2025/01/20 更新

写真a

ササキ タカアキ
佐々木 高明
SASAKI Takaaki
所属
病院 診療科 内科(呼吸器・脳神経)
外部リンク

学位

  • 医学博士 ( 2008年3月   旭川医科大学 )

研究キーワード

  • 肺がん

  • EML4-ALK

  • 分子標的治療

  • 呼吸器病学 腫瘍学

  • 国際情報交換

研究分野

  • ライフサイエンス / 呼吸器内科学

学歴

  • 旭川医科大学   大学院医学系研究科

    - 2008年

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    国名: 日本国

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  • 旭川医科大学   医学部   医学科

    - 2001年

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    国名: 日本国

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経歴

  • 旭川医科大学 医学部   医学部   助教

    2012年

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所属学協会

  • 日本アレルギー学会

    2018年4月 - 現在

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  • 日本結核病学会

    2018年4月 - 現在

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  • 日本腫瘍循環器学会

    2018年4月 - 現在

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  • 日本癌学会

    2016年4月 - 現在

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  • American Society of Clinical Oncology

    2015年4月 - 現在

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  • 日本がん分子標的治療学会

    2013年4月 - 現在

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  • 日本臨床腫瘍学会

    2002年4月 - 現在

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  • 日本臨床細胞学会

    2002年4月 - 現在

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  • International Association for the Study of Lung Cancer

    2002年4月 - 現在

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  • 日本肺癌学会

    2002年4月 - 現在

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  • American Association for Cancer Research

    2002年4月 - 現在

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  • 日本呼吸器内視鏡学会

    2002年4月 - 現在

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  • 日本内科学会

    2001年4月 - 現在

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▼全件表示

委員歴

  • 日本結核・非結核性抗酸菌症学会   第79回 北海道支部学術集会 会長  

    2024年2月   

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    団体区分:学協会

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  • 日本呼吸器学会   第127回 北海道支部学術集会 会長  

    2024年2月   

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    団体区分:学協会

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  • 日本呼吸器内視鏡学会   評議員  

    2023年4月 - 現在   

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    団体区分:学協会

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  • 日本肺癌学会   学術・産学連携小委員会委員  

    2022年12月 - 現在   

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    団体区分:学協会

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  • 日本肺癌学会   アーリーキャリア支援委員会委員  

    2022年12月 - 現在   

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    団体区分:学協会

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  • 世界肺癌学会   The Career Development & Fellowship Committee  

    2021年5月 - 現在   

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    団体区分:学協会

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  • 日本呼吸器学会   J-OSLER呼吸器 プログラム統括責任者(旭川医科大学病院群)  

    2021年4月 - 現在   

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    団体区分:学協会

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  • 日本呼吸器学会   財務委員会委員  

    2020年4月 - 2022年4月   

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    団体区分:学協会

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  • 日本呼吸器学会   倫理委員会委員  

    2020年4月 - 2022年4月   

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    団体区分:学協会

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  • 日本呼吸器学会   代議員  

    2019年4月 - 現在   

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    団体区分:学協会

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  • 日本腫瘍循環器学会   評議員  

    2018年 - 現在   

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    団体区分:学協会

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  • 日本肺癌学会   評議員  

    2016年12月 - 現在   

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    団体区分:学協会

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  • 日本肺癌学会   会員委員  

    2016年12月 - 現在   

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    団体区分:学協会

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  • 日本肺癌学会   日本肺癌学会ガイドライン検討委員会  

    2014年11月 - 2022年11月   

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    団体区分:学協会

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論文

  • Treatment of lung adenocarcinoma with chemotherapy helps mitigate chronic myeloid leukaemia progression: A case report. 国際誌

    Kazunori Nagasue, Ryotaro Kida, Ryota Shigaki, Kiichi Nitanai, Akari Yagita, Hiraku Yanada, Yasuhiro Umekage, Chie Mori, Yoshinori Minami, Takuya Funayama, Masayo Yamamoto, Mishie Tanino, Ryohei Yoshida, Takaaki Sasaki

    Oncology letters   29 ( 1 )   31 - 31   2025年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Treatment outcomes for inoperable advanced non-small cell lung cancer have improved in recent years. However, information on coexisting haematological tumours is lacking. The present patient was a 65-year-old woman with stage IVA lung adenocarcinoma. The patient was administered a combination of platinum therapy and immune checkpoint inhibitors. The patient was subsequently diagnosed with chronic myeloid leukaemia (CML) following leukocytosis. Carboplatin and pemetrexed combination therapy resulted in shrinkage of lung cancer. Improvements in peripheral blood leukocyte counts and bone marrow findings were observed. These results suggested that the treatment of lung cancer may control the course of CML.

    DOI: 10.3892/ol.2024.14777

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  • Real-World Efficacy of Ensitrelvir in Hospitalized Patients With COVID-19 in Japan: A Retrospective Observational Study. 国際誌

    Ryohei Yoshida, Takaaki Sasaki, Yoshinobu Ohsaki

    Cureus   16 ( 5 )   e61048   2024年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND AIM: The coronavirus disease 2019 (COVID-19) pandemic necessitates continuously evaluating antiviral treatments, especially for high-risk groups, including older individuals. This study aimed to compare the efficacy of three antiviral drugs, including remdesivir, molnupiravir, and ensitrelvir, in hospitalized patients as measured by our own institution's antigen test, focusing on outcomes, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen levels, hospitalization duration, and fever resolution. METHODS: This retrospective observational study was conducted at Yoshida Hospital, Asahikawa City, Japan, enrolling 154 patients who received antiviral treatment upon COVID-19 diagnosis from July 1, 2022, to September 15, 2023. The diagnosis was confirmed by proprietary antigen tests or loop-mediated isothermal amplification assays. Patients who received treatment outside the hospital or with consistently negative antigen results were excluded. Drug administration was determined by attending physicians, considering oral administration challenges and renal dysfunction. The data were statistically analyzed using an unpaired two-tailed Student's t-test and one-way analysis of variance complemented by the Tukey post-hoc test for detailed group comparisons. RESULTS: No significant differences were observed in the initial antigen levels among the treatment groups. By day 10, the ensitrelvir group showed lower antigen levels than the other groups, but not significantly. The ensitrelvir group had a higher antigen-negative conversion rate and a significantly shorter hospital stay than the molnupiravir group. However, no significant differences were noted in the fever resolution time among the groups. CONCLUSION: This study suggests the potential benefits of ensitrelvir in reducing antigen levels and hospitalization duration. However, the overall efficacy of the antiviral agents for symptomatic relief appears similar. These findings underscore the need for further research to optimize COVID-19 management by considering personalized treatment approaches and long-term outcomes.

    DOI: 10.7759/cureus.61048

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  • AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells. 国際誌

    Kenji Morimoto, Tadaaki Yamada, Soichi Hirai, Yuki Katayama, Sarina Fukui, Ryo Sawada, Yusuke Tachibana, Yohei Matsui, Ryota Nakamura, Masaki Ishida, Hayato Kawachi, Kei Kunimasa, Takaaki Sasaki, Makoto Nishida, Naoki Furuya, Satoshi Watanabe, Shinsuke Shiotsu, Naoya Nishioka, Mano Horinaka, Toshiyuki Sakai, Hisanori Uehara, Seiji Yano, Bo-Kyung Son, Shinsaku Tokuda, Koichi Takayama

    Cancer letters   587   216692 - 216692   2024年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

    DOI: 10.1016/j.canlet.2024.216692

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  • 最新技術を用いた消化器診療 当院における大腸癌に対するがんゲノムプロファイリング検査の現状

    田邊 裕貴, 佐藤 広崇, 大竹 晋, 小林 進, 高橋 裕之, 山本 昌代, 高橋 慶太郎, 田中 宏樹, 佐々木 高明, 高橋 賢治, 菊地 順子, 大原 克仁, 木下 一郎, 水上 裕輔

    日本消化器病学会北海道支部例会・日本消化器内視鏡学会北海道支部例会プログラム・抄録集   134回・128回   34 - 34   2024年3月

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    記述言語:日本語   出版者・発行元:日本消化器病学会-北海道支部  

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  • Results of a Survey on Early Careers Among Members of the Japan Lung Cancer Society in Fiscal Year 2023,2023 年度 日本肺癌学会会員におけるアーリーキャリアに関するアンケート調査結果

    Fukuizumi, A., Akamatsu, H., Asakura, K., Kogure, Y., Sakakibara, R., Shinno, H., Yamada, T., Sasaki, T., Takenaka, T., Tanaka, K., Tanaka, Y., Notsuda, H., Hata, A., Fukui, M., Furumoto, H., Tsuchida, M.

    Japanese Journal of Lung Cancer   64 ( 3 )   2024年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.2482/haigan.64.151

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  • An advanced NSCLC patient with ALK-RNF144A and HIP1-ALK fusions treated with ALK-TKI combination therapy: a case report. 国際誌

    Hui Li, Jingjing Liu, Shaowei Lan, Rui Zhong, Yanan Cui, Petros Christopoulos, Erin L Schenk, Takaaki Sasaki, Ying Cheng

    Translational lung cancer research   12 ( 12 )   2538 - 2549   2023年12月

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    記述言語:英語  

    BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement is one of the most important drivers in non-small cell lung cancer (NSCLC). Despite the effectiveness to canonical 3'-ALK fusions, the clinical efficacy of ALK inhibitors in patients with complex ALK fusions, such as nonreciprocal/reciprocal translocation remains uncertain. Exploring the optimal therapeutic regimens for this subset of patients is of crucial clinical significance. CASE DESCRIPTION: We reported a female patient diagnosed with stage IVB lung adenocarcinoma (LUAD) harboring a novel ALK-RNF144A fusion, concurrent with a Huntingtin-interacting protein 1 (HIP1)-ALK fusion and a RB1 loss-of-function variant. The patient sequentially received multiple lines of treatment with ALK-tyrosine kinase inhibitor (TKI), chemotherapy, radiotherapy and ALK-TKI combined with anti-angiogenesis. Disease progression accompanied by a squamous cell carcinoma transformation was indicated after ALK-TKI combined with anti-angiogenesis and both ALK-RNF144A and HIP1-ALK fusions were retained in the tumor. The patient was subsequently treated with a third generation ALK-TKI, lorlatinib, in combination with albumin-bound paclitaxel and anlotinib, and then achieved stable disease. The patient remained on the treatment as of the last follow-up resulting in an overall survival (OS) of more than 18 months. CONCLUSIONS: We have reported an advanced NSCLC patient with a complex nonreciprocal/reciprocal ALK translocation containing a novel ALK-RNF144A fusion, concurrent with a RB1 loss-of-function mutation, who subsequently experienced pathological squamous cell carcinoma transformation. The combined treatment with ALK-TKI, chemotherapy, and anti-angiogenesis demonstrates clinical efficacy and may provide optional therapeutic strategies for this phenotype.

    DOI: 10.21037/tlcr-23-656

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  • Monitoring SARS-CoV-2 Viral Load and CD4+ T-cell Count After ART in a Patient Diagnosed With AIDS Following SARS-CoV-2 Infection: A Case Report. 国際誌

    Yasuhiro Umekage, Mayumi Hatayama, Akari Yagita, Kiichi Nitanai, Hiraku Yanada, Ryota Shigaki, Yoshinori Minami, Takaaki Sasaki

    Cureus   15 ( 12 )   e51189   2023年12月

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    記述言語:英語  

    We describe the case of a 36-year-old man diagnosed with human immunodeficiency virus (HIV) following prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. The patient had a complication of pneumocystis pneumonia. Upon initiating highly active antiretroviral therapy, we monitored HIV RNA levels, CD4+ T-cell count, SARS-CoV-2 viral load, and IgG antibodies against SARS-CoV-2. At 167 days post SARS-CoV-2 diagnosis, the patient's CD4+ T-cell count increased to 180 cells/μL. IgG antibodies against SARS-CoV-2 were undetectable despite a decreased SARS-CoV-2 viral load. HIV screening is necessary in cases of prolonged SARS-CoV-2 pneumonia or persistent SARS-CoV-2 shedding. When diagnosed with HIV infection, it is advisable to consider the possibility of pneumocystis pneumonia.

    DOI: 10.7759/cureus.51189

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  • Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019-2020: General view of the pathogens' antibacterial susceptibility. 国際誌

    Issei Tokimatsu, Tetsuya Matsumoto, Hiroki Tsukada, Yuji Fujikura, Makoto Miki, Yoshitomo Morinaga, Junko Sato, Tomotaro Wakamura, Hiroshi Kiyota, Kazuhiro Tateda, Hideji Yanagisawa, Takaaki Sasaki, Hideki Ikeda, Hiroshi Horikawa, Hiroshi Takahashi, Masafumi Seki, Yoshiaki Mori, Hiroaki Takeda, Daisuke Kurai, Naoki Hasegawa, Yoshifumi Uwamino, Makoto Kudo, Masaki Yamamoto, Yuko Nagano, Sakika Nomura, Takafumi Tetsuka, Miyuki Hosokai, Nobuki Aoki, Yoshihiro Yamamoto, Yoshitsugu Iinuma, Hiroshige Mikamo, Hiroyuki Suematsu, Takaya Maruyama, Atsushi Kawabata, Yoshiko Sugaki, Atsushi Nakamura, Yasunori Fujikawa, Tatsuya Fukumori, Akira Ukimura, Hiroshi Kakeya, Makoto Niki, Koichiro Yoshida, Yoshihiro Kobashi, Hirokazu Tokuyasu, Kazuhiro Yatera, Hiroaki Ikegami, Masaki Fujita, Takemasa Matsumoto, Katsunori Yanagihara, Junichi Matsuda, Kazufumi Hiramatsu, Takashi Shinzato

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy   29 ( 8 )   731 - 743   2023年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were β-lactamase-producing ampicillin resistant and β-lactamase-negative ampicillin resistant, respectively. Extended-spectrum β-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-β-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

    DOI: 10.1016/j.jiac.2023.04.008

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  • Detection of resistance mutations in patients with anaplastic lymphoma kinase-rearranged lung cancer through liquid biopsy. 国際誌

    Takaaki Sasaki, Ryohei Yoshida, Kiichi Nitanai, Takashi Watanabe, Toshiyuki Tenma, Ryotaro Kida, Chie Mori, Yasuhiro Umekage, Noriko Hirai, Yoshinori Minami, Shunsuke Okumura

    Translational lung cancer research   12 ( 7 )   1445 - 1453   2023年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Tyrosine kinase inhibitors (TKIs) significantly improve clinical outcomes in patients with non-small cell lung cancer due to anaplastic lymphoma kinase (ALK) gene rearrangement. However, the rate of relapse with TKIs is high owing to the development of resistance mutations during treatment. Repeated biopsies during disease progression are crucial for elucidating the molecular mechanisms underlying the development of resistance to ALK inhibitors. Analysis of cell-free DNA (cfDNA) obtained from plasma is a novel approach for tumor genotyping. METHODS: In this mixed prospective and retrospective observational cohort study, we investigated the clinical feasibility of continuous quantitative monitoring of ALK-acquired mutations in plasma obtained from patients with ALK+ non-small cell lung cancer by using a highly sensitive and specific droplet digital polymerase chain reaction (ddPCR) assay. We enrolled nine patients, including three treatment-naïve patients recently diagnosed with ALK+ non-small cell lung cancer via tissue biopsy and expected to receive ALK TKIs and six patients already receiving ALK TKIs. Plasma samples were collected from these patients every 3 months. cfDNA was extracted from 66 samples during the study period, and 10 ALK mutations were simultaneously evaluated. RESULTS: The numbers of samples showing the G1202R, C1156Y, G1269A, F1174L, T1151ins, and I1171T mutations were 32, 16, 5, 4, 1, and 1, respectively. The L1196M, L1152R, V1180L, and S1206Y mutations were not detected. Correlation analyses between progression-free survival and the time from treatment initiation (or treatment modification) to the detection of resistance mutations revealed that although resistance mutations may occur before a drug change becomes necessary, there is a duration during which the disease does not progress. CONCLUSIONS: Our findings suggest that real-time quantitative monitoring of ALK resistance mutations during the response period could provide a time course of changes while acquiring resistance mutations. This information would be beneficial for designing an appropriate treatment strategy.

    DOI: 10.21037/tlcr-22-671

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  • 小児気道異物の摘出において極細径気管支鏡が有用であった2例

    奈良岡 妙佳, 似内 貴一, 志垣 涼太, 天満 紀之, 木田 涼太郎, 梅影 泰寛, 森 千惠, 吉田 遼平, 南 幸範, 奥村 俊介, 長内 忍, 佐々木 高明

    気管支学   45 ( Suppl. )   S296 - S296   2023年6月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器内視鏡学会  

    J-GLOBAL

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  • 肺サルコイドーシス疑い症例に対する気管支鏡162例の検討

    木田 涼太郎, 奈良岡 妙佳, 志垣 涼太, 似内 貴一, 天満 紀之, 梅影 泰寛, 森 千惠, 吉田 遼平, 南 幸範, 奥村 俊介, 佐々木 高明, 長内 忍

    気管支学   45 ( Suppl. )   S218 - S218   2023年6月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器内視鏡学会  

    J-GLOBAL

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  • 浸潤性粘液性腺癌に対し気管支鏡検査を施行した26例の臨床的検討

    志垣 涼太, 奈良岡 妙佳, 似内 貴一, 天満 紀之, 木田 涼太郎, 梅影 泰寛, 森 千惠, 吉田 遼平, 南 幸範, 奥村 俊介, 長内 忍, 佐々木 高明

    気管支学   45 ( Suppl. )   S317 - S317   2023年6月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器内視鏡学会  

    J-GLOBAL

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  • Two Cases of SMARCA4-Deficient Non-small Cell Lung Cancer (NSCLC) with Improved Performance Status (PS) after Treatment with Immune Checkpoint Inhibitors (ICIs) 国際誌

    Akiko Koizumi, Yukiho Tamura, Ryohei Yoshida, Chie Mori, Yusuke Ono, Mishie Tanino, Yusuke Mizukami, Takaaki Sasaki

    Cureus   15 ( 4 )   e37656   2023年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations are commonly reported in non-small cell lung cancer (NSCLC) and are associated with a poor prognosis. There is insufficient evidence regarding the efficacy of immune checkpoint inhibitors (ICIs) in SMARCA4-deficient NSCLC patients with poor performance status (PS). We report two cases of advanced SMARCA4-deficient NSCLC treated with ICIs, in which marked regression of the tumor and improved general condition of the patients were achieved.

    DOI: 10.7759/cureus.37656

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  • 化学療法中に慢性骨髄性白血病を発症した肺腺癌の1例

    永末 一徳, 木田 涼太郎, 奈良岡 妙佳, 志垣 涼太, 天満 紀之, 梅影 泰寛, 森 千惠, 吉田 遼平, 南 幸範, 奥村 俊介, 佐々木 高明, 長内 忍

    肺癌   63 ( 2 )   128 - 128   2023年4月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Sotorasibが奏功したKRAS G12C変異陽性の浸潤性粘液性腺癌の2例

    似内 貴一, 吉田 遼平, 奈良岡 妙佳, 志垣 涼太, 天満 紀之, 木田 涼太郎, 梅影 泰寛, 森 千恵, 南 幸範, 奥村 俊介, 佐々木 高明

    日本呼吸器学会誌   12 ( 増刊 )   329 - 329   2023年3月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器学会  

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  • Case Report: Case series: association between blood concentration and side effects of sotorasib. 国際誌

    Ryota Shigaki, Ryohei Yoshida, Akari Yagita, Kazunori Nagasue, Taeka Naraoka, Kiichi Nitanai, Hiraku Yanada, Toshiyuki Tenma, Ryotaro Kida, Yasuhiro Umekage, Chie Mori, Yoshinori Minami, Hideki Sato, Kuninori Iwayama, Yasuhisa Hashino, Masahide Fukudo, Takaaki Sasaki

    Frontiers in oncology   13   1269991 - 1269991   2023年

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    記述言語:英語  

    INTRODUCTION: Sotorasib is a crucial therapeutic agent for patients with non-small cell lung cancer (NSCLC) harboring the KRAS p.G12C mutation. Despite its efficacy, the relationship between blood sotorasib concentrations and side effects remains largely unexplored. METHODS: This study enrolled five patients with KRAS p.G12C-positive NSCLC treated with sotorasib (LUMAKRAS® Tablets, Amgen, Japan) between July 2022 and February 2023 at Asahikawa Medical University Hospital. Blood sotorasib levels were monitored, and their association with adverse events was examined, with no adjustments made to drug dosages based on these levels. RESULTS: Variable blood sotorasib levels were observed among the participants. Notably, one patient developed interstitial pneumonitis, although a definitive attribution to sotorasib was uncertain due to prior pembrolizumab treatment. The study revealed no consistent association between blood sotorasib levels and adverse events or therapeutic outcomes, with some patients experiencing severe side effects at higher concentrations, while others did not. CONCLUSION: Preliminary findings suggested that monitoring blood sotorasib levels may aid in anticipating adverse events in this small cohort. However, future studies with larger sample sizes and extended follow-up periods are required to validate these initial observations. Such studies could potentially offer insights into personalized dosing strategies, thereby mitigating adverse effects and enhance patient care for individuals with KRAS p.G12C-positive NSCLC.

    DOI: 10.3389/fonc.2023.1269991

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  • 髄膜癌腫症と診断された非小細胞肺癌患者に対する全脳照射の有効性の検討(NEJ049)

    芦沼 宏典, 宮内 栄作, 鈴木 綾, 古川 恵, 荒井 大輔, 下西 淳, 細川 忍, 堀田 尚誠, 猪又 峰彦, 森田 智視, 高 遼, 大熊 裕介, 佐々木 高明, 解良 恭一, 小林 国彦, 杉浦 久敏

    肺癌   62 ( 6 )   638 - 638   2022年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 当院における浸潤性粘液性腺癌32例の検討

    木田 涼太郎, 湯澤 明夏, 奈良岡 妙佳, 志垣 涼太, 天満 紀之, 梅影 泰寛, 森 千惠, 吉田 遼平, 南 幸範, 奥村 俊介, 谷野 美智枝, 佐々木 高明

    肺癌   62 ( 6 )   640 - 640   2022年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • クライオ生検時の挿管困難症例に対する当科での工夫

    木田 涼太郎, 奈良岡 妙佳, 志垣 涼太, 天満 紀之, 梅影 泰寛, 森 千惠, 吉田 遼平, 南 幸範, 奥村 俊介, 佐々木 高明

    気管支学   44 ( 6 )   458 - 458   2022年11月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器内視鏡学会  

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  • MET遺伝子増幅を獲得したEGFR遺伝子変異陽性肺がんへの新規免疫療法の開発

    吉田 遼平, 佐々木 高明, Barbie David

    肺癌   62 ( 6 )   656 - 656   2022年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 髄膜癌腫症と診断された非小細胞肺癌患者に対する全脳照射の有効性の検討(NEJ049)

    芦沼 宏典, 宮内 栄作, 鈴木 綾, 古川 恵, 荒井 大輔, 下西 淳, 細川 忍, 堀田 尚誠, 猪又 峰彦, 森田 智視, 高 遼, 大熊 裕介, 佐々木 高明, 解良 恭一, 小林 国彦, 杉浦 久敏

    肺癌   62 ( 6 )   638 - 638   2022年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Pembrolizumabで5年以上の長期奏効が得られた全身状態不良なSMARCA4欠損非小細胞癌の一例

    小泉 明子, 奈良岡 妙佳, 志垣 涼太, 天満 紀之, 木田 涼太郎, 梅影 泰寛, 森 千恵, 吉田 遼平, 南 幸範, 奥村 俊介, 佐々木 高明

    肺癌   62 ( 6 )   789 - 789   2022年11月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • METex14 skipping変異非小細胞肺癌における細胞形態学的特徴の解析

    宮川 京大, 吉岡 治彦, 湯澤 明夏, 南 宏樹, 小田嶋 広和, 秋山 直子, 鵜野 裕治, 佐々木 高明, 渡邉 純, 谷野 美智枝

    日本臨床細胞学会雑誌   61 ( Suppl.1 )   182 - 182   2022年5月

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    記述言語:日本語   出版者・発行元:(公社)日本臨床細胞学会  

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  • SETD2 and miR-21 as therapeutic targets for NUT midline carcinoma 査読

    Yoshida N., Okumura S., Sasaki T., Chiba S.-i, Sado M., Oyama K., Yoshida R., Hirai N., Minami Y., Kitada M.

    Journal of Cancer Science and Clinical Therapeutics   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

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  • Osimertinib投与中にうっ血性心不全を認めた1例

    渡邊 皐嗣, 平井 理子, 木田 涼太郎, 梅影 泰寛, 森 千惠, 吉田 遼平, 天満 紀之, 南 幸範, 奥村 俊介, 佐々木 高明

    肺癌   62 ( 1 )   69 - 69   2022年2月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • A Randomized Phase 2 Study of 5-Aminolevulinic Acid Hydrochloride and Sodium Ferrous Citrate for the Prevention of Nephrotoxicity Induced by Cisplatin-Based Chemotherapy of Lung Cancer 国際誌

    Kodai Kawamura, Hidekazu Matsushima, Hiroshi Sakai, Akira Iwashima, Sukeyuki Nakamura, Tohru Kojima, Shinichi Sasaki, Takehiko Shigenaga, Ichiro Natsume, Takaaki Sasaki, Yoshinobu Ohsaki, Kentaro Iwanaga, Koichi Nishi, Yoichiro Mitsuishi, Hirokazu Taniguchi, Kazuhiro Sato, Mitsugu Yamauchi, Motowo Nakajima, Kazuhisa Takahashi

    Oncology   100 ( 11 )   620 - 632   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Cisplatin-based chemotherapy was established in the 1980s, and it has been improved by the development of a short hydration protocol in lung cancer therapy. However, cisplatin-based chemotherapy is still associated with renal toxicity. Because 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) is known to be a mitochondrial activator and a heme oxygenase-1 (HO-1) inducer, 5-ALA with SFC is speculated to mitigate cisplatin-induced renal inflammation. METHODS: We investigated the effects of oral administration of 5-ALA with SFC for preventing cisplatin-based nephrotoxicity in patients with lung cancer and evaluated its benefits for patients who received cisplatin-based chemotherapy. The primary endpoint was the significance of the difference between the serum creatinine (sCr) levels of the patients administered 5-ALA with SFC and those given placebo after course 1 of chemotherapy. The difference in the estimated glomerular filtration rate (eGFR) between the two groups was also evaluated as the secondary endpoint. RESULTS: The double-blind, randomized two-arm studies were conducted at 15 medical facilities in Japan; 54 male and 20 female patients with lung cancer who received cisplatin-based chemotherapy between the ages of 42 and 75 years were included in the study. The compliance rate was greater than 94% in the primary assessment and subsequent drug administration periods. All enrolled patients completed the four cycles of cisplatin-based chemotherapy with short hydration. The average level of sCr on day 22 of course 1 was 0.707 mg/dL in the group treated with 5-ALA and SFC and 0.735 mg/dL in the placebo group, respectively, and the sCr in the test group was significantly lower than that in the placebo group (p = 0.038). In addition, the eGFR was significantly higher in the SPP-003 group than in the placebo group up to day 1 of course 3 (84.66 and 75.68 mL/min/1.73 m2, respectively, p = 0.02) and kept better even after the last administration of the study drug (82.37 and 73.49 mL/min/1.73 m2, respectively, p = 0.013). CONCLUSIONS: The oral administration of 5-ALA with SFC is beneficial to patients undergoing cisplatin-based chemotherapy for lung cancer with short hydration.

    DOI: 10.1159/000526977

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  • First-line osimertinib in elderly patients with epidermal growth factor receptor-mutated advanced non-small cell lung cancer: a retrospective multicenter study (HOT2002). 国際誌

    Gaku Yamamoto, Hajime Asahina, Osamu Honjo, Toshiyuki Sumi, Atsushi Nakamura, Kenichiro Ito, Hajime Kikuchi, Fumihiro Hommura, Ryoichi Honda, Keiki Yokoo, Yuka Fujita, Satoshi Oizumi, Ryo Morita, Yasuyuki Ikezawa, Hisashi Tanaka, Nozomu Kimura, Takaaki Sasaki, Noriaki Sukoh, Taichi Takashina, Toshiyuki Harada, Hirotoshi Dosaka-Akita, Hiroshi Isobe

    Scientific reports   11 ( 1 )   23140 - 23140   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Osimertinib is a standard of care therapy for previously untreated epidermal growth factor receptor mutation-positive non-small cell lung cancer. However, limited data exist regarding the efficacy and safety of osimertinib as a first-line therapy for elderly patients aged 75 years or older. To assess the potential clinical benefits of osimertinib in this population, this retrospective multi-institutional observational study included 132 patients with non-small cell lung cancer (age ≥ 75 years), who received osimertinib as first-line treatment. The proportion of patients with 1-year progression-free survival was 65.8% (95% confidence interval 57.1-73.5). The median progression-free survival was 19.4 (95% confidence interval 15.9-23.9) months. The median overall survival was not reached (95% confidence interval 24.6-not reached). The frequency of pneumonitis was 17.4%, with a grade 3 or higher rate of 9.1%. More than two-thirds of treatment discontinuations due to pneumonitis occurred within 3 months of starting osimertinib, and the prognosis of patients with pneumonitis was unsatisfactory. Osimertinib is one of the effective first-line therapeutic options for patients aged 75 years or older; however, special caution should be exercised due to the potential development of pneumonitis.

    DOI: 10.1038/s41598-021-02561-z

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  • 当院の肺末梢病変に対するクライオ生検導入期の成績

    木田 涼太郎, 渡邊 皐嗣, 天満 紀之, 梅影 泰寛, 森 千恵, 吉田 遼平, 平井 理子, 南 幸範, 奥村 俊介, 佐々木 高明, 長内 忍, 谷野 美智枝

    気管支学   43 ( 6 )   691 - 691   2021年11月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器内視鏡学会  

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  • 当院の光線力学療法(PDT)の複数回施行症例の検討

    天満 紀之, 渡邊 皐嗣, 木田 涼太郎, 梅影 泰寛, 森 千惠, 吉田 遼平, 平井 理子, 南 幸範, 奥村 俊介, 佐々木 高明, 長内 忍

    気管支学   43 ( 6 )   691 - 691   2021年11月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器内視鏡学会  

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  • 高齢者EGFR遺伝子変異陽性非小細胞肺癌に対するオシメルチニブ初回治療の検討(HOT2002)

    本庄 統, 山本 岳, 朝比奈 肇, 角 俊行, 中村 敦, 伊藤 健一郎, 菊池 創, 本村 文宏, 本田 亮一, 横尾 慶紀, 藤田 結花, 大泉 聡史, 守田 亮, 池澤 靖元, 田中 寿志, 木村 望, 佐々木 高明, 須甲 憲明, 秋田 弘俊, 磯部 宏

    肺癌   61 ( 6 )   566 - 566   2021年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer. 国際誌

    Noriko Hirai, Yutaka Hatanaka, Kanako C Hatanaka, Yuji Uno, Shin-Ichi Chiba, Yasuhiro Umekage, Yoshinori Minami, Shunsuke Okumura, Yoshinobu Ohsaki, Takaaki Sasaki

    Translational lung cancer research   10 ( 9 )   3737 - 3744   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Combination therapy with the B-Raf inhibitor, dabrafenib, and the MEK inhibitor, trametinib (DT) is commonly used to treat patients with B-Raf proto-oncogene, serine/threonine kinase V600E (BRAF V600E)-mutated non-small cell lung cancer (NSCLC). However, the mechanisms through which cancer develops DT resistance are unclear. Here, we investigated new mechanisms underlying acquired DT-resistant NSCLC with the BRAF V600E mutation. METHODS: We compared genomic signatures before and after DT treatment in patients with NSCLC. RESULTS: Two of four patients treated with DT developed carcinomatous pleuritis within 3 months. Target DNA sequencing and quantitative polymerase chain reaction (PCR) analyses revealed the increased expression level of cyclin-dependent kinase 4 (CDK4). We also found prominent protein expression of CDK4 after DT treatment. Induction of CDK4 expression in a cell line derived from a patient with the BRAF V600E mutation resulted in partial resistance to dabrafenib. CONCLUSIONS: Our findings suggest a possible relationship between CDK4 upregulation and acquired resistance to DT therapy.

    DOI: 10.21037/tlcr-21-415

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  • A stealth antigen SPESP1, which is epigenetically silenced in tumors, is a suitable target for cancer immunotherapy. 国際誌

    Akemi Kosaka, Yuki Yajima, Mayumi Hatayama, Katsuya Ikuta, Takaaki Sasaki, Noriko Hirai, Syunsuke Yasuda, Marino Nagata, Ryusuke Hayashi, Shohei Harabuchi, Kenzo Ohara, Mizuho Ohara, Takumi Kumai, Kei Ishibashi, Yui Hirata-Nozaki, Toshihiro Nagato, Kensuke Oikawa, Yasuaki Harabuchi, Esteban Celis, Toshikatsu Okumura, Yoshinobu Ohsaki, Hiroya Kobayashi, Takayuki Ohkuri

    Cancer science   112 ( 7 )   2705 - 2713   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

    DOI: 10.1111/cas.14973

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  • BRAF V600E変異肺腺癌の細胞形態 スコアリング法による半定量解析

    宮川 京大, 吉岡 治彦, 秋山 直子, 鵜野 裕治, 南 宏樹, 小田嶋 広和, 湯澤 明夏, 佐々木 高明, 渡邉 純, 谷野 美智枝

    日本臨床細胞学会雑誌   60 ( Suppl.1 )   207 - 207   2021年5月

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    記述言語:日本語   出版者・発行元:(公社)日本臨床細胞学会  

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  • The feasibility of circulating tumor DNA analysis as a marker of recurrence in triple-negative breast cancer 国際誌

    Satoshi Okazaki, Takaaki Sasaki, Shunsuke Yasuda, Masahiro Abe, Nana Yoshida, Ryohei Yoshida, Kei Ishibashi, Yoshinori Minami, Shunsuke Okumura, Shinichi Chiba, Hidehiro Takei, Ryusuke Hayashi, Toshihiro Nagato, Hiroya Kobayashi, Ayumu Sugitani, Yusuke Ono, Yusuke Mizukami, Masahiro Kitada, Yoshinobu Ohsaki

    Oncology Letters   21 ( 5 )   420 - 420   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Spandidos Publications  

    Triple-negative breast cancer (TNBC) has a poorer prognosis than other breast cancer subtypes; therefore, identifying markers of early recurrence is important. The present study aimed to establish a liquid biopsy protocol for droplet digital PCR-based detection of frequently mutated genes in patients with TNBC. Tumor DNA from 36 patients with TNBC who relapsed within 2 years after surgical resection was retrospectively analyzed. Somatic mutational profiles were evaluated using targeted sequencing to identify frequently mutated genes and genes associated with molecularly targeted therapies. The association between genetic alterations and associated protein phosphorylation was investigated using immunohistochemical analysis. Recurrent hot spot mutations in the plasma were monitored over time. Mutation-specific probes were used to successfully detect mutations in the blood samples of patients who were positive for PIK3CA H1047R and AKT1 E17K mutations. Somatic mutations in AKT1 (14.9%) and PIK3CA (25.5%) were frequently identified in the data. Robust phosphorylation of AKT and S6RP was more common in tumors with PIK3CA H1047R and AKT1 E17K mutational background than in tumors with wild-type PIK3CA and AKT1. In conclusion, the present study evaluated a high-sensitivity detection system for frequently mutated genes that was also applicable for cell-free DNA. The PI3K/AKT pathway was revealed to be activated in patients harboring PIK3CA H1047R and AKT1 E17K mutations; therefore, the PI3K/AKT pathway may be a promising candidate for targeted therapy in these patients.

    DOI: 10.3892/ol.2021.12681

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  • Monitoring EGFR C797S mutation in Japanese NSCLC patients with serial cell free DNA evaluation using digital droplet PCR 国際誌

    Ryo Ariyasu, Ken Uchibori, Takaaki Sasaki, Mika Tsukahara, Kazuma Kiyotani, Ryohei Yoshida, Yusuke Ono, Satoru Kitazono, Hironori Ninomiya, Yuichi Ishikawa, Yusuke Mizukami, Noriko Yanagitani, Naoya Fujita, Makoto Nishio, Ryohei Katayama

    Cancer Science   112 ( 6 )   2371 - 2380   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.

    DOI: 10.1111/cas.14879

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1111/cas.14879

  • Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations. 国際誌

    Kiichiro Ninomiya, Shunsuke Teraoka, Yoshitaka Zenke, Hirotsugu Kenmotsu, Yukiko Nakamura, Yusuke Okuma, Akihiro Tamiya, Kaname Nosaki, Masahiro Morise, Keiju Aokage, Yuko Oya, Toshiyuki Kozuki, Tomohiro Sakamoto, Kentaro Tanaka, Hisashi Tanaka, Junko Tanizaki, Satoru Miura, Hideaki Mizutani, Eisaku Miyauchi, Ou Yamaguchi, Noriyuki Ebi, Yasushi Goto, Takaaki Sasaki, Haruko Daga, Satoshi Morita, Takeharu Yamanaka, Shinsuke Amano, Kazuo Hasegawa, Chiyo K Imamura, Kenichi Suzuki, Kazuko Nakajima, Hitomi Nishimoto, Satoshi Oizumi, Toyoaki Hida, Katsuyuki Hotta, Yuichi Takiguchi

    JTO clinical and research reports   2 ( 1 )   100107 - 100107   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

    DOI: 10.1016/j.jtocrr.2020.100107

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  • 気管支擦過ブラシ洗浄液によるHER2エクソン20挿入変異の検索

    佐々木 高明, 平井 理子, 天満 紀之, 梅影 泰寛, 梁田 啓, 木田 涼太郎, 吉田 遼平, 大崎 能伸, 宮川 京大, 谷野 美智枝, 千葉 伸一, 南 幸範, 奥村 俊介

    肺癌   60 ( 6 )   568 - 568   2020年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • Interstitial growth patternの肺内進展をきたした肉腫型悪性胸膜中皮腫の1例

    宮川 京大, 山本 雅大, 佐々木 高明, 湯澤 明夏, 武井 英博, 大崎 能伸, 谷野 美智枝

    日本サルコイドーシス/肉芽腫性疾患学会雑誌   40 ( 1-2 )   59 - 59   2020年10月

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    記述言語:日本語   出版者・発行元:日本サルコイドーシス  

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  • アファチニブ耐性後におけるオシメルチニブの治療効果に関する検討

    梁田 啓, 吉田 遼平, 鳴海 圭倫, 藤田 結花, 天満 紀之, 木田 涼太郎, 梅影 泰寛, 平井 理子, 風林 佳大, 南 幸範, 奥村 俊介, 山本 泰司, 長内 忍, 大崎 能伸, 福士 将秀, 佐々木 高明

    肺癌   60 ( 6 )   580 - 580   2020年10月

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    記述言語:日本語   出版者・発行元:(NPO)日本肺癌学会  

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  • 北海道支部3大学共同ワーキンググループの取り組み

    長井 桂, 清水 薫子, 宮島 さつき, 橋本 みどり, 佐々木 高明, 高村 圭, 岡本 佳裕, 千葉 弘文, 長内 忍, 日本呼吸器学会北海道支部将来計画委員会/男女共同参画委員会

    日本呼吸器学会誌   9 ( 増刊 )   78 - 78   2020年8月

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    記述言語:日本語   出版者・発行元:(一社)日本呼吸器学会  

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  • Immunotherapy-related hepatitis and thrombocytopaenia induced by the very low dose of only 90 mg of atezolizumab. 国際誌

    Yoko Tsukita, Eisaku Miyauchi, Masahide Fukudo, Takaaki Sasaki, Masakazu Ichinose

    European journal of cancer (Oxford, England : 1990)   133   22 - 24   2020年7月

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  • Clinical trial of photodynamic therapy for peripheral-type lung cancers using a new laser device in a pilot study. 査読 国際誌

    Jitsuo Usuda, Tatsuya Inoue, Takaaki Tsuchida, Keishi Ohtani, Sachio Maehara, Norihiko Ikeda, Yoshinobu Ohsaki, Takaaki Sasaki, Kiyoshi Oka

    Photodiagnosis and photodynamic therapy   30   101698 - 101698   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION/AIM: Photodynamic therapy (PDT) involves the use of a tumor-specific photosensitizer and laser irradiation, and is one of the treatment options recommended for early centrally located lung cancers, but not yet for peripheral-type lung cancers. We developed a new laser probe, the composite-type optical fiberscope (COF), which allows accurate laser irradiation of a cancer lesion with simultaneous visualization of the lesion. In this study, we attempted a new endobronchial PDT technique using the new laser probe, and evaluated the effectiveness and feasibility of this novel PDT technique for peripheral lung cancers. METHODS: This phase I study was conducted in 7 patients with peripheral lung cancers (primary tumor ≤20 mm in diameter). We performed endobronchial PDT for these patients using the new laser probe and talaporfin sodium as the photosensitizer. RESULTS: We performed PDT for 3 patients with peripheral lung cancer using a laser dose of 50 J/cm2 at 120 mW, and confirmed the feasibility of using this dose. Then, we escalated the laser dose to 100 J/cm2 in 4 additional patients. A total of 7 patients met our inclusion criteria. Evaluation at 2 weeks and 3 months after the PDT revealed no complication such as pneumonia or pneumothorax. At the evaluation conducted 6 months later, we found CR in 3 cases and SD in the remaining 4 cases. CONCLUSION: PDT was found to be a feasible and non-invasive treatment modality for early peripheral-type lung cancer. In the future, PDT could become a standard treatment option for peripheral-type lung cancer.

    DOI: 10.1016/j.pdpdt.2020.101698

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  • Novel ALK-specific mRNA in situ hybridization assay for non-small-cell lung carcinoma. 国際誌

    Noriko Hirai, Takaaki Sasaki, Shunsuke Okumura, Masatoshi Sado, Naoko Akiyama, Masahiro Kitada, Hidehiro Takei, Yoshinobu Ohsaki

    Translational lung cancer research   9 ( 2 )   257 - 268   2020年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: A recent technical advance in mRNA in situ hybridization (mRNA-ISH) assays provides simultaneous signal amplification and background suppression with a unique probe design that enables single-molecule visualization. We assessed the utility of the mRNA-ISH assay as a diagnostic tool for detecting anaplastic lymphoma receptor tyrosine kinase (ALK) mRNA in non-small-cell lung carcinoma (NSCLC). We compared the mRNA-ISH assay with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Methods: The study included 279 surgically resected lung adenocarcinomas and 44 transbronchial-biopsied (TBB) adenocarcinomas. mRNA-ISH was conducted using the RNAscope 2.0 system, which includes pre-designed probes for detecting the tyrosine kinase domain encoded in ALK mRNA. IHC was conducted on all 323 samples using ALK-specific antibodies. mRNA-ISH was performed on 279 surgical samples and 6 TBB samples. Break-apart FISH was used to examine samples that were mRNA-ISH-positive or IHC-positive. Results: ALK protein expression was detected in 11 of 279 specimens (3.9%). ALK mRNA was also detected with mRNA-ISH in ALK-positive samples, and 9 of the 11 specimens (81%) were also positive for ALK using break-apart FISH. Using the IHC results as a reference, the sensitivity and specificity of mRNA-ISH was 100%. In the TBB cohort, ALK protein expression was observed in 3 of 44 specimens (6.8%), in which ALK mRNA expression was also detected. Conclusions: The ALK mRNA-ISH data were highly correlated with the IHC data, and ALK mRNA-ISH detected ALK mRNA expression in every FISH-positive sample. We conclude that mRNA-ISH could serve as an alternative or complementary method for diagnosing ALK rearrangements in NSCLC.

    DOI: 10.21037/tlcr.2020.03.04

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  • PD-1 Blockers: Staying Long in the Body and Delayed Toxicity Risks. 査読 国際誌

    Masahide Fukudo, Takaaki Sasaki, Yoshinobu Ohsaki

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   15 ( 3 )   e42-e44   2020年3月

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  • Acute eosinophilic pneumonia following inhalation of turpentine oil: A case report. 国際誌

    Yasuhiro Umekage, Shunsuke Okumura, Toshiyuki Tenma, Yoshihiro Kazebayashi, Noriko Hirai, Yoshinori Minami, Kazushi Doshita, Takaaki Sasaki, Yasushi Yamamoto, Yoshinobu Ohsaki

    Respiratory medicine case reports   31   101143 - 101143   2020年

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    記述言語:英語  

    Acute eosinophilic pneumonia (AEP) is an eosinophilic lung disease associated with environmental substances including smoking. Although the etiology of AEP has not been fully elucidated, it has been hypothesized that IL-33 plays a central role in the pathogenesis of AEP. Turpentine oil, from resins of pine trees, is not only used in paints, but also utilized in experimental animal models of inflammation because it leads to the production of inflammatory cytokines including IL-33. Here, we report the first case of AEP following turpentine oil inhalation. A 67-year-old woman reported using urushiol with turpentine oil to repair home goods. She had fever and persistent cough after turpentine inhalation over a very short period of time. The chest X-ray image showed consolidation in the upper right lung field. Laboratory findings indicated that there was no evidence of infection, collagen vascular diseases, and other allergic diseases that cause pneumonia, but analysis of the bronchoalveolar lavage fluid revealed 29% eosinophils with a small number of lipid-laden macrophages. With these findings, the diagnostic criteria of AEP was met. We rendered a diagnosis of AEP by inhalation of turpentine because no other cause for AEP was identified even with a structured questionnaire survey. The manifestations resolved immediately after steroid therapy. This is the first report of a case of AEP caused by the inhalation of turpentine oil.

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  • Monomerization of ALK Fusion Proteins as a Therapeutic Strategy in ALK-Rearranged Non-small Cell Lung Cancers. 国際誌

    Noriko Hirai, Takaaki Sasaki, Shunsuke Okumura, Yoshinori Minami, Shinichi Chiba, Yoshinobu Ohsaki

    Frontiers in oncology   10   419 - 419   2020年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Objective: Oncogenic echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) (EML4-ALK) fusion proteins found in non-small cell lung cancers (NSCLC) are constitutively phosphorylated and activated by dimerization via the coiled-coil domain (cc) within EML4. Here, we investigated whether disruption of ALK fusion protein oligomerization via competitive cc mimetic compounds could be a therapeutic strategy for EML4-ALK NSCLC. Methods: A Ba/F3 cell model was created that expressed an ALK intracellular domain in which the dimer/monomer state is ligand-regulated. This novel cell model was used to investigate the effect of disrupting ALK fusion protein oligomerization on tumor cell growth in vitro and in vivo using nude mice. Subsequently, the antiproliferative effects of endogenous cc domain co-expression and mimetic cc peptides were assayed in EML4-ALK cancer cell lines. Results: Cells induced to express monomeric ALK in vitro did not survive. When transplanted into mice, induction of monomers abrogated tumor formation. Using a fluorescent protein system to quantify protein-protein interactions of EML4-ALK and EML4cc, we demonstrated that co-expression of EML4cc suppressed EML4-ALK assembly concomitant with decreasing the rate of tumor growth in vitro and in vivo. In EML4-ALK cancer cell lines, administration of synthetic EML4cc peptide elicited a decrease of phosphorylation of ALK leading to reduction in tumor cell growth. Conclusions: Our findings support the monomerization of ALK fusion proteins using EML4cc peptides for competitive inhibition of dimerization as a promising therapeutic strategy for EML4-ALK NSCLC. Further studies are warranted to explore the use of specific cc peptide as a therapeutic option for other lung cancers harboring driver fusion genes containing a cc or oligomerization domain within the fusion partner.

    DOI: 10.3389/fonc.2020.00419

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  • Response to Crizotinib Re-administration After Progression on Lorlatinib in a Patient With ALK-rearranged Non-small-cell Lung Cancer. 査読 国際誌

    Jun Sakakibara-Konishi, Hidenori Kitai, Yasuyuki Ikezawa, Yutaka Hatanaka, Takaaki Sasaki, Ryohei Yoshida, Shinichi Chiba, Shingo Matsumoto, Koichi Goto, Hidenori Mizugaki, Naofumi Shinagawa

    Clinical lung cancer   20 ( 5 )   e555-e559   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.cllc.2019.06.021

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  • The Japanese Lung Cancer Society Guideline for non-small cell lung cancer, stage IV. 査読

    Hiroaki Akamatsu, Kiichiro Ninomiya, Hirotsugu Kenmotsu, Masahiro Morise, Haruko Daga, Yasushi Goto, Toshiyuki Kozuki, Satoru Miura, Takaaki Sasaki, Akihiro Tamiya, Shunsuke Teraoka, Yukari Tsubata, Hiroshige Yoshioka, Yoshihiro Hattori, Chiyo K Imamura, Yuki Katsuya, Reiko Matsui, Yuji Minegishi, Hidenori Mizugaki, Kaname Nosaki, Yusuke Okuma, Setsuko Sakamoto, Takashi Sone, Kentaro Tanaka, Shigeki Umemura, Takeharu Yamanaka, Shinsuke Amano, Kazuo Hasegawa, Satoshi Morita, Kazuko Nakajima, Makoto Maemondo, Takashi Seto, Nobuyuki Yamamoto

    International journal of clinical oncology   24 ( 7 )   731 - 770   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.

    DOI: 10.1007/s10147-019-01431-z

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  • Fluorodynamic diagnosis of thoracic malignancies

    Yoshinobu Ohsaki, Ryohei Yoshida, Takaaki Sasaki, Shunsuke Okumura, Yoshinori Minami, Yoshihiro Kazebayashi, Noriko Hirai, Kei Ishibashi, Nana Yoshida, Yasushi Yamamoto, Masahiro Kitada

    Proceedings of SPIE - The International Society for Optical Engineering   11070   2019年

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    記述言語:英語   掲載種別:研究論文(国際会議プロシーディングス)   出版者・発行元:SPIE  

    In the area of neurosurgical tumor diagnosis, clinical research on photodynamic diagnosis using 5-aminolevulinic acid (5-ALA) has already been undertaken, and the safety of 5-ALA has also been demonstrated. 5-ALA is approved in the diagnosis of brain tumor and bladder tumor by the Ministry of Health, Labour and Welfare. 5-ALA is a natural amino acid contained in a living body and is a precursor of hemoglobin. When absorbed into the body by oral ingestion, porphyrin synthesis by heme synthesis is specifically performed in a tumor-specific manner, and accumulation of fluorescent protoporphyrin IX (pp IX) is observed. However, pp IX is metabolized and disappeared in normal tissues. When tumor tissue is irradiated with excitation light, at the site where pp IX accumulates, it exhibits red fluorescence. We applied 5-ALA for photodynamic diagnostic in thoracic malignancies.

    DOI: 10.1117/12.2527526

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  • Highly sensitive detection of ALK resistance mutations in plasma using droplet digital PCR. 査読 国際誌

    Ryohei Yoshida, Takaaki Sasaki, Yasuhiro Umekage, Sachie Tanno, Yusuke Ono, Munehiko Ogata, Shinichi Chiba, Yusuke Mizukami, Yoshinobu Ohsaki

    BMC cancer   18 ( 1 )   1136 - 1136   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: On-target resistance mechanisms found in one-third of patients receiving anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are secondary ALK mutations in ALK-rearranged non-small cell lung cancer (NSCLC). There are large variations in the resistant mutations, unlike the epithelial growth factor receptor (EGFR) T790 M seen with the use of EGFR-TKIs. Liquid biopsy approaches using cell-free DNA (cfDNA) are used for screening and monitoring of mutations in NSCLC. However, feasible protocol for the simultaneous detection of multiple secondary ALK mutations using droplet digital PCR (ddPCR) has not been developed. An efficient strategy using cfDNA in cancer diagnostics, the development of more accurate and cost-effective tools to identify informative multiple secondary ALK mutations is clinically required. METHODS: To establish a feasible assay to monitor ALK-TKI resistance mutations, we first evaluated the feasibility of ddPCR-based screening for cfDNA mutation detection of 10 distinct secondary ALK mutations. Positive samples were then re-analyzed using mutation-specific probes to track the growth of mutation clones with a high sensitivity. RESULTS: Blood samples from seven ALK-positive patients were analyzed using the ddPCR protocol. Secondary G1202R ALK mutations were identified in 2 of 7 patients by the screening assay. Using the mutation-specific probes, monitoring the resistant clone during the clinical course of the disease was well demonstrated in each of the patients. CONCLUSION: The protocol for ddPCR-based liquid biopsy has a feasibility for the screening of secondary ALK-TKI resistance mutations and offers a tool for a cost-effective monitoring of progression in NSCLC.

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  • Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report. 査読 国際誌

    Yoshitsugu Narumi, Ryohei Yoshida, Yoshinori Minami, Yasushi Yamamoto, Shiori Takeguchi, Kohei Kano, Kae Takahashi, Tsukasa Saito, Jun Sawada, Hiroya Terui, Takayuki Katayama, Takaaki Sasaki, Yoshinobu Ohsaki

    BMC cancer   18 ( 1 )   95 - 95   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Immune checkpoint blockade is developed as standard treatment for non-small cell lung cancer. However immune-related adverse events (irAE) have still unknown complications. Here, we report a patient with lung squamous cell carcinoma who developed neuromyelitis optica spectrum disorder with nivolumab. CASE PRESENTATION: A 75-year-old Japanese man with lung squamous cell carcinoma was administered nivolumab as second-line treatment. Two months after treatment with nivolumab, he presented acute paralysis in the bilateral lower limbs, sensory loss. Spinal magnetic resonance imaging showed T2 hyperintense lesions between C5-6 and Th12-L1. He was diagnosed with neuromyelitis optica spectrum disorder (NMOSD) by anti-aquaporin-4 antibody-positive in the serum and other examinations. After treatment, steroid reactivity was poor. CONCLUSION: This is the first patient who developed anti-AQP4 antibody-positive NMOSD as a nivolumab-induced irAE. Clinicians should be aware of this kind of potential neurological complication by using immune check point inhibitor and start the treatment of this irAE as soon as possible.

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  • Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer. 査読 国際誌

    Ryohei Yoshida, Takaaki Sasaki, Yoshinori Minami, Yukiko Hibino, Shunsuke Okumura, Masatoshi Sado, Naoyuki Miyokawa, Satoshi Hayashi, Masahiro Kitada, Yoshinobu Ohsaki

    International journal of oncology   51 ( 5 )   1533 - 1540   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, crizotinib, and recently the more highly potent alectinib and ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were ceritinib or lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK-NSCLC with acquired resistance to ALK inhibitors.

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  • EGFR and KRAS Mutations in Triple-Mutated Lung Cancer. 査読 国際誌

    Yoshida R, Sasaki T, Ohsaki Y

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   12 ( 7 )   e92-e93 - e93   2017年7月

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  • Observation of Zn-photoprotoporphyrin red Autofluorescence in human bronchial cancer using color-fluorescence endoscopy. 査読 国際誌

    Yoshinobu Ohsaki, Takaaki Sasaki, Satoshi Endo, Masahiro Kitada, Shunsuke Okumura, Noriko Hirai, Yoshihiro Kazebayashi, Eri Toyoshima, Yasushi Yamamoto, Kaneyoshi Takeyama, Susumu Nakajima, Isao Sakata

    BMC cancer   17 ( 1 )   289 - 289   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    BACKGROUND: We observed red autofluorescence emanating from bronchial cancer lesions using a sensitive color-fluorescence endoscopy system. We investigated to clarify the origin of the red autofluorescence. METHODS: The wavelengths of the red autofluorescence emanating from lesions were measured in eight patients using a spectrum analyzer and compared based on pathologic findings. Red autofluorescence at 617.3, 617.4, 619.0, and 617.1 nm was emitted by normal bronchus, inflamed tissue, tissue exhibiting mild dysplasia, and malignant lesions, respectively. Protoporphyrin, uroporphyrin, and coproporphyrin, the major porphyrin derivatives in human blood, were purchased to determine which porphyrin derivative is the source of red fluorescence when acquired de novo. We synthesized photoporphyrin, Zn-protoporphyrin and Zn-photoprotoporphyrin from protoporphyrin. RESULTS: Coproporphyrin and uroporphyrin emitted only weak fluorescence. Fluorescence was emitted by our synthesized Zn-photoprotoporphyrin at 625.5 nm and by photoprotoporphyrin at 664.0 nm. CONCLUSIONS: From these results, we conclude that Zn-photoprotoporphyrin was the source of the red autofluorescence observed in bronchial lesions. Zn-protoporphyrin is converted to Zn-photoprotoporphyrin by radiation with excitation light. Our results suggest that red autofluorescence emanating from Zn-photoprotoporphyrin in human tissues could interfere with photodynamic diagnosis using porphyrin derivatives such as Photofrin® and Lazerphyrin® with a sensitive endoscopy system, because color cameras cannot differentiate Zn-photoprotoporphyrin red fluorescence from that of other porphyrin derivatives.

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  • Rikkunshito for Preventing Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients: Results from 2 Prospective, Randomized Phase 2 Trials. 査読 国際誌

    Toshiyuki Harada, Toraji Amano, Tomoo Ikari, Kei Takamura, Takahiro Ogi, Toshiaki Fujikane, Yuka Fujita, Kageaki Taima, Hisashi Tanaka, Takaaki Sasaki, Shunsuke Okumura, Shunichi Sugawara, Hiroshi Yokouchi, Noriyuki Yamada, Naoto Morikawa, Hirotoshi Dosaka-Akita, Hiroshi Isobe, Masaharu Nishimura

    Frontiers in pharmacology   8   972 - 972   2017年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The herbal medicine rikkunshito has the potential to improve chemotherapy-induced nausea and vomiting (CINV) by stimulating ghrelin secretion. We aimed to evaluate the efficacy and safety of rikkunshito in preventing CINV for patients with lung cancer. Two separate prospective, randomized, phase II parallel design studies were conducted in patients with lung cancer. Fifty-eight and sixty-two patients scheduled to receive highly emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC), respectively, were randomized 1:1 to receive either standard antiemetic therapy in accordance with international guidelines (S group) or standard antiemetic therapy plus oral rikkunshito (R group). The primary endpoint was overall complete response (CR)-that is, no emesis and rescue medication in the first 120 h post-chemotherapy. Secondary endpoints included CR in the acute (0-24 h) and delayed (>24-120 h) phases and safety. Fifty-seven patients (S group, 28; R group, 29) receiving HEC and sixty-two patients (S group, 30; R group, 32) receiving MEC with comparable characteristics were evaluated. The CR rates were similar across the S and R groups for the HEC study in the overall (67.9% vs. 62.1%), acute (96.4% vs. 89.6%), and delayed (67.9% vs. 62.1%) phases, respectively, and for the MEC study in the overall (83.3% vs. 84.4%), acute (100% vs. 100%), and delayed (83.3% vs. 84.4%) phases, respectively. No severe adverse events were observed. Although rikkunshito was well tolerated, it did not demonstrate an additional preventative effect against CINV in lung cancer patients receiving HEC or MEC. Clinical Trial Registry Information: This study is registered with the University Hospital Medical Information Network (UMIN) Clinical Trial Registry, identification numbers UMIN 000014239 and UMIN 000014240.

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  • Evaluation of a Quantitative Serological Assay for Diagnosing Chronic Pulmonary Aspergillosis. 査読 国際誌

    Satoru Fujiuchi, Yuka Fujita, Hokuto Suzuki, Kazushi Doushita, Hikaru Kuroda, Masaaki Takahashi, Yasuhiro Yamazaki, Tadakatsu Tsuji, Toshiaki Fujikane, Shinobu Osanai, Takaaki Sasaki, Yoshinobu Ohsaki

    Journal of clinical microbiology   54 ( 6 )   1496 - 1499   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The purpose of this study was to evaluate the clinical utility of a quantitative Aspergillus IgG assay for diagnosing chronic pulmonary aspergillosis. We examined Aspergillus-specific IgG levels in patients who met the following criteria: (i) chronic (duration of >3 months) pulmonary or systemic symptoms, (ii) radiological evidence of a progressive (over months or years) pulmonary lesion with surrounding inflammation, and (iii) no major discernible immunocompromising factors. Anti-Aspergillus IgG serum levels were retrospectively analyzed according to defined classifications. Mean Aspergillus IgG levels were significantly higher in the proven group than those in the possible and control groups (P < 0.01). Receiver operating characteristic curve analysis revealed that the Aspergillus IgG cutoff value for diagnosing proven cases was 50 mg of antigen-specific antibodies/liter (area under the curve, 0.94; sensitivity, 0.98; specificity, 0.84). The sensitivity and specificity for diagnosing proven cases using this cutoff were 0.77 and 0.78, respectively. The positive rates of Aspergillus IgG in the proven and possible groups were 97.9% and 39.2%, respectively, whereas that of the control group was 6.6%. The quantitative Aspergillus IgG assay offers reliable sensitivity and specificity for diagnosing chronic pulmonary aspergillosis and may be an alternative to the conventional precipitin test.

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  • Successful alectinib treatment after crizotinib-induced interstitial lung disease. 査読 国際誌

    Satoru Fujiuchi, Yuka Fujita, Takaaki Sasaki, Yoshinobu Ohsaki

    Respirology case reports   4 ( 3 )   e00156   2016年5月

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    記述言語:英語  

    A 70-year-old woman with lung adenocarcinoma, harbouring anaplastic lymphoma kinase gene rearrangement, was treated with crizotinib as third-line chemotherapy. After 2 months, crizotinib was discontinued because of the development of crizotinib-induced interstitial lung disease (ILD). Steroid treatment was then introduced and tapered off. Following complete resolution of the interstitial shadow, cytotoxic chemotherapy was initiated, and continued for over 2 years, until new intrapulmonary lesions developed. Although there was a risk of drug-induced interstitial pneumonia, alectinib was initiated as the fifth-line therapy, without steroid supplementation, as there was no alternative treatment. No recurrence of ILD was noted at 10 months. To our knowledge, this is the first report of successful alectinib treatment after the development of crizotinib-induced ILD without the use of prednisolone.

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  • Analysis of garenoxacin distribution in the mediastinum using endobronchial ultrasound-guided transbronchial needle aspiration. 査読 国際誌

    Satoshi Endo, Takaaki Sasaki, Kaori Onishi, Yoshihiro Kazebayashi, Noriko Hirai, Yoshinori Minami, Eri Toyoshima, Yasushi Yamamoto, Satoshi Kishino, Yoshinobu Ohsaki

    International journal of antimicrobial agents   46 ( 6 )   721 - 2   2015年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier {BV}  

    DOI: 10.1016/j.ijantimicag.2015.10.001

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  • Histamine H1 antagonist levocetirizine as a potential cause of lung injury. 査読 国際誌

    Satoshi Endo, Yasushi Yamamoto, Yoshinori Minami, Shunsuke Okumura, Takaaki Sasaki, Yoshinobu Ohsaki

    Respirology case reports   3 ( 2 )   64 - 7   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Histamine H1 antagonists rarely cause drug-induced lung injury (DLI). A woman in her 60s, who had been taking antihistaminic levocetirizine for 2 months, presented with progressive cough and shortness of breath. A chest radiograph showed patchy infiltrations on both lower lung fields. Chest computed tomography findings were consistent with non-specific interstitial pneumonia. Serum markers associated with interstitial pneumonias were elevated. Room air arterial blood gas analysis revealed hypoxemia. Restrictive ventilatory impairment was noted with reduced diffusing capacity. Transbronchial lung biopsy specimens demonstrated unclassifiable alveolitis. Steroid pulse therapy was introduced for respiratory distress, but the initial response to treatment was poor. A drug lymphocyte stimulation test was positive for levocetirizine. The interstitial pneumonia improved following withdrawal of levocetirizine. Her illness has not recurred under steroid therapy and the discontinuation of levocetirizine. Antihistaminics may have a potential risk of DLI.

    DOI: 10.1002/rcr2.101

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  • Prostaglandin I2 analog suppresses lung metastasis by recruiting pericytes in tumor angiogenesis. 査読 国際誌

    Yoshinori Minami, Takaaki Sasaki, Hiroki Bochimoto, Jun-Ichi Kawabe, Satoshi Endo, Yoshiki Hira, Tsuyoshi Watanabe, Shunsuke Okumura, Naoyuki Hasebe, Yoshinobu Ohsaki

    International journal of oncology   46 ( 2 )   548 - 54   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Prostaglandin I2 (PGI2) agonist has been reported to reduce tumor metastasis by modifying tumor angiogenesis; however, the mechanisms of how PGI2 affects the endothelial cells or pericytes in tumor vessel maturation are still unclear. The purpose of this study was to clarify the effects of PGI2 on tumor metastasis in a mouse lung metastasis model using Lewis lung carcinoma (LLC) cells. The mice were treated continuously with beraprost sodium (BPS), a PGI2 analog, for 3 weeks and then examined for lung metastases. The number and size of lung metastases were decreased significantly by BPS treatment. In addition, scanning electron microscopy and immunohistochemistry revealed that BPS increased the number of tumor‑associated pericytes and improved intratumor hypoxia. Collectively, this study suggests that BPS attenuated vascular functional maturation in metastatic tumors.

    DOI: 10.3892/ijo.2014.2783

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  • Interstitial lung disease associated with human papillomavirus vaccination. 査読 国際誌

    Yasushi Yamamoto, Yoshihiro Kazebayashi, Noriko Hirai, Takaaki Sasaki, Yoshinobu Ohsaki

    Respiratory medicine case reports   16   15 - 7   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier {BV}  

    Vaccinations against the human papillomavirus (HPV) have been recommended for the prevention of cervical cancer. HPV-16/18 AS04-adjuvanted vaccines (Cervarix) are said to have favourable safety profiles. Interstitial lung diseases (ILDs) can occur following exposure to a drug or a biological agent. We report a case of ILD associated with a Cervarix vaccination. A woman in her 40's, with a history of conisation, received three inoculations of Cervarix. Three months later, she presented with a cough and shortness of breath. Findings from a computed tomography of the chest and a transbronchial lung biopsy were consistent with non-specific interstitial pneumonia. Workup eliminated all other causes of the ILD, except for the vaccination. Over the 11 months of the follow-up period, her symptoms resolved without steroid therapy. The onset and spontaneous resolution of the ILD showed a chronological association with the HPV vaccination. The semi-quantitative algorithm revealed that the likelihood of an adverse drug reaction to Cervarix was "Probable". The outcome was relatively good, but more attention should be paid to a potential risk for HPV vaccinations to cause ILDs. Wherever possible, chest radiographic examinations should be performed in order not to overlook any ILDs.

    DOI: 10.1016/j.rmcr.2015.06.003

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  • Feasibility of adjuvant chemotherapy with S-1 consisting of a 4-week administration and a two-week rest period in patients with completely resected non-small cell lung cancer. 査読 国際誌

    Shunsuke Okumura, Takaaki Sasaki, Kazuhiro Satoh, Masahiro Kitada, Atsushi Nagase, Eiji Yatsuyanagi, Yoshinobu Ohsaki

    Molecular and clinical oncology   1 ( 1 )   124 - 130   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The efficacy of adjuvant chemotherapy with S-1 in patients with completely resected non-small cell lung cancer (NSCLC) has yet to be clarified, and the appropriate schedule for the adjuvant chemotherapy with S-1 remains unknown. A phase II study was conducted to evaluate the feasibility and efficacy of adjuvant chemotherapy with S-1. Patients enrolled in this study were 20-75 years old, had pathological stage IB-IIIA NSCLC, and had received complete resection of NSCLC. S-1 (80 mg/m2) was administered orally to the patients for four weeks followed by a two-week rest period (conventional schedule), for a maximum of eight cycles. The primary endpoint was relative dose intensity (RDI), while the secondary endpoints were safety and 1 year of disease-free survival (1y-DFS). Between May 2007 and October 2009, 28 patients were enrolled. The RDI was 63.1% (95% CI, 48.6-77.7). No grade 3 or worse hematological toxicity was observed. Grade 3 non-hematological toxicities were observed in four patients. No grade 4 or worse hematological toxicity was detected. The probability of 1y-DFS was 85.7% (95% CI, 72.8-98.6). In the subgroup analysis, the median RDI of patients over 65 years old was lower compared to the other patients (44.8 vs. 100%; P=0.013; Mann-Whitney U test). Creatinine clearance (CCr) was lower in the older group, with more grade 2 or 3 non-hematological toxicities in the elderly patients. These results suggest that the conventional schedule of adjuvant chemotherapy with S-1 is not likely to be feasible in older patients with completely resected NSCLC.

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  • Nicotinamide phosphoribosyltransferase: a potent therapeutic target in non-small cell lung cancer with epidermal growth factor receptor-gene mutation. 査読 国際誌

    Shunsuke Okumura, Takaaki Sasaki, Yoshinori Minami, Yoshinobu Ohsaki

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   7 ( 1 )   49 - 56   2012年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:1  

    BACKGROUND: Non-small cell lung cancer (NSCLC) often has an epidermal growth factor receptor (EGFR) gene mutation. Growth of EGFR-gene-mutated NSCLC depends predominantly on EGFR signaling and requires a large amount of intracellular ATP to activate EGFR signal transduction. Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis, and it regulates intracellular ATP levels in mammalian cells. The effect of NAMPT inhibition on NSCLC has not been completely understood. METHODS: We aimed to clarify the hypothesis that NAMPT inhibition suppresses growth of EGFR-gene-mutated NSCLC through reduction of intracellular ATP levels, using NAMPT-siRNA transfection and NAMPT inhibitor FK866. We used four lung adenocarcinoma cell lines, including H358 (Wild type EGFR), LC2 (EGFR), PC9 (EGFR), and H1975 (EGFR), and evaluated the effect of FK866 on these cells and its mechanisms, using cell proliferation, Western blot, ATP, and apoptosis assay. RESULTS: We found that (1) H358, LC2, and H1975 cell lines highly expressed NAMPT-mRNA; (2) NAMPT-specific siRNA and FK866 suppressed proliferation of these NSCLCs; (3) FK866 reduced intracellular ATP levels in H1975 cells; (4) FK866 dephosphorylated EGFR signal proteins, including EGFR, Akt, Map kinase kinase 1/2, and extracellular signal-regulated kinase 1/2 (ERK 1/2); (5) FK866 induced apoptosis of H1975 cells; and (6) FK866 suppressed growth of H1975 xenograft tumors and attenuated expression of phospho-ERK 1/2 in the tumors in a tumor-bearing mouse model. CONCLUSION: These findings indicate that NAMPT is a potent therapeutic target in the treatment of EGFR-gene-mutated NSCLC.

    DOI: 10.1097/JTO.0b013e318233d686

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  • An amino-indazole scaffold with spectrum selective kinase inhibition of FLT3, PDGFRα and kit. 査読 国際誌

    Deng X, Zhou W, Weisberg E, Wang J, Zhang J, Sasaki T, Nelson E, Griffin JD, Jänne PA, Gray NS

    Bioorganic & medicinal chemistry letters   22 ( 14 )   4579 - 84   2012年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:14  

    DOI: 10.1016/j.bmcl.2012.05.107

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  • New strategies for treatment of ALK-rearranged non-small cell lung cancers. 査読 国際誌

    Takaaki Sasaki, Pasi A Jänne

    Clinical cancer research : an official journal of the American Association for Cancer Research   17 ( 23 )   7213 - 8   2011年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:American Association for Cancer Research ({AACR})  

    The identification of oncogenic alterations in subsets of patients with non-small cell lung cancer (NSCLC) is transforming clinical care. Genomic rearrangements in anaplastic lymphoma kinase (ALK) are detected in 3% to 7% of patients with NSCLC. The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and was recently approved by the U.S. Food and Drug Administration. Crizotinib is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, new challenges in the diagnosis and treatment of this subset of NSCLC have emerged, including the need to determine the most effective means of diagnosing ALK-rearranged NSCLC and the emergence of acquired drug resistance to crizotinib. In this review, we discuss current strategies for treatment and diagnosis, as well as the current knowledge about mechanisms of acquired resistance to crizotinib. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.

    DOI: 10.1158/1078-0432.CCR-11-1404

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  • [The add-on effect of omalizumab on patients with uncontrolled bronchial asthma]. 査読

    Yoshinori Minami, Satoshi Endo, Shunsuke Okumur, Takaaki Sasaki, Yasushi Yamamoto, Toshiyuki Ogasa, Shinobu Osanai, Yoshinobu Ohsaki

    Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society   49 ( 11 )   793 - 9   2011年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:11  

    A high-dose administration of inhaled corticosteroid is effective in the majority of patients with bronchial asthma, but is often difficult to attain sufficient control in certain subsets of patients. Omalizumab has recently emerged as a promising drug for bronchial asthma. To assess its add-on effect we administered omalizumab to patients with uncontrolled atopic asthma for more than 16 weeks and gave them questionnaires. The study population comprised 9 patients with frequent asthmatic symptoms despite the administration of high-dose inhaled corticosteroid and other disease controllers. We scored disease control using the Asthma Health Questionnaire-33-Japan and the Asthma Control Test, and evaluated the frequencies of short-acting beta2-agonist use for rescue and drip infusion of theophyllines and/or systemic steroids in a retrospective fashion. Asthmatic scores were significantly improved after 16 weeks of omalizumab therapy. The frequencies of reliever use and drip infusion were also decreased. These trends were present even in patients in whom no aeroallergen-specific IgE antibodies were detected. No statistically significant side effects were observed. Our study confirmed the add-on effect of omalizumab based on evaluation by simple questionnaires. Further studies are needed to clarify whether omalizumab therapy is suitable for patients without specific IgE antibodies.

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  • A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. 査読 国際誌

    Takaaki Sasaki, Jussi Koivunen, Atsuko Ogino, Masahiko Yanagita, Sarah Nikiforow, Wei Zheng, Christopher Lathan, J Paul Marcoux, Jinyan Du, Katsuhiro Okuda, Marzia Capelletti, Takeshi Shimamura, Dalia Ercan, Magda Stumpfova, Yun Xiao, Stanislawa Weremowicz, Mohit Butaney, Stephanie Heon, Keith Wilner, James G Christensen, Michel J Eck, Kwok-Kin Wong, Neal Lindeman, Nathanael S Gray, Scott J Rodig, Pasi A Jänne

    Cancer research   71 ( 18 )   6051 - 60   2011年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.

    DOI: 10.1158/0008-5472.CAN-11-1340

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  • Discovery of 3,5-diamino-1,2,4-triazole ureas as potent anaplastic lymphoma kinase inhibitors 査読

    Deng, X., Wang, J., Zhang, J., Sim, T., Kim, N.D., Sasaki, T., Luther, W., George, R.E., Jänne, P.A., Gray, N.S.

    ACS Medicinal Chemistry Letters   2 ( 5 )   379 - 384   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by 15a, 20a, and 23a, which exhibited antiproliferative IC50 values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, 15a and 23a potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy.

    DOI: 10.1021/ml200002a

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  • The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. 査読 国際誌

    Takaaki Sasaki, Katsuhiro Okuda, Wei Zheng, James Butrynski, Marzia Capelletti, Liping Wang, Nathanael S Gray, Keith Wilner, James G Christensen, George Demetri, Geoffrey I Shapiro, Scott J Rodig, Michael J Eck, Pasi A Jänne

    Cancer research   70 ( 24 )   10038 - 43   2010年12月

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    記述言語:英語   出版者・発行元:24  

    The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.

    DOI: 10.1158/0008-5472.CAN-10-2956

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  • Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene. 査読 国際誌

    Zhao Chen, Takaaki Sasaki, Xiaohong Tan, Julian Carretero, Takeshi Shimamura, Danan Li, Chunxiao Xu, Yuchuan Wang, Guillaume O Adelmant, Marzia Capelletti, Hyun Joo Lee, Scott J Rodig, Christa Borgman, Seung-Il Park, Hyeong Ryul Kim, Robert Padera, Jarrod A Marto, Nathanael S Gray, Andrew L Kung, Geoffrey I Shapiro, Pasi A Jänne, Kwok-Kin Wong

    Cancer research   70 ( 23 )   9827 - 36   2010年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRASor EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement.

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  • p130Cas, Crk-Associated Substrate Plays Essential Roles in Liver Development by Regulating Sinusoidal Endothelial Cell Fenestration 査読

    Tatsuya Tazaki, Takaaki Sasaki, Kenta Uto, Norimasa Yamasaki, Satoshi Tashiro, Ryuichi Sakai, Minoru Tanaka, Hideaki Oda, Zen-Ichiro Honda, Hiroaki Honda

    HEPATOLOGY   52 ( 3 )   1089 - 1099   2010年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JOHN WILEY & SONS INC  

    p130Cas, Crk-associated substrate (Cas), is an adaptor/scaffold protein that plays a central role in actin cytoskeletal reorganization. We previously showed that mice in which Cos was deleted (Cas(-/-)) died in utero because of early cardiovascular maldevelopment. To further investigate the in vivo roles of Gas, we generated mice with a hypomorphic Gas allele lacking the exon 2-derived region (Cas(Delta ex2/Delta ex2).) which encodes Src homology domain 3 (SH3) of Cas.Cas(Delta ex2/Delta ex2) mice again died as embryos, but they particularly showed progressive liver degeneration with hepatocyte apoptosis. Because Cas expression in the liver is preferentially detected in sinusoidal endothelial cells (SECs), the observed hepatocyte apoptosis was most likely ascribable to impaired function of SECs. To address this possibility, we stably introduced a Gas mutant lacking the SH3 domain (Gas ASH3) into an SEC line (NP31). Intriguingly, the introduction of Gas ASH3 induced a loss of fenestrae, the characteristic cell-penetrating pores in SECs that serve as a critical route for supplying oxygen and nutrients to hepatocytes. The disappearance of fenestrae in Gas ASH3-expressing cells was associated with an attenuation of actin stress fiber formation, a marked reduction in tyrosine phosphorylation of Gas, and defective binding of Gas to CrkII. Conclusion: Gas plays pivotal roles in liver development through the reorganization of the actin cytoskeleton and formation of fenestrae in SECs. (HEPATOLOGY 2010;52:1089-1099)

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  • The biology and treatment of EML4-ALK non-small cell lung cancer. 査読 国際誌

    Takaaki Sasaki, Scott J Rodig, Lucian R Chirieac, Pasi A Jänne

    European journal of cancer (Oxford, England : 1990)   46 ( 10 )   1773 - 80   2010年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:10  

    The fusion between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) has recently been identified in a subset of non-small cell lung cancers (NSCLCs). EML4-ALK is most often detected in never smokers with lung cancer and has unique pathologic features. EML4-ALK is oncogenic both in vitro and in vivo and ALK kinase inhibitors are quite effective in pre-clinical model systems. More recently ALK inhibitors have entered clinical development and remarkably clinical efficacy has been observed in NSCLC patients harbouring EML4-ALK translocations. This review will focus on the biology, clinical characteristics, diagnosis and treatment of EML4-ALK NSCLC.

    DOI: 10.1016/j.ejca.2010.04.002

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  • Prostaglandin I2 promotes recruitment of endothelial progenitor cells and limits vascular remodeling. 査読 国際誌

    Jun-Ichi Kawabe, Koh-Ichi Yuhki, Motoi Okada, Takayasu Kanno, Atsushi Yamauchi, Naohiko Tashiro, Takaaki Sasaki, Shunsuke Okumura, Naoki Nakagawa, Youko Aburakawa, Naofumi Takehara, Takayuki Fujino, Naoyuki Hasebe, Shuh Narumiya, Fumitaka Ushikubi

    Arteriosclerosis, thrombosis, and vascular biology   30 ( 3 )   464 - 70   2010年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:3  

    OBJECTIVE: Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I(2) plays a role in the regulation of the function of EPCs to limit vascular remodeling. METHODS AND RESULTS: EPCs (Lin(-)cKit(+)Flk-1(+) cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I(2) receptor IP (IP(-/-) mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP(-/-) mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling. CONCLUSIONS: These findings clearly indicate that the prostaglandin I(2)-IP system is essential for EPCs to accomplish their function and plays a critical role in the regulation of vascular remodeling.

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  • 別冊 領域別症候群シリーズ 2021年11月号 「呼吸器症候群(第3版) IV」No.20

    佐々木高明他( 担当: 共著)

    日本臨牀  2021年11月 

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    記述言語:日本語   著書種別:学術書

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  • 臨床薬理の進歩 PD-1阻害薬のPK/PD-ADAの母集団解析

    福士将秀, 佐々木高明, 大崎能伸( 担当: 共著)

    (公財)臨床薬理研究振興財団  2021年6月 

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    記述言語:日本語   著書種別:学術書

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  • 肺癌診療ガイドライン2021年版

    日本肺癌学会, ガイドライン委員会( 担当: 共著)

    日本肺癌学会  2020年12月 

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    記述言語:日本語   著書種別:学術書

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  • 肺癌診療ガイドライン2020年版

    日本肺癌学会ガイドライン委員会( 担当: 共著)

    金原出版  2019年12月 

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    記述言語:日本語   著書種別:学術書

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  • 分担翻訳 フレイザー編 呼吸器病学エッセンス (大崎能伸,佐々木高明,澁川紀代子pp.643-664)

    西村書店  2009年 

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MISC

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講演・口頭発表等

  • Osimertinib投与中にうっ血性心不全を認めた1例

    渡邊皐嗣, 佐々木高明

    第47回日本肺癌学会北海道支部学術集会 

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    開催年月日: 2021年10月

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • 当院の肺末梢病変に対するクライオ生検導入期の成績

    木田涼太郎, 佐々木高明

    呼吸器内視鏡学会 

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    開催年月日: 2021年6月

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • Triple negative乳癌手術症例におけるdriver変異頻度の検討

    岡崎智, 佐々木高明

    第122回日本外科学会総会 

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    開催年月日: 2021年4月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:熊本城ホール  

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  • 長期間経過観察の後に診断した気管原発MALTリンパ腫の1例

    木田涼太郎, 佐々木高明

    第 42 回 日本呼吸器内視鏡学会北海道支部会 

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    開催年月日: 2020年10月

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • dPCRで同定されたBRAFV600E変異陽性肺癌の臨床的・画像的検討

    平井理子, 佐々木高明

    第60回日本肺癌学会学術集会 

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    開催年月日: 2019年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • coiled-coilを標的としたEML4-ALK融合蛋白の単量体化がもたらす抗腫瘍効果の検討

    平井理子, 佐々木高明

    第60回日本肺癌学会学術集会 

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    開催年月日: 2019年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • メディカルスタッフが知っておくべき肺癌ゲノム診療 だれでもわかるがんゲノムの基本

    佐々木高明

    第60回日本肺癌学会学術集会 

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    開催年月日: 2019年12月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  • AIによる画像解析によるH&E画像とBRAF_V600E遺伝子の予測

    佐々木高明ら

    第60回日本肺癌学会学術集会 

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    開催年月日: 2019年12月

    記述言語:日本語   会議種別:口頭発表(一般)  

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  • 肺結節影診断における写真加工方法についての検討

    堂下和志, 佐々木高明

    第60回日本肺癌学会学術集会 

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    開催年月日: 2019年12月

    記述言語:日本語   会議種別:ポスター発表  

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  • トリプルネガティブ乳癌症例における遺伝子解析と新規治療法の可能性

    岡崎智, 佐々木高明

    第57回日本癌治療学会学術集会 

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    開催年月日: 2019年10月

    記述言語:英語   会議種別:口頭発表(一般)  

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共同研究・競争的資金等の研究課題

  • がんゲノム構造異常による、がん遺伝子の活性化メカニズムに関する研究

    研究課題/領域番号:21K08171  2021年4月 - 2024年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    佐々木 高明, 水上 裕輔, 平井 理子

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    配分額:3,900,000円 ( 直接経費:3,000,000円 、 間接経費:900,000円 )

    がんはゲノム異常の疾患です。網羅的遺伝子解析の手法でゲノムが解析され、臨床診断に応用され対応する分子標的治療等の治療が行われてきています。しかしこの網羅的遺伝子解析でも治療標的となる遺伝子異常が見つからず、有効な治療にたどり着かない患者も多く存在し、未知のがんゲノム異常が発がんに寄与している可能性があります。従来の網羅的遺伝子解析の手法では、未知の融合遺伝子、選択的スプライスバリアントによるエクソン欠失、繰り返し配列といったゲノム構造異常は検出されません。本研究は、特に肺癌細胞におけるがんゲノム構造異常による、がん遺伝子の活性化メカニズムに関して研究します。またゲノム構造異常の新たな検出方法が開発されれば、これに対する有効な治療法の開発につながります。
    効率よく未知の融合遺伝子、選択的スプライスバリアントによるエクソン欠失、繰り返し配列といったゲノム構造異常を検出するために、がん細胞の細胞膜上に発現している、受容体型チロシンキナーゼに標的を絞って、遺伝子解析を進めていきます。なかでもMET遺伝子のエクソン14欠失変異に関して、ゲノム上には大きな構造異常をきたしていると報告があり、MET異常を検出できる実験系を確立しているところです。
    今後は、ドライバー遺伝子陰性の肺癌細胞株あるいは、EGFR, HER2, BRAF, KRAS, ALK, ROS1, RETなどドライバー遺伝子陽性で薬剤耐性の機序としてのゲノム構造異常を満たしているかどうかを検討していくところです。

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  • Coiled-coil領域の重合阻害を誘導する薬剤による融合遺伝子肺癌の治療開発

    研究課題/領域番号:18K08132  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    佐々木 高明, 大崎 能伸

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    配分額:4,420,000円 ( 直接経費:3,400,000円 、 間接経費:1,020,000円 )

    EML4-ALK融合遺伝子を有する非小細胞肺癌に対して、EML4の重合阻害を引き起こすペプチドを創薬した。EML4のcoiled-coil(CC)領域に一致したペプチドを作成し、また、CC領域の三量体結合部位を変異させた変異CC領域、さらにCC領域のペプチドを安定化させるためにペプチド間をstaple構造架橋を加えて固定し、細胞内透過性やペプチド安定性を増した試薬を作成した。
    EML4-ALK融合遺伝子を有する、非小細胞肺癌細胞株であるH3122細胞株に対してこれらのペプチドを添加して細胞増殖抑制効果を各種濃度で検討したが、30 ng/mlの濃度で添加した場合、細胞増殖アッセイで-20%の増殖抑制を認めた。市販のiDimerizer kitを用いALKの細胞内ドメインを人工的に2量体化/単量体化する実験系を作成し、マウス由来のIL6依存性B細胞株であるBaF3細胞に遺伝子導入した。単量体ではALKリン酸化活性を失い、細胞増殖は止まり、免疫不全マウスの皮下腫瘍移植モデルでは、単量体化することで腫瘍は縮小することが明らかになった。ALKが単量体で活性を有するF1174L変異体に関する検討も行っている。野生型より細胞増殖抑制効果が低いことを確認している。
    現在、このペプチドの細胞内移行性を調整し、安定化させるためにCC領域ペプチド各種修飾を行っている。今後より有効な細胞内デリバリーを検討しペプチド創薬とつなげていく予定。

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  • 癌の蛍光診断を応用した肺癌胸膜浸潤とリンパ節転移に対する新たな低侵襲診断法の開発

    研究課題/領域番号:18K08775  2018年4月 - 2021年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    北田 正博, 大崎 能伸, 佐々木 高明, 石橋 佳

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    配分額:1,560,000円 ( 直接経費:1,200,000円 、 間接経費:360,000円 )

    【はじめに】胸腔内悪性病変に対する画像診断や手術時の可視診断には限界があり、
    低侵襲で確実かつ客観的、な評価、診断システムの開発が希求されている。我々は自
    家蛍光観察システムを応用した光学的診断法の研究を行ってきた。自家蛍光観察シス
    テムとは400~420nm前後の励起光に対する正常組織が放つ520nm前後の緑色自家蛍光と、悪性腫瘍組織で起きる蛍光発生物質の減少による色調の変化を観察、診断方法である。しかし、画像の鮮明さ、明瞭な色調差が足りない、血液や反射光の影響があるなどの問題点もあり、改善を期待して光増感物質の5ALAを併用した。経口投与した5ALAはプロトポルフイリンIX(PpIX)に代謝、悪性細胞内に留まり、630nm程度の赤色~ピンク色の発光を呈する事象を利用した光学的診断である。肺癌胸膜浸潤を含めた、転移性肺腫瘍や悪性胸膜中脾腫などの胸膜悪性病変に対する低侵襲診断の有用性を検討した。【対象と方法】2017年1月より2018年2月までに、CT上胸膜浸潤の可能性がある肺癌42例、転移性肺腫瘍12例、胸膜腫瘍4例,良性腫瘍3例の合計61例に対し本手技を施行した。手術開始3-4時間前に15~20mg/kgの5ALAを経口投与し自家蛍光観察システムを用いて胸腔内の観察を行った。【結果】1) 描出状態:白色光では不明瞭な腫瘍部が、本手技では比較的明瞭な境界線を示した赤色蛍光が描出された。2)描出状況:術前PL1以上と診断するも病理診断でpl0であったのは21例(50%)であった。肺癌腫瘍部位に赤色蛍光が確認可能であったのは35/42(83.3%)であった。pl1~pl3は11/12(91.7%)、pl0症例は23/30(76.6%)であったがすべてPL1と術前診断した症例であった。【結語】5ALAを用いることで、胸膜悪性病変の局在診断が可能になった。早期の胸膜中皮腫の診断や微小な播種性病変の発見の他、肺癌胸膜浸潤診断による区域切除等の縮小手術の可否への応用も期待できる。

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  • 血液を利用したMolecular Biopsyによる肺癌薬剤耐性のモニタリング

    研究課題/領域番号:15K09239  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    丹野 幸恵, 水上 裕輔, 小野 裕介, 佐々木 高明, 吉田 遼平

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    配分額:4,810,000円 ( 直接経費:3,700,000円 、 間接経費:1,110,000円 )

    肺腺癌外科切除例を対象とした手術前後の血漿解析でのデジタルPCRによるEGFR、KRAS遺伝子変異について解析を行った。5例中2例でEGFR活性型遺伝子変異を検出し、肺生検時の遺伝子型と一致していたが、症例により血漿中遊離DNA量が少ないため検出感度以下になることや、血漿への遊離がない場合も考えられた。
    進行期肺癌症例は74例、103検体採取した。EGFR遺伝子変異を検体、ALK融合遺伝子変異を27検体、KRAS症例を1検体、ROS1融合遺伝子を1検体解析した。

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  • 光線力学的手法を応用した胸部悪性病変とリンパ節転移に対する新たな診断法の開発

    研究課題/領域番号:15K10251  2015年4月 - 2018年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    北田 正博, 大崎 能伸, 佐々木 高明

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    配分額:2,210,000円 ( 直接経費:1,700,000円 、 間接経費:510,000円 )

    光感受性物質のアミノレブリン酸を併用した胸腔内悪性病変に対する局在診断法の開発を行った。アミノレブリン酸は代謝され悪性細胞で赤色蛍光を呈する。自家蛍光観察システムを用い、正常組織の緑色自家蛍光との色調差で局在診断を行った。胸膜面に存在している悪性病変では、自家蛍光観察カメラでは周囲正常組織で発生する緑色自家蛍光と対比し、明瞭な境界線を示したピンク色の腫瘍部位が描出された。原発性肺癌症例で赤色光が確認可能であったのは、pl1~pl3症例は100%の描出、pl0症例は27.7%であり、全例PL1症例であった。今後、精度の高い悪性病変の局在診断により、光線力学治療にも応用できる可能性がある。

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  • 肺癌における分子標的薬耐性機序の解明と治療戦略の開発

    研究課題/領域番号:26860595  2014年4月 - 2016年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    佐々木 高明

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:3,770,000円 ( 直接経費:2,900,000円 、 間接経費:870,000円 )

    肺がんの分子標的治療の最大の難関は、耐性獲得である。これを克服するための新戦略を開発した。まず、ALK陽性肺癌において耐性獲得後も重要な細胞内シグナルを同定し、この経路を阻害することで耐性を克服することが可能となった。このシグナルはCrk-Srcシグナル系で、今回の我々の検討では、Srcシグナルを抑制する薬剤を併用することで、耐性にかかわるバイパス経路のチロシンリン酸化受容体を幅広く抑制することが示された。
    このSrc阻害薬とALK阻害薬の併用効果は、細胞実験のみならず、マウス皮下移植モデルにおいてもALK耐性細胞の増殖を完全に制御できた。

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  • 肺癌の新たな個別化治療の確立を目指したNampt遺伝子の変異解析とその機能解析

    研究課題/領域番号:24591147  2012年4月 - 2015年3月

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    大崎 能伸, 奥村 俊介, 佐々木 高明, 南 幸範, 遠藤 哲史

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    配分額:5,460,000円 ( 直接経費:4,200,000円 、 間接経費:1,260,000円 )

    我々が行った研究により、KRAS遺伝子変異を有する肺癌に対してNampt阻害剤が高い抗腫瘍効果を有する可能性をつきとめた。これらの研究活動・成果の一部は、2015年4月に、国際学会の1つAmerican Association for Cancer Research Annual Meetingで報告している。

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  • 新規ALK阻害薬に対する耐性機序の解明

    研究課題/領域番号:24790798  2012年4月 - 2014年3月

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    佐々木 高明

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:2,990,000円 ( 直接経費:2,300,000円 、 間接経費:690,000円 )

    新規ALK阻害薬アレクチニブによる肺癌細胞株の耐性機序を解明した。
    ALK陽性H3122細胞株にアレクチニブを長期暴露し耐性株を作成し、①EGFRリン酸化の亢進、②METシグナルによるALK下流シグナルの代償を見出した。またこれらを克服する方法として、EGFR阻害薬、MET阻害薬との併用療法をマウス腫瘍皮下移植モデルで有効性を確認した。

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その他

  • Thoracic Oncology Perspective (TOP) 編集委員

    2018年4月 - 現在

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    肺癌関連雑誌の編集委員

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社会貢献活動

  • 北海道アレルギー疾患医療連絡協議会委員

    2021年4月 - 現在

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学術貢献活動

  • 日本呼吸器内視鏡学会 評議員

    2023年4月 - 現在

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    評議員

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  • 日本肺癌学会 アーリーキャリア支援委員会委員

    2022年12月 - 現在

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  • 日本肺癌学会 学術・産学連携小委員会委員

    2022年12月 - 現在

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  • 日本結核・非結核性抗酸菌症学会

    2022年6月

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    第97回・日本結核・非結核性抗酸菌症学会 学術講演会 事務局長

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  • 世界肺癌学会 Career Development and Fellowship Committee 国際学術貢献

    2021年10月 - 現在

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  • 日本呼吸器学会 J-OSLER呼吸器 プログラム統括責任者

    2021年4月 - 現在

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  • 日本呼吸器学会 倫理委員会委員 国際学術貢献

    2020年4月 - 2022年3月

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  • 日本呼吸器学会 財務委員会委員 国際学術貢献

    2020年4月 - 2022年3月

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  • 日本呼吸器学会 代議員 国際学術貢献

    2019年4月 - 現在

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  • 日本肺癌学会 評議員 国際学術貢献

    2018年11月 - 現在

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  • 日本腫瘍循環器学会 評議員 国際学術貢献

    2018年4月 - 現在

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  • 日本肺癌学会 会員委員会 国際学術貢献

    2016年11月 - 現在

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    2022年12月~ 副委員長

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  • 日本肺癌学会 ガイドライン委員会

    2014年11月 - 2022年12月

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    薬物及び集学的治療 小委員会

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