SUDA Kenichi

Researcher Information

URL

http://kaken.nii.ac.jp/d/r/30631593.ja.html

J-Global ID

• 201401016376303693

Research Areas

• Life sciences / Tumor diagnostics and therapeutics
• Life sciences / Respiratory surgery
• Life sciences / Cardiovascular surgery

Academic & Professional Experience

• 2018/04 - Today  Kindai University Faculty of MedicineDivision of Thoracic Surgery, Department of Surgery

Published Papers

• 症例報告 胸壁浸潤肺癌に対して術前化学放射線治療後にロボット支援併用下に根治切除した1例

  濵田 顕; 宗 淳一; 千葉 眞人; 下治 正樹; 須田 健一; 津谷 康大

  日本内視鏡外科学会雑誌 株式会社医学書院 29 (2) 127 - 132 1344-6703 2024/03
• 【肺がん,悪性胸膜中皮腫,胸腺腫瘍】免疫チェックポイント阻害薬による非小細胞肺がんの術前治療と術後治療の使い分け

  深見 朋世; 須田 健一; 濱田 顕; 津谷 康大

  腫瘍内科 (有)科学評論社 32 (6) 625 - 630 1881-6568 2023/12
• 低侵襲手術のエビデンスを熟考する 原発性肺癌に対するロボット支援下手術の段階的発展を目指した取り組み

  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 (NPO)日本肺癌学会 63 (5) 407 - 407 0386-9628 2023/10
• 周術期治療の新時代:プラクティスはどう変わったか? PD-L1高発現EGFR変異肺がん外科切除例の検討 術後補助療法の観点から考える

  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 (NPO)日本肺癌学会 63 (5) 412 - 412 0386-9628 2023/10
• 区域切除術後気管支断端瘻・膿胸に対し小開窓術・EWS・閉鎖陰圧療法を組み合わせた後に閉鎖術を行った一例

  老木 華; 千葉 眞人; 宗 淳一; 深見 朋世; 福田 祥大; 小原 秀太; 濱田 顕; 伊藤 正興; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大

  肺癌 (NPO)日本肺癌学会 63 (5) 530 - 530 0386-9628 2023/10
• 正確かつ迅速な肺癌診断への挑戦!(Minimal Residul Disease)

  須田 健一; 小原 秀太; 宗 淳一; 津谷 康大; 光冨 徹哉

  日本癌治療学会学術集会抄録集 (一社)日本癌治療学会 61回 OWS14 - 6 2023/10
• Recent Advances in Perioperative Immunotherapies in Lung Cancer.

  Shota Fukuda; Kenichi Suda; Akira Hamada; Yasuhiro Tsutani

  Biomolecules 13 (9) 2023/09 

  Several clinical trials have been revolutionizing the perioperative treatment of early-stage non-small cell lung cancer (NSCLC). Many of these clinical trials involve cancer immunotherapies with antibody drugs that block the inhibitory immune checkpoints programmed death 1 (PD-1) and its ligand PD-L1. While these new treatments are expected to improve the treatment outcome of NSCLC patients after pulmonary resection, several major clinical questions remain, including the appropriate timing of immunotherapy (neoadjuvant, adjuvant, or both) and the identification of patients who should be treated with neoadjuvant and/or adjuvant immunotherapies, because some early-stage NSCLC patients are cured by surgical resection alone. In addition, immunotherapy may induce immune-related adverse events that will require permanent treatment in some patients. Based on this fact as well, it is desirable to select appropriate patients for neoadjuvant/adjuvant immunotherapies. So far, data from several important trials have been published, with findings demonstrating the efficacy of adjuvant atezolizumab (IMpower010 trial), neoadjuvant nivolumab plus platinum-doublet chemotherapy (CheckMate816 trial), and several perioperative (neoadjuvant plus adjuvant) immunotherapies (AEGEAN, KEYNOTE-671, NADIM II, and Neotorch trials). In addition to these key trials, numerous clinical trials have reported a wealth of data, although most of the above clinical questions have not been completely answered yet. Because there are so many ongoing clinical trials in this field, a comprehensive understanding of the results and/or contents of these trials is necessary to explore answers to the clinical questions above as well as to plan a new clinical trial. In this review, we comprehensively summarize the recent data obtained from clinical trials addressing such questions.
• Secondary mutations of the EGFR gene that confer resistance to mobocertinib in EGFR exon 20 insertion.

  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 2023/09 

  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 (NPO)日本肺癌学会 63 (3) 255 - 255 0386-9628 2023/06
• ロボット支援下手術に特有に起きる合併症とその対策 ロボット支援下解剖学的肺切除術時の気管支損傷を考察する

  宗 淳一; 武本 智樹; 福田 祥大; 小原 秀太; 濱田 顕; 千葉 眞人; 下治 正樹; 須田 健一; 津谷 康大

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 37 (3) WS2 - 6 0919-0945 2023/06
• 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 (一社)日本呼吸器外科学会 37 (3) O51 - 4 0919-0945 2023/06
• 臨床病期I期非小細胞肺癌におけるRAVATを用いた画像的標準化PET/CT定量値の有用性

  濱田 顕; 須田 健一; 宗 淳一; 吉田 幸弘; 橋本 昌樹; 竹ヶ原 京志郎; 長谷川 誠紀; 臼田 実男; 津谷 康大; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 37 (3) O56 - 2 0919-0945 2023/06
• 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 (一社)日本呼吸器外科学会 37 (3) O60 - 1 0919-0945 2023/06
• 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 (一社)日本呼吸器外科学会 37 (3) P11 - 6 0919-0945 2023/06
• 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 (NPO)日本肺癌学会 63 (3) 255 - 255 0386-9628 2023/06
• Prognostic role of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography with an image-based harmonization technique: A multicenter retrospective study.

  Akira Hamada; Kazuhiro Kitajima; Kenichi Suda; Takamasa Koga; Junichi Soh; Hayato Kaida; Kimiteru Ito; Tetsuro Sekine; Kyoshiro Takegahara; Hiromitsu Daisaki; Masaki Hashimoto; Yukihiro Yoshida; Takanobu Kabasawa; Takashi Yamasaki; Seiichi Hirota; Jitsuo Usuda; Kazunari Ishii; Tetsuya Mitsudomi

  JTCVS open 14 502 - 522 2023/06 

  OBJECTIVES: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography-based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non-small cell lung cancer. METHODS: We retrospectively examined 495 patients with clinical stage I non-small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. RESULTS: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. CONCLUSIONS: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non-small cell lung cancers.
• Performance of Ultra-Rapid Idylla™ EGFR Mutation Test in Non-Small-Cell Lung Cancer and Its Potential at Clinical Molecular Screening.

  Kenichi Suda; Kazuko Sakai; Tatsuo Ohira; Takaaki Chikugo; Takao Satou; Jun Matsubayashi; Toshitaka Nagao; Norihiko Ikeda; Yasuhiro Tsutani; Tetsuya Mitsudomi; Kazuto Nishio

  Cancers 15 (9) 2023/05 

  BACKGROUND: The Idylla™ EGFR Mutation Test is an ultra-rapid single-gene test that detects epidermal growth factor receptor (EGFR) mutations using formalin-fixed paraffin-embedded specimens. Here, we compared the performance of the Idylla EGFR Mutation Test with the Cobas® EGFR Mutation Test v2. METHODS: Surgically resected NSCLC specimens obtained at two Japanese institutions (N = 170) were examined. The Idylla EGFR Mutation Test and the Cobas EGFR Mutation Test v2 were performed independently and the results were compared. For discordant cases, the Ion AmpliSeq Colon and Lung Cancer Research Panel V2 was performed. RESULTS: After the exclusion of five inadequate/invalid samples, 165 cases were evaluated. EGFR mutation analysis revealed 52 were positive and 107 were negative for EGFR mutation in both assays (overall concordance rate: 96.4%). Analyses of the six discordant cases revealed that the Idylla EGFR Mutation Test was correct in four and the Cobas EGFR Mutation Test v2 was correct in two. In a trial calculation, the combination of the Idylla EGFR Mutation Test followed by a multi-gene panel test will reduce molecular screening expenses if applied to a cohort with EGFR mutation frequency >17.9%. CONCLUSIONS: We demonstrated the accuracy and potential clinical utility of the Idylla EGFR Mutation Test as a molecular screening platform in terms of turnaround time and molecular testing cost if applied to a cohort with a high EGFR mutation incidence (>17.9%).
• 癌免疫療法時代における外科医の役割 肺がん外科領域におけるがん免疫療法の進歩と呼吸器外科医の役割

  須田 健一; 濱田 顕; 宗 淳一; 小原 秀太; 千葉 眞人; 武本 智樹; 光冨 徹哉; 津谷 康大

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 123回 SY - 4 2023/04
• 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 (一社)日本外科学会 123回 WS - 6 2023/04
• 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 (一社)日本外科学会 123回 SF - 3 2023/04
• 癌免疫療法時代における外科医の役割 肺がん外科領域におけるがん免疫療法の進歩と呼吸器外科医の役割

  須田 健一; 濱田 顕; 宗 淳一; 小原 秀太; 千葉 眞人; 武本 智樹; 光冨 徹哉; 津谷 康大

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 123回 SY - 4 2023/04
• 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 (一社)日本外科学会 123回 WS - 6 2023/04
• 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 (一社)日本外科学会 123回 SF - 3 2023/04
• 低侵襲胸腔鏡手術が肺癌治療にもたらしたもの Uniportal VATSの発展と適応拡大

  千葉 眞人; 宗 淳一; 福田 祥大; 小原 秀太; 濱田 顕; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大

  肺癌 (NPO)日本肺癌学会 62 (6) 540 - 540 0386-9628 2022/11
• 低侵襲胸腔鏡手術が肺癌治療にもたらしたもの Uniportal VATSの発展と適応拡大

  千葉 眞人; 宗 淳一; 福田 祥大; 小原 秀太; 濱田 顕; 下治 正樹; 武本 智樹; 須田 健一; 光冨 徹哉; 津谷 康大

  肺癌 (NPO)日本肺癌学会 62 (6) 540 - 540 0386-9628 2022/11
• 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 (NPO)日本肺癌学会 62 (5) 439 - 439 0386-9628 2022/10
• 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 (NPO)日本肺癌学会 62 (5) 439 - 439 0386-9628 2022/10
• EGFR遺伝子変異肺がんの初回オシメルチニブ治療における腫瘍内AXL高発現の意義(High levels of AXL expression in untreated EGFR-mutated lung cancer negatively impact the use of Osimertinib)

  山田 忠明; 芹澤 昌邦; 谷村 恵子; 上原 久典; 大熊 裕介; 渡部 聡; 竹田 隆之; 千原 佑介; 西山 明宏; 須田 健一; 光冨 徹哉; 矢野 聖二; 釼持 広知

  日本癌学会総会記事 (一社)日本癌学会 81回 E - 1049 0546-0476 2022/09
• EGFR遺伝子変異肺がんの初回オシメルチニブ治療における腫瘍内AXL高発現の意義(High levels of AXL expression in untreated EGFR-mutated lung cancer negatively impact the use of Osimertinib)

  山田 忠明; 芹澤 昌邦; 谷村 恵子; 上原 久典; 大熊 裕介; 渡部 聡; 竹田 隆之; 千原 佑介; 西山 明宏; 須田 健一; 光冨 徹哉; 矢野 聖二; 釼持 広知

  日本癌学会総会記事 (一社)日本癌学会 81回 (2) E - 1049 0546-0476 2022/09 

  For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, the initial therapeutic interventions will have crucial impacts on their clinical outcomes. Drug tolerant factors reportedly have an impact on EGFR-tyrosine kinase inhibitor sensitivity. This prospective study investigated the impacts of drug tolerant-related protein expression in tumors based on the efficacy of osimertinib in the first-setting of EGFR-mutated advanced NSCLC patients. A total of 92 patients with EGFR-mutated advanced or postoperative recurrent NSCLC were analyzed and treated with osimertinib at 14 institutions in Japan. AXL, p53, and programmed death-ligand 1 (PD-L1) expression in patient tumors was determined using immunohistochemistry. The AXL signaling pathway was investigated using a cell line-based assay and AXL-related gene expression in The Cancer Genome Atlas (TCGA) database. High levels of AXL and positive-p53 expression were detected in 26.1% and 53.3% of the pretreatment EGFR-mutated NSCLC tumors, respectively. High AXL expression levels were significantly associated with a shorter progression-free survival compared with low AXL expression levels, irrespective of the EGFR activating mutation status (p = 0.026). Cell line-based assays indicated that the overexpression of AXL protein accelerated PD-L1 expression, which induced insensitivity to osimertinib. In the TCGA database, AXL RNA levels were positively correlated with PD-L1 expression in the lung adenocarcinoma cohort. The results show that high AXL expression levels in tumors impact clinical predictions when using osimertinib to treat EGFR-mutated NSCLC patients. Trial Registration: UMIN000043942.
• Expert consensus on perioperative treatment for non-small cell lung cancer.

  Jianchun Duan; Fengwei Tan; Nan Bi; Chun Chen; Ke-Neng Chen; Ying Cheng; Qian Chu; Di Ge; Jie Hu; Yunchao Huang; Tao Jiang; Hao Long; You Lu; Meiqi Shi; Jialei Wang; Qiming Wang; Fan Yang; Nong Yang; Yu Yao; Jianming Ying; Caicun Zhou; Qing Zhou; Qinghua Zhou; Stefano Bongiolatti; Alessandro Brunelli; Alfonso Fiorelli; Elisa Gobbini; Cesare Gridelli; Thomas John; Jae Jun Kim; Steven H Lin; Giulio Metro; Fabrizio Minervini; Nuria M Novoa; Dwight H Owen; Maria Rodriguez; Ichiro Sakanoue; Marco Scarci; Kenichi Suda; Fabrizio Tabbò; Terence Chi Chun Tam; Masanori Tsuchida; Junji Uchino; Luca Voltolini; Jie Wang; Shugeng Gao

  Translational lung cancer research 11 (7) 1247 - 1267 2022/07
• Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation.

  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 2022/06 

  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.
• TKI耐性2次的変異を同定する手法としてのBa/F3細胞モデルの有用性

  須田 健一; 古賀 教将; 藤野 智大; 濱田 顕; 宗 淳一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 62 (3) 258 - 258 0386-9628 2022/06
• Loss of STING expression is prognostic in non-small cell lung cancer.

  Zoltan Lohinai; David Dora; Charles Caldwell; Christopher J Rivard; Kenichi Suda; Hui Yu; Gareth Rivalland; Kim Ellison; Leslie Rozeboom; Rafal Dziadziuszko; Paul Mitchell; Thomas John; Inigo S Millan; Shengxiang Ren; Fred R Hirsch

  Journal of surgical oncology 125 (6) 1042 - 1052 2022/05 

  BACKGROUND: Stimulator of interferon (IFN) genes (STING) is a protein that promotes type I IFN production essential for T-cell activation. In this study, we aim to characterize STING expression comprehensively using The Cancer Genome Atlas (TCGA) database, cell lines, and patient tumor samples stained with immunohistochemistry. METHODS: Two cohorts were evaluated comprising 721 non-small cell lung cancer (NSCLC) patients and 55 NSCLC cell lines for STING and cyclic GMP-AMP synthase (cGAS) expression using immunohistochemistry. Moreover, an independent cohort of n = 499 patients from the TCGA database was analyzed. Methylation was evaluated on STING and cGAS in five STING-negative NSCLC cell lines. RESULTS: STING RNA expression positively correlates with T cell function and development genes, negatively correlates with cell proliferation and associated with increased survival (5-year-overall survival [OS] 47.3% vs. 38.8%, p = 0.033). STING protein expression is significantly higher in adenocarcinoma (AC) and is lost with increasing stages of AC. STING-positivity is significantly higher in mutant EGFR and KRAS tumors. STING-positive NSCLC patients identified with immunohistochemistry (H-score > 50) have increased survival (median OS: 58 vs. 35 months, p = 0.02). Treatment of STING-negative cell lines with a demethylating agent restores STING expression. CONCLUSIONS: STING is ubiquitously expressed in NSCLC and associated with T cell function genes, AC histology, EGFR, and KRAS mutations and improved overall survival.
• Clinical characteristics, surgical treatments, prognosis, and prognostic factors of primary tracheal cancer patients: 20-year data of the National Cancer Center, China.

  Jiagen Li; Fengwei Tan; Yalong Wang; Qi Xue; Yushun Gao; Juwei Mu; Yousheng Mao; Jun Zhao; Dali Wang; Xiaoli Feng; Susheng Shi; Kenichi Suda; Giuseppe Cardillo; Luca Bertolaccini; Maurizio V Infante; Paul E Van Schil; Shugeng Gao; Jie He

  Translational lung cancer research 11 (5) 735 - 743 2022/05 

  BACKGROUND: Tracheal cancer is a rare malignancy of which previous reports are mostly case reports or small series. Herein, we sought to evaluate the clinical characteristics, surgical treatments, and prognosis of surgically treated primary tracheal cancer patients. METHODS: Patients with primary tracheal cancer who had received surgery in our center between January 2000 and December 2020 were enrolled. Clinical and surgical features were collected by retrospective review of medical records and follow-up was done by telephone interview. The statistical tests were two-sided. RESULTS: A total of 128 patients were included in the study, 49.2% of whom were male, and the average age was 49.4±13.6 years. The most common histological subtype was adenoid cystic carcinoma (ACC; 78/128, 60.9%) followed by squamous cell carcinoma (SCC; 24/128, 18.8%). The percentage of tumors located in the cervical trachea, thoracic trachea, and carina were 50%, 41.4%, and 8.6%, respectively. Among those analyzed, 32.0% of the primary tumors had invaded adjacent organs (E2 disease) and 7.8% of patients had lymph node involvement. Tracheal resection plus reconstruction (with or without thyroidectomy) was the predominant surgical procedure, followed by carinal resection with neocarina. Radical resection (R0) was performed on 61.7% of patients and 63 (49.2%) patients received adjuvant therapy. Compared to ACC, SCC patients had significantly higher risk of tumor of the carina, nodal metastasis, and complications. The 5-year overall survival (OS) for the entire cohort was 84.5% and factors associated with poor prognosis included carinal tumor [hazard ratio (HR) =10.206; P<0.001], E2 disease (HR =8.870; P=0.001), lymph node metastasis (HR =15.197; P<0.001), and postoperative complications (HR =12.497; P=0.001). CONCLUSIONS: The two major subtypes of tracheal cancer are ACC and SCC. Tumor location, extension, lymph node metastasis and complication are survival related factors for surgically treated patients.
• Presence of a Ground-Glass Opacity Component Is the True Prognostic Determinant in Clinical Stage I NSCLC.

  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 2022/05 

  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.
• Uniportal VATSの習得と発展を目指した手術教育プログラム 動物心肺ハイブリッドモデル・VR・オンラインカンファレンスの活用

  千葉 眞人; 小原 秀太; 藤野 智大; 濱田 顕; 下治 正樹; 須田 健一; 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 (一社)日本外科学会 122回 SP - 3 2022/04
• 胸部悪性腫瘍のトランスレーショナルリサーチ【International】肺がん分子標的治療薬に対するon-targetの獲得耐性機序の同定とその克服

  須田 健一; 古賀 教将; 西野 将矢; 藤野 智大; 濱田 顕; 下治 正樹; 千葉 眞人; 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 (一社)日本外科学会 122回 WS - 4 2022/04
• 同一期間に実施した肺がんハイブリッド手術・単孔式手術・ロボット支援下手術の比較検討

  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

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 122回 SF - 1 2022/04
• インシデント・アクシデント報告から考える手術室におけるノンテクニカルスキルの重要性

  武本 智樹; 辰巳 陽一; 小原 秀太; 藤野 智大; 濱田 顕; Chiba Masato; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 122回 SF - 4 2022/04
• 気管食道領域の基礎研究 肺癌切除症例におけるctDNA解析の有用性

  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

  日本気管食道科学会会報 (NPO)日本気管食道科学会 73 (2) 168 - 168 0029-0645 2022/04
• Uniportal VATSの習得と発展を目指した手術教育プログラム 動物心肺ハイブリッドモデル・VR・オンラインカンファレンスの活用

  千葉 眞人; 小原 秀太; 藤野 智大; 濱田 顕; 下治 正樹; 須田 健一; 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 (一社)日本外科学会 122回 SP - 3 2022/04
• 胸部悪性腫瘍のトランスレーショナルリサーチ【International】肺がん分子標的治療薬に対するon-targetの獲得耐性機序の同定とその克服

  須田 健一; 古賀 教将; 西野 将矢; 藤野 智大; 濱田 顕; 下治 正樹; 千葉 眞人; 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 (一社)日本外科学会 122回 WS - 4 2022/04
• 同一期間に実施した肺がんハイブリッド手術・単孔式手術・ロボット支援下手術の比較検討

  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

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 122回 SF - 1 2022/04
• インシデント・アクシデント報告から考える手術室におけるノンテクニカルスキルの重要性

  武本 智樹; 辰巳 陽一; 小原 秀太; 藤野 智大; 濱田 顕; Chiba Masato; 下治 正樹; 須田 健一; 宗 淳一; 光冨 徹哉

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 122回 SF - 4 2022/04
• 気管食道領域の基礎研究 肺癌切除症例におけるctDNA解析の有用性

  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

  日本気管食道科学会会報 (NPO)日本気管食道科学会 73 (2) 168 - 168 0029-0645 2022/04
• HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway.

  Kai Guo; Zhiqiang Ma; Yujiao Zhang; Lu Han; Changjian Shao; Yingtong Feng; Fei Gao; Shouyin Di; Zhipei Zhang; Jiao Zhang; Fabrizio Tabbò; Simon Ekman; Kenichi Suda; Federico Cappuzzo; Jing Han; Xiaofei Li; Xiaolong Yan

  Journal of experimental & clinical cancer research : CR 41 (1) 91 - 91 2022/03 

  BACKGROUND: Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. METHODS: A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan-Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus-meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. RESULTS: The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor-node-metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. CONCLUSIONS: Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.
• Utility of the Ba/F3 cell system for exploring on-target mechanisms of resistance to targeted therapies for lung cancer.

  Takamasa Koga; Kenichi Suda; Tetsuya Mitsudomi

  Cancer science 113 (3) 815 - 827 2022/03 

  Molecular targeted therapies are the standard of care for front-line treatment of metastatic non-small-cell lung cancers (NSCLCs) harboring driver gene mutations. However, despite the initial dramatic responses, the emergence of acquired resistance is inevitable. Acquisition of secondary mutations in the target gene (on-target resistance) is one of the major mechanisms of resistance. The mouse pro-B cell line Ba/F3 is dependent on interleukin-3 for survival and proliferation. Upon transduction of a driver gene, Ba/F3 cells become independent of interleukin-3 but dependent on the transduced driver gene. Therefore, the Ba/F3 cell line has been a popular system to generate models with oncogene dependence and vulnerability to specific targeted therapies. These models have been used to estimate oncogenicity of driver mutations or efficacies of molecularly targeted drugs. In addition, Ba/F3 models, together with N-ethyl-N-nitrosourea mutagenesis, have been used to derive acquired resistant cells to investigate on-target resistance mechanisms. Here, we reviewed studies that used Ba/F3 models with EGFR mutations, ALK/ROS1/NTRK/RET fusions, MET exon 14 skipping mutations, or KRAS G12C mutations to investigate secondary/tertiary drug resistant mutations. We determined that 68% of resistance mutations reproducibly detected in clinical cases were also found in Ba/F3 models. In addition, sensitivity data generated with Ba/F3 models correlated well with clinical responses to each drug. Ba/F3 models are useful to comprehensively identify potential mutations that induce resistance to molecularly targeted drugs and to explore drugs to overcome the resistance.
• 肺癌の分子標的治療の現状と展望

  須田 健一; 光冨 徹哉

  胸部外科 (株)南江堂 75 (1) 53 - 66 0021-5252 2022/01 

  肺癌の分子標的治療の現状と展望について、以下の項目に分けて概説した。1)非小細胞肺癌(NSCLC)におけるドライバー変異の検出法、2)切除不能・再発NSCLCに対するドライバー変異(EGFR変異、ALK転座、ROS1転座、BRAF変異、NTRK転座、METエクソン14欠失変異、RET転座)ごとの分子標的治療薬の実際、3)分子標的治療薬に対する獲得耐性とその克服、4)周術期治療に分子標的治療薬を応用する試み、として述べた。
• [Current Status and Future Perspectives of Molecular Targeted Therapies for Lung Cancer].

  Kenichi Suda; Tetsuya Mitsudomi

  Kyobu geka. The Japanese journal of thoracic surgery 75 (1) 53 - 66 0021-5252 2022/01 

  Molecular targeted therapies are now guideline-recommended treatments for unresectable non-small cell lung cancer( NSCLC) patients harboring driver gene mutations as a front-line treatment. Currently, 17 agents have been approved in Japan for the treatment of patients with NSCLC harboring EGFR mutation, ALK/ROS1/NTRK/RET fusions, BRAF V600E mutation, or MET exon 14 skipping mutation. In addition, many novel agents are being developed against NSCLCs with the other driver mutations such as EGFR or HER2 exon 20 insertion mutations and KRAS G12C mutation. In the era of personalized medicine, thoracic surgeons are expected to play an important role, as one of specialists for multidisciplinary treatments of NSCLCs, at the tumor boards/cancer boards, therefore, the knowledge of genetic testing and molecular targeted drugs is becoming essential for thoracic surgeons. In this review, from the standpoint of thoracic surgeons, we briefly summarize current topics on molecular testing in NSCLCs, approved molecular targeted drugs in Japan, acquired resistance mechanisms to these agents, and attempts to use molecular targeted drugs in adjuvant/neoadjuvant settings.
• Frequent EGFR Mutations and Better Prognosis in Positron Emission Tomography-Negative, Solid-Type Lung Cancer.

  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  2022/01 

  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.
• 最新のがん 早期肺がんへのLiquid biopsyの応用 再発予測としてのMinimal Residual Disease検出の意義

  小原 秀太; 須田 健一; 光冨 徹哉

  近畿大学医学雑誌 近畿大学医学会 46 (3-4) 73 - 78 0385-8367 2021/12 

  近年、liquid biopsyのひとつである腫瘍由来血漿中可溶性DNA(circulating tumor DNA:ctDNA)の検出が、進行期肺癌の実臨床でも用いられるようになった。具体的には、EGFR変異検査に用いられるCobas EGFR変異検出キットやMET exon14 skipping変異の検出に用いられるArcher METによる血漿検体の遺伝子解析結果をもってそれぞれの治療薬の投与が可能となっている。さらに本年3月には、包括的ゲノムプロファイリングであるFoundation One Liquidがんゲノムプロファイルも製造販売承認された。しかし、腫瘍量が比較的少ない外科切除を受ける肺がん患者において、ctDNAを含むliquid biopsyが有用であるかについては十分明らかではない。われわれは最近、臨床病期II-IIIA期の肺がん外科切除例を対象に、術前と術後にctDNAを測定するパイロットスタディを実施した。その結果、術前のctDNA陽性は腫瘍径と関連すること、術後のctDNA陽性は分化度と関連すること、再発予測のバイオマーカーとしては、術前のctDNAよりも術後のctDNAのほうが優れていることが示された。本総説ではこのパイロットスタディの結果を紹介すると共に、本領域における現時点でのエビデンスと今後の展望について総括する。(著者抄録)
• 最新のがん 早期肺がんへのLiquid biopsyの応用 再発予測としてのMinimal Residual Disease検出の意義

  小原 秀太; 須田 健一; 光冨 徹哉

  近畿大学医学雑誌 近畿大学医学会 46 (3-4) 73 - 78 0385-8367 2021/12 

  近年、liquid biopsyのひとつである腫瘍由来血漿中可溶性DNA(circulating tumor DNA:ctDNA)の検出が、進行期肺癌の実臨床でも用いられるようになった。具体的には、EGFR変異検査に用いられるCobas EGFR変異検出キットやMET exon14 skipping変異の検出に用いられるArcher METによる血漿検体の遺伝子解析結果をもってそれぞれの治療薬の投与が可能となっている。さらに本年3月には、包括的ゲノムプロファイリングであるFoundation One Liquidがんゲノムプロファイルも製造販売承認された。しかし、腫瘍量が比較的少ない外科切除を受ける肺がん患者において、ctDNAを含むliquid biopsyが有用であるかについては十分明らかではない。われわれは最近、臨床病期II-IIIA期の肺がん外科切除例を対象に、術前と術後にctDNAを測定するパイロットスタディを実施した。その結果、術前のctDNA陽性は腫瘍径と関連すること、術後のctDNA陽性は分化度と関連すること、再発予測のバイオマーカーとしては、術前のctDNAよりも術後のctDNAのほうが優れていることが示された。本総説ではこのパイロットスタディの結果を紹介すると共に、本領域における現時点でのエビデンスと今後の展望について総括する。(著者抄録)
• In vitro validation study of HER2 and HER4 mutations identified in an ad hoc secondary analysis of the LUX-Lung 8 randomized clinical trial.

  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 2021/12 

  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.
• resectable肺癌に対する分子標的治療 EGFR肺がん外科切除例の特徴と予後 周術期分子標的治療を視野に入れて

  須田 健一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 61 (6) 500 - 500 0386-9628 2021/10
• EGFR遺伝子変異陽性非小細胞肺がんのオシメルチニブ初回治療でのAXL発現の検討 多施設共同前向き観察研究

  吉村 彰紘; 山田 忠明; 大熊 裕介; 渡部 聡; 竹田 隆之; 千原 佑介; 竹本 真之輔; 原田 大司; 平沼 修; 白井 由紀奈; 矢野 聖二; 後藤 康洋; 塩津 伸介; 國政 啓; 上原 久典; 須田 健一; 光冨 徹哉; 釼持 広知; 高橋 利明; 高山 浩一

  肺癌 (NPO)日本肺癌学会 61 (6) 644 - 644 0386-9628 2021/10
• ロボット支援下左上葉切除術における左肺動脈第一分枝(A3)切離のアプローチ法の考察

  宗 淳一; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 須田 健一; 光冨 徹哉

  日本胸部外科学会定期学術集会 (一社)日本胸部外科学会 74回 LOD21 - 4 2021/10
• 病理病期IB-IIA期EGFR変異陽性肺がんに対するUFT術後補助療法の有用性

  須田 健一; 濱田 顕; 小原 秀太; 藤野 智大; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 61 (6) 594 - 594 0386-9628 2021/10
• 原発性肺癌術後早期の再入院リスクの検討

  小原 秀太; 宗 淳一; 須田 健一; 藤野 智大; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 61 (6) 633 - 633 0386-9628 2021/10
• MET exon 14 skipping変異肺癌に対するType I MET-TKI耐性二次的変異とその克服

  藤野 智大; 須田 健一; 小原 秀太; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 61 (6) 645 - 645 0386-9628 2021/10
• ロボット支援下左上葉切除術における左肺動脈第一分枝(A3)切離のアプローチ法の考察

  宗 淳一; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 須田 健一; 光冨 徹哉

  日本胸部外科学会定期学術集会 (一社)日本胸部外科学会 74回 LOD21 - 4 2021/10
• Intra-tumor and inter-tumor heterogeneity in MET exon 14 skipping mutations and co-mutations in pulmonary pleomorphic carcinomas

  Toshio Fujino; Kenichi Suda; Kazuko Sakai; Isao Murakami; Shigeki Shimizu; Shuta Ohara; Takamasa Koga; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi

  Clinical Lung Cancer Elsevier BV 23 (3) e185-e195  1525-7304 2021/09 

  BACKGROUND: MET exon 14 skipping mutation is a driver mutation in lung cancer and is highly enriched in pulmonary pleomorphic carcinomas (PPCs). Whether there is intratumor or intertumor heterogeneity in MET exon 14 skipping status or in co-occurring genetic alterations in lung cancers driven by MET exon 14 skipping is unknown. METHODS: We analyzed tumor specimens obtained from 23 PPC patients (10 autopsied and 13 surgically resected). MET exon 14 skipping was detected by RT-PCR. For patients with MET exon 14 skipping mutation, further analyses were performed. Genomic DNA (gDNA) was extracted from various histological components for each patient who underwent surgical resection (to assess intratumor heterogeneity). In autopsied patients, gDNA and total RNA were extracted from all metastatic lesions (to assess intertumor heterogeneity). RESULTS: MET exon 14 skipping mutation was detected in 4 patients (4/23, 17.4%): two surgically resected and two autopsied patients. We found no intratumor or intertumor heterogeneity in MET exon 14 skipping mutation status in these patients. We observed intratumor and intertumor heterogeneity in the copy number variations and/or mutational status of cancer-related genes; some of these differences may have an impact on MET tyrosine kinase inhibitor (TKI) efficacy. CONCLUSION: In our exploratory analysis of four cases, we observed that MET exon 14 skipping mutations are distributed homogeneously throughout histological components and between metastatic lesions. Our results also suggest that there is marked intertumor and intratumor heterogeneity in co-occurring genetic alterations, and therapeutic implications of such heterogeneity should be evaluated in future studies.
• 【がん治療のリアル】がん治療 医師の立場から

  小原 秀太; 須田 健一; 光冨 徹哉

  理学療法ジャーナル (株)医学書院 55 (8) 834 - 839 0915-0552 2021/08 

  ＜文献概要＞Point ●治療法を選択するうえで「がんのステージ分類」と「年齢を含む患者の全身状態」が重要である●エビデンスが不十分かつ治療選択肢が2つ以上ある場合には,「shared decision making」という考え方が必要である●がん患者の多様な要望に対してそれぞれの専門を生かしたチームアプローチが重要である
• Activity and mechanism of acquired resistance to tarloxotinib in HER2 mutant lung cancer: an in vitro study.

  Takamasa Koga; Kenichi Suda; Masaya Nishino; Toshio Fujino; Shuta Ohara; Akira Hamada; Junichi Soh; Vijaya Tirunagaru; Avanish Vellanki; Robert C Doebele; Tetsuya Mitsudomi

  Translational lung cancer research 10 (8) 3659 - 3670 2021/08 

  BACKGROUND: HER2 (ERBB2) activating mutations are present in 2-3% of lung adenocarcinomas; however, no targeted therapy is approved for HER2-altered lung cancers. A novel pan-HER inhibitor, tarloxotinib, is designed to release the active form (tarloxotinib-E) under hypoxic conditions in tumor tissues after being administered as a prodrug. Following the evaluation of the in vitro activity of tarloxotinib-E in HER2-mutant cells, we explored the mechanisms of resistance to tarloxotinib-E in these cells. METHODS: Growth inhibitory assays were performed with tarloxotinib-E and its prodrug using Ba/F3 cells expressing one of six HER2 mutations or wild-type (WT) HER2, in addition to H1781 cells with HER2 exon 20 insertions. Resistant clones were established from N-ethyl-N-nitrosourea (ENU)-treated HER2-mutant Ba/F3 cells and H1781 cells by chronic exposure to tarloxotinib-E. RESULTS: Tarloxotinib-E showed potent activity against HER2-mutant Ba/F3 cells and H1781 cells. Furthermore, the half maximal inhibitory concentration (IC50) of tarloxotinib (inactive form) for WT HER2 was 180 times higher than that of tarloxotinib-E, indicating a wide therapeutic window of tarloxotinib. We established 30 resistant clones with secondary mutations of HER2 by ENU mutagenesis, all of which harbored C805S in exon 20. In the analysis of H1781 cells that acquired resistance to tarloxotinib-E, we found that increased HER3 expression was the molecular mechanism of tarloxotinib-E resistance. CONCLUSIONS: Tarloxotinib-E exhibited potent activity against cell line models with HER2 mutations. We identified a secondary C805S HER2 mutation and HER3 overexpression as the mechanisms of acquired resistance to tarloxotinib-E.
• KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments.

  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 2021/08 

  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.
• Drug Tolerance to EGFR Tyrosine Kinase Inhibitors in Lung Cancers with EGFR Mutations.

  Kenichi Suda; Tetsuya Mitsudomi

  Cells 10 (7) 2021/06 

  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) serve as the standard of care for the first-line treatment of patients with lung cancers with EGFR-activating mutations. However, the acquisition of resistance to EGFR TKIs is almost inevitable, with extremely rare exceptions, and drug-tolerant cells (DTCs) that demonstrate reversible drug insensitivity and that survive the early phase of TKI exposure are hypothesized to be an important source of cancer cells that eventually acquire irreversible resistance. Numerous studies on the molecular mechanisms of drug tolerance of EGFR-mutated lung cancers employ lung cancer cell lines as models. Here, we reviewed these studies to generally describe the features, potential origins, and candidate molecular mechanisms of DTCs. The rapid development of an optimal treatment for EGFR-mutated lung cancer will require a better understanding of the underlying molecular mechanisms of the drug insensitivity of DTCs.
• 胸腔原発巨大Ewing肉腫の1切除例

  岡内 義隆; 須田 健一; 宗 淳一; 西野 将矢; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉; 田中 薫; 中川 和彦

  肺癌 (NPO)日本肺癌学会 61 (3) 238 - 238 0386-9628 2021/06
• Uniportal VATSにおけるエンブロックな縦隔リンパ節郭清

  千葉 眞人; 宗 淳一; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 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 (NPO)日本呼吸器外科学会 35 (3) RV9 - 1 0919-0945 2021/05
• 【撤回論文】肺葉切除における単孔式手術とロボット支援下手術の利点・欠点を踏まえたベストマッチアプローチ法の検討

  宗 淳一; 千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 西野 将矢; 下治 正樹; 須田 健一; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 35 (3) O19 - 6 0919-0945 2021/05 

  【撤回論文】---当論文については「日本呼吸器外科学会雑誌」35巻3号(2021年発行)の巻末に演題取り下げのお知らせが掲載された。
• 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 (NPO)日本呼吸器外科学会 35 (3) V11 - 7 0919-0945 2021/05
• 胸腺腫瘍切除例におけるCT値とWHO分類の関連

  下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 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 (NPO)日本呼吸器外科学会 35 (3) MO6 - 5 0919-0945 2021/05
• 高齢者肺癌葉切除における縦隔リンパ節郭清の意義

  西野 将矢; 宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 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 (NPO)日本呼吸器外科学会 35 (3) MO70 - 1 0919-0945 2021/05
• 左B1+2分岐異常領域に発生した小型肺癌の1切除例

  藤野 智大; 須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 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 (NPO)日本呼吸器外科学会 35 (3) MO90 - 3 0919-0945 2021/05
• 「pN陽性」非小細胞肺がんにおけるすりガラス成分の有無の予後因子としての意義

  須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 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 (NPO)日本呼吸器外科学会 35 (3) MO99 - 5 0919-0945 2021/05
• Activity of tarloxotinib-E in cells with EGFR exon-20 insertion mutations and mechanisms of acquired resistance.

  Masaya Nishino; Kenichi Suda; Takamasa Koga; Shuta Ohara; Toshio Fujino; Junichi Soh; Vijaya Tirunagaru; Avanish Vellanki; Robert C Doebele; Tetsuya Mitsudomi

  Thoracic cancer 12 (10) 1511 - 1516 2021/05 

  BACKGROUND: Approximately 10% of non-small cell lung cancers (NSCLCs) that harbor epidermal growth factor receptor (EGFR) gene mutations have in-frame insertions in exon 20 of the EGFR gene. These tumors do not usually respond to currently available EGFR-tyrosine kinase inhibitors (TKIs). Tarloxotinib is a novel hypoxia-activated prodrug that releases a potent, irreversible pan-ERBB TKI (tarloxotinib-E) under solid tumor hypoxia. METHODS: We examined the efficacy of tarloxotinib-E against several types of Ba/F3 cells with introduced EGFR exon 20 mutations (EGFR A763insFQEA, V769insASV, D770insSVD, H773insH and H773insNPH mutations). We assayed growth inhibition for tarloxotinib (prodrug), tarloxotinib-E (active form), poziotinib, afatinib, and osimertinib in Ba/F3 cells with each EGFR exon 20 mutation. We also explored acquired resistance mechanisms to tarloxotinib-E by establishing cells with resistance to tarloxotinib-E via chronic drug exposure after N-ethyl-N-nitrosourea mutagenesis treatment. RESULTS: Among all tested Ba/F3 cell lines, IC50 was ≥72.1 times higher for tarloxotinib than for tarloxotinib-E, which implies a wide therapeutic window with this prodrug strategy. Tarloxotinib-E was efficacious against all tested Ba/F3 cells except for H773insH, which was less sensitive to all tested EGFR-TKIs. As acquired resistance mechanisms to tarloxotinib-E, we identified either T790M or C797S secondary mutations, depending on the original EGFR exon 20 mutation. CONCLUSIONS: These findings indicate that tarloxotinib-E could be effective for NSCLC with EGFR exon 20 mutations. Our results also show that T790M or C797S mutations can confer acquired resistance to tarloxotinib-E; and suggest that resistance mechanisms are influenced by the baseline EGFR exon 20 mutations.
• 外科における多施設臨床試験の意義と方向性 肺癌における医師主導治験の経験

  濱田 顕; 宗 淳一; 小原 秀太; 藤野 智大; 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

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 121回 NES - 1 2021/04
• 肺癌根治術におけるアプローチ法の優劣:特にリンパ節郭清について-RATS、multiple port VATS、single port VATS- 当院におけるUniportal VATSリンパ節郭清の工夫

  千葉 眞人; 中野 大哉; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 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 (一社)日本外科学会 121回 DB - 2 2021/04
• ヒト胸郭モデルと豚心肺モデルを用いたハンズオンによる手技の教育と修練システムの構築

  武本 智樹; 櫻井 真倫; 神波 奈央子; 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

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 121回 SF - 1 2021/04
• ロボット支援下肺葉切除術時の胸壁損傷を考察する

  宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 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 (一社)日本外科学会 121回 SF - 5 2021/04
• 胸腺上皮性腫瘍切除例におけるFDG-PETのSUVmax値と病理学的所見の関連

  下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 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 (一社)日本外科学会 121回 PS - 4 2021/04
• EGFR野生型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の検討

  小原 秀太; 須田 健一; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 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 (一社)日本外科学会 121回 PS - 6 2021/04
• 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 (一社)日本外科学会 121回 RS - 3 2021/04
• 右肺S3区域切除後の残存上葉に高度鬱血をきたしたが、保存的加療で軽快した1切除例

  櫻井 真倫; 武本 智樹; 神波 奈央子; 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

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 121回 RS - 9 2021/04
• MET exon14 skipping変異陽性肺多形癌におけるintra-およびinter-tumor heterogeneityの検討

  藤野 智大; 須田 健一; 坂井 和子; 清水 重喜; 小原 秀太; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 西尾 和人

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 121回 SF - 4 2021/04
• MET exon14 skipping変異陽性肺多形癌におけるintra-およびinter-tumor heterogeneityの検討

  藤野 智大; 須田 健一; 坂井 和子; 清水 重喜; 小原 秀太; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 下治 正樹; 武本 智樹; 宗 淳一; 西尾 和人

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 121回 SF - 4 2021/04
• Dose-dependence in acquisition of drug tolerant phenotype and high RYK expression as a mechanism of osimertinib tolerance in lung cancer.

  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 2021/04 

  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.
• Metastatic pulmonary tumor from type 3 gastric neuroendocrine tumor

  Shuta Ohara; Atsushi Yasuda; Shigeki Shimizu; Kenichi Suda; Tetsuya Mitsudomi

  Human Pathology: Case Reports Elsevier BV 23 200481 - 200481 2214-3300 2021/03
• Inter- and Intratumor Heterogeneity of EGFR Compound Mutations in Non-Small Cell Lung Cancers: Analysis of Five Cases.

  Kenichi Suda; Kazuko Sakai; Keiko Obata; Shuta Ohara; Toshio Fujino; Takamasa Koga; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi

  Clinical lung cancer 22 (2) e141-e145  2021/03 

  BACKGROUND: Several clinical and preclinical studies suggest that non-small cell lung cancers (NSCLCs) with EGFR compound mutations were associated with lower efficacies of first-generation EGFR inhibitors than tumors with single EGFR mutation. Some researchers hypothesize that EGFR mutation status is heterogeneous in such tumors and that second-generation EGFR inhibitors may eliminate cancer cells with uncommon EGFR mutations from tumors with EGFR compound mutations. However, this hypothesis is currently unproven; therefore, we performed the current study to determine if tumor cells with EGFR compound mutations are present in heterogeneous or homogeneous manners. PATIENTS AND METHODS: Multiregion analysis was performed for surgically resected primary NSCLC tumors with EGFR compound mutations to examine the intratumor heterogeneity of EGFR compound mutations. In addition, we evaluated the intertumor heterogeneity of EGFR compound mutations using 2 pleural disseminations obtained from a patient with NSCLC at exploratory thoracotomy and 9 primary or metastatic lesions obtained from 2 autopsied NSCLC patients. Digital polymerase chain reaction, target sequencing, or direct sequencing were used to detect EGFR mutations. RESULTS: This study included 5 NSCLC cases; their compound mutations were L858R+S768I, G719X+S768I, G719A+R776H, L858R+E709G, and L858R+I759M. Noncancerous pulmonary tissues from each patient did not harbor EGFR mutations, which revealed that all mutations were somatic. We did not detect any intra- or intertumor heterogeneity in these EGFR compound mutations. CONCLUSION: No intra- or intertumor heterogeneity was observed for EGFR compound mutations. Our results indicate that both EGFR mutations were truncal and selective elimination of cancer cells with uncommon EGFR mutations is unrealistic.
• Recent Advances in Cancer Immunotherapy.

  Kenichi Suda

  Biomolecules 11 (2) 2021/02 

  The strategy to use the immune system to fight cancer is not a novel concept; in 1891, Coley reported the treatment of three cases of sarcoma by inoculation with erysipelas [...].
• The prevalence and risk factors associated with preoperative deep venous thrombosis in lung cancer surgery.

  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 2021/02 

  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.
• Cell Line Models for Acquired Resistance to First-Line Osimertinib in Lung Cancers-Applications and Limitations.

  Shuta Ohara; Kenichi Suda; Tetsuya Mitsudomi

  Cells 10 (2) 2021/02 

  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are first-line drugs for lung cancers with activating EGFR mutations. Although first- and second-generation EGFR-TKIs were standard first-line treatments, acquired resistance (AR) to these drugs is almost inevitable. Cell line models have been widely used to explore the molecular mechanisms of AR to first- and second-generation EGFR-TKIs. Many research groups, including ours, have established AR cell lines that harbor the EGFR T790M secondary mutation, MET gene amplification, or epithelial-mesenchymal transition (EMT) features, which are all found in clinical specimens obtained from TKI-refractory lesions. Currently, many oncologists prescribe osimertinib, a third-generation EGFR-TKI that can overcome T790M-mediated resistance, as a first-line TKI. Although few clinical data are available about AR mechanisms that arise when osimertinib is used as a first-line therapy, many research groups have established cell lines with AR to osimertinib and have reported on their AR mechanisms. In this review, we summarize the findings on AR mechanisms against first-line osimertinib obtained from analyses of cell line models.
• Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges.

  Toshio Fujino; Kenichi Suda; Tetsuya Mitsudomi

  Lung Cancer (Auckland, N.Z.) 12 35 - 50 2021 

  MET exon 14 skipping mutation (MET∆ex14) is present about 3% of non-small cell lung cancers (NSCLCs). NSCLC patients with MET∆ex14 are characterized by an average age of over 70 years at diagnosis, a smoking history and a higher frequency in pleomorphic carcinoma and adenosquamous cell carcinoma than in adenocarcinoma. It has also been reported that NSCLCs with MET∆ex14 often have codriver alterations such as EGFR amplification (6-28%), FGFR1 alterations (5-17%), KRAS alterations (~8%), BRAF alterations (~21%), or PIK3CA mutation/amplification (~14%). In 2020, the approval of two MET-tyrosine kinase inhibitors (TKIs), capmatinib and tepotinib, for NSCLCs carrying MET∆ex14 dawned a new era for MET-targeted therapy. These drugs yielded progression-free survival of 5.4-12.4 months in clinical trials; however, it has also been reported that one-third to half of patients show inherent resistance to MET-TKIs. In addition, the emergence of acquired resistance to MET-TKIs is inevitable. In this review, we summarize the clinical and molecular characteristics of NSCLCs with MET∆ex14, the efficacy and safety of capmatinib and tepotinib, the inherent and acquired resistance mechanisms to MET-TKIs, and new treatment strategies for NSCLCs with MET∆ex14 in the near future.
• Clinical Impacts of EGFR Mutation Status: Analysis of 5780 Surgically Resected Lung Cancer Cases.

  Kenichi Suda; Tetsuya Mitsudomi; Yasushi Shintani; Jiro Okami; Hiroyuki Ito; Takashi Ohtsuka; Shinichi Toyooka; Takeshi Mori; Shun-Ichi Watanabe; Hisao Asamura; Masayuki Chida; Hiroshi Date; Shunsuke Endo; Takeshi Nagayasu; Ryoichi Nakanishi; Etsuo Miyaoka; Meinoshin Okumura; Ichiro Yoshino

  The Annals of thoracic surgery 111 (1) 269 - 276 2021/01 [Refereed]
   

  BACKGROUND: To elucidate the clinical, pathologic, and prognostic impacts of epidermal growth factor receptor (EGFR) mutation and mutation subtypes in early-stage lung cancer, the study investigators conducted a retrospective analysis of the Japanese Joint Committee of Lung Cancer Registry database (a nationwide database for patients with surgically resected lung cancer; n = 18,973). METHODS: Of 13,951 patients classified as having nonsquamous non-small cell lung cancer in the database, 5780 patients (41.0%) had been tested for an EGFR mutation and were included in this study. RESULTS: An EGFR mutation was detected in 2410 patients (41.7%), and the presence of an EGFR mutation was significantly correlated with clinicopathologic factors such as the presence of ground-glass opacity (P < .001) and better prognosis. Analysis of initial recurrence sites identified significantly higher frequencies of brain and adrenal gland metastases in patients with and without an EGFR mutation, respectively. Of 2410 patients with EGFR mutations, 983 (40.8%) had an exon 19 deletion (Exon 19 Del), 1170 (48.5%) had an L858R mutation, and 257 (10.7%) had other EGFR mutations. A higher smoking rate was found in patients with other EGFR mutations (P = .02). In the comparison of Exon 19 Del and L858R, we found that Exon 19 Del correlated with younger age (P < .001), a higher rate of pure solid tumors (P < .001), advanced pathologic stage (trend P < .001), and poorer recurrence-free survival (P = .001). CONCLUSIONS: In addition to the clinicopathologic and prognostic impacts of EGFR mutation status, tumors with Exon 19 Del have a more aggressive phenotype and patients have a poorer prognosis than with L858R in early-stage lung cancers.
• 早期肺癌治療へのliquid biopsyの応用

  須田 健一

  上原記念生命科学財団研究報告集 (公財)上原記念生命科学財団 34 1 - 4 2020/12
• Emerging oncogenic fusions other than ALK, ROS1, RET, and NTRK in NSCLC and the role of fusions as resistance mechanisms to targeted therapy.

  Kenichi Suda; Tetsuya Mitsudomi

  Translational lung cancer research 9 (6) 2618 - 2628 2020/12 

  Recent evidence has shown that gene fusions caused by chromosomal rearrangements are frequent events in the initiation and during progression of solid tumors, including non-small cell lung cancers (NSCLCs). Since the discoveries of ALK and ROS1 fusions in 2007 and the subsequent successes of pharmacological targeting for these fusions, numerous efforts have identified additional oncogenic driver fusions in NSCLCs, especially in lung adenocarcinomas. In this review, we will summarize recent advances in this field focusing on novel oncogenic fusions other than ALK, ROS1, NTRK, and RET fusions, which are summarized in other articles in this thematic issue. These novel gene fusions include neuregulin-1 (NRG1) fusions, MET fusions, fusion genes involving fibroblast growth factor receptor (FGFR) family members, EGFR fusions, and other rare fusions. In addition, evidence has suggested that acquisition of gene fusions by cancer cells can be a molecular mechanism of acquired resistance to targeted therapies. Most of the current data are from analyses of resistance mechanisms to EGFR tyrosine kinase inhibitors in lung cancers with oncogenic EGFR mutations. However, a few recent studies suggest that gene fusions can also be a resistance mechanism to ALK-tyrosine kinase inhibitors in lung cancers with oncogenic ALK fusions. Detection, validation, and pharmacological inhibition of these fusion genes are becoming more important in the treatment of NSCLC patients.
• Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity.

  Won-Chul Lee; Alexandre Reuben; Xin Hu; Nicholas McGranahan; Runzhe Chen; Ali Jalali; Marcelo V Negrao; Shawna M Hubert; Chad Tang; Chia-Chin Wu; Anthony San Lucas; Whijae Roh; Kenichi Suda; Jihye Kim; Aik-Choon Tan; David H Peng; Wei Lu; Ximing Tang; Chi-Wan Chow; Junya Fujimoto; Carmen Behrens; Neda Kalhor; Kazutaka Fukumura; Marcus Coyle; Rebecca Thornton; Curtis Gumbs; Jun Li; Chang-Jiun Wu; Latasha Little; Emily Roarty; Xingzhi Song; J Jack Lee; Erik P Sulman; Ganesh Rao; Stephen Swisher; Lixia Diao; Jing Wang; John V Heymach; Jason T Huse; Paul Scheet; Ignacio I Wistuba; Don L Gibbons; P Andrew Futreal; Jianhua Zhang; Daniel Gomez; Jianjun Zhang

  Genome biology 21 (1) 271 - 271 2020/11 

  BACKGROUND: Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. RESULTS: We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. CONCLUSIONS: Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
• Prognostic value of plasma fibrinogen and D-dimer levels in patients with surgically resected non-small cell lung cancer.

  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 2020/11 [Refereed]
   

  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.
• 肺葉切除における単孔式手術とロボット支援下手術の特性と注意点 両術式の導入経験から

  宗 淳一; 千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 濱田 顯; 古賀 教将; 西野 将矢; 下治 正樹; 須田 健一; 光冨 徹哉

  日本胸部外科学会定期学術集会 (一社)日本胸部外科学会 73回 LRS1 - 10 2020/10
• LUX-Lung 8試験で検出されたHER2変異を有する肺扁平上皮癌におけるアファチニブの有効性に関する検証研究

  濱田 顕; 須田 健一; 藤野 智大; 宗 淳一; 光冨 徹哉

  日本癌学会総会記事 (一社)日本癌学会 79回 PJ14 - 7 0546-0476 2020/10
• EGFR変異肺がんにおけるEGFRチロシンキナーゼ阻害剤耐性克服を目指したトランスレーショナルリサーチ

  須田 健一; 光冨 徹哉

  日本癌学会総会記事 (一社)日本癌学会 79回 YIA - 10 0546-0476 2020/10
• KRAS G12C阻害剤の感受性ならびに耐性二次変異の検索

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 宗 淳一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 60 (6) 533 - 533 0386-9628 2020/10
• 臨床病期I期肺扁平上皮癌における画像的特徴と治療成績の検討

  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 (NPO)日本肺癌学会 60 (6) 611 - 611 0386-9628 2020/10
• 第1/2世代EGFRキナーゼ阻害剤に対する獲得耐性機序のinter-tumor heterogeneityとその臨床的意義

  須田 健一; 村上 功; 小畑 慶子; 藤野 智大; 坂井 和子; 宗 淳一; 西尾 和人; 光冨 徹哉

  日本癌学会総会記事 (一社)日本癌学会 79回 OE14 - 4 0546-0476 2020/10
• Prognostic implications of preoperative versus postoperative circulating tumor DNA in surgically resected lung cancer patients: a pilot study.

  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 2020/10 

  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).
• Spatial heterogeneity of acquired resistance mechanisms to 1st/2nd generation EGFR tyrosine kinase inhibitors in lung cancer.

  Kenichi Suda; Isao Murakami; Keiko Obata; Kazuko Sakai; Toshio Fujino; Takamasa Koga; Shuta Ohara; Akira Hamada; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 148 100 - 104 2020/10 [Refereed]
   

  BACKGROUND: Overcoming acquired resistance against targeted therapies to improve outcomes of lung cancer patients harboring driver mutations is a critical issue. While drug therapy oriented to a resistance mechanism appears attractive, spatial heterogeneity of resistance mechanisms in each patient will diminish treatment efficacy. However, the frequency, clinical backgrounds, clinical implications, and patterns of spatial heterogeneity in resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs) are largely unknown. PATIENTS AND METHODS: This study included 128 specimens from 24 autopsied patients with lung adenocarcinoma harboring EGFR mutation. Acquired resistance mechanisms reported as relatively frequent in lung cancer, e.g., T790 M and other secondary EGFR mutations, MET and ERBB2 gene amplification, and histological transformation, were retrospectively examined. All patients had received 1st/2nd generation EGFR-TKI and showed acquired resistance to the drug before death. No patient received osimertinib. RESULTS: No resistance mechanism was identified in two patients. T790M mutation was detected in 20 patients (83 %); however, nine of these patients also had lesions without T790M mutation. Among 22 patients whose resistance mechanisms were identified, ten had spatial heterogeneity of resistance mechanisms (45 %), and these patients had significantly shorter time-to-treatment failure compared with those without heterogeneity (median 4.7 months vs. 14.7 months, p = 0.0004). CONCLUSION: We observed significant spatial heterogeneity of acquired resistance mechanisms to EGFR-TKIs in lung adenocarcinoma. Our results also indicate that the incidence of resistance mechanisms may vary based on the biopsied tumor locations.
• Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution.

  David Dora; Christopher Rivard; Hui Yu; Paul Bunn; Kenichi Suda; Shengxiang Ren; Shivaun Lueke Pickard; Viktoria Laszlo; Tunde Harko; Zsolt Megyesfalvi; Judit Moldvay; Fred R Hirsch; Balazs Dome; Zoltan Lohinai

  Molecular oncology 14 (9) 1947 - 1965 2020/09 [Refereed]
   

  Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)-high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3-dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T-cell infiltration (P = 0.003) in NE-low vs NE-high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE-low primary tumors (vs NE-high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE-low (vs NE-high, P = 0.004) tumors. TIM3 expression was significantly increased in NE-low (vs NE-high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE-low SCLCs are associated with increased immune cell infiltration compared to NE-high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies.
• Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer.

  Toshio Fujino; Kenichi Suda; Tetsuya Mitsudomi

  Expert opinion on emerging drugs 25 (3) 229 - 249 2020/09 [Refereed]
   

  Introduction MET aberrations, including MET exon 14 skipping mutation and amplification, are present in ~5% of non-small cell lung cancer (NSCLC) cases, and these levels are comparable to the frequency of ALK fusion. MET amplification also occurs as an acquired resistance mechanism in EGFR-mutated NSCLC after EGFR tyrosine kinase inhibitors (TKI) treatment failure. Therefore, the development of therapies for activated MET is urgently needed. Areas covered This review summarizes (1) the mechanisms and frequencies of MET aberrations in NSCLC, (2) the efficacies and toxicities of MET-TKIs under clinical development and (3) the mechanisms of inherent and acquired resistance to MET-TKIs. Expert opinion Type Ia, Ib and II MET-TKIs are currently under clinical development, and phase I/II studies have shown the potent activities of tepotinib, capmatinib and savolitinib; in fact, tepotinib and capmatinib were approved for use by health authorities. However, inherent and acquired resistance through on- and off-target mechanisms has been detected, and strategies to overcome this resistance are being developed.
• 新規低侵襲(単孔式・ロボット支援)手術におけるヒヤリハット Uniportal VATSにおけるヒヤリハット 逸脱例からの考察

  千葉 眞人; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 34 (3) VWS2 - 2 0919-0945 2020/08
• ロボット支援下肺葉切除術導入時のヒヤリハットを考察する 胸壁損傷とその対策

  宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顯; 千葉 眞人; 須田 健一; 武本 智樹; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 34 (3) V1 - 4 0919-0945 2020/08
• 80代IA期非小細胞肺癌の手術成績 GGO成分の有無別の検討

  濱田 顕; 須田 健一; 西野 将矢; 千葉 眞人; 武本 智樹; 宗 淳一; 塩野 知志; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 34 (3) O35 - 1 0919-0945 2020/08
• 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 (NPO)日本呼吸器外科学会 34 (3) O39 - 4 0919-0945 2020/08
• 切除肺に10個以上の病変を認めた多発肺腺癌の3例

  古賀 教将; 須田 健一; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 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 (NPO)日本呼吸器外科学会 34 (3) MO10 - 6 0919-0945 2020/08
• 異所性子宮内膜症由来が疑われた横隔膜明細胞癌の1切除例

  波江野 真大; 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; 太田 真見子; 前西 修; 宗 淳一; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 34 (3) MO29 - 1 0919-0945 2020/08
• 非小細胞肺癌における術前NLR高値は、腫瘍のPD-L1発現と関連する

  藤野 智大; 須田 健一; 下治 正樹; 濱田 顕; 小原 秀太; 古賀 教将; 西野 将矢; 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 (NPO)日本呼吸器外科学会 34 (3) MO36 - 5 0919-0945 2020/08
• 掻把術にて根治できなかった難治性術後膿胸に対するクリスタルバイオレットを用いた胸腔内洗浄の有用性

  須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 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 (NPO)日本呼吸器外科学会 34 (3) MO59 - 1 0919-0945 2020/08
• 【進行期肺癌治癒への道-がんゲノム医療と免疫プレシジョン医療の接点】分子標的治療薬最前線 肺癌診療にゲノム診断をどう生かすのか?

  藤野 智大; 須田 健一; 光冨 徹哉

  呼吸器ジャーナル (株)医学書院 68 (3) 346 - 353 2432-3268 2020/08 

  ＜文献概要＞Point ・非小細胞肺癌の薬物療法においては,コンパニオン診断(CDx)でドライバー遺伝子変異を検出することが治療方針の決定に必須である.・2019年より,CDxにNGSを用いた遺伝子パネル検査が利用できるようになり,検査の効率化が期待されるが,サンプルの質,量には十分配慮が必要である.・CDxと治療薬の厳格すぎる紐付けによって不合理な混乱と治療機会の逸失がもたらされており,早期解決が望まれる.・将来は,より多くのゲノム情報を用いることでさらなる個別化による治療成績改善が期待される.
• Personalized post-surgical care?-possible strategies for NSCLCs with EGFR mutation.

  Kenichi Suda

  Translational lung cancer research 9 (3) 441 - 445 2020/06 [Refereed]
  
• Inter-tumor heterogeneity of PD-L1 status: is it important in clinical decision making?

  Kenichi Suda; Tetsuya Mitsudomi

  Journal of thoracic disease 12 (5) 1770 - 1775 2020/05 [Refereed]
  
• 胸腺カルチノイドを契機として発見された多発性内分泌腫瘍(MEN)1型の1症例

  松本 正孝; 武本 智樹; 小原 秀太; 須田 健一; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 34 (2) 121 - 125 0919-0945 2020/03 

  症例は38歳男性。近医にて前縦隔腫瘍を指摘され当科紹介となった。CTで境界明瞭な4×3.5×3cmの充実性腫瘍を前縦隔に認め、PETでは同部位にSUVmax 7.04の異常集積を認めた。またPET検査において、膵鉤部にもSUVmax 3.65のFDG異常集積を認めた。高Ca血症とCTで副甲状腺腺腫が疑われること、父がMEN1型であることからMEN1型に合併した胸腺カルチノイドと診断し、胸腺全摘術を施行した。病理診断は腫瘍部位に卵円形核を持つ多角形細胞が増生し、ロゼット構造が散見、免疫染色では神経内分泌マーカーが陽性であった。核分裂像は8個/10HPFであり非定型的カルチノイドと診断された。MEN1型は胸腺カルチノイドの25%に合併するとされ、特に非定型的カルチノイドは予後不良とされている。(著者抄録)
• Targeting the reversible drug-tolerant state: aurora kinase A, is that the final answer?

  Kenichi Suda

  TRANSLATIONAL CANCER RESEARCH AME PUBL CO 8 S564 - S568 2218-676X 2019/12
• Comparative expression analysis in small cell lung carcinoma reveals neuroendocrine pattern change in primary tumor versus lymph node metastases.

  Zoltan Lohinai; Zsolt Megyesfalvi; Kenichi Suda; Tunde Harko; Shengxiang Ren; Judit Moldvay; Viktoria Laszlo; Christopher Rivard; Balazs Dome; Fred R Hirsch

  Translational lung cancer research 8 (6) 938 - 950 2019/12 [Refereed]
   

  Background: Recent preclinical data suggest that neuroendocrine (NE) subtype of small cell lung cancer (SCLC) has strong therapeutic relevance. NE high tumors are associated with immune desert and NE low tumors are considered to have an immune oasis phenotype. Our aim was to investigate the NE phenotypes of surgically resected SCLC tumors according to inter-tumor heterogeneity. Methods: Expression analysis for 2,560 genes was performed in 32 surgically resected SCLC patients' primary tumors and corresponding lymph node (LN) metastases. To analyze tumor heterogeneity, we examined the differences in the gene expression of primary tumors versus LN metastases. We performed cluster analysis and heat map to divide patients into NE high and low subtypes by using the top NE-associated genes described in preclinical studies. Results: We found 6% (n=154) genes with significant differences and only 13.1% (n=336) of all genes in the panel had a strong correlation between the primary tumor and LN metastases. Cluster analysis clearly distinguished SCLC NE high versus low subtypes both in primary tumor (20 vs. 12, respectively) and LNs (23 vs. 9, respectively). As for inter-tumor heterogeneity, in case of five patients, a change in the NE pattern was observed. Specifically, we found significant downregulation of the NE-associated genes CAV1 (P=0.004), CAV2 (P=0.029) and ANXA3 (P=0.035) in their LN metastases compared to their primary tumor. Conclusions: Our data confirm the results of preclinical studies and clearly distinguish NE low and high differentiation clusters in SCLC. Moreover, they highlight the gene expression discordance between primary tumors and corresponding LN metastases suggesting that the NE pattern of metastatic LNs might not reflect that of the primary tumor. Altogether, by shedding light on the diversity of SCLC, the current study might help to improve patient selection and treatment in this devastating disease. Keywords: Small cell lung cancer (SCLC); neuroendocrine tumor; lymph node metastasis; tumor heterogeneity; RNA sequencing.
• For a better adjuvant strategy for resected lung cancer-lessons from treatment failure patterns of the ADJUVANT trial (CTONG 1104).

  Kenichi Suda

  Translational lung cancer research 8 (Suppl 4) S395-S399  2019/12 [Refereed]
  
• Sensitivity and Resistance of MET Exon 14 Mutations in Lung Cancer to Eight MET Tyrosine Kinase Inhibitors In Vitro.

  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 2019/10 [Refereed]
   

  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.
• Comparison of PD-L1 Expression Status between Pure-Solid Versus Part-Solid Lung Adenocarcinomas.

  Kenichi Suda; Masaki Shimoji; Shigeki Shimizu; Katsuaki Sato; Masato Chiba; Kenji Tomizawa; Toshiki Takemoto; Junichi Soh; Tetsuya Mitsudomi

  Biomolecules 9 (9) 2019/09 [Refereed]
   

  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.
• NAB2-STAT6融合遺伝子を確認できた肺実質内発生孤立性線維性腫瘍の1切除例

  下治 正樹; 須田 健一; 富沢 健二; 武本 智樹; 谷田部 恭; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 33 (6) 613 - 618 0919-0945 2019/09 

  孤立性線維性腫瘍(solitary fibrous tumor、SFT)は主に胸膜に発生し、NAB2-STAT6融合遺伝子がそのdriver変異として報告されている。肺実質内発生は稀であるが、今回我々はその1切除例を経験し、NAB2-STAT6融合遺伝子を同定できたため報告する。症例は73歳、男性。近医で胸部腫瘤陰影の増大を認め、当科紹介となった。胸部CTでは右肺S8に境界明瞭な腫瘍があり、FDG-PETでは同部位にSUVmax2.59の軽度のFDG集積を認めた。気管支鏡下生検では確定診断に至らず、診断・治療を兼ねて右肺下葉切除術を施行した。病理組織学的所見では、短紡錘状の核を有する細胞が束状・渦状に密な増生を示し、免疫組織化学染色ではCD34、CD99、bcl-2、STAT6陽性でありSFTと診断した。腫瘍よりRNAを抽出しRT-PCRを施行、NAB2-STAT6融合を確認した。(著者抄録)
• Primary pulmonary mucosa-associated lymphoid tissue lymphoma with amyloid light chain-type amyloidosis.

  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 2019/06 [Refereed]
   

  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.
• Early-Stage NSCLC: Advances in Thoracic Oncology 2018.

  Raymond U Osarogiagbon; Giulia Veronesi; Wentao Fang; Simon Ekman; Kenichi Suda; Joachim G Aerts; Jessica Donington

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 (6) 968 - 978 2019/06 [Refereed]
   

  2018 was a banner year for all thoracic oncology, but especially for early-stage NSCLC. Three seminal events occurred in the approximately 18 months from mid-2017 to the end of 2018: in June 2017 at the American Society of Clinical Oncology Annual Meeting a small, relatively unheralded study from Max Diehn's group at Stanford University reported on the use of a novel "cancer personalized profiling by deep sequencing" circulating tumor-DNA technology to identify minimal residual disease in patients after curative-intent radiation or surgery for NSCLC; in April 2018 at the American Association for Cancer Research Annual Meeting, Drew Pardoll presented a small pilot study of 21 patients who had received two doses of preoperative nivolumab; in September 2018, at the 19th World Conference on Lung Cancer, Harry J. De Koning presented the long-awaited results of the Dutch-Belgian Lung Cancer Screening Trial (NELSON). These three seminal studies, along with others which are reviewed in this paper, promise to accelerate our progress towards a world in which lung cancer is identified early, more patients undergo curative-intent treatment that achieves the promised cure, and those at risk for failure after treatment are identified early, when the cancer remains most vulnerable. The day is around the corner when lung cancer is defanged and no longer the worldwide terror it currently is. We herein present an overview of the most recent body of work that moves us inexorably towards that day.
• Life-threatening complications after pulmonary resection for lung cancer in patients on chronic hemodialysis.

  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 0941-1291 2019/06 [Refereed]
   

  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.
• 【肺がん・頭頸部がん】第3世代EGFR阻害薬の耐性機構とその克服

  西野 将矢; 須田 健一; 光冨 徹哉

  腫瘍内科 (有)科学評論社 23 (5) 449 - 455 1881-6568 2019/05
• The ABCs of preventing hyperprogressive disease after immunotherapy: awareness, biomarkers, and combination.

  Kenichi Suda

  Journal of thoracic disease 11 (Suppl 3) S347-S351  2019/03 [Refereed]
  
• 術前COPD患者に対して運動療法と吸気筋トレーニングの併用により横隔膜動態、肺機能、運動耐容能の改善を認めた1症例

  水澤 裕貴; 白石 匡; 藤田 修平; 杉谷 竜司; 釜田 千聡; 須田 健一; 武本 智樹; 木村 保; 光冨 徹哉; 福田 寛二

  近畿理学療法学術大会 (公社)日本理学療法士協会-近畿ブロック 58回 5 - 5 1881-6975 2019/01
• EGFR-directed monoclonal antibodies in combination with chemotherapy for treatment of non-small-cell lung cancer: an updated review of clinical trials and new perspectives in biomarkers analysis.

  Francesco Agustoni; Kenichi Suda; Hui Yu; Shengxiang Ren; Christopher J Rivard; Kim Ellison; Charles Caldwell Jr; Leslie Rozeboom; Kristine Brovsky; Fred R Hirsch

  Cancer treatment reviews 72 15 - 27 2019/01 [Refereed]
   

  Lung cancer still represents one of the most common and fatal neoplasm, accounting for nearly 30% of all cancer-related deaths. Targeted therapies based on molecular tumor features and programmed death-1 (PD-1)/programmed death ligand-1 (PDL-1) blockade immunotherapy have offered new therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC). Activation of the epidermal growth factor receptor (EGFR)-pathway promotes tumor growth and progression, including angiogenesis, invasion, metastasis and inhibition of apoptosis, providing a strong rationale for targeting this pathway. EGFR expression is detected in up to 85% of NSCLC and has been demonstrated to be associated with poor prognosis. Two approaches for blocking EGFR signaling are available: prevention of ligand binding to the extracellular domain with monoclonal antibodies (mAbs) and inhibition of the intracellular tyrosine kinase activity with small molecules. There is a strong rationale to consider the tumor's level of EGFR expression as one of the most significant predictive biomarkers in this setting. In this paper we provide an update focusing on the current status of EGFR-directed mAbs use for the treatment of patients with advanced NSCLC, through a review of all clinical trials involving anti-EGFR mAbs in combination with chemotherapy (CT) for advanced disease and with chemo-radiotherapy for stage III disease. Here we also discuss the current status of predictive biomarkers for anti-EGFR mAbs when added to first-line CT in patients with advanced NSCLC. Finally, we focused on the relevance of EGFR fluorescence in situ hybridization (FISH)+ and immunohistochemistry (IHC)-Score ≥ 200 as predictive biomarkers for the selection of patients who would be most likely to derive a clinical benefit from treatment with CT in combination with anti-EGFR mAbs, with particular reference also to histology.
• In vitro evaluation of EGFR secondary mutations at front-line osimertinib progression in lung cancers

  Nishino Masaya; Suda Kenichi; Ohara Shuta; Fujino Toshio; Koga Takamasa; Kobayashi Yoshihisa; Chiba Masato; Shimoji Masaki; Tomizawa Kenji; Takemoto Toshiki; Mitsudomi Tetsuya

  CANCER SCIENCE 109 1184  1349-7006 2018/12 [Refereed]
  
• Effects of secondary EGFR mutations on resistance against upfront osimertinib in cells with EGFR-activating mutations in vitro.

  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 2018/12 [Refereed]
   

  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.
• Activity of a novel HER2 inhibitor, poziotinib, for HER2 exon 20 mutations in lung cancer and mechanism of acquired resistance: An in vitro study.

  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 2018/12 [Refereed]
   

  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.
• The immune checkpoint, HVEM may contribute to immune escape in non-small cell lung cancer lacking PD-L1 expression.

  Shengxiang Ren; Qinrui Tian; Nadav Amar; Hui Yu; Christopher J Rivard; Charles Caldwell; Terry L Ng; Megan Tu; Yiwei Liu; Dexiang Gao; Kim Ellison; Kenichi Suda; Leslie Rozeboom; Gareth Rivalland; Paul Mitchell; Caicun Zhou; Fred R Hirsch

  Lung cancer (Amsterdam, Netherlands) 125 115 - 120 2018/11 [Refereed]
   

  BACKGROUND: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC. METHODS: A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used. RESULTS: HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p < 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r=-0.162, p = 0.352). CONCLUSION: HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co-relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients.
• Successful treatment of lung adenocarcinoma with gefitinib based on EGFR gene amplification.

  Chunguo Wang; Feng Xu; Jianfei Shen; Linna Zhang; Jian Zhang; Jiang Jin; Luca Ampollini; Paul van Schil; Hideharu Kimura; Francesco Grossi; Kenichi Suda; Bo Zhang; Dehua Ma

  Journal of thoracic disease 10 (11) E779-E783  2018/11 [Refereed]
  
• 肺切除後における訪問看護ステーションとの連携の有用性の検討

  武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 須田 健一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 58 (6) 556 - 556 0386-9628 2018/10
• 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 (NPO)日本肺癌学会 58 (6) 557 - 557 0386-9628 2018/10
• In vitroモデルにおけるMET Exon14 mutationに対する最適なMET-TKIの探索

  藤野 智大; 須田 健一; 小林 祥久; 古賀 教将; 西野 将矢; 小原 秀太; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 58 (6) 602 - 602 0386-9628 2018/10
• 臨床病期I期の肺神経内分泌癌切除症例の検討

  古賀 教将; 須田 健一; 吉本 健太郎; 小原 秀太; 藤野 智大; 西野 将矢; 千葉 眞人; 下治 正樹; 白石 健治; 池田 公英; 脇本 譲二; 森 毅; 武本 智樹; 久保田 伊知郎; 鈴木 実; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 58 (6) 722 - 722 0386-9628 2018/10
• Innate Genetic Evolution of Lung Cancers and Spatial Heterogeneity: Analysis of Treatment-Naïve Lesions.

  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 2018/10 [Refereed]
   

  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.
• CD44 Facilitates Epithelial-to-Mesenchymal Transition Phenotypic Change at Acquisition of Resistance to EGFR Kinase Inhibitors in Lung Cancer.

  Kenichi Suda; Isao Murakami; Hui Yu; Jihye Kim; Aik-Choon Tan; Hiroshi Mizuuchi; Leslie Rozeboom; Kim Ellison; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch

  Molecular cancer therapeutics 17 (10) 2257 - 2265 2018/10 [Refereed]
   

  Epithelial-to-mesenchymal transition (EMT) is one of the acquired resistance mechanisms to EGFR tyrosine kinase inhibitors (TKI) in lung cancers. Because EMT is related to tumor invasion, metastases, and resistance to various treatments, it is important to prevent the emergence of EMT. However, molecular mechanism(s) underlying EMT phenotypic changes, as well as biomarker(s) that predict the emergence of EMT in EGFR-mutated lung cancers, are unclear to date. Through the comparison of expression data between isogenic lung cancer cell lines that acquired resistance to EGFR-TKI(s), we identified that high CD44 expression is related to a mesenchymal phenotype and that shRNA-mediated knockdown of CD44 reversed the EMT change. High membranous CD44 expression was identified in lesions with mesenchymal phenotype that were obtained from lung cancer patients who developed acquired resistance to gefitinib or afatinib, whereas isogenic lesions without EMT change showed negative/weak staining for CD44. Immunohistochemistry for treatment-naïve lung cancer cell lines with EGFR mutations found those that acquire resistance to EGFR-TKIs via EMT (HCC4006 and H1975 cells) had strong membranous CD44 expression compared with non-EMT-transforming lines which demonstrated negative or weak staining (Fisher exact test P value = 0.036). shRNA-mediated CD44 knockdown in HCC4006 cells prevented the emergence of EMT after chronic exposure to osimertinib. These results suggest that upregulation of CD44 facilitates EMT-phenotypic change in lung cancers with EGFR mutations when treated with EGFR-TKIs. In addition, our results suggest that CD44 can be a useful biomarker to predict the emergence of EMT upon EGFR-TKI monotherapy. Mol Cancer Ther; 17(10); 2257-65. ©2018 AACR.
• A miRNA Panel Predicts Sensitivity of FGFR Inhibitor in Lung Cancer Cell Lines.

  Shengxiang Ren; Christopher J Rivard; Hui Yu; Carlo Genova; Leslie Rozenboom; Dexiang Gao; Trista K Hinz; Brad A Rikke; Murry W Wynes; Charles Caldwell; Francesco Agustoni; Kenichi Suda; Tao Jiang; Caicun Zhou; Lynn E Heasley; Fred R Hirsch

  Clinical lung cancer 19 (5) 450 - 456 2018/09 [Refereed]
   

  PURPOSE: To test whether a microRNA (miRNA) panel may serve as an alternative biomarker of fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor sensitivity in lung cancer. METHODS: Histologically diverse lung cancer cell lines were submitted to assays for ponatinib and AZD4547 sensitivity. miRNAs, FGFR1 messenger RNA, gene copy number, and protein expression were detected by real-time quantitative PCR, fluorescence in-situ hybridization, and immunoblotting in 34 lung cancer cell lines. RESULTS: Among 34 cell lines, 14 exhibited ponatinib sensitivity and 20 exhibited AZD4547 sensitivity (drug concentration causing 50% inhibition values < 100 nmol/L). A total of 39 of the 377-miRNA set were initially identified from the 4 paired ponatinib-sensitive or -insensitive cell lines to have at least an 8-fold differential expression and then were detected in all the 34 cell lines. A predictive panel of 3 miRNAs (let-7c, miRNA155, and miRNA218) was developed that had an area under the curve (AUC) of 0.886 with a sensitivity of 71.4% and specificity of 77.3% to predict response to ponatinib. The miRNA panel performed similar to FGFR1 protein expression (AUC = 0.864) and messenger RNA expression (AUC = 0.939), and better than FGFR1 amplification (AUC = 0.696). Furthermore, we validated this panel using data for sensitivity to AZD4547 in the cell line cohort with an AUC of 0.931 and a sensitivity of 73.3% and specificity of 76.2%, respectively. CONCLUSION: The developed miRNA panel (let-7c, miRNA155, and miRNA218) may be useful in predicting response to FGFR tyrosine kinase inhibitors, either ponatinib or AZD4547 in lung cancer cell lines, and warrants further validation in the clinical setting.
• Intraoperative molecular imaging-a bright navigator for thoracic surgeons in the era of limited resection.

  Kenichi Suda

  Translational lung cancer research 7 (Suppl 3) S232-S235  2018/09 [Refereed]
  
• 【がんのPrecision Medicine(精密医療)-SCRUM-Japanの取り組みを中心に-】 がんのPrecision Medicineとは何か

  藤野 智大; 須田 健一; 光冨 徹哉

  Progress in Medicine (株)ライフ・サイエンス 38 (9) 953 - 957 0287-3648 2018/09
• 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 (NPO)日本呼吸器外科学会 32 (3) P75 - 6 0919-0945 2018/04
• DNA shedding in non-small-cell lung cancer: useful to assess?

  Kenichi Suda

  The Lancet. Respiratory medicine 6 (2) 77 - 78 2018/02 [Refereed]
  
• Tumor-associated macrophages-additional effectors at anti-PD-1/PD-L1 therapy?

  Kenichi Suda

  Journal of thoracic disease 9 (11) 4197 - 4200 2017/11 [Refereed]
  
• 【分子標的療法は外科治療をどう変えるか】 肺癌

  須田 健一; 光冨 徹哉

  日本外科学会雑誌 (一社)日本外科学会 118 (6) 616 - 621 0301-4894 2017/11 

  2002年9月のゲフィチニブの承認を皮切りに、本邦でも数多くの非小細胞肺癌に対する分子標的治療薬が臨床応用されてきた。現在では、進行・再発期の非小細胞肺癌の治療において、分子標的治療薬はもはや必要不可欠な薬剤となっている。これらの分子標的治療薬を、術前または術後補助療法に応用する試みは自然な流れであり、現在も多くの臨床試験が進行・計画中である。一方、進行期の非小細胞肺癌の治療では、分子標的治療薬を用いた薬物療法の前後でしばしば生検が行われ、生検結果に基づいた治療薬の選択が行われることも多い。これらの生検はCTガイド下や気管支鏡下に行われることが多いが、腫瘍の部位によっては外科的生検が考慮されることもある。また、進行期の非小細胞肺癌の治療に分子標的治療薬が広く用いられるようになって以降、oligo-progressionと呼ばれる局所のみの病勢増悪が、殺細胞性抗癌剤のみの時代と比較してより一般的に知られるようになった。これらのoligo-progressionに対して外科治療や放射線治療などの局所療法を行うことで、分子標的治療薬によるさらなる長期の病勢コントロールが可能となることも報告されている。分子標的治療薬の発展に伴い、肺癌診療における外科治療の重要性、外科医の役割はますます大きくなっている。(著者抄録)
• 【がん転移学(上)-がん転移のメカニズムと治療戦略:その基礎と臨床-】 がん転移学の基礎研究 がんの発生進展の分子機構 非小細胞肺癌の分子機構

  須田 健一; 光冨 徹哉

  日本臨床 (株)日本臨床社 75 (増刊8 がん転移学(上)) 164 - 168 0047-1852 2017/11
• Clinical significance of tumor cavitation in surgically resected early-stage primary lung cancer.

  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) ELSEVIER IRELAND LTD 112 57 - 61 0169-5002 2017/10 [Refereed]
   

  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.
• Overcoming resistance to EGFR tyrosine kinase inhibitors in lung cancer, focusing on non-T790M mechanisms.

  Kenichi Suda; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch

  Expert review of anticancer therapy 17 (9) 779 - 786 2017/09 [Refereed]
   

  INTRODUCTION: despite initial dramatic efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer patients, emergence of acquired resistance is almost inevitable. The EGFR T790M secondary mutation that accounts for ~50% of resistance is now treatable with osimertinib. However, for the remaining 50% of patients who develop resistance mechanisms other than T790M mutation, cytotoxic chemotherapies are still the standard of care and novel treatment strategies are urgently needed. Areas covered: In this review, we discuss current experimental and clinical evidence to develop better treatment strategies to overcome or prevent acquired resistance to EGFR-TKIs in lung cancers, focusing on non-T790M mechanisms. Expert commentary: There are numerous non-T790M resistant mechanisms to EGFR-TKIs, and therefore, strategies that can be applied to many of these resistance mechanisms may be reasonable and useful in clinical practice. Although the combination of cytotoxic chemotherapy plus an EGFR-TKI has proved to be detrimental following front-line EGFR-TKI treatment failure, promising experimental and/or early clinical data have been reported for the combination of bevacizumab or anti-EGFR monoclonal antibody plus EGFR-TKIs. Upfront polytherapy, which co-targets potential resistance mechanisms or other important signaling for EGFR-mutant lung cancer cells, is also a promising strategy.
• Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells.

  Kenichi Suda; Leslie Rozeboom; Christopher J Rivard; Hui Yu; Kim Ellison; Mary Ann C Melnick; Trista K Hinz; Daniel Chan; Lynn E Heasley; Katerina Politi; Tetsuya Mitsudomi; Fred R Hirsch

  Lung cancer (Amsterdam, Netherlands) 109 1 - 8 2017/07 [Refereed]
   

  OBJECTIVES: Immunotherapy that targets the programmed death-1/programmed death-ligand 1 (PD-L1) axis has been approved for treatment of non-small cell lung cancer (NSCLC) patients in many countries. However, our current understanding of the role of immunotherapies on NSCLC patients with epidermal growth factor receptor (EGFR) mutation, following acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs), is so far unclear. Especially, there is little data on if each acquired resistance mechanism to EGFR-TKIs alters PD-L1 expression status which is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents. MATERIALS AND METHODS: Lung cancer cell lines (HCC827, HCC4006, PC9, H1975, H358, SW900, and H647) and their daughter cells that acquired resistance to EGFR-TKIs or cytotoxic drugs (cisplatin or vinorelbine) were examined. PD-L1 expression was analyzed by immunohistochemistry, immunoblotting, and/or fluorescent imaging. Published microarray data were also employed to evaluate our findings. RESULTS AND CONCLUSION: We found correlations between therapy-induced E-cadherin downregulation and decreased PD-L1 expression using our cell lines and published microarray data. ShRNA mediated E-cadherin knockdown decreased PD-L1 expression in parental cells, and dual immunofluorescent staining of E-cadherin and PD-L1 suggests co-localization of both molecules. We also observed marked downregulation of PD-L1 in cells with E-cadherin downregulation after chronic treatment with vinorelbine. These results indicate a correlation between therapy-induced E-cadherin downregulation and decreased PD-L1 expression, highlighting the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the evaluation of resistance mechanisms but also for the determination of PD-L1 expression status.
• Heterogeneity in Immune Marker Expression after Acquisition of Resistance to EGFR Kinase Inhibitors: Analysis of a Case with Small Cell Lung Cancer Transformation.

  Kenichi Suda; Isao Murakami; Hui Yu; Jihye Kim; Kim Ellison; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 12 (6) 1015 - 1020 2017/06 [Refereed]
   

  INTRODUCTION: Expression of immune markers is of scientific interest because of their potential roles as predictive biomarkers for immunotherapy. Although the microenvironment of metastatic tumors and/or therapy-inducible histological transformation may affect the expression of these immune markers, there are few data regarding this context. METHODS: A 76-year-old never-smoking female with EGFR-mutated lung adenocarcinoma (AC) acquired resistance to gefitinib. After her death, an autopsy revealed SCLC transformation and EGFR T790M secondary mutation (T790M) as mutually exclusive resistance mechanisms occurring differently in different metastases; two liver metastases (SCLC versus AC with T790M) and two lymph node metastases (SCLC versus AC with T790M) were analyzed to compare the expression status of immune markers by immunohistochemistry and by an immune oncology gene expression panel. RESULTS: Programmed death ligand 1 (PD-L1) protein was partially expressed in tumor cells with AC lesions (T790M) but not in tumor cells with SCLC transformation. The liver metastasis with SCLC transformation showed no stromal PD-L1 expression and scant tumor-infiltrating lymphocytes, whereas the other lesions demonstrated stromal PD-L1 staining and infiltration of CD8-positive T cells. Data generated using an immuno-oncology gene expression panel indicated a higher level of T-cell costimulatory molecules and lower expression of type I interferon-regulated genes in lesions with SCLC transformation. CONCLUSION: These data highlight the heterogeneity of expression of immune markers depending on the metastatic sites and histological transformation and indicate that the biopsy specimen from one lesion may not be representative of immune marker status for all lesions.
• LAG-3 Protein Expression in Non-Small Cell Lung Cancer and Its Relationship with PD-1/PD-L1 and Tumor-Infiltrating Lymphocytes.

  Yayi He; Hui Yu; Leslie Rozeboom; Christopher J Rivard; Kim Ellison; Rafal Dziadziuszko; Kenichi Suda; Shengxiang Ren; Chunyan Wu; Likun Hou; Caicun Zhou; Fred R Hirsch

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 12 (5) 814 - 823 2017/05 [Refereed]
   

  INTRODUCTION: Immunotherapy targeting the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) checkpoint has shown promising efficacy in patients with NSCLC. Lymphocyte activating 3 gene (LAG-3) is another important checkpoint, and its role in NSCLC is still not clear. In this study we investigated lymphocyte activing 3 (LAG-3) protein expression; its correlation with PD-1, PD-L1, and tumor-infiltrating lymphocytes (TILs); and its association with survival in NSCLC. METHODS: The expression of LAG-3 (EPR4392 [Abcam, Cambridge, MA]) protein was assessed in 55 NSCLC cell lines by immunohistochemistry. LAG-3, PD-1 (NAT 105 [Cell Marque, Rocklin, CA]), and PD-L1 (22C3 [Dako, Carpenteria, CA]) protein expression was evaluated by immunohistochemistry, and TIL abundance was scored in 139 surgically resected specimens from patients with NSCLC. We also verified results in samples from 62 patients with untreated NSCLC and detected a correlation between LAG-3 expression and EGFR and KRAS mutation and echinoderm microtubule associated protein like 4 gene (EML4)-anaplastic lymphoma receptor tyrosine kinase gene (ALK) rearrangement. RESULTS: LAG-3 was not expressed on any of the 55 NSCLC cell lines. However, LAG-3 was expressed on the TILs in 36 patients with NSCLC (25.9%). Sixty patient samples (43.2%) were positive for PD-1 on the TILs, and 25 (18.0%) were positive for PD-L1 on tumor cells. Neither LAG-3 nor PD-1 was expressed on the tumor cells. LAG-3 was overexpressed on the TILs in nonadenocarcinoma compared with in adenocarcinoma (p = 0.031). LAG-3 expression on TILs was significantly correlated with that of PD-1 on TILs (p < 0.001) and PD-L1 on tumor cells (p = 0.041) but not with TIL percentage (p = 0.244). With the logistic regression model, the ORs for LAG-3 were 0.320 (95% confidence interval [CI]: 0.110-0.929) and 4.364 (95% CI: 1.898-10.031) when nonadenocarcinoma was compared with adenocarcinoma and TILs that were negative for PD-1 were compared with those positive for PD-1. Recurrence-free survival was significantly different in patients whose TILs were LAG-3-negative as opposed to LAG-3-positive (1.91 years [95% CI: 0.76-3.06] versus 0.87 years [95% CI: 0.27-1.47] [p = 0.025]). Likewise, LAG-3 status of TILs (negative versus positive) did significantly affect overall survival (OS) (3.04 years [95% CI: 2.76-3.32] versus 1.08 years [95% CI: 0.42-1.74] [p = 0.039]). Using Kaplan-Meier analysis, we found that patients with both PD-L1-negative tumor cells and LAG-3-negative TILs have longer recurrence-free survival than patients who are either PD-L1- or LAG-3-positive or both PD-L1- and LAG-3-positive (2.09 years [95% CI: 0.90-3.28] versus 1.42 years [95% CI: 0.46-2.34] versus 0.67 years [95% CI: 0.00-1.45] [p = 0.007]). In the verification stage, high expression of LAG-3 was also significantly correlated with higher expression of PD-1 on TILs (p = 0.016) and PD-L1 on tumor cells (p = 0.014). There was no correlation between LAG-3 expression and EGFR (p = 0.325) and KRAS mutation (p = 1.000) and ALK fusion (p = 0.562). CONCLUSIONS: LAG-3 is expressed on TILs in tumor tissues of some patients with NSCLC. Its expression was higher in nonadenocarcinoma and correlated with PD-1/PD-L1 expression. LAG-3 positivity or both LAG-3 and PD-L1 positivity was correlated with early postoperative recurrence. LAG-3 was related to poor prognosis.
• EGFR-TKIの歴史と新たな展開

  須田 健一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 57 (2) 69 - 74 0386-9628 2017/04 

  上皮成長因子受容体(EGFR)遺伝子変異を有する肺癌は、本邦を含む東アジア人で頻度が高い。ここ数年、肺癌領域でも癌免疫治療の発展とその臨床応用が大きな注目を集めているが、EGFR変異肺癌には現在の癌免疫治療薬はあまり有効ではないとされている。したがって、EGFR変異肺癌に対してはこれまで同様、EGFRチロシンキナーゼ阻害剤(EGFR-TKIs)を主軸とした治療戦略の構築が重要である。2005年のT790M二次変異の報告以降、T790M変異を克服し得るEGFR-TKIsも数多く開発されており(オシメルチニブは本邦でも既に承認済み)、T790M以外のEGFR-TKI耐性機序も数多く報告されている。本稿ではEGFR-TKI開発の歴史について振り返りつつ、新規EGFR-TKIsの基礎・臨床データについて詳述する。また、EGFR-TKIと他薬剤の併用療法の可能性についても、基礎・臨床データをもとに概説する。(著者抄録)
• EGFR-TKIの歴史と新たな展開

  須田 健一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 57 (2) 69‐74(J‐STAGE) - 74 1348-9992 2017/04 

  上皮成長因子受容体(EGFR)遺伝子変異を有する肺癌は、本邦を含む東アジア人で頻度が高い。ここ数年、肺癌領域でも癌免疫治療の発展とその臨床応用が大きな注目を集めているが、EGFR変異肺癌には現在の癌免疫治療薬はあまり有効ではないとされている。したがって、EGFR変異肺癌に対してはこれまで同様、EGFRチロシンキナーゼ阻害剤(EGFR-TKIs)を主軸とした治療戦略の構築が重要である。2005年のT790M二次変異の報告以降、T790M変異を克服し得るEGFR-TKIsも数多く開発されており(オシメルチニブは本邦でも既に承認済み)、T790M以外のEGFR-TKI耐性機序も数多く報告されている。本稿ではEGFR-TKI開発の歴史について振り返りつつ、新規EGFR-TKIsの基礎・臨床データについて詳述する。また、EGFR-TKIと他薬剤の併用療法の可能性についても、基礎・臨床データをもとに概説する。(著者抄録)
• Effect of dasatinib on EMT-mediated-mechanism of resistance against EGFR inhibitors in lung cancer cells.

  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 2017/02 [Refereed]
   

  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.
• Primary Double-Strike Therapy for Cancers to Overcome EGFR Kinase Inhibitor Resistance: Proposal from the Bench.

  Kenichi Suda; Paul A Bunn Jr; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 12 (1) 27 - 35 2017/01 [Refereed]
   

  Diverse molecular mechanisms that confer acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung cancers with sensitive EGFR mutations have been reported. However, it is not realistic to analyze for all these mechanisms at the time of resistance in clinical practice and establish adequate treatment targeting these numerous resistance mechanisms. Therefore, we believe that we should move our research focus from the exploration of "established" diverse resistance mechanisms to the elucidation of molecular mechanisms that enable cancer cells to remain alive at the early phase of the treatment. Here in this review, we summarize up-to-date molecular mechanisms that maintain residual tumor cells against EGFR TKI monotherapy in lung cancers with EGFR mutations. We classified these mechanisms into three categories. The first is a preexisting minor subpopulation with a resistance mechanism such as a pretreatment T790M mutation that can be detected by highly sensitivity methods. The second is the reversible drug-tolerant state that is often observed in cell line models and accounts for the lack of complete response and continued survival of cells exposed to EGFR TKIs in patients. And the last is the role of the microenvironment, including survival signaling from fibroblasts or dying cancer cells and the role of poor vascularization. Primary double-strike cancer therapy, or even initial multiple-strike therapy, to cancer cells that cotarget EGFR and survival mechanism(s) simultaneously would be a promising strategy to improve the outcomes of patients with EGFR mutations.
• [Molecular Biology for Surgical Treatment of Lung Cancer].

  Kenichi Suda; Tetsuya Mitsudomi

  Kyobu geka. The Japanese journal of thoracic surgery 70 (1) 4 - 8 0021-5252 2017/01 [Refereed]
   

  Progress in lung cancer research achieved during the last 10 years was summarized. These include identification of novel driver mutations and application of targeted therapies, resistance mechanisms to targeted therapies, and immunotherapy with immune checkpoint inhibitors. Molecular biology also affects the field of surgical treatment. Several molecular markers have been reported to predict benign/ malignant or stable/growing tumors, although far from clinical application. In perioperative period, there is a possibility of atrial natriuretic peptide to prevent cancer metastasis. As adjuvant settings, although biomarker-based cytotoxic therapies failed to show clinical efficacy, several trials are ongoing employing molecular targeted agents (EGFR-TKI or ALK-TKI) or immune checkpoint inhibitors. In clinical practice, mutational information is sometimes used to distinguish 2nd primary tumors from pulmonary metastases of previous cancers. Surgery also has important role for oligo-progressive disease during molecular targeted therapies.
• Potential effect of spliceosome inhibition in small cell lung cancer irrespective of the MYC status.

  Kenichi Suda; Leslie Rozeboom; Hui Yu; Kim Ellison; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch

  PloS one 12 (2) e0172209  2017 [Refereed]
   

  Small cell lung cancer (SCLC) is a highly aggressive malignancy with few therapeutic advances in the treatment in recent decades. Based on a recent study that identified the spliceosome as a therapeutic vulnerability in MYC-driven breast cancers, we evaluated the efficacy of a spliceosome inhibitor in SCLC cell lines and analyzed the correlation with MYC status. Among 23 SCLC cell lines examined, eight showed high MYC protein expression (> 80% positive cells) by immunohistochemistry (IHC), while 10 cell lines demonstrated no staining for MYC. The remaining five cell lines showed weak staining (< 40% positive cells). All four cell lines that were previously demonstrated to have MYC gene amplification were positive for MYC by IHC. Four cell lines with high MYC expression and four with low MYC expression were used in further analysis. A spliceosome inhibitor, pladienolide B, showed high efficacy (IC50 < 12nM) in all eight cell lines tested, irrespective of the MYC IHC or MYC gene amplification status. We observed that the four cell lines with higher sensitivity to the spliceosome inhibitor were established from patients with prior chemotherapy. Therefore we chronically treated H1048 cells, that were established from a treatment-naïve patient, with cisplatin for 4 weeks, and found that H1048-cisplatin treated cells became more sensitive to pladienolide B. In conclusion, our in vitro results indicate that spliceosome inhibitors would be promising molecular target drugs in SCLC irrespective of the MYC status, especially in the second-line settings after an effective front-line chemotherapy.
• Increased EGFR Phosphorylation Correlates with Higher Programmed Death Ligand-1 Expression: Analysis of TKI-Resistant Lung Cancer Cell Lines.

  Kenichi Suda; Leslie Rozeboom; Koh Furugaki; Hui Yu; Mary Ann C Melnick; Kim Ellison; Christopher J Rivard; Katerina Politi; Tetsuya Mitsudomi; Fred R Hirsch

  BioMed research international 2017 7694202 - 7694202 2017 [Refereed]
   

  Despite the recent development of immunotherapies that target programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) treatment, these therapies are less effective in NSCLC patients with epidermal growth factor receptor (EGFR) mutations. However, the molecular mechanisms underlying this lower efficacy of immunotherapies in EGFR mutant lung cancers are still unclear. In this study, we analyzed PD-L1 protein expression in lung cancer cell lines with EGFR mutations prior to and after acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs). We found that parental lung cancer cell lines harboring EGFR mutations showed negative (PC9 and H3255 cells) and positive (HCC827 cells) staining for PD-L1 by immunohistochemistry. Comparing PD-L1 expression between EGFR-TKI resistant cell lines and their parental cells, we found that increased phosphorylation of EGFR was related to increased expression of PD-L1. Increased phosphorylation of EGFR was accompanied by the T790M secondary mutation. Acquired resistance cells with MET amplification or EGFR loss both showed decreased phosphorylation of EGFR and decreased PD-L1 expression. Our results indicate that lung cancer cell lines with EGFR mutations (parental cells) do not harbor high PD-L1 protein expression. In addition, EGFR phosphorylation affects PD-L1 expression after acquisition of resistance to EGFR-TKIs.
• 【胸部外科 最新の進歩と将来展望】 癌の外科治療における分子生物学

  須田 健一; 光冨 徹哉

  胸部外科 (株)南江堂 70 (1) 4 - 8 0021-5252 2017/01
• Molecular Factors Associated with Pemetrexed Sensitivity According to Histological Type in Non-small Cell Lung Cancer.

  Tsukihisa Yoshida; Tatsuro Okamoto; Tokujiro Yano; Kazuki Takada; Mikihiro Kohno; Kenichi Suda; Mitsuhiro Takenoyama; Yoshinao Oda; Yoshihiko Maehara

  Anticancer research 36 (12) 6319 - 6326 2016/12 [Refereed]
   

  BACKGROUND: This study was designed to investigate potential molecules that predict chemosensitivity to pemetrexed (Alimta®) in surgically resected non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Chemosensitivity to ALM and other drugs was assessed by succinate dehydrogenase inhibition (SDI) test in 69 NSCLC samples (55 adenocarcinomas, and 14 squamous cell carcinomas). The mRNA expression levels of Alimta®-target enzymes [thymidylate synthase (TYMS); dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyltransferase (GARFT)], Alimta®-metabolizing enzymes [γ-glutamyl hydrase (GGH) and folylpolyglutamate synthase] and an Alimta® transporter [reduce folate carrier (RFC)] were measured and examined for potential correlations to chemosensitivity. RESULTS: The squamous cell carcinoma samples showed higher TYMS expression and lower RFC expression than did the adenocarcinoma samples. In the adenocarcinoma sample analyses, GGH expression was inversely correlated to sensitivity. CONCLUSION: The histology-dependent differences in chemosensitivity to Alimta® may be attributed to the histology-dependent differences in TYMS and RFC expression. In adenocarcinomas, GGH potentially represents a marker for chemosensitivity to Alimta®.
• Prognostic impact of pleural lavage cytology in patients with primary lung cancer.

  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 2016/12 [Refereed]
   

  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.
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人

  近畿大学医学雑誌 近畿大学医学会 41 (3-4) 20A - 20A 0385-8367 2016/12
• Heterogeneity of EGFR Aberrations and Correlation with Histological Structures: Analyses of Therapy-Naive Isogenic Lung Cancer Lesions with EGFR Mutation.

  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 2016/10 [Refereed]
   

  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.
• New and emerging targeted treatments in advanced non-small-cell lung cancer.

  Fred R Hirsch; Kenichi Suda; Jacinta Wiens; Paul A Bunn Jr

  Lancet (London, England) 388 (10048) 1012 - 24 2016/09 [Refereed]
   

  Targeted therapies are substantially changing the management of lung cancers. These treatments include drugs that target driver mutations, those that target presumed important molecules in cancer cell proliferation and survival, and those that inhibit immune checkpoint molecules. This area of research progresses day by day, with novel target discoveries, novel drug development, and use of novel combination treatments. Researchers and clinicians have also extensively investigated the predictive biomarkers and the molecular mechanisms underlying inherent or acquired resistance to these targeted therapies. We review recent progress in the development of targeted treatments for patients with advanced non-small-cell lung cancer, especially focusing on data from published clinical trials.
• Clinical and pathologic features of lung cancer expressing programmed cell death ligand 1 (PD-L1).

  Masaki Shimoji; Shigeki Shimizu; Katsuaki Sato; Kenichi Suda; Yoshihisa Kobayashi; Kenji Tomizawa; Toshiki Takemoto; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 98 69 - 75 2016/08 [Refereed]
   

  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.
• Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non-Small Cell Lung Cancer: Double-Edged Sword of DDR2.

  Masato Terashima; Yosuke Togashi; Katsuaki Sato; Hiroshi Mizuuchi; Kazuko Sakai; Kenichi Suda; Yu Nakamura; Eri Banno; Hidetoshi Hayashi; Marco A De Velasco; Yoshihiko Fujita; Shuta Tomida; Tetsuya Mitsudomi; Kazuto Nishio

  Clinical cancer research : an official journal of the American Association for Cancer Research 22 (14) 3663 - 71 2016/07 [Refereed]
   

  PURPOSE: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. EXPERIMENTAL DESIGN: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro RESULTS: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. CONCLUSIONS: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. Clin Cancer Res; 22(14); 3663-71. ©2016 AACR.
• 【分子標的薬を用いた周術期治療】 免疫チェックポイント阻害薬を用いた非小細胞肺がん術後補助療法の可能性(Division of Medical Oncology, University of Colorado Anschutz Medical Campus)

  須田 健一; 光冨 徹哉

  がん分子標的治療 (株)メディカルレビュー社 14 (2) 180 - 184 1347-6955 2016/07 

  臨床病期I/II期(および一部のIIIA期)非小細胞肺がん(NSCLC)治療の第1選択は、外科的切除である。日本では、外科的切除後にテガフール・ウラシル配合薬(UFT)の1〜2年間内服(腫瘍径2cm超の病理病期I期)またはプラチナ製剤併用化学療法(病理病期II期以上)の術後補助化学療法が行われているが、その治療効果は高くなく、副作用のため治療を完遂できないことも多い。一方、進行・再発NSCLCの治療においては免疫チェックポイント阻害薬の比較的高い有効性と忍容性が示されつつあり、免疫チェックポイント阻害薬を術後補助療法に用いた複数の第III相臨床試験がすでに開始されている。本稿では、免疫チェックポイント機構の基礎とこれらの臨床試験について総括する。(著者抄録)
• Heterogeneity in Tumors and Resistance to EGFR TKI Therapy-Letter.

  Kenichi Suda; Christopher J Rivard; Tetsuya Mitsudomi; Fred R Hirsch

  Cancer research 76 (10) 3109 - 10 2016/05 [Refereed]
  
• Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor in lung cancer.

  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 2016/04 [Refereed]
   

  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.
• Impact of bevacizumab in combination with erlotinib on EGFR-mutated non-small cell lung cancer xenograft models with T790M mutation or MET amplification.

  Koh Furugaki; Junko Fukumura; Toshiki Iwai; Keigo Yorozu; Mitsue Kurasawa; Mieko Yanagisawa; Yoichiro Moriya; Kaname Yamamoto; Kenichi Suda; Hiroshi Mizuuchi; Tetsuya Mitsudomi; Naoki Harada

  International journal of cancer 138 (4) 1024 - 32 2016/02 [Refereed]
   

  Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL.
• Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer.

  Kenichi Suda; Isao Murakami; Kazuko Sakai; Kenji Tomizawa; Hiroshi Mizuuchi; Katsuaki Sato; Kazuto Nishio; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 91 36 - 40 2016/01 [Refereed]
   

  OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients. MATERIALS AND METHODS: We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed. RESULTS AND CONCLUSION: We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M+MET gene copy number gain, and mutant EGFR loss+unknown). We also identified quantitative heterogeneity in EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF compared with those who developed single resistance mechanism (p=0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p=0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations.
• Clinical, Pathological, and Molecular Features of Lung Adenocarcinomas with AXL Expression.

  Katsuaki Sato; Kenichi Suda; Shigeki Shimizu; Kazuko Sakai; Hiroshi Mizuuchi; Kenji Tomizawa; Toshiki Takemoto; Kazuto Nishio; Tetsuya Mitsudomi

  PloS one 11 (4) e0154186  2016 [Refereed]
   

  The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations.
• A rare case of thymic tuberculosis undergoing surgical resection for an anterior mediastinal tumor

  Nishino Masaya; Suda Kenichi; Iwasaki Takuya; Enoki Eisuke; Sato Takao; Mitsudomi Tetsuya

  The Journal of the Japanese Association for Chest Surgery The Japanese Association for Chest Surgery 30 (1) 31 - 35 0919-0945 2016 

  A 55-year-old woman, who had been treated for nephrotic syndrome, was referred to our department due to an asymptomatic nodule at the anterior mediastinum. She had a past history of intestinal tuberculosis. The anterior mediastinal nodule was 2 cm in diameter, adhering to the left upper lobe of the lung, as revealed by computed tomography. FDG-PET scan showed a strong accumulation of FDG in the mediastinal nodule (SUVmax: 6.93), and weak accumulation of FDG was also noted in the supraclavicular, mediastinal, and hilar lymph nodes. As a diagnostic and therapeutic procedure, surgical resection using video-assisted thoracic surgery (VATS) was performed, with combined resection of the left upper lobe of the lung. The tumor was filled with pus that was positive for Mycobacterium tuberculosis on by PCR examination. Pathological examination identified epithelioid granuloma with caseous necrosis in the thymic tissue. Although thymic tuberculosis is a rare disease, the possibility of it should be kept in mind when treating a patient with an anterior mediastinal nodule irrespective of the past history of tuberculosis.
• EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.

  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 2015/12 [Refereed]
   

  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.
• Prognosis and segment-specific nodal spread of primary lung cancer in the right lower lobe.

  Kenji Tomizawa; Kenichi Suda; Toshiki Takemoto; Tetsuya Mizuno; Hiroaki Kuroda; Noriaki Sakakura; Takuya Iwasaki; Masahiro Sakaguchi; Hiroyuki Kuwano; Tetsuya Mitsudomi; Yukinori Sakao

  Thoracic cancer 6 (6) 672 - 7 2015/11 [Refereed]
   

  BACKGROUND: Although lobe-specific nodal spread of primary lung cancer has been recently described, segment-specific nodal spread remains unclear. We investigated the frequency of hailer and mediastinal lymph node involvement and survival in patients with tumors located in the superior segment (SS) and basal segment (BS) in the right lower lobe. METHODS: Two hundred and sixty-three patients with primary lung cancer originating in the right lower lobe underwent lobectomy with systematic mediastinal lymph node dissection. Patients were categorized into two groups: SS (n = 114) or BS (n = 149). RESULTS: Frequencies of metastasis to station 11s and 11i were significantly higher in the SS (P < 0.0001) and BS groups (P = 0.022), respectively. Both the SS and BS groups showed a high frequency of subcarinal mediastinal zone (station 7) metastasis (96.9% and 90.6%, respectively; P = 0.271). The frequencies of superior mediastinal zone (station 2R and 4R) metastasis were 37.5% in the SS and 35.8% in the BS group (P = 0.878). In patients with pN2 disease, three-year disease-free survival was significantly shorter in the SS (22.6%) than the BS group (42.1%; P = 0.020). In the BS group, the independent predictive factors of a poor or good prognosis were metastasis to station 11i or skip metastasis, respectively; however, we did not detect an independent prognostic factor in the SS group. In the right lower lung lobe, there was no segment-specific nodal spread. CONCLUSION: When segmentectomy is undertaken, mediastinal lymph node dissection should be performed in proportion to lobectomy.
• 胸水洗浄細胞診 胸水洗浄細胞診陽性が肺癌術後再発に及ぼす意義

  富沢 健二; 須田 健一; 瀬角 裕一; 小林 祥久; 千葉 眞人; 佐藤 克明; 下治 正樹; 武本 智樹; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (5) 402 - 402 0386-9628 2015/10
• EGFR-TKI耐性におけるOncogene swap oncogene addictionの変化

  瀬角 裕一; 水内 寛; 須田 健一; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 富沢 健二; 武本 智樹; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (5) 469 - 469 0386-9628 2015/10
• COPDを合併したc-Stage IA肺癌手術時におけるCOPD病期分類の臨床的意義

  武本 智樹; 瀬角 裕一; 佐藤 克明; 小林 祥久; 千葉 眞人; 下治 正樹; 須田 健一; 富沢 健二; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (5) 599 - 599 0386-9628 2015/10
• T790M変異またはMET増幅NSCLC株に対するbevacizumabとerlotinibとの併用効果の検討

  古垣 耕; 山本 要; 原田 直樹; 須田 健一; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (5) 695 - 695 0386-9628 2015/10
• PD-L1発現陽性肺腺癌の臨床病理学的特徴

  下治 正樹; 清水 重喜; 瀬角 裕一; 佐藤 克明; 小林 祥久; 千葉 眞人; 須田 健一; 富沢 健二; 武本 智樹; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (5) 473 - 473 0386-9628 2015/10
• 非小細胞肺がんにおけるDDR2変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 佐藤 克明; 須田 健一; 水上 拓郎; 坂野 恵里; 中村 雄; De Velasco Marco; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人

  日本癌学会総会記事 (一社)日本癌学会 74回 P - 2223 0546-0476 2015/10
• Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.

  Kenichi Suda; Isao Murakami; Kazuko Sakai; Hiroshi Mizuuchi; Shigeki Shimizu; Katsuaki Sato; Kenji Tomizawa; Shuta Tomida; Yasushi Yatabe; Kazuto Nishio; Tetsuya Mitsudomi

  Scientific reports 5 14447 - 14447 2015/09 [Refereed]
   

  Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.
• Progression after spontaneous regression in lung large cell neuroendocrine carcinoma: Report of a curative resection.

  Kenji Tomizawa; Kenichi Suda; Toshiki Takemoto; Takuya Iwasaki; Masahiro Sakaguchi; Hiroyuki Kuwano; Tetsuya Mitsudomi

  Thoracic cancer 6 (5) 655 - 8 2015/09 [Refereed]
   

  We present the first reported case of lung large cell neuroendocrine carcinoma (LCNEC) with spontaneous regression followed by progression. An 85-year-old woman presented with a 2.8-cm nodule in the right upper lung lobe on chest computed tomography. After four months, the tumor decreased to 1.8 cm and remained unchanged in size for the next three months, but it grew to 8.6 cm and invaded the mediastinal fat tissue after approximately one year. Ultrasound echo-guided percutaneous biopsy revealed the tumor to be LCNEC. The patient underwent a right upper lobectomy with lymph node dissection. She had a good postoperative course with no complications. Physicians and surgeons should be aware that radiographic regression of a pulmonary nodule does not necessarily exclude the possibility of lung cancer.
• 胸水洗浄細胞診陽性と病理病期の関係

  富沢 健二; 須田 健一; 瀬角 裕一; 小林 祥久; 千葉 眞人; 佐藤 克明; 下治 正樹; 武本 智樹; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (4) 308 - 308 0386-9628 2015/08
• リンパ節転移を認めたsclerosing pneumocytoma(SP)の1例

  瀬角 裕一; 須田 健一; 佐藤 克明; 武本 智樹; 阪口 全宏; 光冨 徹哉; 土手 健作; 佐藤 隆夫

  肺癌 (NPO)日本肺癌学会 55 (4) 314 - 314 0386-9628 2015/08
• Role of EGFR mutations in lung cancers: prognosis and tumor chemosensitivity.

  Kenichi Suda; Tetsuya Mitsudomi

  Archives of toxicology 89 (8) 1227 - 40 2015/08 [Refereed]
   

  Lung cancers with an epidermal growth factor receptor (EGFR) gene mutation account for ~40 % of adenocarcinomas in East Asians and ~15 % of those in Caucasians and African Americans, which makes them one of the most common molecularly defined lung cancer subsets. The discriminative clinical and pathological features of lung cancers with EGFR mutations have been intensively studied, and the predictive role of an EGFR mutation for treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) is well established. However, controversial issues remain regarding the clinical and therapeutic implications of EGFR mutations in lung cancers. These include the prognostic impact of the EGFR mutation, its predictive implication for successful treatment with anticancer agents other than EGFR-TKIs, appropriate cytotoxic agents for lung cancers with this mutation, and the chemosensitivity of EGFR-mutation-positive lung cancers after acquisition of resistance to EGFR-TKIs. In this review, we discuss these unanswered but important questions, referring to in vitro studies, basic research, retrospective analyses, and the results of phase III clinical trials.
• 呼吸器外科手術患者における術前深部静脈血栓症のintensive screeningに関する検討

  武本 智樹; 小林 祥久; 佐藤 克明; 下治 正樹; 須田 健一; 冨沢 健二; 阪口 全宏; 保田 知生; 光冨 徹哉

  静脈学 (一社)日本静脈学会 26 (2) 160 - 160 0915-7395 2015/06
• IASLC/ATS/ERS分類に基づいた肺腺癌組織亜型の分子生物学的特徴 既知の予後予測マーカーとの関連

  佐藤 克明; 須田 健一; 水内 寛; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  近畿大学医学雑誌 近畿大学医学会 40 (1-2) 47 - 54 0385-8367 2015/06 

  肺腺癌におけるIASLC/ATS/ERS分類が2011年に発表され、その予後予測因子としての役割や分子病理学的特徴が報告されつつある。肺腺癌においてはこれまでも上皮間葉転換マーカーや癌幹細胞関連マーカーなどが予後予測因子として報告されているが、IASLC/ATS/ERS分類とこれらの分子マーカーとの関連は不明である。2007-2009年の原発性肺腺癌切除例161名を対象とし、IASLC/ATS/ERS分類と上記分子マーカーとの関連を検討した。患者の内訳は、男性74名(46%)、年齢中央値68歳、喫煙者78名(52%)、CEA高値54名(34%)、病理病期I:111名(69%)、II:25名(16%)、III:23名(14%)、IV:2名(1%)であった。病理学的には、微小浸潤癌1名、浸潤性粘液産生性腺癌9名、浸潤腺癌151名であった。浸潤腺癌は既報に準じてlow grade(lepidic/papillary/acinar)129名とhigh grade(micropapillary/solid)22名に分類した。浸潤性粘液産生性腺癌と浸潤腺癌との間に臨床背景の差は無かったが、免疫組織化学染色では前者で癌幹細胞関連マーカーの発現率が有意に高かった。浸潤腺癌においては、high gradeの症例で若年、喫煙者、CEA高値例、進行例が有意に多かった。またhigh grade症例ではMib-1 index高値例、TTF-1陰性例、vimentin発現例、E-cadherin発現低下例、P-glycoprotein発現例の割合が有意に多かった。本研究においてIASLC/ATS/ERS分類による組織形態と様々な分子マーカーとの関連を認めた。(著者抄録)
• ALK陽性完全切除不能進行肺癌に対し化学療法および分子標的治療後にサルベージ手術を行った1例

  阪口 全宏; 須田 健一; 岩崎 拓也; 武本 智樹; 富沢 健二; 佐藤 克明; 水内 寛; 下治 正樹; 小林 祥久; 岡部 崇記; 金田 裕靖; 中川 和彦; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 29 (3) O2 - 4 0919-0945 2015/04
• pN1原発性肺癌におけるリンパ節転移数と予後解析

  富沢 健二; 水内 寛; 小林 祥久; 佐藤 克明; 下治 正樹; 須田 健一; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 29 (3) O41 - 5 0919-0945 2015/04
• 肺腺癌における病理学的・分子生物学的予後予測因子とその関連

  佐藤 克明; 須田 健一; 清水 重喜; 水内 寛; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 29 (3) O35 - 4 0919-0945 2015/04
• 呼吸器 呼吸器外科手術患者における術前深部静脈血栓症のintensive screeningに関する検討

  武本 智樹; 水内 寛; 小林 祥久; 佐藤 克明; 下治 正樹; 須田 健一; 冨沢 健二; 岩崎 拓也; 阪口 全宏; 保田 知生; 光冨 徹哉

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 115回 OP - 7 2015/04
• 呼吸器 画像的分類による小型肺扁平上皮癌の臨床病理学的特徴

  富沢 健二; 水内 寛; 小林 祥久; 佐藤 克明; 下治 正樹; 須田 健一; 武本 智樹; 岩崎 拓也; 坂口 全宏; 光冨 徹哉

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 115回 OP - 5 2015/04
• 呼吸器 第3世代EGFR-TKI耐性獲得機序の解明

  水内 寛; 須田 健一; 佐藤 克明; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  日本外科学会定期学術集会抄録集 (一社)日本外科学会 115回 OP - 8 2015/04
• 末梢型肺扁平上皮癌の臨床病理学的特徴

  富沢 健二; 水内 寛; 小林 祥久; 佐藤 克明; 下治 正樹; 須田 健一; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (1) 73 - 74 0386-9628 2015/02
• 自然退縮後に再増大した肺大細胞神経内分泌癌の1切除例

  川口 晃平; 富沢 健二; 水内 寛; 小林 祥久; 佐藤 克明; 下治 正樹; 須田 健一; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 55 (1) 77 - 77 0386-9628 2015/02
• 肺腺癌組織亜型の分子生物学的特徴

  佐藤 克明; 須田 健一; 水内 寛; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉; 清水 重喜

  肺癌 (NPO)日本肺癌学会 55 (1) 70 - 71 0386-9628 2015/02
• Racial differences in lung cancer genetics.

  Kenichi Suda; Tetsuya Mitsudomi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10 (2) 230 - 1 2015/02 [Refereed]
  
• 胸腺原発大細胞神経内分泌癌の1切除例

  武本 智樹; 水内 寛; 佐藤 克明; 須田 健一; 岩崎 拓也; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 29 (1) 62 - 66 0919-0945 2015/01 

  症例は71歳女性、定期検査の胸部X線写真で異常指摘され精査加療目的に紹介となった。CTにて前縦隔に6cmの腫瘤を認め、上大静脈や右肺・心膜と境界不明瞭であった。FDG-PET/CTにてFDGの集積亢進(SUVmax:13.51)を認めた。浸潤性胸腺腫もしくは胸腺癌を疑い胸骨縦切開腫瘍摘出術、上大静脈・心膜・右肺合併切除術を施行した。腫瘍は白色充実性腫瘍で、病理組織学的に胸腺原発大細胞神経内分泌癌(LCNEC)と診断された。術後12ヵ月で縦隔リンパ節再発と多発肝転移を認め、CBDCA+VP-16療法を4クール施行し、縮小傾向認めたが、新たに多発骨転移を認めた。極めて稀な胸腺原発LCNECの1切除例を経験したので報告する。(著者抄録)
• 鑑別に苦慮した肺腺癌合併前縦隔悪性リンパ腫の一例

  藤下 卓才; 須田 健一; 河野 幹寛; 吉田 月久; 岡本 龍郎; 前原 喜彦

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 29 (1) 78 - 83 0919-0945 2015/01 

  鑑別に苦慮した肺腺癌合併前縦隔悪性リンパ腫の一例を経験した。62歳女性。胸部X線異常で当院受診した。胸部CTで右肺上葉、前縦隔、胸骨上窩に結節影を認めた。肺病変は経気管支肺生検にて腺癌の診断となった。前縦隔結節は最大径22mm、胸骨上窩結節は最大径9mmであり、いずれもFDG-PETで高集積を認めた。MRI信号パターンから胸腺由来と考えられた。腫瘍マーカーはsIL2-Rを含め正常範囲内であった。右上葉肺腺癌及び前縦隔腫瘍(胸腺癌疑い)の診断のもと、右肺上葉切除+縦隔リンパ節郭清術及び縦隔腫瘍・胸腺摘出術を施行した。縦隔腫瘍及び胸骨上窩結節は病理診断でdiffuse large B-cell lymphomaと診断された。本症例は比較的高齢であり、腫瘍も比較的小さく、臨床経過からも悪性リンパ腫としては非特異的であり、画像所見でも悪性リンパ腫は否定的と考えられた。術前の画像所見に関わらず悪性リンパ腫は常に鑑別に置く必要があると考えられた。(著者抄録)
• Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib.

  Hiroshi Mizuuchi; Kenichi Suda; Katsuaki Sato; Shuta Tomida; Yoshihiko Fujita; Yoshihisa Kobayashi; Yoshihiko Maehara; Yoshitaka Sekido; Kazuto Nishio; Tetsuya Mitsudomi

  PloS one 10 (4) e0123901  2015 [Refereed]
   

  Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.
• Solitary pulmonary metastasis from malignant melanoma of the bulbar conjunctiva presenting as a pulmonary ground glass nodule: Report of a case.

  Hiroshi Mizuuchi; Kenichi Suda; Hirokazu Kitahara; Shinichiro Shimamatsu; Mikihiro Kohno; Tatsuro Okamoto; Yoshihiko Maehara

  Thoracic cancer 6 (1) 97 - 100 2015/01 [Refereed]
   

  We herein report a case of solitary pulmonary metastasis from malignant melanoma that presented as a pulmonary ground glass nodule. A 57-year-old man who had undergone resection of a malignant melanoma of the right bulbar conjunctiva at the age of 51 was referred to our hospital for management of ground glass opacity in his left lung. Because radiological examination suggested the nodule was an adenocarcinoma in situ, computed tomography (CT) follow-up was planned. CT examination performed nine months later showed that the nodule had grown from 6 mm to 8 mm. Moreover, CT performed one and a half years after first detection revealed that the nodule had grown up to 10 mm. The patient, therefore, underwent partial resection of the lung for diagnosis and treatment. Pathological examination of the resected specimen revealed atypical cells with melanin granules proliferating in a lepidic-like fashion. The cells were positive on S-100 staining, indicating a pulmonary metastasis from malignant melanoma. Thus, metastatic tumors from malignant melanoma can present as ground glass opacities.
• Recent evidence, advances, and current practices in surgical treatment of lung cancer.

  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 2014/11 [Refereed]
   

  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.
• エルロチニブ耐性獲得株HCC4006ERはABCB1過剰発現により微小管阻害剤耐性を示す

  水内 寛; 須田 健一; 佐藤 克明; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 54 (5) 319 - 319 0386-9628 2014/10
• T790M変異非小細胞肺癌細胞株に対するbevacizumabとerlotinibとの併用効果の検討

  古垣 耕; 山本 要; 守屋 陽一郎; 萬 啓悟; 須田 健一; 水内 寛; 光冨 徹哉; 原田 直樹

  肺癌 (NPO)日本肺癌学会 54 (5) 463 - 463 0386-9628 2014/10
• 原発区域による右下葉肺癌の縦隔リンパ節転移頻度と予後解析

  富沢 健二; 水内 寛; 小林 祥久; 佐藤 克明; 須田 健一; 武本 智樹; 岩崎 拓也; 阪口 全宏; 桑野 博行; 坂尾 幸則; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 54 (5) 687 - 687 0386-9628 2014/10
• 肺腺癌新国際分類によるリンパ節転移巣の再評価とその臨床的意義

  須田 健一; 佐藤 克明; 清水 重喜; 水内 寛; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 54 (5) 530 - 530 0386-9628 2014/10
• The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor.

  Kenichi Suda; Hiroshi Mizuuchi; Katsuaki Sato; Toshiki Takemoto; Takuya Iwasaki; Tetsuya Mitsudomi

  International journal of cancer 135 (4) 1002 - 6 2014/08 [Refereed]
   

  Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR.
• CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation.

  Kenichi Suda; Hiroshi Mizuuchi; Isao Murakami; Hidetaka Uramoto; Fumihiro Tanaka; Katsuaki Sato; Toshiki Takemoto; Takuya Iwasaki; Yoshitaka Sekido; Yasushi Yatabe; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 85 (2) 147 - 51 2014/08 [Refereed]
   

  OBJECTIVES: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs. MATERIALS AND METHODS: We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined. RESULTS AND CONCLUSION: In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations.
• Prognostic and therapeutic implications of aromatase expression in lung adenocarcinomas with EGFR mutations.

  Mikihiro Kohno; Tatsuro Okamoto; Kenichi Suda; Mototsugu Shimokawa; Hirokazu Kitahara; Shinichiro Shimamatsu; Hideyuki Konishi; Tsukihisa Yoshida; Mitsuhiro Takenoyama; Tokujiro Yano; Yoshihiko Maehara

  Clinical cancer research : an official journal of the American Association for Cancer Research 20 (13) 3613 - 22 2014/07 [Refereed]
   

  PURPOSE: Lung adenocarcinomas among never-smokers are more common in females than in males. This implies that gender-dependent hormones promote smoking unrelated lung adenocarcinoma. We therefore investigated mRNA expression of aromatase, an intrinsic estrogen synthetase, in lung adenocarcinoma and assessed its correlation to clinicopathologic factors, including EGFR mutations and postsurgical prognosis. EXPERIMENTAL DESIGN: Aromatase mRNA expression in primary tumor samples from 110 patients with lung adenocarcinoma was evaluated with qRT-PCR. Inhibitory effects of the aromatase inhibitor exemestane were assessed in lung adenocarcinoma cell lines (11-18 and HCC4006), which have EGFR mutations, separately and combined with EGFR tyrosine kinase inhibitor erlotinib. RESULTS: Aromatase gene expression was not correlated with patients' clinicopathologic factors, including EGFR mutation status. High aromatase expression was associated with poor prognosis for both recurrence-free survival (P = 0.004) and overall survival (P = 0.003). In addition, the prognostic significance of aromatase expression was limited to females, never-smokers, and patients with EGFR mutations, but not in their counterparts. HCC4006, which has a low aromatase mRNA expression level, was not sensitive to exemestane, either alone or combined with erlotinib. In contrast, growth of 11-18 cells, which have high aromatase expression, was significantly inhibited by exemestane, both alone and combined with erlotinib. CONCLUSIONS: Aromatase is a candidate prognostic factor in patients with lung adenocarcinoma, especially in those with EGFR mutations, and may also be a beneficial therapeutic target in those patients.
• [Development of molecular targeted therapies in lung cancers].

  Kenichi Suda; Tetsuya Mitsudomi

  Nihon Geka Gakkai zasshi 115 (3) 130 - 6 0301-4894 2014/05 [Refereed]
   

  Human cancers usually possess cumulative genetic aberrations. However, recent studies have revealed that the proliferation and survival of specific subsets of lung cancer depend on a few somatic mutation(s), so-called driver mutations. Representative driver mutations include the EGFR mutation and ALK translocation identified in about 40% and 3% of lung adenocarcinomas in Japan, respectively. These tumors are extremely sensitive to the respective tyrosine kinase inhibitors. This sensitivity has encouraged researchers and clinicians to explore novel driver mutations in lung cancers as future molecular targets. Driver mutations reported so far include the HER2 mutation, BRAF mutation, ROS1 translocation, RET translocation, and NTRK translocation in lung adenocarcinomas, and FGFR1 amplification, DDR2 mutation, and FGFR3 translocation in lung squamous cell carcinomas. However, despite initial dramatic responses, the acquisition of resistance to molecular targeted drugs is almost inevitable. Overcoming resistance to molecular targeted drugs, the key drugs at this time, is an urgent issue to improve the outcomes of lung cancer patients.
• 新たな大腸癌肺転移の予後分類(Grade分類)に基づく、当院大腸癌肺転移手術例の予後の検討

  武本 智樹; 西野 将矢; 水内 寛; 佐藤 克明; 須田 健一; 岩崎 拓也; 南 憲司; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 28 (3) O13 - 2 0919-0945 2014/04
• 上肢深部静脈血栓症に伴う肺塞栓症を呈した浸潤型胸腺腫の1例

  岩崎 拓也; 西野 将矢; 水内 寛; 佐藤 克明; 須田 健一; 武本 智樹; 南 憲司; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 28 (3) 2 - 10 0919-0945 2014/04
• 非小細胞肺癌細胞株における受容体型チロシンキナーゼリン酸化状態の解析

  水内 寛; 須田 健一; 佐藤 克明; 武本 智樹; 岩崎 拓也; 南 憲司; 光冨 徹哉

  日本外科学会雑誌 (一社)日本外科学会 115 (臨増2) 632 - 632 0301-4894 2014/03
• EGFR野生型肺癌におけるエルロチニブ獲得耐性機序の探索

  須田 健一; 水内 寛; 佐藤 克明; 武本 智樹; 岩崎 拓也; 南 憲司; 光冨 徹哉

  日本外科学会雑誌 (一社)日本外科学会 115 (臨増2) 926 - 926 0301-4894 2014/03
• 【最新がん薬物療法学-がん薬物療法の最新知見-】臓器別がんの薬物療法 肺がん 肺がんの分子分類別薬物療法

  須田 健一; 佐藤 克明; 水内 寛; 光冨 徹哉

  日本臨床 (株)日本臨床社 72 (増刊2 最新がん薬物療法学) 355 - 359 0047-1852 2014/02
• Successes and limitations of targeted cancer therapy in lung cancer.

  Kenichi Suda; Tetsuya Mitsudomi

  Progress in tumor research 41 62 - 77 2014 [Refereed]
   

  Human cancers usually evolve through multistep processes. These processes are driven by the accumulation of abundant genetic and epigenetic abnormalities. However, some lung cancers depend on a single activated oncogene by somatic mutation, termed 'driver oncogenic mutations', for their proliferation and survival. EGFR(epidermal growth factor receptor) mutations and ALK(anaplastic lymphoma kinase) rearrangement are typical examples of such driver oncogenic mutations found in lung adenocarcinomas. EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs significantly improved treatment outcomes compared with conventional cytotoxic chemotherapy in patients with lung cancers harboring EGFR mutations or ALK rearrangement, respectively. Therefore, treatment strategies for lung cancers have dramatically changed from a 'general and empiric' to a 'personalized and evidence-based' approach according to the driver oncogenic mutation. Several novel driver oncogenic mutations, which are candidates as novel targets, such as ERBB2, BRAF, ROS1, and RET, have been discovered. Despite these successes, several limitations have arisen. One example is that some lung cancers do not respond to treatments targeting driver oncogenic mutations, as exemplified in KRAS-mutated lung cancers. Another is resistance to molecular-targeted drugs. Such resistance includes de novo resistance and acquired resistance. A number of molecular mechanisms underlying such resistance have been reported. These mechanisms can be roughly divided into three categories: alteration of the targeted oncogenes themselves by secondary mutations or amplification, activation of an alternative oncogenic signaling track, and conversion of cellular characteristics. Overcoming resistance is a current area of urgent clinical research.
• Prognostic implication of predominant histologic subtypes of lymph node metastases in surgically resected lung adenocarcinoma.

  Kenichi Suda; Katsuaki Sato; Shigeki Shimizu; Kenji Tomizawa; Toshiki Takemoto; Takuya Iwasaki; Masahiro Sakaguchi; Tetsuya Mitsudomi

  BioMed research international HINDAWI PUBLISHING CORPORATION 2014 645681 - 645681 2314-6133 2014 [Refereed]
   

  The International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) proposed a new classification for lung adenocarcinoma (AD) based on predominant histologic subtypes, such as lepidic, papillary, acinar, solid, and micropapillary; this system reportedly reflects well outcomes of patients with surgically resected lung AD. However, the prognostic implication of predominant histologic subtypes in lymph nodes metastases is unclear so far. In this study, we compared predominant subtypes between primary lung tumors and lymph node metastatic lesions in 24 patients with surgically treated lung adenocarcinoma with lymph node metastases. Additionally, we analyzed prognostic implications of these predominant histologic subtypes. We observed several discordance patterns between predominant subtypes in primary lung tumors and lymph node metastases. Concordance rates were 22%, 64%, and 100%, respectively, in papillary-, acinar-, and solid-predominant primary lung tumors. We observed that the predominant subtype in the primary lung tumor (HR 12.7, P = 0.037), but not that in lymph node metastases (HR 0.18, P = 0.13), determines outcomes in patients with surgically resected lung AD with lymph node metastases.
• 大腸癌気管転移に対し気管切除再建術を施行した一例

  佐藤 克明; 岩崎 拓也; 西野 将矢; 水内 寛; 須田 健一; 武本 智樹; 南 憲司; 光冨 徹哉

  日本臨床外科学会雑誌 日本臨床外科学会 74 (増刊) 794 - 794 1345-2843 2013/10
• RTKアレイを用いた肺癌における分子標的候補の網羅的解析

  水内 寛; 須田 健一; 佐藤 克明; 武本 智樹; 岩崎 拓也; 南 憲司; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 53 (5) 460 - 460 0386-9628 2013/10
• 左B4、5の転位性分岐異常による左中葉肺癌の1切除例

  武本 智樹; 西野 将矢; 水内 寛; 佐藤 克明; 須田 健一; 岩崎 拓也; 南 憲司; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 53 (5) 638 - 638 0386-9628 2013/10
• Unintentional weakness of cancers: the MEK-ERK pathway as a double-edged sword.

  Kenichi Suda; Tetsuya Mitsudomi

  Molecular cancer research : MCR 11 (10) 1125 - 8 2013/10 [Refereed]
   

  Recent advances in molecular targeted therapies have greatly improved treatment outcomes for cancers driven by oncogenic mutations. Despite initial and dramatic clinical responses, tumors eventually acquire resistance to these targeted therapies, showing flexible and diverse responses. Interestingly, cancer cells sometimes overadapt to the drug treatment environment, leading to a state in which cancer cells cannot survive without the drug. This interesting phenomenon (often called "drug dependency" or "drug addiction") is exemplified in preclinical acquired resistance models of BRAF-mutated melanoma treated with vemurafenib and EGFR-mutated lung cancer treated with EGFR tyrosine kinase inhibitors. A number of intriguing parallels in drug-addicted cancers became apparent in a comparison of the two models: (i) overexpression of driver oncogenes as causes of acquired resistance; (ii) overexpression of driver oncogenes causing MEK-ERK hyperactivation under drug-free conditions; (iii) hyperactivation of the MEK-ERK pathway as critical to this drug addiction phenomenon; (iv) ongoing dependence on the oncogenic driver; and (v) morphologic changes in resistant cells under drug-free conditions. This Perspective article not only focuses on this interesting and peculiar phenomenon but also discusses weapon strategies to exploit this unintentional weakness of cancers.
• 肺嚢胞性疾患に対する外科的切除を施行した3症例

  北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 須田 健一; 岡本 龍郎; 前原 喜彦

  日本外科系連合学会誌 日本外科系連合学会 38 (3) 699 - 699 0385-7883 2013/05
• 非小細胞肺癌におけるたばこの腫瘍生物学的影響

  岡本 龍郎; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 須田 健一; 前原 喜彦

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 27 (3) 367 - 367 0919-0945 2013/04
• 持続腹膜透析患者に合併した横隔膜交通症に対する手術例3例の検討

  河野 幹寛; 北原 大和; 島松 晋一郎; 吉田 月久; 須田 健一; 岡本 龍郎; 前原 喜彦

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 27 (3) P67 - 01 0919-0945 2013/04
• 術前診断が困難であった前縦隔悪性リンパ腫の1切除例

  須田 健一; 河野 幹寛; 北原 大和; 島松 晋一郎; 吉田 月久; 岡本 龍郎; 前原 喜彦

  日本呼吸器外科学会雑誌 (NPO)日本呼吸器外科学会 27 (3) P89 - 02 0919-0945 2013/04
• Solitary pulmonary metastasis from lung cancer harboring EML4-ALK after a 15-year disease-free interval.

  Kenji Tomizawa; Simon Ito; Kenichi Suda; Takayuki Fukui; Noriyasu Usami; Shunzo Hatooka; Hiroyuki Kuwano; Yasushi Yatabe; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 80 (1) 99 - 101 2013/04 [Refereed]
   

  It is often difficult to differentiate metachronous primary lung cancers from local pulmonary recurrences when the histopathological findings are similar. A 43-year-old man underwent right upper lobectomy with lymph node dissection for primary lung adenocarcinoma (p-T2aN0M0, stage IB). Fifteen years later, he developed a lung nodule in his right middle lobe. The tumor was preoperatively thought to be a metachronous second primary lung adenocarcinoma, and was surgically resected. Histopathological findings for both tumors were of poorly differentiated adenocarcinoma with mucus production. Both tumors also harbored the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene (variant 3a+b). Based on this molecular finding, the pulmonary nodule was considered to be a recurrence after very long latent period.
• Surgery for NSCLC in the era of personalized medicine.

  Tetsuya Mitsudomi; Kenichi Suda; Yasushi Yatabe

  Nature reviews. Clinical oncology 10 (4) 235 - 44 2013/04 [Refereed]
   

  The discovery in 2004 of activating mutations in the EGFR gene opened the era of personalized medicine in thoracic oncology. Treatment with drugs that target EGFR typically results in dramatic tumour response compared with conventional chemotherapy in patients with non-small-cell lung cancer. Subsequently, newer driver oncogenes such as ALK, ROS1 and RET have been discovered. Nevertheless, surgery has become safer and less invasive in the past 10-15 years. In the era of personalized medicine, thoracic surgeons have to think about their evolving roles. In this article, we discuss four topics relevant to this issue. Firstly, the value of surgical specimens as opposed to biopsy specimens for further understanding tumour biology is discussed. Secondly, extended indication of surgery in the era of targeted therapy is considered. Thirdly, in clinical trials that examine neoadjuvant therapy in patients selected by appropriate biomarkers, the important role of surgeons is highlighted. Finally, the possibility of personalizing the surgical procedure itself according to lung cancer subtypes defined by biomarkers is reviewed.
• 肺手術における安全な低侵襲手術 ステープラーを用いない肺組織切離法

  岡本 龍郎; 池田 哲夫; 須田 健一; 吉田 月久; 河野 幹寛; 島松 晋一郎; 北原 大和; 前原 喜彦

  日本外科学会雑誌 (一社)日本外科学会 114 (臨増2) 175 - 175 0301-4894 2013/03
• 肺癌術後再発に対する治療戦略 長期生存を目指して 肺癌術後oligometastases再発の概念と治療戦略

  矢野 篤次郎; 岡本 龍郎; 福山 誠一; 須田 健一; 岡崎 寛士; 吉田 月久; 河野 幹寛; 島松 晋一郎; 北原 大和; 前原 喜彦

  日本外科学会雑誌 (一社)日本外科学会 114 (臨増2) 311 - 311 0301-4894 2013/03
• 超高齢者に対する外科治療の問題点 胸部外科 80歳以上の超高齢者肺癌に対する外科治療の適応、術式選択および治療成績

  吉田 月久; 北原 大和; 島松 晋一郎; 河野 幹寛; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦

  日本外科学会雑誌 (一社)日本外科学会 114 (臨増2) 323 - 323 0301-4894 2013/03
• Development of personalized treatments in lung cancer: focusing on the EGFR mutations and beyond.

  Kenichi Suda; Tetsuya Mitsudomi

  Lung Cancer (Auckland, N.Z.) 4 43 - 53 2013 [Refereed]
   

  Lung cancers with epidermal growth factor receptor (EGFR) gene mutation account for ∼40% of adenocarcinoma in East Asians and ∼15% of that in Caucasians, which makes them one of the most common molecularly defined lung cancer subsets. The role of EGFR mutation as a strong predictive biomarker of response to EGFR-tyrosine kinase inhibitors (TKIs) was finally confirmed by the biomarker analysis of Iressa Pan-Asian Study (IPASS). Since the 2004 discovery of EGFR mutation in lung cancer, the EGFR mutation and EGFR-TKI treatment have been widely studied. These include characteristics of lung cancers with EGFR mutations; clinical efficacies and adverse effects of EGFR-TKIs in patients with EGFR-mutated lung cancers; development of novel EGFR-TKIs that may prolong progression-free survival of these patients or overcome resistance to first-generation EGFR-TKIs (gefitinib and erlotinib); optimal treatment schedules for EGFR-TKIs to delay emergence of resistance; molecular mechanisms of acquired resistance to EGFR-TKIs; treatment strategies after patients acquire resistance to EGFR-TKIs; and predictive biomarkers for EGFR-TKIs among patients with EGFR-mutated lung cancers. Some of these results are widely accepted, while others are apparent only in cell line models, preclinical animal models, or retrospective analyses (and sometimes conflict with each other). In this review, we summarize accumulated reports from the past decade, especially focusing on unanswered but important clinical questions in treating patients with EGFR-mutated lung cancers.
• Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.

  Kenichi Suda; Hiroshi Mizuuchi; Yoshihiko Maehara; Tetsuya Mitsudomi

  Cancer metastasis reviews 31 (3-4) 807 - 14 2012/12 [Refereed]
   

  Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.
• Impact of age on epidermal growth factor receptor mutation in lung cancer.

  Tsuyoshi Ueno; Shinichi Toyooka; Kenichi Suda; Junichi Soh; Yasushi Yatabe; Shinichiro Miyoshi; Keitaro Matsuo; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 78 (3) 207 - 11 2012/12 [Refereed]
   

  Aging is one of the best, but rarely referred, risk factors for various types of cancer including lung cancer, because age could be a surrogate for accumulation of genetic events in cancers. Smoking inversely associates with the presence of epidermal growth factor receptor (EGFR) mutation in lung cancer, but its strong confounding with age and sex makes it difficult to evaluate sole impact of age. To clarify an impact of age on EGFR mutation, we conducted a cross-sectional study based on data of 1262 lung cancer patients. The associations between EGFR mutation and age, considering sex, smoking and histology, were evaluated using logistic regression models. In multivariate analysis, we found a significant increase of EGFR mutation prevalence by increase of age (p-trend=0.0004). Consistent trend was observed among never-smoking females (p-trend=0.011) and never-smoking males also showed similar trend although not significant. These were consistently observed when we limit the subject to those with adenocarcinoma. In conclusion, age independently associates with EGFR mutation among lung cancer. Positive association between EGFR mutation and age among never-smokers regardless of sex might indicate that EGFR mutation occurs cumulatively by unidentified internal/external factors other than smoking.
• Genetic and Prognostic Differences of Non-small Cell Lung Cancer between Elderly Patients and Younger Counterparts.

  Kenichi Suda; Kenji Tomizawa; Hiroshi Mizuuchi; Simon Ito; Hirokazu Kitahara; Shinichiro Shimamatsu; Mikihiro Kohno; Tsukihisa Yoshida; Tatsuro Okamoto; Yoshihiko Maehara; Yasushi Yatabe; Tetsuya Mitsudomi

  Aging and disease 3 (6) 438 - 43 2152-5250 2012/12 [Refereed]
   

  Many elderly patients suffer from lung cancers, but it is not clear if their lung cancers differ from those of younger patients. In this study, we compared genetic and prognostic characteristics of lung cancers of patients aged ≥75 years with those of patients aged ≤ 64 years. In the genetic analysis, we explored 292 surgically treated non-squamous cell lung cancers with known mutational status of epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK). In the prognostic analysis, we retrospectively analyzed 405 surgically treated non-small cell lung cancers (NSCLCs) before the era of routine clinical application of post-surgical adjuvant chemotherapy. Postsurgical recurrence-free survival (RFS) was compared between elderly patients and younger counterparts. The genetic analysis showed elderly non-squamous cell lung cancer patients to have higher prevalence of EGFR mutations (53.1 % vs 42.0%, P = 0.15) and lower prevalence of the ALK translocation (0 % vs 4.5%, P = 0.23) than their younger counterparts. The prognostic analysis showed postsurgical RFS was similar between the elderly NSCLC patients and the younger patients. However in multivariate analysis, adjusting for gender, smoking status, pathological stage, and histology, elderly patients had significantly worse prognoses (HR 1.57, 95% CI, 1.08-2.29; P = 0.02) compared with younger patients. These results suggest differences in genetic and prognostic aspects between elderly lung cancer patients and younger lung cancer patients.
• 【分子標的薬-がんから他疾患までの治癒をめざして-】基礎研究 分子標的薬耐性化メカニズムの解明 EGFR変異肺がんにおけるEGFR-TKI耐性化メカニズム

  須田 健一; 光冨 徹哉

  日本臨床 (株)日本臨床社 70 (増刊8 分子標的薬) 341 - 345 0047-1852 2012/11
• Knockdown of the epidermal growth factor receptor gene to investigate its therapeutic potential for the treatment of non-small-cell lung cancers.

  Kazuhiko Shien; Tsuyoshi Ueno; Kazunori Tsukuda; Junichi Soh; Kenichi Suda; Takafumi Kubo; Masashi Furukawa; Takayuki Muraoka; Yuho Maki; Norimitsu Tanaka; Hiromasa Yamamoto; Katsuyuki Kiura; Tetsuya Mitsudomi; Shinichi Toyooka; Shinichiro Miyoshi

  Clinical lung cancer 13 (6) 488 - 93 2012/11 [Refereed]
   

  BACKGROUND: Epidermal growth factor receptor (EGFR) is often overexpressed in non-small-cell lung cancer (NSCLC). Anti-EGFR agents, including EGFR-tyrosine kinase inhibitors are considered to be effective when a drug-sensitive EGFR mutation is present. However, inherent and acquired resistances are major problems of EGFR-targeting therapies. In this study, we performed EGFR knockdown by using small interfering RNAs in NSCLC cell lines to examine the significance of targeting EGFR for NSCLC therapy. METHODS: We treated 13 NSCLC cell lines, including 8 EGFR mutant and 5 EGFR wild type by using gefitinib or small interfering RNAs against EGFR (siEGFR). Three cell lines (PC-9-GR1, RPC-9, and HCC827-ER) were experimentally established with acquired resistance to EGFR-tyrosine kinase inhibitors. The antitumor effect was determined by using an 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium, inner salt (MTS) or colony formation assay. The protein expression was evaluated by using Western blotting. RESULTS: All 13 cell lines expressed EGFR protein, and siEGFR downregulated EGFR protein expression in all. The cell viability was suppressed by siEGFR in 6 of 8 EGFR-mutant cell lines (suppressed 57%-92% of control cells), including PC-9-GR1 and RPC-9. The NCI-H1650 and HCC827-ER harbored EGFR mutations but were not suppressed. Of note, PTEN (phosphatase and tensin homolog) was deleted in NCI-H1650, and c-MET was amplified in HCC827-ER. It was not suppressed in any of the EGFR wild-type cells except in the NCI-H411, in which EGFR is phosphorylated, which indicates its activation. CONCLUSIONS: Analysis of the results indicated that EGFR can be a therapeutic target in NSCLCs with EGFR activation. In contrast, targeting EGFR is not appropriate for tumors in which EGFR is not activated, even if EGFR is expressed.
• Highly sensitive detection of EGFR T790M mutation using colony hybridization predicts favorable prognosis of patients with lung cancer harboring activating EGFR mutation.

  Yoshihiko Fujita; Kenichi Suda; Hideharu Kimura; Kazuko Matsumoto; Tokuzo Arao; Tomoyuki Nagai; Nagahiro Saijo; Yasushi Yatabe; Tetsuya Mitsudomi; Kazuto Nishio

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7 (11) 1640 - 4 2012/11 [Refereed]
   

  INTRODUCTION: Approximately 50% of lung cancer patients with epidermal growth factor receptor (EGFR)-mutations (deletion in exon 19 or L858R) who develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) reportedly carry a secondary EGFR T790M mutation. This mutation has been suggested to be present in tumor cells before EGFR-TKI treatment in a small population of individuals. Here, we use a highly sensitive colony hybridization technique in an attempt to evaluate the actual incidence of T790M in pretreatment tumor specimens. METHODS: DNA was extracted from surgically resected tumor tissues of 38 patients with the EGFR mutation and examined for the presence of T790M, using a standard polymerase chain reaction based method followed by a modified colony hybridization (CH) technique with an analytical sensitivity of approximately 0.01%. Associations between the T790M status and clinical characteristics including time to treatment failure (TTF) for EGFR-TKI were evaluated. RESULTS: The T790M mutation analysis of the specimens from the 38 patients detected 30 mutants (79%). The median TTF was 9 months for the patients with pretreatment T790M and 7 months for the patients without the T790M mutation (p = 0.44). When the patients with T790M were divided into strongly positive and modestly positive subgroups in terms of the frequency of positive signals observed using CH technique, the 7 patients with strong positivity had a TTF that was significantly longer than that of the 8 patients without T790M (p = 0.0097) and of the 23 patients with modest positivity (p = 0.0019). CONCLUSIONS: Our highly sensitive CH method showed that a subgroup of non-small-cell lung cancer patients with the EGFR mutation harbored the rare T790M allele before EGFR-TKI treatment. A high proportion of T790M allele may define a clinical subset with a relatively favorable prognosis.
• [Acquired resistance mechanisms to EGFR-TKIs in EGFR mutated lung cancers].

  Kenichi Suda; Tetsuya Mitsudomi

  Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 341 - 5 0047-1852 2012/11 [Refereed]
  
• EML4-ALK肺癌と最新治療 (特集 新しい局面を迎えた肺癌診療) -- (非小細胞肺癌の治療の実際)

  須田 健一; 富沢 健二; 光冨 徹哉

  内科 南江堂 110 (5) 729 - 735 0022-1961 2012/11
• HER2変異肺癌に対するHER2キナーゼ阻害薬耐性機序

  富沢 健二; 須田 健一; 水内 寛; 冨田 秀太; 森 俊輔; 千葉 眞人; 小林 祥久; 伊藤 志門; 宇佐美 範恭; 波戸岡 俊三; 桑野 博行; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 52 (5) 562 - 562 0386-9628 2012/10
• 喫煙者肺腺癌と非喫煙者肺腺癌間の分子生物学的差異に関する検討

  河野 幹寛; 伊藤 謙作; 北原 大和; 島松 晋一郎; 須田 健一; 岡本 龍郎; 竹之山 光広; 矢野 篤次郎; 前原 喜彦

  肺癌 (NPO)日本肺癌学会 52 (5) 582 - 582 0386-9628 2012/10
• 発症年齢と非小細胞肺癌の悪性度との関連

  須田 健一; 水内 寛; 富沢 健二; 伊藤 志門; 北原 大和; 島松 晋一郎; 河野 幹寛; 岡本 龍郎; 竹之山 光広; 光冨 徹哉; 前原 喜彦

  肺癌 (NPO)日本肺癌学会 52 (5) 635 - 635 0386-9628 2012/10
• 肺腺癌のごく近傍より発生した小細胞肺癌の一例

  島松 晋一郎; 岡本 龍郎; 北原 大和; 河野 幹寛; 吉田 月久; 須田 健一; 古賀 孝臣; 竹之山 光広; 前原 喜彦

  肺癌 (NPO)日本肺癌学会 52 (5) 721 - 721 0386-9628 2012/10
• Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer.

  Takayuki Nakagawa; Shinji Takeuchi; Tadaaki Yamada; Shigeki Nanjo; Daisuke Ishikawa; Takako Sano; Kenji Kita; Takahiro Nakamura; Kunio Matsumoto; Kenichi Suda; Tetsuya Mitsudomi; Yoshitaka Sekido; Toshimitsu Uenaka; Seiji Yano

  Molecular cancer therapeutics 11 (10) 2149 - 57 2012/10 [Refereed]
   

  Although the EGF receptor tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown dramatic effects against EGFR mutant lung cancer, patients become resistant by various mechanisms, including gatekeeper EGFR-T790M mutation, Met amplification, and HGF overexpression, thereafter relapsing. Thus, it is urgent to develop novel agents to overcome EGFR-TKI resistance. We have tested the effects of the mutant-selective EGFR-TKI WZ4002 and the mutant-selective Met-TKI E7050 on 3 EGFR mutant lung cancer cell lines resistant to erlotinib by different mechanisms: PC-9/HGF cells with an exon 19 deletion, H1975 with an L858R mutation, and HCC827ER with an exon 19 deletion, with acquired resistance to erlotinib because of HGF gene transfection, gatekeeper T790M mutation, and Met amplification, respectively. WZ4002 inhibited the growth of H1975 cells with a gatekeeper T790M mutation, but did not inhibit the growth of HCC827ER and PC-9/HGF cells. HGF triggered the resistance of H1975 cells to WZ4002, whereas E7050 sensitized HCC827ER, PC-9/HGF, and HGF-treated H1975 cells to WZ4002, inhibiting EGFR and Met phosphorylation and their downstream molecules. Combined treatment potently inhibited the growth of tumors induced in severe-combined immunodeficient mice by H1975, HCC827ER, and PC-9/HGF cells, without any marked adverse events. These therapeutic effects were associated with the inhibition of EGFR and Met phosphorylation in vivo. The combination of a mutant-selective EGFR-TKI and a Met-TKI was effective in suppressing the growth of erlotinib-resistant tumors caused by gatekeeper T790M mutation, Met amplification, and HGF overexpression. Further evaluations in clinical trials are warranted.
• Molecular Classification of Non-small Cell Lung Cancers and EGFR-mutated Lung Cancers

  須田 健一; 光冨 徹哉

  最新医学 最新医学社 67 (855) 2104 - 2115 0370-8241 2012/09
• Hsp90 inhibition overcomes HGF-triggering resistance to EGFR-TKIs in EGFR-mutant lung cancer by decreasing client protein expression and angiogenesis.

  Hitomi Koizumi; Tadaaki Yamada; Shinji Takeuchi; Takayuki Nakagawa; Kenji Kita; Takahiro Nakamura; Kunio Matsumoto; Kenichi Suda; Tetsuya Mitsudomi; Seiji Yano

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 7 (7) 1078 - 85 2012/07 [Refereed]
   

  INTRODUCTION: The three major clinically relevant mechanisms of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR mutant lung cancer are a second mutation in the EGFR gene (T790M), Met amplification, and increased expression of hepatocyte growth factor (HGF). Heat shock protein90 (Hsp90) is a 90 kDa molecular chaperone for proteins that include EGFR, Met, and echinoderm microtubule-associated proetin-like-4-the anaplastic lymphoma kinase. Here, we determined whether inhibition of Hsp90 could overcome HGF-triggered EGFR-TKI resistance in EGFR mutant lung cancer cells. METHODS: The effects of the Hsp90 inhibitor 17-demethoxygeldanamycin (17-DMAG) on the growth of lung cancer cells resistant to the EGFR-TKI were examined in the presence and absence of HGF, and in cells transfected with the HGF gene in vitro and in vivo. RESULTS: EGFR-TKI erlotinib did not inhibit the growth of HGF-gene transfected Ma-1 (Ma-1/HGF) cells and H1975 cells, containing the EGFR L858R and T790M mutations, respectively. Erlotinib also did not inhibit the growth of PC-9 and Ma-1 cells, with deletions in EGFR exon19, in the presence of HGF. However, 17-DMAG induced apoptosis and markedly inhibited the growth of these cell lines, even in the presence of HGF. This inhibition by 17-DMAG was associated with decreased expression of EGFR and Met in tumor cells. An in vivo model of HGF-triggered erlotinib-resistance, which used Ma-1/HGF cells, showed that 17-DMAG markedly suppressed tumor growth by decreasing angiogenesis and increasing apoptosis. CONCLUSIONS: Hsp90 inhibitors may overcome HGF-triggered resistance to EGFR-TKIs and may result in more successful treatment of patients with EGFR-mutant lung cancers.
• Conversion from the "oncogene addiction" to "drug addiction" by intensive inhibition of the EGFR and MET in lung cancer with activating EGFR mutation.

  Kenichi Suda; Kenji Tomizawa; Hirotaka Osada; Yoshihiko Maehara; Yasushi Yatabe; Yoshitaka Sekido; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 76 (3) 292 - 9 2012/06 [Refereed]
   

  Emergence of acquired resistance is virtually inevitable in patients with a mutation in the epidermal growth factor receptor gene (EGFR) treated with EGFR tyrosine kinase inhibitors (TKIs). Several novel TKIs that may prevent or overcome the resistance mechanisms are now under clinical development. However, it is unknown how tumor cells will respond to intensive treatment using these novel TKIs. We previously established HCC827EPR cells, which are T790M positive, through combined treatment with erlotinib and a MET-TKI from erlotinib-hypersensitive HCC827 cells. In this study, we treated HCC827EPR cells sequentially with an irreversible EGFR-TKI, CL-387,785, to establish resistant cells (HCC827CLR), and we analyzed the mechanisms responsible for resistance. In HCC827CLR cells, PTEN expression was downregulated and Akt phosphorylation persisted in the presence of CL-387,785. Akt inhibition restored CL-387,785 sensitivity. In addition, withdrawal of CL-387,785 reduced cell viability in HCC827CLR cells, indicating that these cells were "addicted" to CL-387,785. HCC827CLR cells overexpressed the EGFR, and inhibition of the EGFR or MEK-ERK was needed to maintain cell proliferation. Increased senescence was observed in HCC827CLR cells in the drug-free condition. Through long-term culture of HCC827CLR cells without CL-387,785, we established HCC827-CL-387,785-independent cells, which exhibited decreased EGFR expression and a mesenchymal phenotype. In conclusion, PTEN downregulation is a newly identified mechanism underlying the acquired resistance to irreversible EGFR-TKIs after acquisition of T790M against erlotinib. This series of experiments highlights the flexibility of cancer cells that have adapted to environmental stresses induced by intensive treatment with TKIs.
• 外科的立場よりみた高齢者非小細胞肺癌の生物学的悪性度の検討 一般俗説の検証

  須田 健一; 尾関 直樹; 伊藤 志門; 千葉 眞人; 小林 祥久; 富沢 健二; 福井 高幸; 波戸岡 俊三; 光冨 徹哉

  日本外科系連合学会誌 日本外科系連合学会 37 (3) 581 - 581 0385-7883 2012/05
• 肺癌切除30年の変遷

  福井 高幸; 伊藤 志門; 須田 健一; 千葉 眞人; 富沢 健二; 小林 祥久; 尾関 直樹; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 52 (2) 271 - 271 0386-9628 2012/04
• 非小細胞肺癌術後5年以降に再発した症例のリスク因子

  小林 祥久; 福井 高幸; 千葉 眞人; 須田 健一; 富沢 健二; 尾関 直樹; 伊藤 志門; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 26 (3) O02 - 07 0919-0945 2012/04
• 予測術後%1秒量をもとにした低肺機能患者への肺癌手術

  千葉 眞人; 伊藤 志門; 福井 高幸; 小林 祥久; 尾関 直樹; 須田 健一; 富沢 健二; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 26 (3) O22 - 02 0919-0945 2012/04
• 非小細胞肺癌術後フォローアップにおけるCEA測定の役割

  尾関 直樹; 伊藤 志門; 千葉 眞人; 須田 健一; 富沢 健二; 小林 祥久; 福井 高幸; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 26 (3) P15 - 10 0919-0945 2012/04
• 肺がん術後経過観察における胸部CT撮影回数の検討

  伊藤 志門; 尾関 直樹; 千葉 眞人; 須田 健一; 富沢 健二; 小林 祥久; 福井 高幸; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 26 (3) P16 - 01 0919-0945 2012/04
• Oncogenic driver mutations in lung cancers

  須田 健一; 光冨 徹哉

  医学のあゆみ 医歯薬出版 240 (13) 1059 - 1065 0039-2359 2012/03
• EGFR-TKIの基礎 (特集 肺癌診療の新しい時代)

  須田 健一; 光冨 徹哉

  成人病と生活習慣病 : 日本成人病(生活習慣病)学会準機関誌 東京医学社 42 (1) 23 - 29 1347-0418 2012/01
• 胃癌肺転移切除例の検討

  小林 祥久; 福井 高幸; 千葉 眞人; 須田 健一; 富沢 健二; 尾関 直樹; 伊藤 志門; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 51 (7) 842 - 842 0386-9628 2011/12
• Ground glass opacityを示す末梢小型肺腫瘍の自然史と手術適応

  小林 祥久; 福井 高幸; 千葉 眞人; 須田 健一; 富沢 健二; 尾関 直樹; 伊藤 志門; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 51 (5) 401 - 401 0386-9628 2011/10
• 脳転移再発111例の検討

  伊藤 志門; 千葉 眞人; 須田 健一; 富沢 健二; 小林 祥久; 尾関 直樹; 福井 高幸; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 51 (5) 406 - 406 0386-9628 2011/10
• 肺癌の術後再発の検討

  尾関 直樹; 伊藤 志門; 千葉 眞人; 須田 健一; 富沢 健二; 小林 祥久; 福井 高幸; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 51 (5) 454 - 454 0386-9628 2011/10
• Prognostic and predictive implications of HER2/ERBB2/neu gene mutations in lung cancers.

  Kenji Tomizawa; Kenichi Suda; Ryoichi Onozato; Takayuki Kosaka; Hideki Endoh; Yoshitaka Sekido; Hisayuki Shigematsu; Hiroyuki Kuwano; Yasushi Yatabe; Tetsuya Mitsudomi

  Lung cancer (Amsterdam, Netherlands) 74 (1) 139 - 44 2011/10 [Refereed]
   

  BACKGROUND: Activating mutation in the kinase domain of the human EGF receptor 2 (HER2) gene (also known as ERBB2 or neu) is reported to be present in a small fraction of lung adenocarcinomas. However its prognostic and predictive implications are not yet established. PATIENTS AND METHODS: We examined 504 Japanese lung cancer patients who underwent pulmonary resection for HER2 mutations by direct sequencing and evaluated their prognostic and predictive implications. Updated prognostic data of 14 Japanese patients with HER2 mutation from previous two reports were also gathered. RESULTS: HER2 mutations were identified in 13 of 504 cases (2.6%). Patients with HER2 mutations were common in female, nonsmokers and adenocarcinomas as those with EGFR mutations. When confined to the subgroup of nonsmokers with adenocarcinoma or adenosquamous cell carcinoma without EGFR mutations, the frequency of HER2 mutations was 14.1% (11/78). There was no difference in the overall survival of patients with HER2 mutations, compared with patients harboring EGFR mutations and patients harboring wild types for both EGFR and HER2. Within the patients with HER2 mutation, two of three with TP53 mutation and one of 13 without TP53 mutation died of the disease, suggesting negative prognostic role of the TP53 mutation. Three patients with HER2 mutations did not respond to platinum-based chemotherapy and EGFR-TKIs. Of note, one patient with the most common HER2 mutations, YVMA776-779ins, responded to trastuzumab plus vinorelbine after failure of multiple round of platinum-based chemotherapy and gefitinib. CONCLUSION: HER2 mutations are present in a subset of patients with lung cancer having distinct clinical features. HER2 mutations were not associated with the prognosis of patients with lung cancers. Patients with HER2 mutations might benefit from anti-HER2 therapy.
• Lung cancers unrelated to smoking: characterized by single oncogene addiction?

  Kenichi Suda; Kenji Tomizawa; Yasushi Yatabe; Tetsuya Mitsudomi

  International journal of clinical oncology 16 (4) 294 - 305 2011/08 [Refereed]
   

  Lung cancer is a major cause of cancer-related mortality worldwide. Currently, adenocarcinoma is its most common histological subtype in many countries. In contrast with small cell lung cancer or squamous cell carcinoma, lung adenocarcinoma often arises in never-smokers, especially in East Asian countries, as well as in smokers. Adenocarcinoma in never-smokers is associated with a lower incidence of genetic alterations (i.e., somatic mutations, loss of heterozygosity, and methylation) than in smokers. In addition, most adenocarcinomas in never-smokers harbor one of the proto-oncogene aberrations that occur in a mutually exclusive manner (EGFR mutation, KRAS mutation, HER2 mutations, or ALK translocation). It is of note that the proliferation and survival of lung cancer cells that harbor one of these oncogenic aberrations depend on the signaling from each aberrantly activated oncoprotein (oncogene addiction). Therefore, most adenocarcinomas in never-smokers can be effectively treated by molecularly targeted drugs that inhibit each oncoprotein. Moreover, from a pathological aspect, lung adenocarcinoma in never-smokers is characterized by terminal respiratory unit-type adenocarcinoma and a particular gene expression profile. Finally, epidemiological analyses have identified many candidate causes of lung cancer in never-smokers (genetic, environmental, and hormonal factors). The elucidation of the particular features of lung cancer unrelated to smoking and the development of new therapeutic modalities may reduce the mortality from lung cancers in the future.
• Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib.

  Kenichi Suda; Kenji Tomizawa; Makiko Fujii; Hideki Murakami; Hirotaka Osada; Yoshihiko Maehara; Yasushi Yatabe; Yoshitaka Sekido; Tetsuya Mitsudomi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 6 (7) 1152 - 61 2011/07 [Refereed]
   

  INTRODUCTION: Mesenchymal status is related to "inherent resistance" to gefitinib or erlotinib in non-small cell lung cancer without epidermal growth factor receptor(EGFR) mutations. In addition, a recent report showed that the epithelial to mesenchymal transition (EMT) plays a role in acquired resistance to gefitinib in A549 cells, which harbor a KRAS mutation. However, recent clinical studies revealed that gefitinib or erlotinib are highly effective in the treatment of non-small cell lung cancer with EGFR mutations. METHODS: We developed resistant cells (HCC4006ER) from erlotinib-sensitive HCC4006 cells harboring an EGFR deletion mutation by chronic exposure to increasing concentrations of erlotinib. Acquired resistance mechanisms of HCC4006ER cells were analyzed. RESULTS: Neither known resistance mechanisms nor novel molecules that may confer erlotinib resistance were identified using candidate or comprehensive analyses. In addition, HCC4006ER cells lost dependency for EGFR. However, we found that HCC4006ER cells acquired a mesenchymal phenotype and exhibited down-regulation of E-cadherin expression (2.7 × 10 times compared with parental cells). We also found that the histone deacetylase inhibitor, MS-275, restored E-cadherin expression and moderate sensitivity to erlotinib in HCC4006ER cells, on the other hand, transforming growth factor beta, an inducer of EMT, led to moderate erlotinib resistance in HCC4006 parental cells. CONCLUSIONS: This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR-mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib.
• 原発性肺癌に対する肺全摘術の検討

  尾関 直樹; 伊藤 志門; 須田 健一; 富沢 健二; 小林 祥久; 厚田 幸子; 丹羽 由紀子; 遠藤 秀樹; 福井 高幸; 安部 哲也; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 25 (3) P26 - 06 0919-0945 2011/04
• 肺癌地域連携パスにおける再発への介入タスクの検討

  伊藤 志門; 尾関 直樹; 小林 祥久; 厚田 幸子; 丹羽 由紀子; 須田 健一; 富沢 健二; 遠藤 秀紀; 福井 高幸; 安部 哲也; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 25 (3) P92 - 03 0919-0945 2011/04
• 遺伝子診断にもとづくこれからの肺がん治療 (肺がんのすべて) -- (肺がんに負けない)

  須田 健一; 光冨 徹哉

  からだの科学 日本評論社 (270) 119 - 123 0453-3038 2011
• Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer.

  Kenichi Suda; Isao Murakami; Tatsuya Katayama; Kenji Tomizawa; Hirotaka Osada; Yoshitaka Sekido; Yoshihiko Maehara; Yasushi Yatabe; Tetsuya Mitsudomi

  Clinical cancer research : an official journal of the American Association for Cancer Research 16 (22) 5489 - 98 2010/11 [Refereed]
   

  PURPOSE: In epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer patients, acquired resistance develops almost inevitably and this limits the improvement in patient outcomes. EGFR T790M mutation and MET amplification are the two main mechanisms underlying this resistance, but the relationship between these two mechanisms is unclear. In this study, we explored their relationship using in vitro models and autopsy specimens. EXPERIMENTAL DESIGN: Erlotinib-resistant HCC827 (HCC827ER) cells were developed by chronic exposure to erlotinib at increasing concentrations. HCC827EPR cells were also developed by chronic exposure to erlotinib in the presence of PHA-665,752 (a MET TKI). The erlotinib-resistant mechanisms of these cells were analyzed. In addition, 33 autopsy tumor samples from 6 lung adenocarcinoma patients harboring multiple gefitinib-refractory tumors were analyzed. RESULTS: HCC827ER developed MET amplification, and clinically relevant resistance occurred at ≥4-fold MET gene copy number gain (CNG). By contrast, HCC827EPR developed T790M without MET CNG. Of six patients harboring gefitinib-refractory tumors, three exhibited T790M only, one exhibited MET amplification only, and the other two exhibited T790M and/or MET amplification depending on the lesion sites. In these gefitinib-refractory tumors, T790M developed in 93% (14 of 15) of tumors without MET gene CNGs, in 80% (4 of 5) of tumors with moderate MET gene CNGs (<4-fold), and in only 8% (1 of 13) of tumors with MET amplification (≥4-fold). CONCLUSIONS: These results indicate a reciprocal and complementary relationship between T790M and MET amplification and the necessity of concurrent inhibition of both for further improving patient outcomes.
• Analysis of ERBB4 mutations and expression in japanese patients with lung cancer.

  Kenji Tomizawa; Kenichi Suda; Ryoichi Onozato; Hiroyuki Kuwano; Yasushi Yatabe; Tetsuya Mitsudomi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 5 (11) 1859 - 61 2010/11 [Refereed]
   

  Only the kinase domain of ERBB4 has been analyzed in East Asian populations, but a recent large-scale mutation analysis has indicated a higher incidence of mutations in the extracellular domain. Mutations in the extracellular and kinase domains of ERBB4 were examined by direct sequencing in 72 patients with primary lung cancer and 8 cell lines. In addition, ERBB4 expression was determined in 60 patients by quantitative real-time polymerase chain reaction. We investigated the relationship between ERBB4 expression and clinicopathologic characteristics including prognosis. One patient possessed Q793Q polymorphism in the kinase domain. However, we detected no mutations in extracellular or kinase domains of ERBB4. There was no significant difference in the clinicopathologic characteristics including prognosis of patients with high or low expression of ERBB4. The clinical significance of ERBB4 in lung cancers is negligible.
• チロシンキナーゼ阻害剤に対する耐性獲得後にペメトレキセドが有効であった肺癌の3例

  小林 祥久; 福井 高幸; 須田 健一; 富沢 健二; 厚田 幸子; 丹羽 由紀子; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 50 (5) 496 - 496 0386-9628 2010/10
• 非小細胞肺癌の剖検検体におけるEGFR遺伝子活性化変異の原発巣と転移巣間のheterogeneityの検討

  村上 功; 片山 達也; 須田 健一; 西村 好史; 増田 憲治; 赤山 幸一; 柴田 諭; 光冨 徹哉; 重藤 えり子

  肺癌 (NPO)日本肺癌学会 50 (5) 535 - 535 0386-9628 2010/10
• 1cm以下小型肺癌の自然史と臨床病理学的特徴

  小野里 良一; 福井 高幸; 須田 健一; 富沢 健二; 厚田 幸子; 丹羽 由紀子; 福本 紘一; 斎藤 卓也; 片山 達也; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 光冨 徹哉

  日本呼吸器外科学会雑誌 (一社)日本呼吸器外科学会 24 (3) 510 - 510 0919-0945 2010/04
• Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation.

  Kenichi Suda; Kenji Tomizawa; Tetsuya Mitsudomi

  Cancer metastasis reviews 29 (1) 49 - 60 2010/03 [Refereed]
   

  KRAS and epidermal growth factor receptor (EGFR) are the two most frequently mutated proto-oncogenes in adenocarcinoma of the lung. The occurrence of these two oncogenic mutations is mutually exclusive, and they exhibit many contrasting characteristics such as clinical background, pathological features of patients harboring each mutation, and prognostic or predictive implications. Lung cancers harboring the EGFR mutations are remarkably sensitive to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib. This discovery has dramatically changed the clinical treatment of lung cancer in that it almost doubled the duration of survival for lung cancer patients with an EGFR mutation. In this review, we describe the features of KRAS mutations in lung cancer and contrast these with the features of EGFR mutations. Recent strategies to combat lung cancer harboring KRAS mutations are also reviewed.
• 女性肺腺癌の病因と病態

  須田健一; 富沢健二; 光冨徹哉

  Annual Review 呼吸器 2010 91 - 99 2010/01
• Efficacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to gefitinib.

  Tatsuya Katayama; Junichi Shimizu; Kenichi Suda; Ryoichi Onozato; Takayuki Fukui; Simon Ito; Shunzo Hatooka; Taijiro Sueda; Toyoaki Hida; Yasushi Yatabe; Tetsuya Mitsudomi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 4 (11) 1415 - 9 2009/11 [Refereed]
   

  INTRODUCTION: The efficacy of high-dose (1250 mg/d) gefitinib for the treatment of leptomeningeal metastasis in a patient with lung cancer harboring a mutation in the epidermal growth factor receptor (EGFR) gene was previously reported. We speculate that erlotinib, instead of high dose of gefitinib, may be also effective for the treatment of central nervous system (CNS) lesions, as trough serum concentration of erlotinib is nine times higher than that of gefitinib. PATIENTS AND METHODS: Patients with lung cancer in whom CNS lesions developed after an initial good response to gefitinib for extra CNS lesions were enrolled in the study. Tumor response, performance status, neurologic symptoms, and survival were retrospectively evaluated. RESULTS: All seven patients had EGFR mutations in their primary tumors except one patient. The median interval between gefitinib withdrawal and erlotinib administration was 5 days. Three patients showed partial response, three had stable disease, and one had progressive disease. Performance status and symptoms improved in five patients. The overall survival from the initiation of erlotinib treatment ranged from 15 to 530 days (median, 88 days). CONCLUSIONS: Erlotinib was a reasonable option for the treatment of CNS diseases that appeared after a good initial response of extra CNS disease to gefitinib.
• 1cm以下小型肺癌切除症例の画像所見と臨床的特徴

  小野里 良一; 福井 高幸; 須田 健一; 富沢 健二; 厚田 幸子; 丹羽 由紀子; 福本 紘一; 斉藤 卓也; 片山 達也; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 光冨 徹哉

  肺癌 (NPO)日本肺癌学会 49 (5) 736 - 736 0386-9628 2009/10
• 食道がん周術期においてGFO(Glutamine Fiber Oligosaccharide)療法は手術侵襲を軽減するか?

  齊藤 卓也; 波戸岡 俊三; 安部 哲也; 丹羽 由紀子; 須田 健一; 厚田 幸子; 小野里 良一; 福本 紘一; 片山 達也; 福井 高幸; 伊藤 志門; 光冨 徹哉; 篠田 雅幸

  日本臨床外科学会雑誌 日本臨床外科学会 70 (増刊) 519 - 519 1345-2843 2009/10
• 肺癌の原因 喫煙と環境因子--最近の話題より (特集 増加する肺癌--早期診断と治療)

  須田 健一; 小野里 良一; 光冨 徹哉

  臨牀と研究 大道学館出版部 86 (7) 818 - 823 0021-4965 2009/07
• 【HGF/c-Met】Interface on Cancer Therapy METの増幅、変異、多型

  小野里 良一; 須田 健一; 高坂 貴行; 光冨 徹哉

  がん分子標的治療 (株)メディカルレビュー社 7 (2) 117 - 123 1347-6955 2009/04 

  近年、がん治療の新たな分子標的として肝細胞増殖因子(HGF)のチロシンキナーゼ受容体であるMETが注目され、MET阻害剤の開発が進んでいる。MET遺伝子増幅は胃がん、大腸がん、肺がんで、MET遺伝子変異は腎がん、頭頸部がん、肝細胞がん、肺がんなどに存在する。MET遺伝子の遺伝子増幅や突然変異などによりMETは活性化され、細胞増殖・生存・形態形成・浸潤などに関与している。MET遺伝子増幅は非小細胞肺がんにおいて、EGFRチロシンキナーゼ阻害剤に対する獲得耐性機序の1つとされる。がんにおけるMETの遺伝子異常を解明するため、研究努力がなされている。(著者抄録)
• 【呼吸器症候群(第2版) その他の呼吸器疾患を含めて】腫瘍性疾患 上皮性(原発性)腫瘍 EGF受容体遺伝子変異を有する肺癌

  須田 健一; 小野里 良一; 高坂 貴行; 光冨 徹哉

  日本臨床 (株)日本臨床社 別冊 (呼吸器症候群III) 5 - 8 0047-1852 2009/03
• A resected case of symptomatic rib-originated fibrous dysplasia

  Suda Kenichi; Shoji Fumihiro; Kometani Takuro; Yano Tokujiro; Maehara Yoshihiko

  The journal of the Japanese Association for Chest Surgery The Japanese Association for Chest Surgery 23 (1) 62 - 65 0919-0945 2009/01 

  Fibrous dysplasia is not a rare disease in the orthopedic department. Ribs (especially the second rib) are sometimes involved, but symptomatic cases which require surgical resection are rare. We report a 48-year-old man with painful fibrous dysplasia which originated from the right second rib. Resection of the involved chest wall and reconstruction was performed, and his symptoms disappeared after surgery.
• EGFR T790M mutation: a double role in lung cancer cell survival?

  Kenichi Suda; Ryoichi Onozato; Yasushi Yatabe; Tetsuya Mitsudomi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 4 (1) 1 - 4 2009/01 [Refereed]
   

  Even though lung cancer patients harboring a mutation in the epidermal growth factor receptor (EGFR) gene exhibit an initial dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance is almost inevitable after a progression-free period of approximately 10 months. A secondary point mutation that substitutes methionine for threonine at amino acid position 790 (T790M) is a molecular mechanism that produces a drug-resistant variant of the targeted kinase. The T790M mutation is present in about half of the lung cancer patients with acquired resistance, and reported to act by increasing the affinity of the receptor to adenosine triphosphate, relative to its affinity to TKIs. Nevertheless, several lines of evidence indicate that the T790M mutation confers growth advantage to cancer cells, and it was shown that mice expressing tetracycline-inducible EGFR transgenes harboring the T790M mutation develop lung tumors. Thus, T790M mutation seems to play a double role in the survival of lung cancer cells. Several second-generation EGFR-TKIs are currently being developed to overcome the acquired resistance caused by the T790M mutation. MET (met proto-oncogene) amplification or activation of IGF1R are reported as alternative mechanisms for acquired resistance to EGFR-TKIs. Clarification of the pathways leading to acquired resistance is essential to maximize the efficacy of EGFR-TKI therapy for patients with lung cancer.
• 治療TODAY 癌治療の分子標的としてのHGF-MET系

  光冨 徹哉; 小野里 良一; 須田 健一

  SRL宝函 (株)エスアールエル 29 (1) 30 - 37 0912-0912 2008/07

MISC

• EGFR陽性肺癌におけるEGFR-TKIを用いた術後補助療法—Adjuvant therapy using EGFR-TKI in resected EGFR-mutated NSCLC—特集 肺癌診療ガイドライン2022年版を読み解く : 薬物治療を中心に ; 周術期治療

  濵田 顕; 須田 健一; 津谷 康大; 光冨 徹哉  呼吸器内科 = Respiratory medicine / 呼吸器内科編集委員会 編  44-  (4)  387  -391  2023/10
• 【外科手術と感染症】呼吸器外科 術後膿胸への対応

  須田 健一  外科  85-  (5)  565  -571  2023/04
• 胸壁浸潤を伴う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  日本ロボット外科学会学術集会プログラム・抄録集  15th-  2023
• 肺がん周術期がん免疫治療の現状とバイオマーカー

  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
• Minimal Residual Disease

  須田健一; 小原秀太; 宗淳一; 津谷康大; 光冨徹哉  日本癌治療学会学術集会(Web)  61st-  2023
• 原発不明癌に対するニボルマブ治療中に肺サルコイド様肉芽腫変化をきたした一例

  川中雄介; 田中薫; 須田健一; 高濱隆幸; 林秀敏  日本肺癌学会学術集会号  64th (CD-ROM)-  2023
• 末梢小型肺癌に対する区域切除における最適な切除マージンの確保-SuReFInDを用いた術中モニタリングの有用性-

  吉川真理子; 須田健一; 千葉眞人; 深見朋世; 小原秀太; 濱田顕; 下治正樹; 伊藤正興; 武本智樹; 宗淳一; 津谷康大  日本胸部外科学会定期学術集会(Web)  76th-  2023
• ロボット支援下胸腔鏡手術における術中損傷のピットフォールを考察する

  下治正樹; 宗淳一; 福田祥大; 老木華; 深見朋世; 小原秀太; 浜田顕; 千葉眞人; 伊藤正興; 須田健一; 武本智樹; 津谷康大  日本胸部外科学会定期学術集会(Web)  76th-  2023
• ロボット支援下解剖学的肺切除術時の気管支損傷を考察する

  宗淳一; 武本智樹; 福田祥大; 小原秀太; 濱田顕; 千葉眞人; 下治正樹; 須田健一; 津谷康大  日本呼吸器外科学会総会(Web)  40th-  2023
• 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総会(Web)  40th-  2023
• 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総会(Web)  40th-  2023
• 臨床病期I期非小細胞肺癌におけるRAVATを用いた画像的標準化PET/CT定量値の有用性

  濱田顕; 須田健一; 宗淳一; 吉田幸弘; 橋本昌樹; 竹ヶ原京志郎; 長谷川誠紀; 臼田実男; 津谷康大; 光冨徹哉  日本呼吸器外科学会総会(Web)  40th-  2023
• 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(Web)  63-  (3)  2023
• 肺がんを知る 飽くなき探求心を引き継いで

  須田 健一  肺癌  62-  (6)  481  -481  2022/11
• 早期肺癌の質的診断と術式決定 臨床病期I期非小細胞肺癌における標準化PET/CT定量値を用いた肺癌予後層別化の多施設共同研究

  濱田 顕; 須田 健一; 宗 淳一; 吉田 幸弘; 橋本 昌樹; 竹ヶ原 京志郎; 長谷川 誠紀; 臼田 実男; 光冨 徹哉  日本呼吸器外科学会雑誌  36-  (Suppl.)  SY1  -5  2022/05
• 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  2022/05
• 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  2022/05
• 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  2022/05
• 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  2022/05
• 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  2022/05
• 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  2022/05
• Uniportal VATSの発展と適応拡大

  千葉眞人; 宗淳一; 福田祥大; 小原秀太; 浜田顕; 下治正樹; 武本智樹; 須田健一; 光冨徹哉; 津谷康大  日本肺癌学会学術集会号  63rd (CD-ROM)-  2022
• 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; 浜田顕; 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(Web)  62-  (5)  2022
• Uniportal VATSの適応拡大-縦隔リンパ節郭清・気管支形成・複雑区域切除への応用-

  千葉眞人; 宗淳一; 福田祥大; 小原秀太; 浜田顕; 下治正樹; 武本智樹; 須田健一; 光冨徹哉; 津谷康大  日本胸部外科学会定期学術集会(Web)  75th-  2022
• Uniportal VATSにおけるエンブロックな縦隔リンパ節郭清

  千葉 眞人; 宗 淳一; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 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  35-  (3)  RV9  -1  2021/05
• 肺葉切除における単孔式手術とロボット支援下手術の利点・欠点を踏まえたベストマッチアプローチ法の検討

  宗 淳一; 千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 西野 将矢; 下治 正樹; 須田 健一; 光冨 徹哉  日本呼吸器外科学会雑誌  35-  (3)  O19  -6  2021/05
• 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  2021/05
• 胸腺腫瘍切除例におけるCT値とWHO分類の関連

  下治 正樹; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 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  35-  (3)  MO6  -5  2021/05
• 高齢者肺癌葉切除における縦隔リンパ節郭清の意義

  西野 将矢; 宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 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  35-  (3)  MO70  -1  2021/05
• 左B1+2分岐異常領域に発生した小型肺癌の1切除例

  藤野 智大; 須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 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  35-  (3)  MO90  -3  2021/05
• 「pN陽性」非小細胞肺がんにおけるすりガラス成分の有無の予後因子としての意義

  須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 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  35-  (3)  MO99  -5  2021/05
• Spatial heterogeneity of acquired resistance mechanisms to 1st/2nd-generation EGFR-TKIs in lung cancer

  Kenichi Suda; Isao Murakami; Keiko Obata; Toshio Fujino; Kazuko Sakai; Junichi Soh; Kazuto Nishio; Tetsuya Mitsudomi  CANCER SCIENCE  112-  444  -444  2021/02
• 術中cone beam CTを用いて肺内小結節を同定し得た胸腔鏡下肺部分切除術の1例

  前川 昌平; 須田 健一; 福田 祥大; 古形 修平; 佐々木 隆士  日本小児外科学会雑誌  56-  (6)  982  -987  2020/10
• KRAS G12C阻害剤の感受性ならびに耐性二次変異の検索

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 濱田 顕; 宗 淳一; 光冨 徹哉  肺癌  60-  (6)  533  -533  2020/10
• 臨床病期I期肺扁平上皮癌における画像的特徴と治療成績の検討

  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  2020/10
• 第1/2世代EGFRキナーゼ阻害剤に対する獲得耐性機序のinter-tumor heterogeneityとその臨床的意義

  須田 健一; 村上 功; 小畑 慶子; 藤野 智大; 坂井 和子; 宗 淳一; 西尾 和人; 光冨 徹哉  日本癌学会総会記事  79回-  OE14  -4  2020/10
• LUX-Lung 8試験で検出されたHER2変異を有する肺扁平上皮癌におけるアファチニブの有効性に関する検証研究

  濱田 顕; 須田 健一; 藤野 智大; 宗 淳一; 光冨 徹哉  日本癌学会総会記事  79回-  PJ14  -7  2020/10
• EGFR変異肺がんにおけるEGFRチロシンキナーゼ阻害剤耐性克服を目指したトランスレーショナルリサーチ

  須田 健一; 光冨 徹哉  日本癌学会総会記事  79回-  YIA  -10  2020/10
• 非小細胞肺癌に対する積極的縮小手術の適応と限界【International】臨床病期I期の充実型非小細胞肺癌患者における部分切除の臨床転帰(Clinical outcome of partial resection in the patients with completely solid non-small cell lung cancer of clinical stage I)

  宗 淳一; 小原 秀太; 藤野 智大; 濱田 顕; 古賀 教将; 西野 将矢; 千葉 眞人; 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  120回-  SY  -6  2020/08
• Nerve Integrity Monitoring(NIM)を用いて反回神経の走行を確認した右側大動脈弓を有する左上葉肺癌の1切除例

  老木 華; 須田 健一; 西野 将矢; 千葉 眞人; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 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  120回-  RS  -1  2020/08
• 肺腫瘍切除検体由来のLung Tumor Organoidの樹立と解析

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顕; 千葉 眞人; 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  120回-  SF  -2  2020/08
• Pure solidを呈するもPET陰性であった原発性肺癌の臨床病理学的特徴

  須田 健一; 小原 秀太; 西野 将矢; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 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  120回-  SF  -7  2020/08
• 非小細胞肺癌切除例における血液型の臨床的意義

  小原 秀太; 須田 健一; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 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  120回-  DP  -2  2020/08
• 非小細胞肺癌切除例における予後栄養指数 低BMI症例においても予後不良因子となるか?

  西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 濱田 顕; 千葉 眞人; 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  120回-  DP  -3  2020/08
• 浸潤性腺癌における亜型の充実型・微小乳頭型の有無による臨床病理学的特徴の解析

  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; 須田 健一; 宗 淳一; 光冨 徹哉  日本外科学会定期学術集会抄録集  120回-  DP  -1  2020/08
• 新規低侵襲(単孔式・ロボット支援)手術におけるヒヤリハット Uniportal VATSにおけるヒヤリハット 逸脱例からの考察

  千葉 眞人; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉  日本呼吸器外科学会雑誌  34-  (3)  VWS2  -2  2020/08
• ロボット支援下肺葉切除術導入時のヒヤリハットを考察する 胸壁損傷とその対策

  宗 淳一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顯; 千葉 眞人; 須田 健一; 武本 智樹; 光冨 徹哉  日本呼吸器外科学会雑誌  34-  (3)  V1  -4  2020/08
• 80代IA期非小細胞肺癌の手術成績 GGO成分の有無別の検討

  濱田 顕; 須田 健一; 西野 将矢; 千葉 眞人; 武本 智樹; 宗 淳一; 塩野 知志; 光冨 徹哉  日本呼吸器外科学会雑誌  34-  (3)  O35  -1  2020/08
• 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  2020/08
• 切除肺に10個以上の病変を認めた多発肺腺癌の3例

  古賀 教将; 須田 健一; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 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  34-  (3)  MO10  -6  2020/08
• 異所性子宮内膜症由来が疑われた横隔膜明細胞癌の1切除例

  波江野 真大; 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; 太田 真見子; 前西 修; 宗 淳一; 光冨 徹哉  日本呼吸器外科学会雑誌  34-  (3)  MO29  -1  2020/08
• 非小細胞肺癌における術前NLR高値は、腫瘍のPD-L1発現と関連する

  藤野 智大; 須田 健一; 下治 正樹; 濱田 顕; 小原 秀太; 古賀 教将; 西野 将矢; 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  34-  (3)  MO36  -5  2020/08
• 掻把術にて根治できなかった難治性術後膿胸に対するクリスタルバイオレットを用いた胸腔内洗浄の有用性

  須田 健一; 小原 秀太; 西野 将矢; 古賀 教将; 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  34-  (3)  MO59  -1  2020/08
• Next-generation sequencing(NGS)を用いたctDNAの外科切除症例における再発予測因子としての意義

  小原 秀太; 須田 健一; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉; 小原 秀太; 坂井 和子; 西尾 和人  肺癌  60-  (2)  156  -157  2020/04
• 肺癌切除検体を用いたLung tumor organoidの樹立と解析

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顯; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  60-  (2)  160  -160  2020/04
• Next-generation sequencing(NGS)を用いたctDNAの外科切除症例における再発予測因子としての意義

  小原秀太; 須田健一; 藤野智大; 古賀教将; 西野将矢; 浜田顕; 千葉眞人; 武本智樹; 宗淳一; 光冨徹哉; 小原秀太; 坂井和子; 西尾和人  肺癌(Web)  60-  (2)  2020
• 近未来の病理診断 Digital Spatial Profiling Technologyを用いての肺原発Carcinosarcomaの検討

  清水 重喜; 坂井 和子; 白石 直樹; 小原 秀太; 須田 健一; 武本 智樹; 筑後 孝章; 佐藤 隆夫; 光冨 徹哉; 西尾 和人  肺癌  59-  (6)  559  -559  2019/11
• 第8版Stage分類の妥当性と問題点 IA期非小細胞肺がんの予後は腫瘍径よりGGO成分の有無に依存する

  濱田 顕; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 千葉 眞人; 武本 智樹; 宗 淳一; 塩野 知志; 光冨 徹哉  肺癌  59-  (6)  565  -565  2019/11
• 早期社会復帰を目指したチーム医療の取り組み 胸部手術患者における早期社会復帰を目指した訪問看護ステーションとの連携

  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; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  591  -591  2019/11
• Occultリンパ節転移の予測因子に関する検討

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顯; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  679  -679  2019/11
• ハイブリッド手術室での胸腔鏡下肺部分切除術における体位固定の工夫

  永田 裕一朗; 高須 健二; 須田 健一  肺癌  59-  (6)  689  -689  2019/11
• MET exon14 skipping変異陽性多形癌におけるInter-tumor Heterogeneityの検討

  藤野 智大; 須田 健一; 村上 功; 小原 秀太; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  695  -695  2019/11
• Next-generation sequencing(NGS)を用いた外科切除症例における再発予測因子としての意義

  小原 秀太; 須田 健一; 坂井 和子; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 西尾 和人; 光冨 徹哉  肺癌  59-  (6)  698  -698  2019/11
• Uniportal VATS導入と定型化

  千葉 眞人; 武本 智樹; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  718  -718  2019/11
• 肺切除術前のCOPD合併患者において吸気筋トレーニングにより横隔膜動態、運動耐容能が改善した1症例

  水澤 裕貴; 東本 有司; 白石 匡; 藤田 修平; 杉谷 竜司; 須田 健一; 武本 智樹; 木村 保; 光冨 徹哉; 福田 寛二  肺癌  59-  (6)  821  -821  2019/11
• 肺切除術施行患者に対し、退院直後から訪問看護・リハビリテーションが有効であった症例

  岡島 聡; 前田 和成; 武本 智樹; 井関 歩; 岸本 英樹; 西野 将矢; 千葉 眞人; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  825  -825  2019/11
• 在宅酸素療法を導入した肺切除術患者に対し、訪問看護の介入が生活の質の改善に有効であった1例

  前田 和成; 岡島 聡; 千葉 眞人; 岩井 真理子; 岡島 章子; 西野 将矢; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  825  -825  2019/11
• 高齢者肺癌切除例における予後因子と術後合併症のリスク因子

  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  2019/11
• 人生100年時代の肺がん治療 外科医の立場から

  宗 淳一; 富沢 健二; 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; 須田 健一; 杉本 誠一郎; 豊岡 伸一; 光冨 徹哉  肺癌  59-  (6)  853  -853  2019/11
• Uniportal VATS導入と定型化

  千葉 眞人; 武本 智樹; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 濱田 顕; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  718  -718  2019/11
• 第8版Stage分類の妥当性と問題点 IA期非小細胞肺がんの予後は腫瘍径よりGGO成分の有無に依存する

  濱田 顕; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 千葉 眞人; 武本 智樹; 宗 淳一; 塩野 知志; 光冨 徹哉  肺癌  59-  (6)  565  -565  2019/11
• 早期社会復帰を目指したチーム医療の取り組み 胸部手術患者における早期社会復帰を目指した訪問看護ステーションとの連携

  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; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  591  -591  2019/11
• Occultリンパ節転移の予測因子に関する検討

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顯; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  679  -679  2019/11
• MET exon14 skipping変異陽性多形癌におけるInter-tumor Heterogeneityの検討

  藤野 智大; 須田 健一; 村上 功; 小原 秀太; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  695  -695  2019/11
• 肺切除術前のCOPD合併患者において吸気筋トレーニングにより横隔膜動態、運動耐容能が改善した1症例

  水澤 裕貴; 東本 有司; 白石 匡; 藤田 修平; 杉谷 竜司; 須田 健一; 武本 智樹; 木村 保; 光冨 徹哉; 福田 寛二  肺癌  59-  (6)  821  -821  2019/11
• 肺切除術施行患者に対し、退院直後から訪問看護・リハビリテーションが有効であった症例

  岡島 聡; 前田 和成; 武本 智樹; 井関 歩; 岸本 英樹; 西野 将矢; 千葉 眞人; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  825  -825  2019/11
• 在宅酸素療法を導入した肺切除術患者に対し、訪問看護の介入が生活の質の改善に有効であった1例

  前田 和成; 岡島 聡; 千葉 眞人; 岩井 真理子; 岡島 章子; 西野 将矢; 須田 健一; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (6)  825  -825  2019/11
• 高齢者肺癌切除例における予後因子と術後合併症のリスク因子

  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  2019/11
• 人生100年時代の肺がん治療 外科医の立場から

  宗 淳一; 富沢 健二; 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; 須田 健一; 杉本 誠一郎; 豊岡 伸一; 光冨 徹哉  肺癌  59-  (6)  853  -853  2019/11
• 近未来の病理診断 Digital Spatial Profiling Technologyを用いての肺原発Carcinosarcomaの検討

  清水 重喜; 坂井 和子; 白石 直樹; 小原 秀太; 須田 健一; 武本 智樹; 筑後 孝章; 佐藤 隆夫; 光冨 徹哉; 西尾 和人  肺癌  59-  (6)  559  -559  2019/11
• Next-generation sequencing(NGS)を用いた外科切除症例における再発予測因子としての意義

  小原 秀太; 須田 健一; 坂井 和子; 藤野 智大; 古賀 教将; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 西尾 和人; 光冨 徹哉  肺癌  59-  (6)  698  -698  2019/11
• がん治療抵抗性の機能解明とその克服法の開発 EGFR変異肺がんにおける併用療法の可能性 drug toleranceと耐性機序の"destiny"(Tolerance to cancer therapy: mechanism and therapeutics Combination strategies for lung cancers with EGFR mutation: drug tolerance and "destiny")

  須田 健一; 光冨 徹哉  日本癌学会総会記事  78回-  IS1  -4  2019/09
• EGFRエクソン20挿入変異モデルにおけるタロキソチニブおよびポジオチニブに対する耐性二次変異としてのT790MおよびC797S(T790M or C797S confers acquired resistance to tarloxotinib and poziotinib in EGFR exon 20 insertion models in vitro)

  西野 将矢; 西野 将矢; 須田 健一; 古賀 教将; 藤野 智大; 小原 秀太; 宗 淳一; Avanish Vellanki; Vijaya Tirunagaru; 光冨 徹哉  日本癌学会総会記事  78回-  P  -2365  2019/09
• MET exon 14 skippingモデルを用いたMET-TKI耐性に関わる二次的変異の探索(Comprehensive analysis of secondary resistant mutations to MET-TKIs for MET exon 14 skipping in vitro)

  藤野 智大; 須田 健一; 小林 祥久; 古賀 教将; 西野 将矢; 小原 秀太; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  日本癌学会総会記事  78回-  P  -3139  2019/09
• がん治療抵抗性の機能解明とその克服法の開発 EGFR変異肺がんにおける併用療法の可能性 drug toleranceと耐性機序の"destiny"(Tolerance to cancer therapy: mechanism and therapeutics Combination strategies for lung cancers with EGFR mutation: drug tolerance and "destiny")

  須田 健一; 光冨 徹哉  日本癌学会総会記事  78回-  IS1  -4  2019/09
• EGFRエクソン20挿入変異モデルにおけるタロキソチニブおよびポジオチニブに対する耐性二次変異としてのT790MおよびC797S(T790M or C797S confers acquired resistance to tarloxotinib and poziotinib in EGFR exon 20 insertion models in vitro)

  西野 将矢; 西野 将矢; 須田 健一; 古賀 教将; 藤野 智大; 小原 秀太; 宗 淳一; Avanish Vellanki; Vijaya Tirunagaru; 光冨 徹哉  日本癌学会総会記事  78回-  P  -2365  2019/09
• MET exon 14 skippingモデルを用いたMET-TKI耐性に関わる二次的変異の探索(Comprehensive analysis of secondary resistant mutations to MET-TKIs for MET exon 14 skipping in vitro)

  藤野 智大; 須田 健一; 小林 祥久; 古賀 教将; 西野 将矢; 小原 秀太; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  日本癌学会総会記事  78回-  P  -3139  2019/09
• 腕神経叢由来の縦隔神経鞘腫に対しUniport腫瘍核出術を施行し症状改善をみた1例

  福田 祥大; 千葉 眞人; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 須田 健一; 武本 智樹; 光冨 徹哉  肺癌  59-  (4)  424  -424  2019/08
• Uniportal VATS 50例の経験

  千葉 眞人; 武本 智樹; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顕; 古賀 教将; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (4)  424  -425  2019/08
• 切除した右上葉と左S6に計12個の病変を認めた多発肺腺癌の1例

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (4)  428  -429  2019/08
• Uniportal VATS 50例の経験

  千葉 眞人; 武本 智樹; 福田 祥大; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顕; 古賀 教将; 須田 健一; 宗 淳一; 光冨 徹哉  肺癌  59-  (4)  424  -425  2019/08
• 切除した右上葉と左S6に計12個の病変を認めた多発肺腺癌の1例

  古賀 教将; 須田 健一; 小原 秀太; 藤野 智大; 西野 将矢; 濱田 顕; 千葉 眞人; 武本 智樹; 宗 淳一; 光冨 徹哉  肺癌  59-  (4)  428  -429  2019/08
• Potent in vitro activity of Tarloxotinib for EGFR C797S and other mutations refractory to current EGFR tyrosine kinase inhibitors

  Kenichi Suda; Masaya Nishino; Takamasa Koga; Toshio Fujino; Yoshihisa Kobayashi; Tetsuya Mitsudomi; Avanish Vellanki; Vijaya G. Tirunagaru  CANCER RESEARCH  79-  (13)  2019/07
• 【肺がん・頭頸部がん】第3世代EGFR阻害薬の耐性機構とその克服

  西野 将矢; 須田 健一; 光冨 徹哉  腫瘍内科  23-  (5)  449  -455  2019/05
• 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  2019/04
• 肺葉切除患者における訪問看護ステーションとの連携の有用性の検討

  武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 須田 健一; 光冨 徹哉  日本外科学会定期学術集会抄録集  119回-  SF  -8  2019/04
• 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  2019/04
• 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  2019/04
• 超重喫煙(BI 2000以上)I期非小細胞肺癌切除例の短期予後と長期予後

  西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 千葉 眞人; 武本 智樹; 光冨 徹哉  日本呼吸器外科学会雑誌  33-  (3)  P113  -6  2019/04
• 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  2019/04
• 肺腺がんにおけるPD‐L1発現―すりガラス陰影の有無との関連

  須田健一; 下治正樹; 西野将矢; 藤野智大; 古賀教将; 小原秀太; 千葉眞人; 武本智樹; 清水重喜; 光冨徹哉  日本外科学会定期学術集会(Web)  119回-  SF  -3  2019/04
• 当院におけるUniportal VATSの導入

  千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 須田 健一; Gonzalez Rivas Diego; Young Timothy; 光冨 徹哉  日本呼吸器外科学会雑誌  33-  (3)  V1  -1  2019/04
• 肺葉切除患者における訪問看護ステーションとの連携の有用性の検討

  武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 須田 健一; 光冨 徹哉  日本外科学会定期学術集会抄録集  119回-  SF  -083  2019/04
• 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  2019/04
• 当院におけるUniportal VATSの導入

  千葉 眞人; 武本 智樹; 小原 秀太; 藤野 智大; 西野 将矢; 古賀 教将; 須田 健一; Gonzalez Rivas Diego; Young Timothy; 光冨 徹哉  日本呼吸器外科学会雑誌  33-  (3)  V1  -1  2019/04
• 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  2019/04
• 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  2019/04
• 超重喫煙(BI 2000以上)I期非小細胞肺癌切除例の短期予後と長期予後

  西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 千葉 眞人; 武本 智樹; 光冨 徹哉  日本呼吸器外科学会雑誌  33-  (3)  P113  -6  2019/04
• 術前COPD患者に対して運動療法と吸気筋トレーニングの併用により横隔膜動態、肺機能、運動耐容能の改善を認めた1症例

  水澤 裕貴; 白石 匡; 藤田 修平; 杉谷 竜司; 釜田 千聡; 須田 健一; 武本 智樹; 木村 保; 光冨 徹哉; 福田 寛二  近畿理学療法学術大会  58回-  5  -5  2019/01
• In vitro evaluation of EGFR secondary mutations at front-line osimertinib progression in lung cancers

  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  2018/12
• 早期非小細胞肺がんにおけるPD-L1発現 腫瘍発生部位に着目した検討

  須田 健一; 下治 正樹; 西野 将矢; 藤野 智大; 古賀 教将; 小原 秀太; 千葉 眞人; 武本 智樹; 清水 重喜; 光冨 徹哉  肺癌  58-  (6)  511  -511  2018/10
• In vitroモデルにおけるMET Exon14 mutationに対する最適なMET-TKIの探索

  藤野 智大; 須田 健一; 小林 祥久; 古賀 教将; 西野 将矢; 小原 秀太; 千葉 眞人; 下治 正樹; 武本 智樹; 光冨 徹哉  肺癌  58-  (6)  602  -602  2018/10
• 早期非小細胞肺がんにおけるPD-L1発現 腫瘍発生部位に着目した検討

  須田 健一; 下治 正樹; 西野 将矢; 藤野 智大; 古賀 教将; 小原 秀太; 千葉 眞人; 武本 智樹; 清水 重喜; 光冨 徹哉  肺癌  58-  (6)  511  -511  2018/10
• 肺切除後における訪問看護ステーションとの連携の有用性の検討

  武本 智樹; 小原 秀太; 藤野 智大; 古賀 教将; 西野 将矢; 小林 祥久; 千葉 眞人; 下治 正樹; 須田 健一; 光冨 徹哉  肺癌  58-  (6)  556  -556  2018/10
• 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  2018/10
• 臨床病期I期の肺神経内分泌癌切除症例の検討

  古賀 教将; 須田 健一; 吉本 健太郎; 小原 秀太; 藤野 智大; 西野 将矢; 千葉 眞人; 下治 正樹; 白石 健治; 池田 公英; 脇本 譲二; 森 毅; 武本 智樹; 久保田 伊知郎; 鈴木 実; 光冨 徹哉  肺癌  58-  (6)  722  -722  2018/10
• 一次治療オシメルチニブに対する耐性二次変異の検討(In vitro evaluation of EGFR secondary mutations at front-line osimertinib progression in lung cancers)

  西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 小林 祥久; 千葉 眞人; 下治 正樹; 富沢 健二; 武本 智樹; 光冨 徹哉  日本癌学会総会記事  77回-  1883  -1883  2018/09
• 一次治療オシメルチニブに対する耐性二次変異の検討(In vitro evaluation of EGFR secondary mutations at front-line osimertinib progression in lung cancers)

  西野 将矢; 須田 健一; 小原 秀太; 藤野 智大; 古賀 教将; 小林 祥久; 千葉 眞人; 下治 正樹; 富沢 健二; 武本 智樹; 光冨 徹哉  日本癌学会総会記事  77回-  1883  -1883  2018/09
• 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  2018/04
• 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  2018/04
• 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  2018/04
• 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  2018/04
• 原発性肺癌術後の脳転移に対する頭部MRIスクリーニング

  富沢 健二; 藤野 智大; 小原 秀太; 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-  2159  -2159  2018/04
• EGFR-TKI獲得耐性に伴う上皮間葉転換(EMT)におけるCD44の役割

  須田 健一; 村上 功; Kim Jihye; Rivard Christopher J; 光冨 徹哉; Hirsch Fred R  日本外科学会定期学術集会抄録集  118回-  2163  -2163  2018/04
• 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  2018/04
• 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  2018/04
• 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  2018/04
• 左上葉肺癌に対して左上葉+S6区域ダブルスリーブ切除を施行した1切除例

  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  日本胸部外科学会定期学術集会(Web)  71st-  ROMBUNNO.2CHAIV3‐1 (WEB ONLY)  2018
• 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(Web)  58-  (2)  155‐156(J‐STAGE)  2018
• 胸腺上皮腫瘍切除例におけるFDG‐PETの臨床病理学的意義

  下治正樹; 須田健一; 小原秀太; 藤野智大; 西野将矢; 古賀教将; 佐藤克明; 千葉眞人; 富沢健二; 武本智樹; 光冨徹哉  日本胸部外科学会定期学術集会(Web)  71st-  ROMBUNNO.1P1HAIP3‐4 (WEB ONLY)  2018
• Acquired Resistance Mechanisms to EGFR Kinase Inhibitors Alter PD-L1 Expression Status in Lung Cancer

  Kenichi Suda; Leslie Rozeboom; Christopher Rivard; Hui Yu; Mary Ann Melnick; Trista Hinz; Kim Ellison; Daniel Chan; Katerina Politi; Lynn Heasley; Tetsuya Mitsudomi; Fred R. Hirsch  JOURNAL OF THORACIC ONCOLOGY  12-  (1)  S433  -S434  2017/01
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 佐藤 克明; 水内 寛; 坂井 和子; 須田 健一; 中村 雄; 坂野 恵里; 林 秀敏; デベラス・マルコ; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人  近畿大学医学雑誌  41-  (3-4)  20A  -20A  2016/12
• 慢性血液透析中の原発性肺癌切除例の臨床的検討

  富沢 健二; 瀬角 裕一; 小林 祥久; 千葉 眞人; 佐藤 克明; 下治 正樹; 須田 健一; 武本 智樹; 阪口 全宏; 光冨 徹哉  日本外科学会定期学術集会抄録集  116回-  PS  -229  2016/04
• 新TNM病期分類(第8版)に従った当院の肺癌切除症例の再分類と予後

  佐藤 克明; 富沢 健二; 瀬角 裕一; 小林 祥久; 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  30-  (3)  O8  -5  2016/04
• 新TNM病期分類(第8版)に基づいた病理病期I期の肺癌切除症例の予後評価

  富沢 健二; 佐藤 克明; 瀬角 裕一; 小林 祥久; 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  30-  (3)  P17  -7  2016/04
• Comparison of various EGFR tyrosine kinase inhibitors (TKIs) for tumors with exon 18 mutations of the EGFR gene

  Tetsuya Mitsudomi; Yoshihisa Kobayashi; Yosuke Togashi; Hiroshi Mizuuchi; Kenichi Suda; Kazuto NIshio  ANNALS OF ONCOLOGY  26-  83  -83  2015/11
• 非小細胞肺がんにおけるDDR2変異の機能解析

  寺嶋 雅人; 冨樫 庸介; 坂井 和子; 佐藤 克明; 須田 健一; 水上 拓郎; 坂野 恵里; 中村 雄; De Velasco Marco; 藤田 至彦; 冨田 秀太; 光冨 徹哉; 西尾 和人  日本癌学会総会記事  74回-  P  -2223  2015/10
• EGFR exon18変異肺癌の治療戦略 afatinibとneratinibに対する高感受性

  小林 祥久; 冨樫 庸介; 谷田部 恭; 水内 寛; 朴 将哲; 近藤 千晶; 須田 健一; 富沢 健二; 樋田 豊明; 西尾 和人; 光冨 徹哉  日本癌学会総会記事  74回-  E  -1176  2015/10
• EGFR exon18変異肺癌の頻度と各世代EGFR-TKIに対する奏効率の違い

  小林 祥久; 冨樫 庸介; 谷田部 恭; 水内 寛; 朴 将哲; 近藤 千晶; 下治 正樹; 佐藤 克明; 須田 健一; 富沢 健二; 武本 智樹; 樋田 豊明; 西尾 和人; 光冨 徹哉  肺癌  55-  (5)  454  -454  2015/10
• EGFR exon18変異肺癌の治療戦略 afatinibとneratinibに対する高感受性

  小林 祥久; 冨樫 庸介; 谷田部 恭; 水内 寛; 朴 将哲; 近藤 千晶; 須田 健一; 富沢 健二; 樋田 豊明; 西尾 和人; 光冨 徹哉  日本癌学会総会記事  74回-  E  -1176  2015/10
• Qualitative and Quantitative Heterogeniety in Acquiring Resistance to EGFR Kinase Inhibitors in Lung Cancer

  Kenichi Suda; Isao Murakami; Kazuko Sakai; Hiroshi Mizuuchi; Katsuaki Sato; Kenji Tomizawa; Kazuto Nishio; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  10-  (9)  S256  -S257  2015/09
• EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs

  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  2015/09
• Prevalence of Preoperative DVT in Japanese Patients Who Underwent Thoracic Surgery by Intensive Screeng

  Toshiki Takemoto; Yuichi Sesumi; Yoshihisa Kobayashi; Katsuaki Sato; Masato Chiba; Masaki Shimoji; Kenichi Suda; Kenji Tomizawa; Masahiro Sakaguchi; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  10-  (9)  S435  -S436  2015/09
• NAB2-STAT6融合遺伝子を有する肺実質内発生の孤立性線維性腫瘍の1切除例

  下治 正樹; 富沢 健二; 瀬角 裕一; 佐藤 克明; 小林 祥久; 千葉 眞人; 須田 健一; 武本 智樹; 坂口 全宏; 光冨 徹哉; 谷田部 恭  肺癌  55-  (4)  310  -310  2015/08
• 遺伝子診断が有用であった悪性軟部腫瘍の1例

  武本 智樹; 瀬角 裕一; 小林 祥久; 佐藤 克明; 千葉 眞人; 下治 正樹; 須田 健一; 富沢 健二; 阪口 全宏; 光冨 徹哉; 谷田部 恭  肺癌  55-  (4)  310  -311  2015/08
• 自然退縮後した巨大胸腺腫の1例

  富沢 健二; 瀬角 裕一; 小林 祥久; 千葉 眞人; 佐藤 克明; 下治 正樹; 須田 健一; 武本 智樹; 阪口 全宏; 光冨 徹哉  肺癌  55-  (4)  315  -316  2015/08
• Beyond PDでのEGFR-TKI投与と局所切除の併用で長期病勢制御し得た肺癌術後再発の1例

  小林 祥久; 水野 鉄也; 谷田部 恭; 朴 将哲; 水内 寛; 佐藤 克明; 下治 正樹; 須田 健一; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 坂尾 幸則; 光冨 徹哉  日本呼吸器外科学会雑誌  29-  (3)  O4  -2  2015/04
• NAB2-STAT6融合遺伝子を有する肺実質内発生の孤立性線維性腫瘍の1切除例

  下治 正樹; 谷田部 恭; 富沢 健二; 佐藤 克明; 水内 寛; 小林 祥久; 須田 健一; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉  日本呼吸器外科学会雑誌  29-  (3)  P35  -4  2015/04
• 肺腺がんにおける遺伝子異常とその病理形態学的特徴

  須田 健一; 佐藤 克明; 清水 重喜; 坂井 和子; 水内 寛; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 西尾 和人; 光冨 徹哉  日本呼吸器外科学会雑誌  29-  (3)  RO4  -7  2015/04
• 呼吸器 AXL陽性肺腺癌の臨床的・病理学的・分子生物学的特徴と予後

  佐藤 克明; 須田 健一; 清水 重喜; 坂井 和子; 水内 寛; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 西尾 和人; 光冨 徹也  日本外科学会定期学術集会抄録集  115回-  OP  -199  2015/04
• 呼吸器 IASLC/ATS/ERS新国際分類に基づく肺腺癌組織亜型における遺伝子変異の探索的検討

  須田 健一; 佐藤 克明; 清水 重喜; 坂井 和子; 水内 寛; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 西尾 和人; 光冨 徹哉  日本外科学会定期学術集会抄録集  115回-  OP  -199  2015/04
• EGFRキナーゼ阻害剤獲得耐性における分子異常のheterogeneityの検討とその克服

  須田 健一; 水内 寛; 村上 功; 坂井 和子; 西尾 和人; 光冨 徹哉  日本外科学会定期学術集会抄録集  115回-  CR  -2  2015/04
• Role of EGFR-TKI in adjuvant settings

  須田 健一; 光冨 徹哉  腫瘍内科 = Clinical oncology  15-  (2)  155  -161  2015/02
• すりガラス陰影(GGO)を呈する肺腺癌の遺伝子的特徴 増大する病変と変化しない病変の違い

  小林 祥久; 光冨 徹哉; 水野 鉄也; 黒田 浩章; 坂倉 範昭; 下治 正樹; 水内 寛; 佐藤 克明; 須田 健一; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 坂尾 幸則; 谷田部 恭  肺癌  54-  (5)  338  -338  2014/10
• 原発性肺癌における受容体型チロシンキナーゼAxlの発現と病理組織学的因子の検討

  佐藤 克明; 清水 重喜; 須田 健一; 水内 寛; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 坂井 和子; 冨田 秀太; 西尾 和人; 光冨 徹哉  肺癌  54-  (5)  389  -389  2014/10
• 上皮間葉転換したEGFR-TKI耐性HCC4006におけるABCB1過剰発現は微小管作用薬の交差耐性を誘導する(ABCB1 overexpression in EGFR-TKI resistant HCC4006 cells with EMT feature causes cross-resistant to anti-tubulin agents)

  水内 寛; 須田 健一; 冨田 秀太; 佐藤 克明; 小林 祥久; 下治 正樹; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 西尾 和人; 光冨 徹哉  日本癌学会総会記事  73回-  E  -1107  2014/09
• EGFR-TKI獲得耐性の分子生物学的・病理学的進展 T790M変異と小細胞肺癌形質転換(Molecular and pathological evolution in acquisition of resistance to EGFR-TKI-T790M mutation and SCLC transformation)

  須田 健一; 村上 功; 佐藤 克明; 冨田 秀太; 水内 寛; 坂井 和子; 清水 重喜; 富沢 健二; 武本 智樹; 阪口 全宏; 西尾 和人; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  73回-  E  -1108  2014/09
• 肺癌術後再発にEGFR-TKIをbeyond PDで計3年半投与後肺切除しさらにTKI継続中の1例

  小林 祥久; 水内 寛; 下治 正樹; 佐藤 克明; 須田 健一; 富沢 健二; 武本 智樹; 岩崎 拓也; 阪口 全宏; 光冨 徹哉; 谷田部 恭; 朴 将哲; 水野 鉄也; 坂尾 幸則  肺癌  54-  (4)  241  -241  2014/08
• PS-029-4 非小細胞肺癌細胞株における受容体型チロシンキナーゼリン酸化状態の解析(PS-029 肺 基礎-1,ポスターセッション,第114回日本外科学会定期学術集会)

  水内 寛; 須田 健一; 佐藤 克明; 武本 智樹; 岩崎 拓也; 南 憲司; 光冨 徹哉  日本外科学会雑誌  115-  (2)  632  -632  2014/03
• PS-176-3 EGFR野生型肺癌におけるエルロチニブ獲得耐性機序の探索(PS-176 基礎 発癌・バイオマーカー・その他-2,ポスターセッション,第114回日本外科学会定期学術集会)

  須田 健一; 水内 寛; 佐藤 克明; 武本 智樹; 岩崎 拓也; 南 憲司; 光冨 徹哉  日本外科学会雑誌  115-  (2)  926  -926  2014/03
• IDENTIFICATION F IGF-1R ACTIVATION AS A CANDIDATE MOLECULAR TARGET IN KRAS-MUTATED LUNG CANCER

  Hiroshi Mizuuchi; Kenichi Suda; Katsuaki Sato; Toshiki Takemoto; Takuya Iwasaki; Kenji Minami; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  8-  S797  -S798  2013/11
• PROPHYLAXIS AGAINST PULMONARY THROMBOEMBOLISM WITH UNFRACTIONATED HEPARIN FOR THE PATIENTS UNDERGOING PULMONARY RESECTION FOR LUNG CANCER

  Toshiki Takemoto; Masaya Nishino; Hiroshi Mizuuchi; Katsuaki Sato; Kenichi Suda; Takuya Iwasaki; Kenji Minami; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  8-  S711  -S712  2013/11
• HER2遺伝子変異を有する肺腺癌細胞株におけるHER2チロシンキナーゼ阻害剤耐性機序(The resistant mechanisms for to HER2-TKIs in a human Lung adenocarcinoma cell line harboring HER2 gene mutation)

  富沢 健二; 須田 健一; 東 陽子; 横堀 武彦; 高坂 貴行; 矢島 俊樹; 茂木 晃; 光冨 徹哉; 桑野 博行  日本癌学会総会記事  72回-  484  -484  2013/10
• 臨床検体より樹立したゲフィチニブ獲得耐性細胞株の解析

  須田 健一; 伊藤 志門; 水内 寛; 武本 智樹; 岩崎 拓也; 南 憲司; 谷田部 恭; 光冨 徹哉  肺癌  53-  (5)  472  -472  2013/10
• 62. 非小細胞肺癌切除例におけるN1臨床診断の精度評価(第36回日本呼吸器内視鏡学会九州支部会)

  岡本 龍郎; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 須田 健一; 前原 喜彦  気管支学 : 日本気管支研究会雑誌  35-  (3)  339  -339  2013/05
• 81. 子宮頸癌由来の転移性肺腫瘍が疑われたReactive lymphoid lesionの1例(第36回日本呼吸器内視鏡学会九州支部会)

  北原 大和; 吉田 月久; 島松 晋一郎; 河野 幹寛; 須田 健一; 岡本 龍郎; 前原 喜彦  気管支学 : 日本気管支研究会雑誌  35-  (3)  342  -342  2013/05
• 118. 診断に苦慮した肺癌合併前縦隔悪性リンパ腫の1例(第36回日本呼吸器内視鏡学会九州支部会)

  藤下 卓才; 須田 健一; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 岡本 龍郎; 前原 喜彦  気管支学 : 日本気管支研究会雑誌  35-  (3)  348  -348  2013/05
• PS-018-3 肺癌におけるSIRT1遺伝子発現と抗がん剤抵抗性への関与(PS ポスターセッション,第113回日本外科学会定期学術集会)

  枝川 真; 吉田 月久; 小西 秀幸; 須田 健一; 北原 大和; 島松 晋一郎; 河野 幹寛; 岡本 龍郎; 竹之山 光広; 矢野 篤次郎; 前原 喜彦  日本外科学会雑誌  114-  (2)  542  -542  2013/03
• PS-017-2 肺扁平上皮癌患者における喫煙の腫瘍生物学的影響(PS ポスターセッション,第113回日本外科学会定期学術集会)

  鈴木 雄三; 岡本 龍郎; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 須田 健一; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  541  -541  2013/03
• PS-018-4 肺癌におけるBCL2-like11(Bim)タンパク発現の臨床的・生物学的意義(PS ポスターセッション,第113回日本外科学会定期学術集会)

  水内 寛; 須田 健一; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 岡本 龍郎; 前原 喜彦  日本外科学会雑誌  114-  (2)  543  -543  2013/03
• PS-146-2 転移性肺腫瘍に対する反復切除の現状とその周術期成績に関する検討(PS ポスターセッション,第113回日本外科学会定期学術集会)

  北原 大和; 須田 健一; 島松 晋一郎; 河野 幹寛; 吉田 月久; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  721  -721  2013/03
• PS-151-4 胸腺腫切除例におけるWHO組織分類と正岡病期分類との関連(PS ポスターセッション,第113回日本外科学会定期学術集会)

  藤下 卓才; 河野 幹寛; 北原 大和; 島松 晋一郎; 吉田 月久; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  729  -729  2013/03
• PS-025-3 原発性肺癌におけるEMT関連遺伝子Brachyuryの発現と生物学的意義(PS ポスターセッション,第113回日本外科学会定期学術集会)

  島松 晋一郎; 波呂 祥; 北原 大和; 河野 幹寛; 吉田 月久; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  553  -553  2013/03
• PD-15-7 EGFR変異肺癌におけるキナーゼ阻害剤治療効果と獲得耐性(PD パネルディスカッション,第113回日本外科学会定期学術集会)

  須田 健一; 岡本 龍郎; 谷田部 恭; 光冨 徹哉; 前原 喜彦  日本外科学会雑誌  114-  (2)  271  -271  2013/03
• WS-12-3-5 80歳以上の超高齢者肺癌に対する外科治療の適応,術式選択および治療成績(WS ワークショップ,第113回日本外科学会定期学術集会)

  吉田 月久; 北原 大和; 島松 晋一郎; 河野 幹寛; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  323  -323  2013/03
• WS-10-1 肺癌術後oligometastases再発の概念と治療戦略(WS ワークショップ,第113回日本外科学会定期学術集会)

  矢野 篤次郎; 岡本 龍郎; 福山 誠一; 須田 健一; 岡崎 寛士; 吉田 月久; 河野 幹寛; 島松 晋一郎; 北原 大和; 前原 喜彦  日本外科学会雑誌  114-  (2)  311  -311  2013/03
• VSY-4-1 ステープラーを用いない肺組織切離法(VSY ビデオシンポジウム,第113回日本外科学会定期学術集会)

  岡本 龍郎; 池田 哲夫; 須田 健一; 吉田 月久; 河野 幹寛; 島松 晋一郎; 北原 大和; 前原 喜彦  日本外科学会雑誌  114-  (2)  175  -175  2013/03
• YT-12-1(YRA) 原発性肺腺癌におけるaromatase発現とその臨床的意義(YT Young Researcher Award & Traveler's Grant,第113回日本外科学会定期学術集会)

  河野 幹寛; 岡本 龍郎; 北原 大和; 島松 晋一郎; 吉田 月久; 須田 健一; 波呂 祥; 矢野 篤次郎; 前原 喜彦  日本外科学会雑誌  114-  (2)  415  -415  2013/03
• VSY-4-1 ステープラーを用いない肺組織切離法(VSY ビデオシンポジウム,第113回日本外科学会定期学術集会)

  岡本 龍郎; 池田 哲夫; 須田 健一; 吉田 月久; 河野 幹寛; 島松 晋一郎; 北原 大和; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PD-15-7 EGFR変異肺癌におけるキナーゼ阻害剤治療効果と獲得耐性(PD パネルディスカッション,第113回日本外科学会定期学術集会)

  須田 健一; 岡本 龍郎; 谷田部 恭; 光冨 徹哉; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• WS-10-1 肺癌術後oligometastases再発の概念と治療戦略(WS ワークショップ,第113回日本外科学会定期学術集会)

  矢野 篤次郎; 岡本 龍郎; 福山 誠一; 須田 健一; 岡崎 寛士; 吉田 月久; 河野 幹寛; 島松 晋一郎; 北原 大和; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• WS-12-3-5 80歳以上の超高齢者肺癌に対する外科治療の適応,術式選択および治療成績(WS ワークショップ,第113回日本外科学会定期学術集会)

  吉田 月久; 北原 大和; 島松 晋一郎; 河野 幹寛; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• YT-12-1(YRA) 原発性肺腺癌におけるaromatase発現とその臨床的意義(YT Young Researcher Award & Traveler's Grant,第113回日本外科学会定期学術集会)

  河野 幹寛; 岡本 龍郎; 北原 大和; 島松 晋一郎; 吉田 月久; 須田 健一; 波呂 祥; 矢野 篤次郎; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PS-017-2 肺扁平上皮癌患者における喫煙の腫瘍生物学的影響(PS ポスターセッション,第113回日本外科学会定期学術集会)

  鈴木 雄三; 岡本 龍郎; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 須田 健一; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PS-018-3 肺癌におけるSIRT1遺伝子発現と抗がん剤抵抗性への関与(PS ポスターセッション,第113回日本外科学会定期学術集会)

  枝川 真; 吉田 月久; 小西 秀幸; 須田 健一; 北原 大和; 島松 晋一郎; 河野 幹寛; 岡本 龍郎; 竹之山 光広; 矢野 篤次郎; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PS-018-4 肺癌におけるBCL2-like11(Bim)タンパク発現の臨床的・生物学的意義(PS ポスターセッション,第113回日本外科学会定期学術集会)

  水内 寛; 須田 健一; 北原 大和; 島松 晋一郎; 河野 幹寛; 吉田 月久; 岡本 龍郎; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PS-025-3 原発性肺癌におけるEMT関連遺伝子Brachyuryの発現と生物学的意義(PS ポスターセッション,第113回日本外科学会定期学術集会)

  島松 晋一郎; 波呂 祥; 北原 大和; 河野 幹寛; 吉田 月久; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PS-146-2 転移性肺腫瘍に対する反復切除の現状とその周術期成績に関する検討(PS ポスターセッション,第113回日本外科学会定期学術集会)

  北原 大和; 須田 健一; 島松 晋一郎; 河野 幹寛; 吉田 月久; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• PS-151-4 胸腺腫切除例におけるWHO組織分類と正岡病期分類との関連(PS ポスターセッション,第113回日本外科学会定期学術集会)

  藤下 卓才; 河野 幹寛; 北原 大和; 島松 晋一郎; 吉田 月久; 須田 健一; 岡本 龍郎; 竹之山 光広; 前原 喜彦  日本外科学会雑誌  114-  (2)  2013/03
• 呼吸器外科領域における基礎研究と治療への展開 EGFR変異肺癌におけるキナーゼ阻害剤治療効果と獲得耐性

  須田 健一; 岡本 龍郎; 谷田部 恭; 光冨 徹哉; 前原 喜彦  日本外科学会雑誌  114-  (臨増2)  271  -271  2013/03
• 肺癌術後再発患者におけるEGFR遺伝子変異の全生存における意義 予後因子と予測因子

  須田 健一; 伊藤 志門; 谷田部 恭; 岡本 龍郎; 竹之山 光広; 前原 喜彦; 光冨 徹哉  日本癌治療学会誌  47-  (3)  1019  -1019  2012/10
• EGFR変異肺癌におけるEGFR-TKI獲得耐性モデルの解析(In vitro acquired resistance model to EGFR-TKIs in EGFR mutated lung cancer)

  須田 健一; 水内 寛; Annette O. Walter; Robert Tjin; 富沢 健二; 岡本 龍郎; 竹之山 光広; 前原 喜彦; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  71回-  294  -294  2012/08
• CO-1686, a novel mutant selective EGFR inhibitor, overcomes T790M mediated resistance in Non-Small Cell Lung Cancer (NSCLC)

  Annette O. Walter; Robert Tjin; Henry Haringsma; Kevin Lin; Alex Dubrovskiy; Kwangho Lee; Thia St Martin; Russell Karp; Zhendong Zhu; Deqiang Nu; Mariana Nacht; Kenichi Suda; Tetsuya Mitsudomi; Russell C. Petter; William F. Westlin; Juswinder Singh; Mitch Raponi; Andrew Allen  CANCER RESEARCH  72-  2012/04
• Detection of EGFR T790M mutation in non-small-cell lung cancer patients using colony hybridization assay

  Yoshihiko Fujita; Kenichi Suda; Hideharu Kimura; Kazuko Matsumoto; Tokuzo Arao; Tomoyuki Nagai; Hidetoshi Hayashi; Kazuyuki Furuta; Hiroaki Kato; Nagahiro Saijo; Yasushi Yatabe; Tetsuya Mitsudomi; Kazuto Nishio  CANCER RESEARCH  72-  2012/04
• Knockdown of EGFR to investigate its therapeutic potential for treatment of non-small cell lung cancers

  Junichi Soh; Kazuhiko Shien; Tsuyoshi Ueno; Kazunori Tsukuda; Kenichi Suda; Takafumi Kubo; Masashi Furukawa; Takayuki Muraoka; Yuho Maki; Norimitsu Tanaka; Hiromasa Yamamoto; Katsuyuki Kiura; Tetsuya Mitsudomi; Shinichi Toyooka; Shinichiro Miyoshi  CANCER RESEARCH  72-  2012/04
• ALK融合遺伝子の存在により15年目の再発と診断した肺腺癌の1例

  富沢 健二; 伊藤 志門; 千葉 眞人; 小林 祥久; 須田 健一; 尾関 直樹; 福井 高幸; 波戸岡 俊三; 光冨 徹哉; 谷田部 恭  肺癌  52-  (2)  268  -268  2012/04
• 肺癌術後再発患者におけるEGFRキナーゼ阻害剤の役割 TKIは術後生存を改善するか

  須田 健一; 伊藤 志門; 尾関 直樹; 小林 祥久; 千葉 眞人; 富沢 健二; 福井 高幸; 波戸岡 俊三; 谷田部 恭; 光冨 徹哉  日本呼吸器外科学会雑誌  26-  (3)  RS02  -01  2012/04
• 同時性多発肺病変を認めた肺癌切除例の臨床像と遺伝子変異解析

  福井 高幸; 須田 健一; 富沢 健二; 千葉 眞人; 小林 よしひさ; 尾関 直樹; 伊藤 志門; 波戸岡 俊三; 谷田部 恭; 光冨 徹哉  日本呼吸器外科学会雑誌  26-  (3)  O16  -06  2012/04
• SF-097-1 In vitroモデルを用いたEGFRキナーゼ阻害剤獲得耐性機序の解析(SF-097 サージカルフォーラム(97)肺 基礎-2,第112回日本外科学会定期学術集会)

  須田 健一; 富沢 健二; 小林 祥久; 福井 高幸; 伊藤 志門; 波戸岡 俊三; 谷田部 恭; 関戸 好孝; 光冨 徹哉  日本外科学会雑誌  113-  (2)  2012/03
• Genetic and genomic difference in lung cancer based on ethnicity

  Tetsuya Mitsudomi; Kenichi Suda; Kenji Tomizawa; Yasushi Yatabe; Keitaro Matsuo  CLINICAL CANCER RESEARCH  18-  (3)  2012/02
• 胸部食道亜全摘を必要とした後縦隔脂肪肉腫の1例

  千葉 眞人; 伊藤 志門; 小林 祥久; 尾関 直樹; 須田 健一; 富沢 健二; 福井 高幸; 波戸岡 俊三; 光冨 徹哉; 谷田部 恭  肺癌  51-  (7)  843  -843  2011/12
• 逐次的な分子標的薬曝露により"EGFR-TKI依存状態"となったEGFR変異肺癌細胞株の解析

  須田 健一; 富沢 健二; 谷田部 恭; 関戸 好孝; 光冨 徹哉  肺癌  51-  (5)  423  -423  2011/10
• ALK融合遺伝子陽性肺腺癌の臨床・画像的特徴

  福井 高幸; 小林 祥久; 富沢 健二; 千葉 眞人; 須田 健一; 尾関 直樹; 伊藤 志門; 波戸岡 俊三; 松尾 恵太郎; 谷田部 恭; 光冨 徹哉  肺癌  51-  (5)  441  -441  2011/10
• 小細胞癌への形態変化でゲフィチニブに耐性化した肺腺癌術後多発肺内再発の一例

  高坂 貴行; 八巻 英; 田中 司玄文; 茂木 晃; 富沢 健二; 須田 健一; 谷田部 恭; 光冨 徹哉; 桑野 博行  肺癌  51-  (5)  489  -489  2011/10
• EGFR variant III変異を有する扁平上皮癌の解析(Analysis for squamous cell carcinomas with EGFR variant III mutation)

  富沢 健二; 須田 健一; 中西 速夫; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  70回-  183  -183  2011/09
• 肺がんの亜分類と標的治療 EGFR変異肺癌におけるチロシンキナーゼ阻害剤獲得耐性(Acquired resistance to kinase inhibitors in EGFR mutated lung cancer)

  須田 健一; 富沢 健二; 長田 啓隆; 関戸 好孝; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  70回-  286  -287  2011/09
• 非小細胞肺がん患者におけるEGFR T790変異の新規検出法(Sensitive detection of EGFR T790M mutation in non-small-cell lung cancer patients)

  藤田 至彦; 須田 健一; 木村 英晴; 松本 和子; 荒尾 徳三; 西條 長宏; 谷田部 恭; 光冨 徹哉; 西尾 和人  日本癌学会総会記事  70回-  374  -374  2011/09
• IDENTIFICATION OF NEW RELATIONSHIP BETWEEN EGFR MUTATION AND CLINICOPATHOLOGICAL FACTORS TO ESTABLISH A PREDICTION MODEL OF EGFR MUTATION IN NON-SMALL-CELL LUNG CANCER.

  Tsuyoshi Ueno; Shinichi Toyooka; Kenichi Suda; Junichi Soh; Keitaro Matsuo; Yasushi Yatabe; Shinichiro Miyoshi; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  6-  (6)  S781  -S782  2011/06
• ANALYSES OF MUTUALLY EXCLUSIVE DRIVER MUTATIONS IN LUNG ADENOCARCINOMAS FROM NEVER-SMOKING PATIENTS

  Kenichi Suda; Kenji Tomizawa; Keitaro Matsuo; Yasushi Yatabe; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  6-  (6)  S511  -S511  2011/06
• IS-10-5 Personalized treatment of lung cancer : EGFR mutations and beyond(IS-10 Treatment of lung cancer in the 21st century : From bench to bedside, further to the OR)

  Suda Kenichi  Journal of Japan Surgical Society  112-  (1)  206  -206  2011/05
• SF-064-4 肺癌手術における多量出血症例の検討(SF-064 サージカルフォーラム(64)肺:その他,第111回日本外科学会定期学術集会)

  伊藤 志門; 小林 祥久; 尾関 直樹; 厚田 幸子; 丹羽 由紀子; 須田 健一; 富澤 健二; 福井 高幸; 安部 哲也; 波戸岡 俊三; 光冨 徹哉  日本外科学会雑誌  112-  (1)  2011/05
• PS-046-6 gefitinib耐性後の剖検症例におけるEGFRおよびMET遺伝子異常のheterogeneity(PS-046 ポスターセッション(46)肺:基礎-2,第111回日本外科学会定期学術集会)

  片山 達也; 村上 功; 須田 健一; 平井 伸司; 谷田部 恭; 光冨 徹哉  日本外科学会雑誌  112-  (1)  2011/05
• Treatment of lung cancer in the 21st century:From bench to bedside、further to the OR 肺癌の個別化治療 EGFR変異とその先へ(Treatment of lung cancer in the 21st century: From bench to bedside, further to the OR Personalized treatment of lung cancer: EGFR mutations and beyo

  須田 健一; 富沢 健二; 片山 達也; 関戸 好孝; 谷田部 恭; 光冨 徹哉  日本外科学会雑誌  112-  (臨増1-2)  206  -206  2011/05
• Acquired epithelial-mesenchymal transition like feature in an EGFR-mutant lung cancer cell line with acquired resistance to erlotinib

  Kenichi Suda; Kenji Tomizawa; Hirotaka Osada; Yoshitaka Sekido; Yasushi Yatabe; Tetsuya Mitsudomi  CANCER RESEARCH  71-  2011/04
• 日本人非喫煙者肺腺癌切除例における相互排他的な"Driver mutation"の検討

  須田 健一; 富沢 健二; 谷田部 恭; 光冨 徹哉  日本呼吸器外科学会雑誌  25-  (3)  O23  -03  2011/04
• 再発EML4-ALK肺癌の化学療法反応性

  富沢 健二; 須田 健一; 小林 祥久; 尾関 直樹; 厚田 幸子; 遠藤 秀紀; 福井 高幸; 伊藤 志門; 谷田部 恭; 光冨 徹哉  日本呼吸器外科学会雑誌  25-  (3)  P86  -01  2011/04
• Reciprocal and Complementary Relationship between Epidermal Growth Factor Receptor T790M Mutation and MET Amplification in Acquired Resistance to Kinase Inhibitors in Lung Adenocarcinoma

  Kenichi Suda; Isao Murakami; Tatsuya Katayama; Kenji Tomizawa; Hirotaka Osada; Yoshitaka Sekido; Yasushi Yatabe; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  5-  (12)  S383  -S383  2010/12
• 肺癌に対する分子標的治療 EGFR-TKI耐性獲得メカニズムにおけるEGFR T790M変異とMET遺伝子増幅の相反関係

  須田 健一; 村上 功; 片山 達也; 富沢 健二; 関戸 好孝; 谷田部 恭; 光冨 徹哉  肺癌  50-  (5)  463  -463  2010/10
• HER2変異陽性肺癌の臨床病理学的特徴と標的治療の可能性

  富沢 健二; 須田 健一; 小野里 良一; 福井 高幸; 伊藤 志門; 谷田部 恭; 光冨 徹哉  肺癌  50-  (5)  502  -502  2010/10
• 分子標的治療 EGFR-TKI耐性獲得肺癌におけるEGFR T790MとMET増幅の相反関係(Molecular target therapy Reciprocal relationship between EGFR T790M and MET amplification in acquired resistance to EGFR-TKIs in lung cancer)

  須田 健一; 村上 功; 富沢 健二; 長田 啓隆; 関戸 好孝; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  69回-  236  -236  2010/08
• 肺がんの分子標的療法〜今後の展望 肺癌におけるEGFRチロシンキナーゼ阻害剤による分子標的治療の現状と展望(Molecular-targetel therapy against lung cancer: future prospectus Future perspectives of EGFR-TKI therapy in lung cancer)

  光冨 徹哉; 須田 健一; 富沢 健二; 谷田部 恭  日本癌学会総会記事  69回-  242  -242  2010/08
• HER2変異陽性肺癌の臨床病理学的特徴(Clinicopathological characteristics of lung cancers with HER2 mutation)

  富沢 健二; 須田 健一; 小野里 良一; 桑野 博行; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  69回-  455  -456  2010/08
• SF-022-3 術後早期に再発をきたしたEGFR遺伝子変異陽性肺癌患者に対するゲフィチニブ治療効果(呼吸器-1,サージカルフォーラム,第110回日本外科学会定期学術集会)

  須田 健一; 富沢 健二; 小野里 良一; 高坂 貴行; 厚田 幸子; 丹羽 由紀子; 福本 紘一; 齊藤 卓也; 片山 達也; 福井 高幸; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 谷田部 恭; 光冨 徹哉  日本外科学会雑誌  111-  (2)  2010/03
• OP-237-4 日本人原発性肺癌切除例におけるHER4の発現と細胞外ドメインとキナーゼドメインの遺伝子変異解析(肺基礎-2,一般口演,第110回日本外科学会定期学術集会)

  富沢 健二; 須田 健一; 厚田 幸子; 丹羽 由紀子; 小野里 良一; 福本 紘一; 齊藤 卓也; 高坂 貴行; 片山 達也; 福井 高幸; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 光冨 徹哉  日本外科学会雑誌  111-  (2)  2010/03
• EGFR遺伝子変異のない非小細胞肺癌患者におけるゲフィチニブ治療の意義

  須田 健一; 小野里 良一; 富沢 健二; 高坂 貴行; 谷田部 恭; 光冨 徹哉  肺癌  49-  (5)  661  -661  2009/10
• EGFR-TKI獲得耐性症例の剖検検体における遺伝子異常のheterogeneity

  片山 達也; 村上 功; 小野里 良一; 須田 健一; 富沢 健二; 福井 高幸; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 谷田部 恭; 光冨 徹哉  肺癌  49-  (5)  661  -661  2009/10
• Analyses of clinical or biological factors for predicting benefit of gefitinib in patients with recurrent non-small cell lung cancer with EGFR mutation after pulmonary resection

  Kenichi Suda; Ryoichi Onozato; Takayuki Kosaka; Yasushi Yatabe; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  4-  (9)  S929  -S929  2009/09
• 日本人非小細胞肺癌切除例におけるSLC34A2-ROS融合遺伝子の解析(Analysis of SLC34A2-ROS fusion gene in surgically resected Japanese non-small cell lung cancer patients)

  須田 健一; 小野里 良一; 富沢 健二; 高坂 貴行; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  68回-  130  -130  2009/08
• 非小細胞肺癌術後再発症例の無再発生存期間と再発後生存期間に影響を及ぼす因子

  片山 達也; 須田 健一; 福本 紘一; 小野里 良一; 小林 零; 斎藤 卓也; 福井 高幸; 伊藤 志門; 波戸岡 俊三; 谷田部 恭; 光冨 徹哉  日本呼吸器外科学会雑誌  23-  (3)  375  -375  2009/04
• SF-023-3 喫煙歴別にみた肺腺癌の生物学的臨床的多様性(肺・気管・気管支(悪性疾患3),サージカルフォーラム,第109回日本外科学会定期学術集会)

  須田 健一; 小野里 良一; 高坂 貴行; 福本 紘一; 齊藤 卓也; 小林 零; 片山 達也; 福井 高幸; 伊藤 志門; 安部 哲也; 波戸岡 俊三; 谷田部 恭; 光冨 徹哉  日本外科学会雑誌  110-  (2)  2009/02
• O-16 EGFR遺伝子変異L858RとExon19欠失変異バリエーションの検討(分子生物学,第49回日本肺癌学会総会号)

  須田 健一; 小野里 良一; 高坂 貴行; 谷田部 恭; 光冨 徹哉  肺癌  48-  (5)  2008/10
• O-133 術後再発症例におけるEGFR遺伝子変異とゲフィチニブの効果 : 134例の検討(分子標的治療2,第49回日本肺癌学会総会号)

  小野里 良一; 高坂 貴行; 須田 健一; 福本 紘一; 小林 零; 片山 達也; 福井 高幸; 伊藤 志門; 波戸岡 俊三; 篠田 雅幸; 谷田部 恭; 光冨 徹哉  肺癌  48-  (5)  2008/10
• O-135 gefitinibが抵抗性となった後にErlotinibを投与した非小細胞肺癌中枢神経転移症例の検討(分子標的治療3,第49回日本肺癌学会総会号)

  片山 達也; 清水 淳市; 須田 健一; 小野里 良一; 斉藤 卓也; 小林 零; 福井 高幸; 伊藤 志門; 波戸岡 俊三; 篠田 雅幸; 樋田 豊明; 谷田部 恭; 光冨 徹哉  肺癌  48-  (5)  2008/10
• P-631 気管支・肺カルチノイド腫瘍切除例の検討(神経内分泌腫瘍,第49回日本肺癌学会総会号)

  小林 零; 福本 紘一; 須田 健一; 小野里 良一; 片山 達也; 福井 高幸; 伊藤 志門; 波戸岡 俊三; 篠田 雅幸; 光冨 徹哉  肺癌  48-  (5)  2008/10
• 原発性肺癌切除例におけるMET遺伝子の活性化についての検討(Analysis of MET activation in primary resected lung cancers)

  小野里 良一; 高坂 貴行; 須田 健一; 谷田部 恭; 光冨 徹哉  日本癌学会総会記事  67回-  216  -216  2008/09

Research Grants & Projects

• Basic Research for Elucidating and Overcoming the Mechanisms of Progression of Early-Stage Lung Adenocarcinoma

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2023/09 -2027/03 

  Author : 宗 淳一; 津谷 康大; 小原 秀太; 須田 健一; 濱田 顕
• EGFR変異肺癌に対する第4世代EGFR-TKIの有用性とその獲得耐性機序の解明

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2022/04 -2025/03 

  Author : 須田 健一
• Targeted therapy for the patient with KRAS mutant lung cancer

  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 -2025/03 

  Author : 宗 淳一; 須田 健一; 光冨 徹哉
• Development of a new treatment strategy for HER2-alterated lung cancer

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2019/04 -2022/03 

  Author : Soh Junichi

   

  We conducted sensitivity testing and investigated the mechanism of acquired resistance using lung, gastric, and breast cancer cell lines for several HER2-targeting agents, and reported the results in several English papers. In addition, we confirmed the sensitivity of a novel HER inhibitor, Tarloxotinib, and identified a new resistance-related mutation, HER2 exon C805S, involved in resistance using Ba/F3 cells transfected with HER2 mutation, which was reported in an English paper. A new afatinib-sensitive HER2 mutation spectrum identified in the LUX-Lung8 study, which evaluated the efficacy of the EGFR/HER2 inhibitor afatinib in patients with squamous cell lung cancer, was introduced into the Ba/F3 cell line and its pathogenicity and drug sensitivity were investigated and reported in an English paper.
• Exploration of predictive molecular biomarkers for acquired resistance mechanisms to EGFR tyrosine kinase inhibitors

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2018/04 -2021/03 

  Author : Suda Kenichi

   

  During the study period, we could not identify pre-treatment molecular biomarkers that predicts the acquired resistance mechanisms to EGFR-tyrosine kinase inhibitors (TKIs). However, we observed that the mechanisms by which cancer cells survive in the early stage of EGFR-TKI exposure differs depending on the type of TKI, and that RYK is one of the mechanisms. We also examined inter-tumor heterogeneity of acquired resistance mechanisms to EGFR-TKIs in the same patients. We observed that two different resistance mechanisms have developed, depending on the metastatic sites, in about half of the patients. In addition, during the study period, several novel molecular-targeted agents have been developed for lung cancers with MET exon 14 skipping mutation, KRAS G12C mutation, EGFR and HER2 exon 20 insertion mutations (and some have been already approved for clinical use), therefore, we also explored acquired resistance mechanisms to these agents.
• Molecular targeted therapy against adenocarcinoma of the lung harboring MET exon 14 skipping mutation

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

  Date (from‐to) : 2016/04 -2019/03 

  Author : MITSUDOMI Tetsuya; SUDA Kenichi; KOBAYASHI Yoshihisa; KOGA Takamasa; FUJINO Toshio; NISHINO Masaya

   

  We established a Ba/F3 cell model with MET exon 14 skipping mutation that is present about3% of lung adenocarcinoma . Using this model, we tested its sensitivities to 8 MET-tyrosine kinase inhibitors (TKI) including 4 type I TKI that binds to the active form of the kinase, 3 type II that binds to the inactive form and one allosteric inhibitor. As a result, capmatinib was found to be most effective. Next, we derived resistant clones for each drug. D1228 and Y1230 were common sites of the secondary MET mutations for resistant cells against type I TKI, whereas L1195 and F1200 were common sites for the type II TKI. In general, the resistance mutation for type I is sensitive to type II, and vice versa.
• 肺癌における薬剤耐性因子のheterogenietyとその克服

  日本学術振興会：科学研究費助成事業 若手研究(B)

  Date (from‐to) : 2015/04 -2016/03 

  Author : 須田 健一

   

  【１】薬剤感受性バイオマーカーのheterogeneityに関する検討 2014年3月までに、高齢や重度の並存疾患などにより化学療法（分子標的治療含む）が施行されなかった未治療肺癌剖検例7名を対象に解析をおこなった。各患者の原発巣・転移巣について、抗PD-1/抗PD-L1抗体による免疫治療の効果予測因子と考えられているPD-L1発現を、免疫化学染色法にて検討した。7名中1名がEGFR遺伝子変異陽性であった。同一患者内の各転移巣のPD-L1発現にheterogeneityは認めなかった。この結果より、抗PD-1/抗PD-L1抗体による免疫治療に際しては、どの部位（原発巣・転移巣）より生検をおこなっても、同等のPD-L1発現の結果が得られると考えられた。 【２】キナーゼ阻害剤獲得耐性機序のheterogeneityに関する検討とその克服 EGFRキナーゼ阻害剤治療に対し上皮観葉転換（EMT）による獲得耐性を生じることがしばしば報告されているHCC4006細胞株を用いて検討をおこなった。EMTを生じた細胞株に対する有効性が示されているdasatinibを、EGFRキナーゼ阻害剤（erlotinib）と併用し、HCC4006細胞株より併用療法の耐性株を作成した。約4ヶ月で耐性株が樹立でき、EMTによる獲得耐性は生じないことを確認した。併用療法による耐性機序はEGFRのT790M 2次的変異であった。この結果より、dasatinib併用により、より治療が難しいEMTではなく、第3世代EGFR阻害剤で治療可能なT790Mへ耐性機序を誘導できる可能性が示された。
• Analysis of acquired resistance mechanisms to next-generation kinase inhibitors in lung cancers with EGFR mutation.

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

  Date (from‐to) : 2013/04 -2015/03 

  Author : SUDA Kenichi; MIZUUCHI Hiroshi; SATO Katsuaki

   

  EGFR kinase inhibitors are the key drugs in the treatment of lung cancer patients with EGFR activating mutations. However, emergence of acquired resistance to these drugs is almost inevitable. There are several unanswered issues to establish best treatment strategies after acquisition of resistance to EGFR kinase inhibitors. These include, (1) if chemosensitivity alters after acquisition of resistance, (2) novel resistance mechanisms other than T790M mutation. MET amplification, ERBB2 amplification, etc, and (3) molecular mechanisms that confer acquired resistance to next-generation EGFR kinase inhibitors. In this work, we analyzed these points, mainly using in vitro models.
• EGFR変異肺癌のキナーゼ阻害剤耐性機序の解明とその克服に向けた新規治療への展開

  日本学術振興会：科学研究費助成事業 研究活動スタート支援

  Date (from‐to) : 2012/08 -2014/03 

  Author : 須田 健一

   

  EGFR遺伝子変異を有する肺癌はEGFRキナーゼ阻害剤（ゲフィチニブ、エルロチニブ）に高い感受性を有する。しかし、約１年以内の獲得耐性の出現はほぼ必発であり、その分子機序の理解や耐性の克服が課題である。 そこで我々は、以前の解析［Suda K, et al. Clin. Cancer Res. 2010］で用いたEGFR変異・KRAS変異・MET遺伝子コピー数についてのデータがそろっている6名のEGFRキナーゼ阻害剤獲得耐性症例（33病変）および以前の解析で作成したin vitro獲得耐性細胞株モデル（HCC827ER, HCC827EPR, HCC4006ER）について、さらなる解析をおこなった。まず、獲得耐性に関わる可能性が指摘されたCRKL分子について遺伝子コピー数を解析した。その結果、獲得耐性症例および細胞株モデルの両者において、CRKL遺伝子コピー数の増加は認めず、獲得耐性におけるCRKLの関与は低い可能性が示された。 一方、アポトーシス関連タンパクであるBIMの多型・遺伝子発現とEGFRキナーゼ阻害剤感受性との関連も近年報告され、注目を集めている。そこで我々は、多くの施設でも実施可能な免疫組織染色法によるBIMタンパク発現解析でもEGFRキナーゼ阻害剤感受性の予測が可能かを調べるため、上記とは別の30名のコホートを用いて検討をおこなった。その結果、BIM遺伝子多型を有する患者ではBIMタンパクの発現は低いものの、BIMタンパク発現とEGFRキナーゼ阻害剤の感受性には関連を認めなかった。 不可逆的EGFRキナーゼ阻害剤に対する獲得耐性株の樹立も試みたが、高濃度の薬剤下でも生存可能な耐性株の樹立には至っていない。今後は、他のEGFRキナーゼ阻害剤を用いて獲得耐性株の樹立を試みるとともに、症例を増やして上記分子異常の獲得耐性における役割をさらに検討することを計画している。

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