS: Between June 2013 and December 2018, 948 consecutive patients underwent lung cancer surgery in Kindai University Hospital. Four patients did not undergo screening for DVT; thus, 944 patients were enrolled in this study. Preoperatively, venous ultrasonography of the lower extremities was performed in patients deemed at risk for DVT, and the prevalence and risk factors for preoperative DVT were examined. RESULTS: Ninety-one patients (9.6%) were diagnosed with preoperative DVT, and postoperative symptomatic pulmonary thromboembolism occurred in one patient (0.11%). A multivariable logistic regression analysis demonstrated that female sex, age ≥ 72 years, history of VTE, a Wells score ≥ 2 points, chronic obstructive pulmonary disease (COPD), and lower hemoglobin levels were significantly associated with preoperative DVT. CONCLUSION: Female sex, age ≥ 72 years, history of VTE, Wells score ≥ 2 points, COPD, and lower hemoglobin levels were identified to be independent risk factors for preoperative DVT. Monitoring for these risk factors and management considering them should help improve the outcomes after lung cancer surgery.
  • Takamasa Koga; Kenichi Suda; Toshio Fujino; Shuta Ohara; Akira Hamada; Masaya Nishino; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Takeo Arita; Michael Gmachl; Marco H Hofmann; Junichi Soh; Tetsuya Mitsudomi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 16 8 1321 - 1332 2021年08月 
    INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.
  • 全身状態(PS)不良が腫瘍に起因すると判断して外科的切除を行いPSの改善を得た原発性肺癌の3例
    神波 奈央子; 須田 健一; 千葉 眞人; 西野 将矢; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉
    日本外科学会定期学術集会抄録集 121回 RS - 3 (一社)日本外科学会 2021年04月
  • Shuta Ohara; Kenichi Suda; Toshio Fujino; Akira Hamada; Takamasa Koga; Masaya Nishino; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 154 84 - 91 2021年04月 
    OBJECTIVE: Emergence of acquired resistance is almost inevitable during EGFR-tyrosine kinase inhibitor therapy for non-small-cell lung cancer (NSCLC) harboring EGFR mutations. Drug tolerance, a reversible state of drug insensitivity in the early phases of tyrosine kinase inhibitor therapy, is considered to serve as the basis of recurrent disease. Therefore, it is important to elucidate the molecular mechanisms of drug tolerance. MATERIALS AND METHODS: Five EGFR-mutated NSCLC cell lines were used in this study. We established drug-tolerant cells (DTCs) via 72 h treatment with osimertinib (600 nM) or afatinib (60 nM). Acquisition of drug tolerance was evaluated by growth inhibitory assay, and the molecular mechanisms of drug tolerance were analyzed by phospho-RTK array. RESULTS: DTCs were successfully induced in PC9, HCC4006, and H1975 cells against osimertinib and in PC9 cells against afatinib. We observed that a high drug concentration was required to induce DTCs, and HCC4006 cells become tolerant when a higher dose of afatinib (>180 nM) was used. In the analysis of HCC4006 DTCs against osimertinib, we observed increased receptor-like tyrosine kinase (RYK) expression, and siRNA-mediated RYK knockdown inhibited the proliferation of DTCs. CONCLUSIONS: These results suggest that induction of DTCs is dose-dependent, and increased RYK expression was the mechanism of drug tolerance in HCC4006 cells against osimertinib.
  • Shuta Ohara; Kenichi Suda; Kenji Tomizawa; Toshiki Takemoto; Toshio Fujino; Akira Hamada; Takamasa Koga; Masaya Nishino; Masato Chiba; Katsuaki Sato; Masaki Shimoji; Junichi Soh; Tetsuya Mitsudomi
    Surgery today 50 11 1427 - 1433 2020年11月 
    PURPOSE: A high plasma level of either fibrinogen or D-dimer has been shown to correlate with a poor prognosis in patients with surgically resected non-small-cell lung cancer (NSCLC). The present study aimed to identify whether or not both markers combined had a superior prognostic value to either alone. METHODS: Of the 1344 patients who underwent surgical resection for NSCLC at our institution between January 2007 and December 2016, 1065 had preoperative plasma fibrinogen and D-dimer data available and were included in the analysis. RESULTS: The recurrence-free survival (RFS) and overall survival (OS) rates were similar for patients with high plasma levels of either or both fibrinogen (> 4.0 g/L) or D-dimer (> 1.0 μg/mL); therefore, these three groups were combined for a further analysis into a single group with high plasma levels of either or both proteins. The high-level group had significantly lower 5-year RFS (53% vs. 68%, p < 0.001) and 5-year OS (65% vs. 80%, p < 0.001) rates than patients with normal plasma levels of fibrinogen and D-dimer (control group). CONCLUSIONS: Our results suggest that preoperative tests for both plasma fibrinogen and D-dimer are necessary to identify patients with surgically resected NSCLC likely to have a poor RFS and OS.
  • Shuta Ohara; Kenichi Suda; Kazuko Sakai; Masaya Nishino; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Toshio Fujino; Takamasa Koga; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi
    Translational lung cancer research 9 5 1915 - 1923 2020年10月 
    BACKGROUND: Recent studies of advanced lung cancer patients have shown that circulating tumor DNA (ctDNA) analysis is useful for molecular profiling, monitoring tumor burden, and predicting therapeutic efficacies and disease progression. However, the usefulness of ctDNA analysis in surgically resected lung cancers is unclear. METHODS: This study included 20 lung cancer patients with clinical stage IIA-IIIA disease. Preoperative and postoperative (3-12 days) plasma samples were collected for ctDNA analysis. Cancer personalized profiling by deep sequencing, which can detect mutations in 197 cancer-related genes, was used for ctDNA detection. The cohort consisted of 18 men and 2 women with a median age of 69 (range, 37-88) years. Sixteen patients (80%) had a history of smoking. Histologically, there were four squamous cell carcinomas, 13 adenocarcinomas, two adenosquamous cell carcinomas, and one small cell carcinoma. RESULTS: At the time of data analysis, the 20 patients had been monitored for a median follow-up of 12 months. Eight patients (40%) were positive for preoperative ctDNA, and this was significantly correlated with tumor size (≥5 vs. <5 cm, P=0.018). Four patients (20%) were positive for postoperative ctDNA, and this was significantly correlated with histological grade (3 vs. 1 or 2, P=0.032). Postoperative positivity for ctDNA also predicted shorter recurrence-free survival (RFS) (P=0.015), while pre- and post-operative carcinoembryonic antigen levels (P=0.150 and P=0.533, respectively) and preoperative positivity for ctDNA (P=0.132) were not correlated with RFS. CONCLUSIONS: Detecting ctDNA postoperatively was a poor prognostic factor in surgically resected lung cancer patients that may suggest there is minimal residual disease (MRD).
  • Shunsuke Eba; Masaki Shimoji; Masahide Hirose; Shinichiro Ota; Yoshinori Okada
    Kyobu geka. The Japanese journal of thoracic surgery 73 8 574 - 577 2020年08月 
    The case was a 56-year-old man. A nodular shadow of the left upper lobe was found in the chest computed tomography, and a diagnosis of adenocarcinoma was obtained by bronchoscopy. Preoperative 3-dimensional computed tomography (3D-CT) angiography indicated an extremely rare pulmonary artery bifurcation abnormality in which A4b+5 and A8+9 bifurcate from the left main pulmonary artery. Thoracoscopic left upper lobectomy and lymph node dissection were performed. Pathological diagnosis was adenocarcinoma with pStage I B. The mediastinal basal pulmonary artery is extremely rare, and to our knowledge, the bifurcation pattern of this case has not been reported elsewhere. The 3D-CT angiography was useful to detect the anatomical vascular abnormalities of the pulmonary artery before surgery, for the safe performance of the thoracoscopic surgery.
  • Shunsuke Eba; Masaki Shimoji; Masahide Hirose; Shinichiro Ota; Yoshinori Okada
    Kyobu geka. The Japanese journal of thoracic surgery 73 3 206 - 209 2020年03月 
    The case is a 50-year-old woman. Video-assisted thoracic surgery (VATS) left upper division segmentectomy was performed for adenocarcinoma through a postero-lateral incision. The pathological result was stage ⅠA. A chest computed tomography (CT) examination 40 months after the operation revealed a nodule in contact with the left 6th rib. A recurrence due to pleural dissemination was suspected in the PET/CT examination, but the possibility of reactive granulation was also considered. Two months later, chest CT reexamination showed an enlargement of the nodule, and reoperation was performed. A fibrous structure that appears to be a silk thread for closing chest at the 1st operation was found on the chest wall. The pathological examination revealed chronic suppurative pleuritis and organizing pneumonia without malignancy, leading to a diagnosis of Schloffer tumor.
  • Toshio Fujino; Yoshihisa Kobayashi; Kenichi Suda; Takamasa Koga; Masaya Nishino; Shuta Ohara; Masato Chiba; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 10 1753 - 1765 2019年10月 
    BACKGROUND: MNNG HOS transforming gene (MET) exon 14 mutations in lung cancer, including exon 14 skipping and point mutations, have been attracting the attention of thoracic oncologists as new therapeutic targets. Tumors with these mutations almost always acquire resistance, which also occurs in other oncogene-addicted lung cancers. However, the resistance mechanisms and treatment strategies are not fully understood. METHODS: We generated Ba/F3 cells expressing MET exon 14 mutations by retroviral gene transfer. The sensitivities of these cells to eight MET-tyrosine kinase inhibitors (TKIs) were determined using a colorimetric assay. In addition, using N-ethyl-N-nitrosourea mutagenesis, we generated resistant clones, searched for secondary MET mutations, and then examined the sensitivities of these resistant cells to different TKIs. RESULTS: Ba/F3 cells transfected with MET mutations grew in the absence of interleukin-3, indicating their oncogenic activity. These cells were sensitive to all MET-TKIs except tivantinib. We identified a variety of secondary mutations. D1228 and Y1230 were common sites for resistance mutations for type I TKIs, which bind the active form of MET, whereas L1195 and F1200 were common sites for type II TKIs, which bind the inactive form. In general, resistance mutations against type I were sensitive to type II, and vice versa. CONCLUSIONS: MET-TKIs inhibited the growth of cells with MET exon 14 mutations. We also identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 mutations.
  • Kenichi Suda; Masaki Shimoji; Shigeki Shimizu; Katsuaki Sato; Masato Chiba; Kenji Tomizawa; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
    Biomolecules 9 9 2019年09月 
    Although lung adenocarcinomas (LADs) with ground-glass opacity (GGO; part-solid tumors) have been shown to differ from those without GGO (pure-solid tumors) in clinicopathological features and prognoses, whether programmed death ligand-1 (PD-L1) protein expression differs between these two tumor types is unclear. This study included 124 patients with clinical T1a-c LAD who received pulmonary resections during 2007-2009. The E1L3N antibody was used to stain for PD-L1 in primary LAD specimens. The specimens were considered PD-L1+ if ≥1% of tumor cells showed membrane staining, and were classified as having a high PD-L1+ tumor proportion score (TPS) if ≥50% of the tumor cells did so. Among the 124 patients, 45 had part-solid tumors and 79 had pure-solid tumors. These two groups did not significantly differ in terms of clinical factors. However, the rates for PD-L1 positivity (4% vs. 25%, p < 0.01) and high PD-L1+ TPS (2% vs. 16%, p = 0.02) were significantly higher in the pure-solid tumors. The multivariate analyses (logistic regression model) showed that the odds ratios for PD-L1 positivity and high PD-L1+ TPS in pure-solid LADs were 5.9 (95% CI; 1.2-29.7) and 8.0 (95% CI; 1.0-63.8), respectively. In conclusion, LADs with GGO were correlated with a lower incidence of PD-L1 expression than pure-solid tumors.
  • Shuta Ohara; Kenji Tomizawa; Shigeki Shimizu; Kenichi Suda; Toshio Fujino; Akira Hamada; Takamasa Koga; Masaya Nishino; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi
    Surgical case reports 5 1 105 - 105 2019年06月 
    BACKGROUND: A total of 75% of patients with Sjögren's syndrome are complicated with pulmonary lesions, of which 12% are lymphoma and 6% are amyloid nodules; the coexistence of both is considered to be rare. CASE PRESENTATION: A 67-year-old female with Sjögren's syndrome presented with multiple pulmonary nodules on chest computed tomography. Since a definitive diagnosis by transbronchial biopsy was not obtained, wedge resection of the nodules was performed. Pathologic diagnosis revealed eosinophilic deposition that stained positive with Congo red. In addition, lymphoepithelial lesions and lymphocytic infiltration were observed. Lymphocytes with monoclonal proliferation predominantly had κ chain. Based on these findings, the nodules were diagnosed as mucosa-associated lymphoid tissue (MALT) lymphoma with amyloid deposition. CONCLUSIONS: The combination of these diseases is very rare, and this is the sixth resected case to the best of our knowledge.
  • Kenji Tomizawa; Katsuaki Sato; Shuta Ohara; Toshio Fujino; Takamasa Koga; Masaya Nishino; Yoshihisa Kobayashi; Masato Chiba; Masaki Shimoji; Kenichi Suda; Toshiki Takemoto; Tetsuya Mitsudomi
    Surgery today 49 6 513 - 520 2019年06月 
    PURPOSE: The morbidity and mortality associated with lung cancer surgery in patients on chronic hemodialysis (CHD) is high; however, the relationship between the severity of postoperative complications and clinicopathological features is unclear. METHODS: Among 1214 consecutive patients who underwent pulmonary resection for primary lung cancer in our institute between 2004 and 2015, we identified 21 patients on CHD, who were the subjects of this study. Life-threatening postoperative complications were defined as grade 4 and 5 per the Clavien-Dindo classification. RESULTS: Fourteen (67%) of these 21 patients suffered postoperative complications, which were life threatening in 5. There was a higher frequency of interstitial pneumonia (IP) in the patients with life-threatening postoperative complications than in those with complications that were not life threatening (p = 0.032). The rates of acute exacerbation and 90-day mortality in the patients with IP were 50% and 75%, respectively. The overall survival (OS) rate of the patients with life-threatening postoperative complications was significantly lower than that of those with complications that were not life threatening (1- and 3-year OS rates: 40% and 0% vs. 80% and 57%, respectively, p = 0.001). CONCLUSIONS: Postoperative mortality and morbidity were high in patients on CHD who underwent pulmonary resection, especially if they had coexisting IP. Although IP is not a contraindication to pulmonary resection, the surgical strategy for CHD patients with IP should be considered carefully.
  • Masaya Nishino; Kenichi Suda; Yoshihisa Kobayashi; Shuta Ohara; Toshio Fujino; Takamasa Koga; Masato Chiba; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 126 149 - 155 2018年12月 
    OBJECTIVES: Non-small cell lung cancers (NSCLCs) that harbor activating mutations for epidermal growth factor receptor (EGFR) show remarkable initial response to EGFR-tyrosine kinase inhibitors (TKIs), but inevitably acquire resistance, half of which are due to a T790 M secondary mutation when first-generation (1 G) or 2 G EGFR-TKIs are used. Osimertinib, a 3 G EGFR-TKI, is a standard of care in this situation, but eventually also evokes resistance, reportedly due to some tertiary EGFR mutations. However, the FLAURA trial showed the superiority of osimertinib over 1 G EGFR-TKIs in treatment-naïve patients, thus providing an option of first-line osimertinib treatment. Resistance in this setting is also inevitable, but its mechanism is unclear. We investigated whether resistance mutations that emerged with T790 M were responsible for the osimertinib resistance in the first-line setting; i.e. without T790 M, and if so, what treatment option was available. MATERIALS AND METHODS: We used literature search to identify EGFR mutations at codons L718, G724, L792, G796, and C797 as mechanisms of osimertinib resistance in the presence of T790 M. These mutations were introduced into Ba/F3 cells in cis with activating EGFR mutations but not with T790 M; inhibitory effects of five EGFR-TKIs were evaluated. RESULTS: Only C797S conferred significant resistance against osimertinib when exon 19 deletion was the activating mutation. However, co-existence of L858R with C797S, C797 G, L718Q, or L718 V mutations all conferred resistance to osimertinib. Erlotinib showed the greatest activity for C797S-mediated resistance. However, 2 G EGFR-TKIs (afatinib or dacomitinib) were effective for other resistance mutations. CONCLUSION: After first-line osimertinib failure, 1 G or 2 G EGFR-TKIs are effective, depending on combinations of secondary and activating mutations.
  • Takamasa Koga; Yoshihisa Kobayashi; Kenji Tomizawa; Kenichi Suda; Takayuki Kosaka; Yuichi Sesumi; Toshio Fujino; Masaya Nishino; Shuta Ohara; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Makoto Suzuki; Pasi A Jänne; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 126 72 - 79 2018年12月 
    OBJECTIVES: Oncogenic HER2 mutations are present in 2-4% of lung adenocarcinomas, but the relevant clinical trials are unsatisfactory. The novel HER2 inhibitor poziotinib was recently developed and clinical trials are ongoing. We compared poziotinib with nine tyrosine kinase inhibitors (TKIs), and derived poziotinib-resistant clones to investigate the resistant mechanism. MATERIALS AND METHODS: We introduced three common HER2 mutations A775_G776insYVMA (YVMA), G776delinsVC (VC) and P780_Y781insGSP (GSP), which account for 94% of HER2 exon 20 insertions in the literature, into Ba/F3 cells. We then compared the activity of poziotinib with that of nine TKIs (erlotinib, afatinib, dacomitinib, neratinib, osimertinib, AZ5104, pyrotinib, lapatinib, and irbinitinib), determined the 90% inhibitory concentration (IC90) through a growth inhibition assay, and defined a sensitivity index (SI) as IC90 divided by the trough concentration at the recommended dose as a surrogate for drug activity in humans. We also generated resistant clones by exposure to poziotinib in the presence of N-ethyl-N-nitrosourea, and HER2 secondary mutations that might serve as a resistance mechanism were searched. RESULTS: YVMA showed resistance to all tested drugs except neratinib, poziotinib and pyrotinib. Poziotinib was the only drug with an SI less than 10 for YVMA, the most common HER2 exon 20 insertion. We established 62 poziotinib-resistant clones, and among these, only C805S of HER2, which is homologous to C797S of the EGFR, was identified as a secondary mutation in 19 clones. We also revealed that heat shock protein (HSP) 90 inhibitors show potent anti-growth activity to the C805S secondary mutant clone. CONCLUSIONS: Poziotinib showed the most potent activity against HER2 exon 20 mutations. We identified the secondary C805S at the covalent binding site of HER2 to poziotinib as a potential mechanism of acquired resistance. HSP90 inhibitors might be a therapeutic strategy for the C805S secondary mutation.
  • Kenichi Suda; Jihye Kim; Isao Murakami; Leslie Rozeboom; Masaki Shimoji; Shigeki Shimizu; Christopher J Rivard; Tetsuya Mitsudomi; Aik-Choon Tan; Fred R Hirsch
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 10 1496 - 1507 2018年10月 
    INTRODUCTION: Data regarding the pre-treatment intertumor heterogeneity of potential biomarkers in advanced-stage lung cancers is limited. A finding of such heterogeneity between primary and metastatic lesions would prove valuable to determine if a metastatic lesion can be a surrogate for the primary tumor, as more biomarkers will likely be used in the future to inform treatment decisions. METHODS: We performed RNA sequencing to analyze intertumor heterogeneity in 30 specimens (primary tumors, intrathoracic, and extrathoracic metastatic lesions) obtained from five treatment-naïve lung cancer patients. RESULTS: The global unsupervised clustering analysis showed that the lesions clustered at the individual patient level rather than on the metastatic sites, suggesting that the characteristics of specific tumor cells have a greater impact on the gene expression signature than the microenvironment in which the metastasis develops. The mutational and transcriptional data highlight the presence of intertumor heterogeneity showing that the primary tumors are usually distinct from metastatic lesions. Through a comparison between metastatic lesions and the primary tumors, we observed that pathways related to cell proliferation were upregulated, whereas immune-related pathways were downregulated in metastatic lesions. CONCLUSION: These data not only provide insight into the evolution of lung cancers, but also imply possibilities and limitations of biomarker-based treatment in lung cancers.
  • Yoshihisa Kobayashi; Toshio Fujino; Masaya Nishino; Takamasa Koga; Masato Chiba; Yuichi Sesumi; Shuta Ohara; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 13 5 727 - 731 2018年05月 
    INTRODUCTION: Dacomitinib was superior to gefitinib in terms of progression-free survival in patients with EGFR-mutant lung cancer in a recent ARCHER 1050 trial. However, despite a marked initial response, lung cancers eventually acquire resistance to these inhibitors. This study aimed to elucidate the mechanisms of acquired resistance to dacomitinib in vitro. METHODS: Dacomitinib-resistant clones were established by exposure to fixed concentrations of dacomitinib by using N-ethyl-N-nitrosourea (ENU) mutagenesis or by chronic exposure to increasing concentrations of dacomitinib without ENU. EGFR secondary mutations were analyzed by Sanger sequencing. Time to resistance in each clone was compared according to the mutational status. EGFR Del19, L858R, and G719A mutations were introduced into Ba/F3 cells by using retroviral vectors. RESULTS: Chronic exposure to dacomitinib without ENU induced T790M in Ba/F3 cells expressing Del19. ENU mutagenesis resulted in 171 dacomitinib-resistant clones. Among these clones, 90% acquired T790M. However, C797S occurred in 11% of L858R-mutant clones (four of 35) and in 24% of G719A-mutant clones (12 of 38) established by using low-dose dacomitinib. Time to resistance was not significantly different between T790M- and C797S-mutant clones in both of L858R clones (p = 0.93) and G719A clones (p = 0.86). Cells expressing Del19 that acquired T790M were sensitive to osimertinib, whereas cells with L858R plus C797S mutations were sensitive to gefitinib or erlotinib. CONCLUSIONS: These in vitro data demonstrate that dacomitinib can directly induce T790M or C797S secondary mutations. Our data suggest the importance of analyzing these secondary mutations because appropriate selection of EGFR inhibitors could overcome acquired resistance to dacomitinib in a subset of lung cancers.
  • Masaya Nishino; Kenji Tomizawa; Syuta Ohara; Toshio Fujino; Yuichi Sesumi; Takamasa Koga; Katsuaki Sato; Yoshihisa Kobayashi; Masato Chiba; Masaki Shimoji; Toshiki Takemoto; Tetsuya Mitsudomi
    Gan to kagaku ryoho. Cancer & chemotherapy 45 1 103 - 105 2018年01月 
    The current case was 73-year-oldwoman. She was referredto our hospital for an abnormal shadow of chest X-ray in the upper right lung field. Chest CT showed 3.5 cm of tumor located at the apex of right lobe with invasion of the chest wall. The tumor was diagnosed as squamous cell carcinoma using CT guided needle biopsy(superior sulcus tumor, clinical T3N0M0, Stage II B). The neoadjuvant therapy, 4 courses of chemotherapy(CBDCA plus PTX)andconcurrent radiotherapy(45 Gy/25 Fr)was performed. Chest CT revealed that tumor size was decreased to 2.3 cm in a diameter, and therapeutic effect was decided as partial response(34%). Upper right lobectomy combinedwith the chest wall(1th to 3th ribs)andmed iastinal lymph node dissection were performed. The pathological specimens showed no residual cancer cells(Ef3, pathological complete response[pCR]). She discharged without complications at 10 days after surgery. It is important to collect cases which obtainedpCR for development of more effective preoperative therapy.
  • Tomonari Kinoshita; Chie Kudo-Saito; Reiko Muramatsu; Tomonobu Fujita; Miyuki Saito; Haruna Nagumo; Toshiharu Sakurai; Shinobu Noji; Emi Takahata; Tomonori Yaguchi; Nobuo Tsukamoto; Yuichiro Hayashi; Kaoru Kaseda; Ikuo Kamiyama; Takashi Ohtsuka; Kenji Tomizawa; Masaki Shimoji; Tetsuya Mitsudomi; Hisao Asamura; Yutaka Kawakami
    European journal of cancer (Oxford, England : 1990) 86 15 - 27 2017年11月 
    We have previously demonstrated that the prognostic significance of tumour-infiltrating CD8+ T cells significantly differs according to histological type and patient smoking habits in non-small cell lung cancer (NSCLC). This work suggested that infiltrating CD8+ T cells may not be activated sufficiently in the immunosuppressive microenvironment in non-smokers with adenocarcinoma. To understand the immunogenic microenvironment in NSCLC, we characterised immune cells comprehensively by performing an immunohistochemical evaluation using an alternative counting method and multicolour staining method (n = 234), and assessed immune-related gene expression by using genetic analytical approaches (n = 58). We found that high infiltration of activated CD8+ T cells expressing interferon gamma (IFN-γ) and granzyme was correlated with postoperative survival in patients with non-adenocarcinoma. On the contrary, CD8+ T-cell accumulation was identified as a worse prognostic factor in patients with adenocarcinoma, particularly in non-smokers. Infiltrating CD8+ T cells were significantly less activated in this microenvironment with high expression of various immunoregulation genes. Potentially immunoregulatory CD8+ FOXP3+ T cells and immunodysfunctional CD8+ GATA3+ T cells were increased in adenocarcinoma of non-smokers. CD4+ FOXP3+ regulatory T cells expressing chemokine receptor-4 (CCR4)- and chemokine ligand (CCL17)-expressing CD163+ M2-like macrophages also accumulated correlatively and significantly in adenocarcinoma of non-smokers. These characteristic immune cells may promote tumour progression possibly by creating an immunosuppressive microenvironment in non-smoking patients with lung adenocarcinoma. Our findings may be helpful for refining the current strategy of personalised immunotherapy including immune-checkpoint blockade therapy for NSCLC.
  • Kenji Tomizawa; Shigeki Shimizu; Shuta Ohara; Toshio Fujino; Masaya Nishino; Yuichi Sesumi; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Kenichi Suda; Toshiki Takemoto; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 112 57 - 61 2017年10月 
    OBJECTIVES: The prognostic impact of tumor cavitation is unclear in patients with early-stage primary lung cancer. The aim of the present study was to examine the clinicopathological features and prognoses of patients with pathological stage I-IIA (p-stage I-IIA) primary lung cancers harboring tumor cavitation. This study was conducted according to the eighth edition of the TNM classification for lung cancer. MATERIALS AND METHODS: We examined 602 patients with p-stage I-IIA primary lung cancer out of 890 patients who underwent pulmonary resection from January 2007 through March 2014 and searched for the presence of tumor cavitation, which is defined as the presence of air space within the primary tumor. RESULTS: A total of 59 out of the 602 patients had tumor cavitation (10%). Compared with patients without tumor cavitation, those with tumor cavitation had a significantly higher frequency of the following characteristics: high serum carcinoembryonic antigen (CEA) level (≥5ng/ml, p=0.027), interstitial pneumonia (p=0.0001), high SUVmax value on FDG-PET scan (≥4.2, p=0.023), tumors located in the lower lobe (p=0.024), large tumor size (>3cm, p=0.002), vascular invasion (66% vs 17%, p<0.0001) and non-adenocarcinoma histology (p=0.025). The overall survival period of patients with tumor cavitation was significantly shorter than that of patients without tumor cavitation (log-rank test: p<0.0001, 5-year OS rate: 56% vs 81%). Tumor cavitation was found to be an independent and significant factor associated with poor prognosis in the multivariate analysis (hazard ratio: 1.76, 95% confidence interval: 1.02-3.10, p=0.042). CONCLUSIONS: Tumor cavitation is an independent factor for poor prognosis in patients with resected p-stage I-IIA primary lung cancer. Based on our analyses, patients with tumor cavitation should be regarded as a separate cohort that requires more intensive follow-up.
  • Yoshihisa Kobayashi; Koichi Azuma; Hiroki Nagai; Young Hak Kim; Yosuke Togashi; Yuichi Sesumi; Masato Chiba; Masaki Shimoji; Katsuaki Sato; Kenji Tomizawa; Toshiki Takemoto; Kazuto Nishio; Tetsuya Mitsudomi
    Molecular cancer therapeutics 16 2 357 - 364 2017年02月 
    Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with first-generation TKIs (1G-TKI). However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib. Afatinib-resistant clones were separately established through N-ethyl-N-nitrosourea (ENU) mutagenesis and exposure to fixed concentrations of afatinib. Rebiopsy samples from patients whose tumors acquired resistance to afatinib were analyzed. Afatinib-resistant cells with Del19, L858R, or G719A developed T790M, whereas those with Del18 acquired novel L792F mutation. ENU mutagenesis screening established 84 afatinib-resistant clones. All Del19 clones and most of the other clones acquired only T790M. However, C797S occurred in subsets of L858R, G719A, and Del18 clones. In addition, subsets of Del18 clones acquired L792F. C797S-acquired cells were sensitive to 1G erlotinib. L792F demonstrated intermediate resistance between T790M and C797S to both 1G- and 3G-TKIs, whereas L792F was the least resistant to 2G-TKIs, particularly dacomitinib. Chronic exposure of Del18 + L792F cells to dacomitinib induced additional T790M. T790M was detected in one of four clinical samples. In conclusion, L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells particularly using a low dose of afatinib, and these minor mutations appear to exhibit sensitivity to dacomitinib and erlotinib, respectively. These secondary mutations should be tested in clinical practice. Mol Cancer Ther; 16(2); 357-64. ©2016 AACRSee related article by Talbert et al., p. 344.
  • Yuichi Sesumi; Kenichi Suda; Hiroshi Mizuuchi; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 104 85 - 90 2017年02月 
    OBJECTIVE: The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells (Wilson et al., 2014). In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells, which tend to acquire resistance to EGFR-TKIs via EMT. MATERIALS AND METHODS: Sensitivity to dasatinib in HCC4006 and HCC4006 erlotinib-resistant (ER) cells with an EMT phenotype was analyzed. HCC4006 cells acquired resistance against the combination of erlotinib and dasatinib (HCC4006EDR) following chronic treatment with these drugs. The expression of EMT markers and the resistance mechanism were analyzed. RESULTS: Short-term or long-term treatment with dasatinib did not reverse EMT in HCC4006ER. In contrast, HCC4006EDR cells maintained an epithelial phenotype, and the mechanism underlying resistance to erlotinib plus dasatinib combination therapy was attributable to a T790M secondary mutation. HCC4006EDR cells, but not HCC4006ER cells, were highly sensitive to a third-generation EGFR-TKI, osimertinib. CONCLUSIONS: Although dasatinib monotherapy did not reverse EMT in HCC4006ER cells, preemptive combination treatment with erlotinib and dasatinib prevented the emergence of acquired resistance via EMT, and led to the emergence of T790M. Our results indicate that preemptive combination therapy may be a promising strategy to prevent the emergence of EMT-mediated resistance.
  • Kenji Tomizawa; Masaya Nishino; Yuichi Sesumi; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Kenichi Suda; Shigeki Shimizu; Takao Sato; Toshiki Takemoto; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 102 60 - 64 2016年12月 
    OBJECTIVES: Positive pleural lavage cytology (PLC) has been reported to have a negative prognostic impact in patients with surgically resected non-small cell lung cancer (NSCLC). However, positive PLC does not upgrade the stage according to the 7th edition of TNM classification for lung cancer. The objectives of this study were to evaluate the prognostic impact of positive PLC in patients with NSCLC and to clarify its contribution to TNM classification. MATERIALS AND METHODS: Seven hundred fifty-four patients who underwent surgical resection of NSCLC from January 2007 through December 2013 were retrospectively studied. PLC was performed using 50ml of saline immediately after thoracotomy. RESULTS: Thirty-eight of the 754 patients were positive for PLC (5.1%). The overall survival (OS) of patients with positive PLC was significantly shorter than that of those with negative PLC (P=0.007, log-rank test). In multivariate analyses of OS, positive PLC was a significant independent prognostic factor (hazard ratio=2.21, 95% confidence interval: 1.21-4.04, P=0.009). The OS of patients with positive PLC was significantly shorter than that of those with negative PLC and pT1 (P<0.0001) or negative PLC and pT2 (P<0.0001) and almost overlapped with that of those with negative PLC and pT3 disease (P=0.601). CONCLUSION: Positive PLC is an independent prognostic factor in patients with resected NSCLC. Based on our analyses, we propose that patients with positive PLC be staged as pT3.
  • Kenichi Suda; Isao Murakami; Hui Yu; Kim Ellison; Masaki Shimoji; Carlo Genova; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch
    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 11 10 1711 - 7 2016年10月 
    INTRODUCTION: EGFR gene somatic mutation is reportedly homogeneous. However, there are few data regarding the heterogeneity of expression of mutant EGFR protein and EGFR gene copy number, especially in extrathoracic lesions. These types of data may enhance our understanding of the biology of EGFR-mutated lung cancer and our understanding of the heterogeneous response patterns to EGFR TKIs. METHODS: An 81-year-old never-smoking female with lung adenocarcinoma could not receive any systemic therapy because of her poor performance status. After her death, 15 tumor specimens from different sites were obtained by autopsy. Expression of mutant EGFR protein and EGFR gene copy numbers were assessed by immunohistochemical analysis and by silver in situ hybridization, respectively. Heterogeneity in these EGFR aberrations was compared between metastatic sites (distant versus lymph node) or histological structures (micropapillary versus nonmicropapillary). RESULTS: All lesions showed positive staining for mutant EGFR protein, except for 40% of the papillary component in one of the pulmonary metastases (weak staining below the 1+ threshold). Expression of mutant-specific EGFR protein, evaluated by H-score, was significantly higher in the micropapillary components than in the nonmicropapillary components (Mann-Whitney U test, p = 0.014). EGFR gene copy number was quite different between lesions but not correlated with histological structure or metastatic form. However, EGFR gene copy numbers were similar between histological structures in each lesion. CONCLUSION: These data indicate that expression of EGFR mutant protein and EGFR gene copy number do not change as a consequence of tumor progression. This also justifies using the biopsy specimens from metastases as a surrogate for primary tumors.
  • Masaki Shimoji; Shigeki Shimizu; Katsuaki Sato; Kenichi Suda; Yoshihisa Kobayashi; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi
    Lung cancer (Amsterdam, Netherlands) 98 69 - 75 2016年08月 
    BACKGROUND: Programmed cell death 1 (PD-1) negatively regulates antigen receptor signaling upon binding by either of its ligands, programmed cell death ligand 1 or 2 (PD-L1/2). Blockade of this interaction with either PD-1 or PD-L1 antibodies has been successful in the treatment of human cancer, especially melanoma and non-small cell lung cancer. PD-L1 expression has been proposed as a predictor of tumor response. However, the relationships between PD-L1 expression and various clinicopathological characteristics remain unclear. MATERIALS AND METHODS: PD-L1 expression was examined in 220 non-small cell lung cancer specimens that were consecutively resected at our hospital after validating the E1L3N antibody immunohistochemical assay by comparing IHC and RT-PCR data for lung cancer cell lines. We evaluated the relationships between PD-L1 positivity, several clinical factors and the immunohistochemical expression of epithelial-mesenchymal transition (EMT), cancer stem cell and proliferative markers. RESULTS: PD-L1 was expressed in 22% of lung adenocarcinomas and 60% of squamous cell lung cancers. There was no significant association between PD-L1 expression and clinicopathological features in squamous cell lung cancer. However, in patients with lung adenocarcinoma, PD-L1 expression was significantly correlated with solid subtype histology, vimentin expression, increased Ki-67 labeling index and poor prognosis by multivariate analysis. CONCLUSION: PD-L1 expression was associated with high proliferative activity and the EMT phenotype in adenocarcinoma but not in squamous cell carcinoma of the lung. PD-L1 expression was a significant poor prognostic factor in patients with lung adenocarcinoma.
  • Hiroshi Mizuuchi; Kenichi Suda; Isao Murakami; Kazuko Sakai; Katsuaki Sato; Yoshihisa Kobayashi; Masaki Shimoji; Masato Chiba; Yuichi Sesumi; Kenji Tomizawa; Toshiki Takemoto; Yoshitaka Sekido; Kazuto Nishio; Tetsuya Mitsudomi
    Cancer science 107 4 461 - 8 2016年04月 
    Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an "oncogene swap." Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, an "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene.
  • Yoshihisa Kobayashi; Yosuke Togashi; Yasushi Yatabe; Hiroshi Mizuuchi; Park Jangchul; Chiaki Kondo; Masaki Shimoji; Katsuaki Sato; Kenichi Suda; Kenji Tomizawa; Toshiki Takemoto; Toyoaki Hida; Kazuto Nishio; Tetsuya Mitsudomi
    Clinical cancer research : an official journal of the American Association for Cancer Research 21 23 5305 - 13 2015年12月 
    PURPOSE: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. EXPERIMENTAL DESIGN: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined. RESULTS: Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature. CONCLUSIONS: Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations.
  • Kenichi Suda; Katsuaki Sato; Hiroshi Mizuuchi; Yoshihisa Kobayashi; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Takuya Iwasaki; Masahiro Sakaguchi; Tetsuya Mitsudomi
    Respiratory investigation 52 6 322 - 9 2014年11月 
    In the last 10-15 years, strategies and modalities of lung cancer treatment have changed dramatically. Meanwhile, the treatment objectives, the lung cancers themselves, have also changed, probably owing to early detection by computed tomography and aging of the population. In particular, the proportions of smaller lung cancers, lung adenocarcinomas with ground-glass opacity, and lung cancers in older patients are increasing. Along with these changes, surgeons have innovated and evaluated novel procedures for pulmonary resection. These include the application of minimally invasive surgical techniques, such as video-assisted thoracoscopic surgery (VATS) and robotic surgery, and sub-lobar resection, such as wedge resection and segmentectomy, for small peripheral lung cancers. Currently, VATS has gained wide acceptance and several institutions in Japan have started using robotic surgery for lung cancers. Two important clinical trials of sub-lobar resection for small peripheral lung cancers are now underway in Japan. In addition, surgery itself is of growing importance in lung cancer treatment. In particular, recent evidence supports the use of surgery in strictly selected patients with locally advanced disease, lung cancers with N2 lymph node metastases, small cell lung cancers, recurrent oligo-metastasis after pulmonary resection, or relapsed tumors after drug treatment. Surgical treatment also provides abundant tumor samples for molecular analysis, which can be used for drug selection in the adjuvant setting or after disease relapse. In the era of personalized treatment, surgery is still one of the most important treatment modalities to combat lung cancer.
  • Chihiro Yamatani; Masato Abe; Masaki Shimoji; Tomohiro Maniwa; Shoji Takahashi; Mitsuhiro Isaka; Yasuhisa Ohde; Reiko Watanabe; Ichiro Ito; Haruhiko Kondo; Takashi Nakajima
    Lung cancer (Amsterdam, Netherlands) 84 1 45 - 50 2014年04月 
    BACKGROUND: Our previous study found unique adenosquamous carcinomas (ADSQs) containing a mucoepidermoid carcinoma (MEC)-like component and a characteristic p63 staining pattern. This study focused on these unique ADSQs. METHODS: Thirty ADSQ cases were studied histologically and by immunohistochemistry for TTF-1 and p63. Of these 30 ADSQs, eight were selected as unique ADSQs. The clinicopathological characteristics of these ADSQs were further studied, and the gene rearrangement of mammalian mastermind-like 2 (MAML2) was investigated by fluorescence in situ hybridization (FISH) for differentiation from pulmonary MEC. RESULTS: The clinicopathological characteristics between the eight ADSQs and the other ADSQ cases showed no statistically significant differences, except for serum CEA level. Histologically, the eight ADSQs contained varying degrees of the MEC-like component, which consisted of solid nests with mucin-filled cysts or a cribriform-like structure. Immunohistochemically, p63-positive nuclei characteristically encircled the tumor nests, although TTF-1 was completely negative. All unique ADSQs not only had a variable degree of squamous cell carcinoma component in addition to the MEC-like component, but also contained a small tubular adenocarcinoma component in three tumors. FISH analysis revealed no MAML2 gene rearrangement in the eight ADSQs. CONCLUSIONS: Of the 30 ADSQs investigated in this study, eight contained a MEC-like component with a characteristic p63 basilar staining pattern similar to that of bronchial basal cells. These unique ADSQs shared clinical characteristics with ordinary ADSQs, but clinicopathologically differed from pulmonary ordinary MEC. Therefore, these unique ADSQs may be either a novel ADSQ subtype originating from bronchial epithelium or variant-type MEC.
  • Morio Yamamoto; Kengo Takeuchi; Masaki Shimoji; Tomohiro Maniwa; Mitsuhiro Isaka; Kazuo Nakagawa; Yasuhisa Ohde; Haruhiko Kondo; Takashi Nakajima
    Cancer science 103 2 390 - 2 2012年02月 
    Echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase (EML4-ALK) 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 EML4-ALK and KIF5B-ALK 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.
  • 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 - 22 2011年12月 
    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.

MISC

  • 宗 淳一; 下治 正樹; 武本 智樹; 深見 朋世; 老木 華; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 伊藤 正興; 須田 健一; 光冨 徹哉; 津谷 康大 肺癌 63 (5) 407 -407 2023年10月
  • 須田 健一; 老木 華; 福田 祥大; 深見 朋世; 小原 秀太; 濱田 顕; 伊藤 正興; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉; 津谷 康大 肺癌 63 (5) 412 -412 2023年10月
  • 須田健一; 小原秀太; 濱田顕; 千葉眞人; 伊藤正興; 下治正樹; 武本智樹; 宗淳一; 光冨徹哉; 津谷康大 日本気管食道科学会総会ならびに学術講演会プログラム・予稿集 74th 2023年
  • 福田祥大; 宗淳一; 小原秀太; 濱田顕; 千葉眞人; 下治正樹; 須田健一; 武本智樹; 津谷康大 日本呼吸器外科学会総会(Web) 40th 2023年
  • 千葉眞人; 福田祥大; 小原秀太; 濱田顕; 下治正樹; 武本智樹; 須田健一; 宗淳一; 光冨徹哉; 津谷康大 日本呼吸器外科学会総会(Web) 40th 2023年
  • 岡本鴻児; 須田健一; 小原秀太; 千葉眞人; 下治正樹; 武本智樹; 宗淳一; 津谷康大 肺癌(Web) 63 (3) 2023年
  • ロボット支援下肺葉切除時の気管支損傷の2例
    武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉 日本呼吸器外科学会雑誌 35 (3) V11 -7 2021年05月
  • 宗 淳一; 富沢 健二; 小原 秀太; 藤野 智大; 濱田 顕; 古賀 教将; 西野 将矢; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉 肺癌 60 (6) 611 -611 2020年10月
  • ヒト胸郭モデルと豚摘出肺を用いた研修医教育の取り組み
    武本 智樹; 福田 祥太; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉 日本呼吸器外科学会雑誌 34 (3) O39 -4 2020年08月
  • 富沢 健二; 佐藤 克明; 下治 正樹; 千葉 眞人; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉 肺癌 59 (6) 853 -853 2019年11月
  • 富沢 健二; 佐藤 克明; 下治 正樹; 千葉 眞人; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉 肺癌 59 (6) 853 -853 2019年11月
  • 腸型肺腺癌の3切除例
    須田 健一; 小原 秀太; 西野 将矢; 藤野 智大; 古賀 教将; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉; 清水 重喜 肺癌 59 (2) 198 -198 2019年04月
  • 肺扁平上皮癌切除例における予後栄養指数の検討
    西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉 日本外科学会定期学術集会抄録集 119回 PS -4 2019年04月
  • 非小細胞肺癌術後5年以降の遅発性再発症例の検討
    古賀 教将; 須田 健一; 西 航; 松島 遼平; 小原 秀太; 藤野 智大; 西野 将矢; 千葉 眞人; 下治 正樹; 吉本 健太郎; 藤野 孝介; 白石 健治; 池田 公英; 脇本 譲二; 武本 智樹; 久保田 伊知郎; 鈴木 実; 光冨 徹哉 日本呼吸器外科学会雑誌 33 (3) P15 -1 2019年04月
  • 肺扁平上皮癌切除例における予後栄養指数の検討
    西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉 日本外科学会定期学術集会抄録集 119回 PS -042 2019年04月
  • 非小細胞肺癌切除例における術前D-dimer/フィブリノゲン値の臨床的意義
    小原 秀太; 須田 健一; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 富沢 健二; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 33 (3) P65 -3 2019年04月
  • Masaya Nishino; Kenichi Suda; Shuta Ohara; Toshio Fujino; Takamasa Koga; Yoshihisa Kobayashi; Masato Chiba; Masaki Shimoji; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi CANCER SCIENCE 109 1184 -1184 2018年12月
  • 原発性肺癌切除例における術前D-dimer値の臨床的意義の検討
    小原 秀太; 富沢 健二; 小林 祥久; 古賀 教将; 西原 将矢; 佐藤 克明; 藤野 智大; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉 肺癌 58 (6) 557 -557 2018年10月
  • 転移性肺腫瘍が疑われた肺原発の類上皮血管内皮腫の1切除例
    小原 秀太; 富沢 健二; 藤野 智大; 古賀 教将; 瀬角 裕一; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉; 清水 重喜 肺癌 58 (2) 155 -156 2018年04月
  • 原発性肺癌術後のせん妄予測における入院時スクリーニング評価の有用性
    小原 秀太; 富沢 健二; 藤野 智大; 古賀 教将; 瀬角 裕一; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P1 -1 2018年04月
  • 右上葉切除術後の中葉無気肺症例の臨床的特徴
    富沢 健二; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P1 -6 2018年04月
  • Uniportal VATS導入のための工夫 Shanghai Pulmonary Hospitalでの研修とウェットラボでの実験を踏まえて
    千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 瀬角 裕一; 小林 祥久; 下治 正樹; 須田 健一; 富沢 健二; Young Timothy; Gonzalez Rivas Diego; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P75 -6 2018年04月
  • 外科的切除を行った胸膜播種、悪性胸水を伴う肺癌手術症例の検討
    藤野 智大; 富沢 健二; 小原 秀太; 古賀 教将; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P79 -8 2018年04月
  • pT3NO-1非小細胞肺癌根治切除例におけるT因子の検討
    西野 将矢; 富沢 健二; 小原 秀太; 藤野 智大; 古賀 教将; 小林 祥久; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P80 -6 2018年04月
  • 原発性肺癌切除例における術前フィブリノゲン値の臨床的意義の検討
    小原 秀太; 富沢 健二; 藤野 智大; 古賀 教将; 瀬角 裕一; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉 日本外科学会定期学術集会抄録集 118回 2522 -2522 2018年04月
  • 原発性肺癌切除例における術前フィブリノゲン値の臨床的意義の検討
    小原 秀太; 富沢 健二; 藤野 智大; 古賀 教将; 瀬角 裕一; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉 日本外科学会定期学術集会抄録集 118回 2522 -2522 2018年04月
  • 転移性肺腫瘍が疑われた肺原発の類上皮血管内皮腫の1切除例
    小原 秀太; 富沢 健二; 藤野 智大; 古賀 教将; 瀬角 裕一; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉; 清水 重喜 肺癌 58 (2) 155 -156 2018年04月
  • 右上葉切除術後の中葉無気肺症例の臨床的特徴
    富沢 健二; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P1 -6 2018年04月
  • Uniportal VATS導入のための工夫 Shanghai Pulmonary Hospitalでの研修とウェットラボでの実験を踏まえて
    千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 瀬角 裕一; 小林 祥久; 下治 正樹; 須田 健一; 富沢 健二; Young Timothy; Gonzalez Rivas Diego; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P75 -6 2018年04月
  • 外科的切除を行った胸膜播種、悪性胸水を伴う肺癌手術症例の検討
    藤野 智大; 富沢 健二; 小原 秀太; 古賀 教将; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉 日本呼吸器外科学会雑誌 32 (3) P79 -8 2018年04月
  • アミロイド沈着を認めた肺原発MALTリンパ腫の1切除例
    小原 秀太; 富沢 健二; 藤野 智大; 瀬角 裕一; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉; 清水 重喜 肺癌 57 (7) 890 -890 2017年12月
  • 繰り返す血痰を契機に発見された左肺底動脈大動脈起始症の1例
    中野 省吾; 下治 正樹; 小原 秀太; 藤野 智大; 西野 将矢; 瀬角 裕一; 小林 祥久; 千葉 眞人; 富沢 健二; 武本 智樹; 光冨 徹哉 日本臨床外科学会雑誌 78 (増刊) 943 -943 2017年10月
  • 富沢 健二; 小原 秀太; 瀬角 裕一; 西野 将矢; 小林 祥久; 千葉 眞人; 佐藤 克明; 下治 正樹; 武本 智樹; 光冨 徹哉 肺癌 57 (5) 448 -448 2017年09月
  • 武本 智樹; 小原 秀太; 藤野 智大; 瀬角 裕一; 西野 将矢; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 富沢 健二; 光冨 徹哉 肺癌 57 (5) 520 -520 2017年09月
  • Yoshihisa Kobayashi; Koichi Azuma; Hiroki Nagai; Young Kim; Yosuke Togashi; Yuichi Sesumi; Masaya Nishino; Masato Chiba; Masaki Shimoji; Katsuaki Sato; Kenji Tomizawa; Toshiki Takemoto; Kazuto Nishio; Tetsuya Mitsudomi JOURNAL OF THORACIC ONCOLOGY 12 (1) S1266 -S1267 2017年01月
  • Yoshihisa Kobayashi; Yosuke Togashi; Yasushi Yatabe; Hiroshi Mizuuchi; Park Jangchul; Chiaki Kondo; Masaki Shimoji; Katsuaki Sato; Kenichi Suda; Kenji Tomizawa; Toshiki Takemoto; Toyoaki Hida; Kazuto Nishio; Tetsuya Mitsudomi JOURNAL OF THORACIC ONCOLOGY 10 (9) S177 -S178 2015年09月
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