Updated on 2021/12/24

写真a

 
Togashi Yosuke
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Professor
Position
Professor
External link

Degree

  • MD, PhD

Research Interests

  • 呼吸器内科

  • 皮膚腫瘍

  • Tumor biology

  • Genome biology

  • Cancer immunology

  • Lung cancer

  • Gastrointestinal cancer

Research Areas

  • Life Science / Respiratory medicine

  • Life Science / Gastroenterology

  • Life Science / Tumor biology

  • Life Science / Genome biology

  • Life Science / Immunology

Education

  • Kindai University, PhD     Faculty of Medicine

    2012.4 - 2015.3

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  • Kyoto University   医学部   医学科

    2000.4 - 2006.3

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Research History

  • Chiba University   Graduate School of Medicine

    2021.6

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  • 岡山大学学術研究院医歯薬学域   教授

    2021.4

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  • Chiba Cancer Center   Division Head

    2019.9 - 2021.3

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  • JSPS Research Fellowship for Young Scientists (PD)

    2017.4 - 2018.3

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  • National Cancer Center   Division of Cancer Immunology   Researcher

    2016.4 - 2019.8

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  • Kindai University   Department of Genome Biology   Assistant Professor

    2015.4 - 2016.3

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  • JSPS Research Fellowship for Young Scientists (DC2)

    2014.4 - 2015.3

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  • Kyoto University   集学的がん診療学講座   Assistant Professor

    2011.4 - 2012.3

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Professional Memberships

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Committee Memberships

  • 日本がん免疫学会   評議員  

    2021.11   

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  • 日本臨床腫瘍学会   TR・臨床薬理学術集会部会副部会長  

    2020.8   

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  • 日本癌学会   評議員  

    2020.1   

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Papers

  • Programmed Death-Ligand 1-Rich Premetastatic Niche in Adjuvant Chemotherapy. Invited Reviewed International journal

    Hiromasa Yamamoto, Yosuke Togashi

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   17 ( 1 )   10 - 12   2022.1

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    Authorship:Last author, Corresponding author   Language:English  

    DOI: 10.1016/j.jtho.2021.10.019

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  • Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer. International journal

    Shinichi Namba, Toshihide Ueno, Shinya Kojima, Kenya Kobayashi, Katsushige Kawase, Yosuke Tanaka, Satoshi Inoue, Fumishi Kishigami, Shusuke Kawashima, Noriko Maeda, Tomoko Ogawa, Shoichi Hazama, Yosuke Togashi, Mizuo Ando, Yuichi Shiraishi, Hiroyuki Mano, Masahito Kawazu

    Communications biology   4 ( 1 )   1320 - 1320   2021.11

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    Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon-intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general.

    DOI: 10.1038/s42003-021-02833-4

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  • Highly immunogenic cancer cells require activation of the WNT pathway for immunological escape. International journal

    Yoshiko Takeuchi, Tokiyoshi Tanegashima, Eiichi Sato, Takuma Irie, Atsuo Sai, Kota Itahashi, Shogo Kumagai, Yasuko Tada, Yosuke Togashi, Shohei Koyama, Esra A Akbay, Takahiro Karasaki, Keisuke Kataoka, Soichiro Funaki, Yasushi Shintani, Izumi Nagatomo, Hiroshi Kida, Genichiro Ishii, Tomohiro Miyoshi, Keiju Aokage, Kazuhiro Kakimi, Seishi Ogawa, Meinoshin Okumura, Masatoshi Eto, Atsushi Kumanogoh, Masahiro Tsuboi, Hiroyoshi Nishikawa

    Science immunology   6 ( 65 )   eabc6424   2021.11

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    [Figure: see text].

    DOI: 10.1126/sciimmunol.abc6424

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  • TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment. Reviewed International journal

    Shusuke Kawashima, Takashi Inozume, Masahito Kawazu, Toshihide Ueno, Joji Nagasaki, Etsuko Tanji, Akiko Honobe, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yasuhiro Nakamura, Tomonori Kawasaki, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Yuzuru Ikehara, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Hiroyuki Matsue, Yosuke Togashi

    Journal for immunotherapy of cancer   9 ( 11 )   2021.11

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    BACKGROUND: Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. METHODS: We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. RESULTS: Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance. CONCLUSIONS: The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.

    DOI: 10.1136/jitc-2021-003134

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  • HLA Class I analysis provides insight into the genetic and epigenetic background of immune evasion in colorectal cancer with high microsatellite instability. Reviewed International journal

    Masahito Kawazu, Toshihide Ueno, Koichi Saeki, Nicolas Sax, Yosuke Togashi, Takayuki Kaneseki, Keigo Chida, Fumishi Kishigami, Kazuhito Sato, Shinya Kojima, Masafumi Otsuka, Akihito Kawazoe, Hitomi Nishinakamura, Yuka Maeda, Yoko Yamamoto, Kazuo Yamashita, Satoshi Inoue, Tokiyoshi Tanegashima, Daisuke Matsubara, Kenta Tane, Yosuke Tanaka, Hisae Iinuma, Yojiro Hashiguchi, Shoichi Hazama, Seik-Soon Khor, Katsushi Tokunaga, Masahiro Tsuboi, Toshiro Niki, Masatoshi Eto, Kohei Shitara, Toshihiko Torigoe, Soichiro Ishihara, Hiroyuki Aburatani, Hiroshi Haeno, Hiroyoshi Nishikawa, Hiroyuki Mano

    Gastroenterology   2021.10

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    BACKGROUND AND AIMS: A detailed understanding of antitumor immunity is essential for optimal cancer immune therapy. Although defective mutations in the B2M and HLA-ABC genes, which encode molecules essential for antigen presentation, have been reported in several studies, the effects of these defects on tumor immunity have not been quantitatively evaluated. METHODS: Mutations in HLA-ABC genes were analyzed in 114 microsatellite instability-high colorectal cancers (MSI-H CRCs) using a long-read sequencer. The data were further analyzed in combination with whole-exome sequencing, transcriptome sequencing, DNA methylation array, and immunohistochemistry data. RESULTS: We detected 101 truncating mutations in 57 (50%) tumors and loss of 61 alleles in 21 (18%) tumors. Based on the integrated analysis that enabled the immunological subclassification of MSI-H CRCs, we identified a subtype of tumors in which lymphocyte infiltration was reduced, partly due to reduced expression of HLA-ABC genes in the absence of apparent genetic alterations. Survival of patients with such tumors was shorter than in patients with other tumor types. Paradoxically, tumor mutation burden was highest in the subtype, suggesting that the immunogenic effect of accumulating mutations was counterbalanced by mutations that weakened immunoreactivity. Various genetic and epigenetic alterations, including frameshift mutations in RFX5 and promoter methylation of PSMB8 and HLA-A, converged on reduced expression of HLA-ABC genes. CONCLUSIONS: Our detailed immunogenomic analysis provides information that will facilitate the improvement and development of cancer immunotherapy.

    DOI: 10.1053/j.gastro.2021.10.010

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  • Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-1. Reviewed International journal

    Junji Koya, Yuki Saito, Takuro Kameda, Yasunori Kogure, Mitsuhiro Yuasa, Joji Nagasaki, Marni B McClure, Sumito Shingaki, Mariko Tabata, Yuki Tahira, Keiichi Akizuki, Ayako Kamiunten, Masaaki Sekine, Kotaro Shide, Yoko Kubuki, Tomonori Hidaka, Akira Kitanaka, Nobuaki Nakano, Atae Utsunomiya, Yosuke Togashi, Seishi Ogawa, Kazuya Shimoda, Keisuke Kataoka

    Blood cancer discovery   2 ( 5 )   450 - 467   2021.9

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    Premalignant clonal expansion of human T-cell leukemia virus type-1 (HTLV-1)-infected cells occurs before viral carcinogenesis. Here we characterize premalignant cells and the multicellular ecosystem in HTLV-1 infection with and without adult T-cell leukemia/lymphoma (ATL) by genome sequencing and single-cell simultaneous transcriptome and T/B-cell receptor sequencing with surface protein analysis. We distinguish malignant phenotypes caused by HTLV-1 infection and leukemogenesis and dissect clonal evolution of malignant cells with different clinical behavior. Within HTLV-1-infected cells, a regulatory T-cell phenotype associates with premalignant clonal expansion. We also delineate differences between virus- and tumor-related changes in the nonmalignant hematopoietic pool, including tumor-specific myeloid propagation. In a newly generated conditional knockout mouse model recapitulating T-cell-restricted CD274 (encoding PD-L1) gene lesions found in ATL, we demonstrate that PD-L1 overexpressed by T cells is transferred to surrounding cells, leading to their PD-L1 upregulation. Our findings provide insights into clonal evolution and immune landscape of multistep virus carcinogenesis. Significance: Our multimodal single-cell analyses comprehensively dissect the cellular and molecular alterations of the peripheral blood in HTLV-1 infection, with and without progression to leukemia. This study not only sheds light on premalignant clonal expansion in viral carcinogenesis, but also helps to devise novel diagnostic and therapeutic strategies for HTLV-1-related disorders.

    DOI: 10.1158/2643-3230.BCD-21-0044

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  • Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer. Reviewed International journal

    Koji Inamori, Yosuke Togashi, Shota Fukuoka, Kiwamu Akagi, Kouetsu Ogasawara, Takuma Irie, Daisuke Motooka, Yoichi Kobayashi, Daisuke Sugiyama, Motohiro Kojima, Norihiko Shiiya, Shota Nakamura, Shoichi Maruyama, Yutaka Suzuki, Masaaki Ito, Hiroyoshi Nishikawa

    JCI insight   6 ( 9 )   2021.5

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Patients with colorectal cancers (CRCs) generally exhibit improved survival through intensive lymph node (LN) dissection. However, recent progress in cancer immunotherapy revisits the potential importance of regional LNs, where T cells are primed to attack tumor cells. To elucidate the role of regional LN, we investigated the immunological status of non-metastatic regional LN lymphocytes (LNLs) in comparison with those in the tumor microenvironment (tumor-infiltrating lymphocytes; TILs) using flow cytometry and next-generation sequencing. LNLs comprised an intermediate level of the effector T cell population between peripheral blood lymphocytes (PBLs) and TILs. Significant overlap of the T-cell receptor (TCR) repertoire was observed in microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) CRCs with high tumor mutation burden (TMB), although limited TCRs were shared between non-metastatic LNs and primary tumors in microsatellite stable (MSS)/MMR proficient (pMMR) CRC patients with low TMB. In line with the overlap of the TCR repertoire, an excessive LN dissection did not provide a positive impact on long-term prognosis in our MSI-H/dMMR CRC cohort (n =130). We propose that regional LNs play an important role in antitumor immunity, particularly in MSI-H/dMMR CRCs with high TMB, requiring to be careful of excessive non-metastatic LN dissection in MSI-H/dMMR CRC patients.

    DOI: 10.1172/jci.insight.137365

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  • Aging, cancer, and antitumor immunity. Invited Reviewed

    Hideki Ikeda, Yosuke Togashi

    International journal of clinical oncology   2021.3

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    Aging leads to numerous changes that affect many components of the immune system, called "immunosenescence". Indeed, elderly individuals exhibit dysregulated immune responses against pathogens, poor responses to vaccination, and increased susceptibility to many diseases including cancer, autoimmune disorders, and other chronic inflammatory diseases. Despite progressed understanding of immunosenescence, its detailed mechanisms are still not fully understood. With advances in medicine, the population of older cancer patients is expected to rapidly increase in the coming years. Cancer immunotherapies, including immune checkpoint inhibitors (ICIs), have been shown to be effective for multiple cancer types, whereas to date, few specific data for elderly individuals have been published. Some systemic reviews have demonstrated that ICIs exhibit similar efficacy in older cancer patients, but they seem to be less effective in very old patients. In addition, toxicities might be more frequently observed in such patients. Here, we provide a summary to better understand immunosenescence and an overview of its relationship with cancer and antitumor immunity, including the efficacy and toxicity of ICIs.

    DOI: 10.1007/s10147-021-01913-z

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  • HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs. Reviewed International journal

    Sho Watanabe, Yasushi Goto, Hiroyuki Yasuda, Takashi Kohno, Noriko Motoi, Yuichiro Ohe, Hiroyoshi Nishikawa, Susumu S Kobayashi, Kazuyoshi Kuwano, Yosuke Togashi

    Thoracic cancer   12 ( 5 )   631 - 642   2021.3

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    BACKGROUND: Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops. METHODS: Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor. RESULTS: NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. CONCLUSIONS: EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance.

    DOI: 10.1111/1759-7714.13839

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  • Potentiality of multiple modalities for single-cell analyses to evaluate the tumor microenvironment in clinical specimens. Reviewed International journal

    Yukie Kashima, Yosuke Togashi, Shota Fukuoka, Takahiro Kamada, Takuma Irie, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Tatsunori Minamide, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Koichiro Inaki, Masataka Chihara, Yukihiko Ebisuno, Sakiyo Tsukamoto, Ryo Fujii, Akihiro Ohashi, Yutaka Suzuki, Katsuya Tsuchihara, Hiroyoshi Nishikawa, Toshihiko Doi

    Scientific reports   11 ( 1 )   341 - 341   2021.1

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Single-cell level analysis is powerful tool to assess the heterogeneity of cellular components in tumor microenvironments (TME). In this study, we investigated immune-profiles using the single-cell analyses of endoscopically- or surgically-resected tumors, and peripheral blood mononuclear cells from gastric cancer patients. Furthermore, we technically characterized two distinct platforms of the single-cell analysis; RNA-seq-based analysis (scRNA-seq), and mass cytometry-based analysis (CyTOF), both of which are broadly embraced technologies. Our study revealed that the scRNA-seq analysis could cover a broader range of immune cells of TME in the biopsy-resected small samples of tumors, detecting even small subgroups of B cells or Treg cells in the tumors, although CyTOF could distinguish the specific populations in more depth. These findings demonstrate that scRNA-seq analysis is a highly-feasible platform for elucidating the complexity of TME in small biopsy tumors, which would provide a novel strategies to overcome a therapeutic difficulties against cancer heterogeneity in TME.

    DOI: 10.1038/s41598-020-79385-w

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  • Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. Reviewed International journal

    Ayumu Arakawa, Hitoshi Ichikawa, Takashi Kubo, Noriko Motoi, Tadashi Kumamoto, Miho Nakajima, Kan Yonemori, Emi Noguchi, Kuniko Sunami, Kouya Shiraishi, Hiroki Kakishima, Hiroshi Yoshida, Tomoro Hishiki, Naonori Kawakubo, Takafumi Kuroda, Takako Kiyokawa, Kyosuke Yamada, Nozomu Yanaihara, Kazuaki Takahashi, Aikou Okamoto, Shinsuke Hirabayashi, Daisuke Hasegawa, Atsushi Manabe, Kentaro Ono, Masaki Matsuoka, Yasuhito Arai, Yosuke Togashi, Tatsuhiro Shibata, Hiroyoshi Nishikawa, Kazunori Aoki, Noboru Yamamoto, Takashi Kohno, Chitose Ogawa

    The New England journal of medicine   384 ( 1 )   42 - 50   2021.1

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    Two cases of pediatric lung cancer (in 23-month-old and 6-year-old boys) resulting from mother-to-infant transmission of uterine cervical tumors were incidentally detected during routine next-generation sequencing of paired samples of tumor and normal tissue. Spontaneous regression of some lesions in the first child and slow growth of the tumor mass in the second child suggested the existence of alloimmune responses against the transmitted tumors. Immune checkpoint inhibitor therapy with nivolumab led to a strong regression of all remaining tumors in the first child. (Funded by the Japan Agency for Medical Research and Development and others; TOP-GEAR UMIN Clinical Trials Registry number, UMIN000011141.).

    DOI: 10.1056/NEJMoa2030391

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  • Heterogeneity in congenital melanocytic nevi contributes to multicentric melanomagenesis. Reviewed International journal

    Akiko Honobe, Kazuko Sakai, Yosuke Togashi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Kazuto Nishio, Takashi Inozume

    Journal of dermatological science   100 ( 3 )   217 - 219   2020.12

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  • The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Reviewed International journal

    Shogo Kumagai, Yosuke Togashi, Takahiro Kamada, Eri Sugiyama, Hitomi Nishinakamura, Yoshiko Takeuchi, Kochin Vitaly, Kota Itahashi, Yuka Maeda, Shigeyuki Matsui, Takuma Shibahara, Yasuho Yamashita, Takuma Irie, Ayaka Tsuge, Shota Fukuoka, Akihito Kawazoe, Hibiki Udagawa, Keisuke Kirita, Keiju Aokage, Genichiro Ishii, Takeshi Kuwata, Kenta Nakama, Masahito Kawazu, Toshihide Ueno, Naoya Yamazaki, Koichi Goto, Masahiro Tsuboi, Hiroyuki Mano, Toshihiko Doi, Kohei Shitara, Hiroyoshi Nishikawa

    Nature immunology   21 ( 11 )   1346 - 1358   2020.11

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)  

    Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1+CD8+ T cells relative to that of PD-1+ regulatory T (Treg) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8+ T cells and Treg cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1+CD8+ T cells and enhanced PD-1+ Treg cell-mediated immunosuppression. A profound reactivation of effector PD-1+CD8+ T cells rather than PD-1+ Treg cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.

    DOI: 10.1038/s41590-020-0769-3

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  • Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial. Reviewed International journal

    Hidetoshi Hayashi, Yuichi Takiguchi, Hironobu Minami, Kohei Akiyoshi, Yoshihiko Segawa, Hiroki Ueda, Yasuo Iwamoto, Chihiro Kondoh, Koji Matsumoto, Shin Takahashi, Hisateru Yasui, Toshiyuki Sawa, Yusuke Onozawa, Yasutaka Chiba, Yosuke Togashi, Yoshihiko Fujita, Kazuko Sakai, Shuta Tomida, Kazuto Nishio, Kazuhiko Nakagawa

    JAMA oncology   2020.10

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    Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.

    DOI: 10.1001/jamaoncol.2020.4643

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  • The critical role of CD4+ T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. Reviewed International journal

    Joji Nagasaki, Yosuke Togashi, Takeaki Sugawara, Makiko Itami, Nobuhiko Yamauchi, Junichiro Yuda, Masato Sugano, Yuuki Ohara, Yosuke Minami, Hirohisa Nakamae, Masayuki Hino, Masahiro Takeuchi, Hiroyoshi Nishikawa

    Blood advances   4 ( 17 )   4069 - 4082   2020.9

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II-expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II-expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I-MHC-II+ tumors but not on MHC-I-MHC-II- tumors, in a cytotoxic CD4+ T-cell-dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II-expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II-expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.

    DOI: 10.1182/bloodadvances.2020002098

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  • Enhanced tumor response to radiotherapy after PD-1 blockade in metastatic gastric cancer. Reviewed

    Akinori Sasaki, Yoshiaki Nakamura, Yosuke Togashi, Hirofumi Kuno, Hidehiro Hojo, Shunichiro Kageyama, Naoki Nakamura, Kenji Takashima, Tomohiro Kadota, Yusuke Yoda, Saori Mishima, Kentaro Sawada, Daisuke Kotani, Akihito Kawazoe, Yasutoshi Kuboki, Hiroya Taniguchi, Takashi Kojima, Toshihiko Doi, Takayuki Yoshino, Tomonori Yano, Tatsushi Kobayashi, Tetsuo Akimoto, Hiroyoshi Nishikawa, Kohei Shitara

    Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association   23 ( 5 )   893 - 903   2020.9

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    BACKGROUND: Immune checkpoint inhibitors may enhance the efficacy of radiotherapy (RT) in cancer treatment but the effect remains unknown in metastatic gastric cancer (mGC). This study aimed to compare the tumor shrinkage by palliative RT for mGC patients with or without previous exposure to anti-PD-1 therapy. METHODS: Data of 36 mGC patients who had received palliative RT from April 2013 to May 2019 were analyzed. Primary tumor responses were evaluated through a volumetric measurement-based method using computed tomography (CT) and endoscopic responses were evaluated in patients who underwent endoscopy before and after RT. Tumor microenvironment (TME) immune status was investigated by analyzing tumor-infiltrating lymphocytes by flow cytometry. RESULTS: Among 36 patients, 18 had previous exposure to anti-PD-1 before RT showing no significant differences in baseline characteristics with the other 18 patients without exposure to anti-PD-1 treatment. Tumor responses were observed in 28% (5/18) and none (0/18) in the anti-PD-1-exposed vs. naïve group, respectively (P = 0.045). Five out of eight patients in the anti-PD-1-exposed group, who underwent endoscopy after RT showed partial response, but none in the anti-PD-1-naïve patients showed response (P = 0.026). Increase in the CD8+ T cell/effector regulatory T cell ratio in TILs after anti-PD-1 therapy was noted in three responders to RT, but not in the other three non-responders. CONCLUSIONS: Prior exposure to anti-PD-1 therapy increases tumor response to RT. Immune profiling suggests that anti-PD-1 therapy may enhance the efficacy of RT by immunoactivation in the TME.

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  • Multicenter phase 1/2 Trial of napabucasin and pembrolizumab in patients with metastatic colorectal cancer (EPOC1503/SCOOP Trial). Reviewed International journal

    Akihito Kawazoe, Yasutoshi Kuboki, Eiji Shinozaki, Hiroki Hara, Tomohiro Nishina, Yoshito Komatsu, Satoshi Yuki, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Masahito Kawazu, Hiroyuki Mano, Yosuke Togashi, Hiroyoshi Nishikawa, Takayuki Yoshino

    Clinical cancer research : an official journal of the American Association for Cancer Research   2020.7

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    PURPOSE: This is a phase 1/2 trial of napabucasin plus pembrolizumab for metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Phase 1 was conducted to determine the recommended phase 2 dose (RP2D) in a dose escalation design of napabucasin (240mg to 480 mg twice daily) with 200mg pembrolizumab every 3 weeks. Phase 2 included cohort A (n = 10, microsatellite instability high) and cohort B (n = 40, microsatellite stable). The primary endpoint was immune-related objective response rate (irORR). PD-L1 combined positive score (CPS), genomic profiles and the consensus molecular subtypes (CMS) of colorectal cancer were assessed. RESULTS: A total of 55 patients were enrolled in this study. In phase 1, no patients experienced dose-limiting toxicities and napabucasin 480 mg was determined as RP2D. The irORR was 50.0% in cohort A and 10.0% in cohort B. In cohort B, the irORR was 0%, 5.3%, and 42.9% in CPS <1, 1≤ CPS <10 and CPS ≥10, respectively. Patients with objective response tended to have higher tumor mutation burden than those without. Of evaluable 18 patients for CMS classification in cohort B, the irORR was 33.3%, 0%, 33.3% and 33.3% in CMS1, CMS2, CMS3 and CMS4, respectively. The common grade 3 or higher treatment-related adverse events included fever (10.0%) in cohort A and decreased appetite (7.5%) and diarrhea (5.0%) in cohort B. CONCLUSIONS: Napabucasin with pembrolizumab showed anti-tumor activity with acceptable toxicities for MSS mCRC patients as well as MSI-H mCRC, although it did not meet the primary end point.

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  • An Oncogenic Alteration Creates a Microenvironment that Promotes Tumor Progression by Conferring a Metabolic Advantage to Regulatory T Cells. Reviewed International journal

    Shogo Kumagai, Yosuke Togashi, Chika Sakai, Akihito Kawazoe, Masahito Kawazu, Toshihide Ueno, Eiichi Sato, Takeshi Kuwata, Takahiro Kinoshita, Masami Yamamoto, Sachiyo Nomura, Tetsuya Tsukamoto, Hiroyuki Mano, Kohei Shitara, Hiroyoshi Nishikawa

    Immunity   53 ( 1 )   187 - 203   2020.7

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    Only a small percentage of patients afflicted with gastric cancer (GC) respond to immune checkpoint blockade (ICB). To study the mechanisms underlying this resistance, we examined the immune landscape of GC. A subset of these tumors was characterized by high frequencies of regulatory T (Treg) cells and low numbers of effector T cells. Genomic analyses revealed that these tumors bore mutations in RHOA that are known to drive tumor progression. RHOA mutations in cancer cells activated the PI3K-AKT-mTOR signaling pathway, increasing production of free fatty acids that are more effectively consumed by Treg cells than effector T cells. RHOA mutant tumors were resistant to PD-1 blockade but responded to combination of PD-1 blockade with inhibitors of the PI3K pathway or therapies targeting Treg cells. We propose that the metabolic advantage conferred by RHOA mutations enables Treg cell accumulation within GC tumors, generating an immunosuppressive TME that underlies resistance to ICB.

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  • Association between the mutational smoking signature and the immune microenvironment in lung adenocarcinoma. Reviewed International journal

    Kei Sato, Sachiyo Mimaki, Riu Yamashita, Yosuke Togashi, Tomoyuki Naito, Hibiki Udagawa, Shinya Katsumata, Shoko Nakasone, Tomohiro Miyoshi, Kenta Tane, Keiju Aokage, Masato Sugano, Motohiro Kojima, Satoshi Fujii, Takeshi Kuwata, Atsushi Ochiai, Koichi Goto, Masahiro Tsuboi, Katsuya Tsuchihara, Genichiro Ishii

    Lung cancer (Amsterdam, Netherlands)   147   12 - 20   2020.7

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    OBJECTIVES: Mutational signatures associated with tobacco smoking (mutational smoking signatures: SS) are characterized mainly by C > A mutations. The aim of this study was to characterize the association between the tumor immune microenvironment and the SS in lung adenocarcinoma. METHODS: Lung adenocarcinomas surgically resected from 96 patients, for which whole exome sequencing data was available, were included in the study. We extracted the SS from whole exome sequencing data, calculated the weights of SS using deconstructSigs, and compared the clinicopathological features of SS positive (SS+) and negative (SS-) adenocarcinomas. We selected 18 tumor pairs from SS + and SS- adenocarcinomas (sex, EGFR mutation, and tumor size-matched) and examined the expression of five immune markers (CD20, CD8, FOXP3, CD204, and PD-L1) by immunohistochemistry. RESULTS: Of 96 specimens, there were 33 (34 %) SS + adenocarcinoma tumors. The smoking index significantly correlated with the weight of the SS (R = 0.43). Between SS + and SS- tumors, there was no significant difference in clinicopathological factors excluding smoking history. Immunohistochemistry revealed that the number of FOXP3 + T cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 58 vs. 36, p < 0.01). Also, the number of CD20 + B cells in SS + adenocarcinomas was significantly higher than that in the SS- adenocarcinomas (median number 77 vs. 29, p < 0.01); however; these phenomena could not be confirmed when stratified by smoking history. CONCLUSION: In lung adenocarcinoma, SS is associated with an immunosuppressive tumor microenvironment.

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  • Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). Reviewed International journal

    Shota Fukuoka, Hiroki Hara, Naoki Takahashi, Takashi Kojima, Akihito Kawazoe, Masako Asayama, Takako Yoshii, Daisuke Kotani, Hitomi Tamura, Yuichi Mikamoto, Nami Hirano, Masashi Wakabayashi, Shogo Nomura, Akihiro Sato, Takeshi Kuwata, Yosuke Togashi, Hiroyoshi Nishikawa, Kohei Shitara

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology   38 ( 18 )   2053 - 2061   2020.6

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    PURPOSE: This is a phase Ib trial of regorafenib plus nivolumab for gastric and colorectal cancer. PATIENTS AND METHODS: Enrolled patients received regorafenib plus nivolumab in a dose-finding part to estimate the maximum tolerated dose. Additional patients were enrolled in a dose-expansion part. Regorafenib of 80-160 mg was administered once daily for 21 days on/7 days off with nivolumab 3 mg/kg every 2 weeks. The primary end point was dose-limiting toxicity (DLT) during the first 4 weeks to estimate the recommended dose. RESULTS: Fifty patients (25 each with gastric and colorectal cancer) were enrolled. All patients had received ≥ 2 previous lines of chemotherapy, including anti-angiogenetic inhibitors in 96% of patients. Seven patients with gastric cancer had previously been treated with immune checkpoint inhibitors. One patient had microsatellite instability-high colorectal cancer, whereas the remaining patients had microsatellite stable or mismatch repair-proficient tumors. Three DLTs (grade 3 colonic perforation, maculopapular rash, and proteinuria) were observed with regorafenib 160 mg; none were observed with 80 or 120 mg. During the dose-expansion part, regorafenib dose was reduced from 120 to 80 mg because of frequent maculopapular rash. The common grade ≥ 3 treatment-related adverse events were rash (12%), proteinuria (12%), and palmar-plantar erythrodysesthesia (10%). Objective tumor response was observed in 20 patients (40%), including 11 with gastric cancer (44%) and 9 with colorectal cancer (36%). Median progression-free survival was 5.6 and 7.9 months in patients with gastric and colorectal cancer, respectively. CONCLUSION: The combination of regorafenib 80 mg plus nivolumab had a manageable safety profile and encouraging antitumor activity in patients with gastric and colorectal cancer, which warrants additional investigations in larger cohorts.

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  • TENERGY: multicenter phase II study of Atezolizumab monotherapy following definitive Chemoradiotherapy with 5-FU plus Cisplatin in patients with unresectable locally advanced esophageal squamous cell carcinoma. Reviewed International journal

    Hideaki Bando, Daisuke Kotani, Takahiro Tsushima, Hiroki Hara, Shigenori Kadowaki, Ken Kato, Keisho Chin, Kensei Yamaguchi, Shun-Ichiro Kageyama, Hidehiro Hojo, Masaki Nakamura, Hidenobu Tachibana, Masashi Wakabayashi, Miki Fukutani, Yosuke Togashi, Nozomu Fuse, Hiroyoshi Nishikawa, Takashi Kojima

    BMC cancer   20 ( 1 )   336 - 336   2020.4

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    BACKGROUND: The standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is definitive chemoradiotherapy (CRT) using 5-FU plus cisplatin. However, complete response (CR) rates are low at 11-25%, resulting in 9-10 months of median overall survival (OS). An improved therapeutic efficacy by combining immunotherapy with radiation has been reported in patients with locally advanced non-small cell lung cancer. The results using ESCC cell lines suggest sequential treatment with anti-PD-L1 agents soon after completion of CRT is the most effective combination. METHODS: TENERGY trial is a multicenter, phase II, proof-of-concept study to assess the efficacy and safety of atezolizumab following definitive CRT in patients with locally advanced ESCC. The main inclusion criteria are unresectable locally advanced ESCC without distant metastasis, completion of 60 Gy of radiation plus two concomitant cycles of chemotherapy (cisplatin 70 mg/m2 on day 1 and 5-FU 700 mg/m2 on days 1-4, every 28 days), and adequate organ function. Within 6 weeks after CRT, participants will start taking 1200 mg of atezolizumab every three weeks and continue until 12 months or disease progression. The primary endpoint is the confirmed CR rate by the investigator's assessment. Secondary endpoints include overall response rate, progression-free survival (PFS), OS, adverse events, and confirmed CR rate by central assessment. We will enroll 50 patients (40 with primary locally advanced ESCC and 10 with postoperative locoregionally recurrent ESCC). We will obtain biopsies from the primary site and will collect blood at 3 time points (before CRT, after CRT, and four weeks after the start of atezolizumab) for an exploratory biomarker study. We will analyze the phenotype of immune-competent cells, neoantigens, tumor mutational burden, PD-L1 status, and Human Leukocyte Antigen haplotyping. DISCUSSION: The synergistic efficacies of the sequential combination of CRT and atezolizumab should improve the CR rate, resulting in survival improvement for patients with unresectable locally advanced ESCC. Because CRT is a standard treatment option for patients with early stage to locally advanced ESCC, the sequential combination of CRT and atezolizumab has the potential to change the standard ESCC treatments. TRIAL REGISTRATION: UMIN000034373, 10/04/2018 and EPOC1802.

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  • The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. Reviewed International journal

    Kumiko Umemoto, Yosuke Togashi, Yasuhito Arai, Hiromi Nakamura, Shinichiro Takahashi, Tokiyoshi Tanegashima, Mikiya Kato, Tsubasa Nishikawa, Daisuke Sugiyama, Motohiro Kojima, Naoto Gotohda, Takeshi Kuwata, Masafumi Ikeda, Tatsuhiro Shibata, Hiroyoshi Nishikawa

    International immunology   32 ( 4 )   273 - 281   2020.4

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    Biliary tract cancer (BTC) is an aggressive cancer with a poor prognosis partially due to the limited success in developing novel therapies, including molecularly targeted therapies and immunotherapies. Programmed cell death-1 (PD-1) blockade therapy is less effective against BTCs, necessitating further studies to understand the detailed immunological status of the tumor microenvironment (TME) in BTC. Here, we examined the immunological status of the TME in 37 BTCs with early- to late-stage disease, especially focusing on PD-1+CD8+ T cells. PD-1+CD8+ T cells, which are reportedly associated with the clinical response to PD-1 blockade therapy, were frequently observed in early-stage BTC and decreased with disease progression. Imaging mass cytometry for representative PD-1+CD8+TIL-high and -low patients demonstrated that tumor-infiltrating PD-1+CD8+ T cells were localized adjacent to tumor cells, whereas PD-1-CD8+ T cells were detected mainly in the stroma of the TME. In a mouse model, PD-1 expression by tumor-infiltrating CD8+ T cells was higher in smaller tumors and decreased with tumor growth. Consequently, large tumors became resistant to PD-1 blockade, while small tumors containing higher numbers of PD-1+CD8+ T cells were sensitive. We propose the important role of tumor-infiltrating PD-1+CD8+ T cells in anti-tumor immunity and the potential application of PD-1 blockade therapy for early-stage BTC.

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  • Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer. Reviewed International journal

    Eri Sugiyama, Yosuke Togashi, Yoshiko Takeuchi, Sayoko Shinya, Yasuko Tada, Keisuke Kataoka, Kenta Tane, Eiichi Sato, Genichiro Ishii, Koichi Goto, Yasushi Shintani, Meinoshin Okumura, Masahiro Tsuboi, Hiroyoshi Nishikawa

    Science immunology   5 ( 43 )   2020.1

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    The clinical efficacy of anti-PD-1 (programmed cell death-1) monoclonal antibody (mAb) against cancers with oncogenic driver gene mutations, which often harbor a low tumor mutation burden, is variable, suggesting different contributions of each driver mutation to immune responses. Here, we investigated the immunological phenotypes in the tumor microenvironment (TME) of epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas, for which anti-PD-1 mAb is largely ineffective. Whereas EGFR-mutated lung adenocarcinomas had a noninflamed TME, CD4+ effector regulatory T cells, which are generally present in the inflamed TME, showed high infiltration. The EGFR signal activated cJun/cJun N-terminal kinase and reduced interferon regulatory factor-1; the former increased CCL22, which recruits CD4+ regulatory T cells, and the latter decreased CXCL10 and CCL5, which induce CD8+ T cell infiltration. The EGFR inhibitor erlotinib decreased CD4+ effector regulatory T cells infiltration in the TME and in combination with anti-PD-1 mAb showed better antitumor effects than either treatment alone. Our results suggest that EGFR inhibitors when used in conjunction with anti-PD-1 mAb could increase the efficacy of immunotherapy in lung adenocarcinomas.

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  • Multiple modalities of single cell analyses to evaluate the tumor microenvironment in clinical specimens Reviewed

    Yukie Kashima, Shota Fukuoka, Yosuke Togashi, Takahiro Kamada, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Akihiro Ohashi, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Kocihiro Inaki, Masataka Chihara, Yutaka Suzuki, Katsuya Tsuchihara, Susumu S. Kobayashi, Hiroyoshi Nishikawa, Toshihiko Doi

    MOLECULAR CANCER THERAPEUTICS   18 ( 12 )   2019.12

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    DOI: 10.1158/1535-7163.TARG-19-C113

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  • Clinical and immune profiling for cancer of unknown primary site. Reviewed

    Haratani K, Hayashi H, Takahama T, Nakamura Y, Tomida S, Yoshida T, Chiba Y, Sawada T, Sakai K, Fujita Y, Togashi Y, Tanizaki J, Kawakami H, Ito A, Nishio K, Nakagawa K

    Journal for immunotherapy of cancer   7 ( 1 )   251   2019.9

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    Other Link: http://link.springer.com/article/10.1186/s40425-019-0720-z/fulltext.html

  • Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids. Reviewed International journal

    Tokunaga A, Sugiyama D, Maeda Y, Warner AB, Panageas KS, Ito S, Togashi Y, Sakai C, Wolchok JD, Nishikawa H

    The Journal of experimental medicine   216 ( 12 )   2701 - 2713   2019.9

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    Patients treated with immune checkpoint blockade (ICB) sometimes experience immune-related adverse events (irAEs), requiring immuno-suppressive drugs such as corticosteroids despite the possibility that immunosuppression may impair the antitumor effects of ICB. Here, we address the dilemma of using corticosteroids for the treatment of irAEs induced by ICB. ICB augments neoantigen-specific CD8+ T cell responses, resulting in tumor regression. In our model, simultaneous, but not late, administration of corticosteroids impaired antitumor responses with reduction of CD8+ T cell proliferation. Secondary challenge using tumors with/without the neoantigen showed selective progression in tumors lacking the neoantigen when corticosteroids were administered. Corticosteroids decreased low- but not high-affinity memory T cells by suppressing fatty acid metabolism essential for memory T cells. In a small cohort of human melanoma patients, overall survival was shorter after treatment with CTLA-4 blockade in patients who received early corticosteroids or had low tumor mutation burden. Together, low-affinity memory T cells are dominantly suppressed by corticosteroids, necessitating careful and thoughtful corticosteroid use.

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  • Analysis of the Tumor Reactivity of Tumor-Infiltrating Lymphocytes in a Metastatic Melanoma Lesion that Lost Major Histocompatibility Complex Class I Expression after Anti-PD-1 Therapy. Reviewed International journal

    Takashi Inozume, Tomonori Yaguchi, Ryo Ariyasu, Yosuke Togashi, Takehiro Ohnuma, Akiko Honobe, Hiroyoshi Nishikawa, Yutaka Kawakami, Tatsuyoshi Kawamura

    The Journal of investigative dermatology   139 ( 7 )   1490 - 1496   2019.7

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    Major histocompatibility complex class I loss due to the abnormality of β2-microglobulin gene is one of the mechanisms underlying delayed relapses in melanoma patients long after the initial positive responses to anti-PD-1 therapy. However, the tumor-specific reactivity of tumor-infiltrating lymphocytes in tumor lesions that lost major histocompatibility complex class I expression has not been well evaluated. We report the case of a 55-year-old woman with two metastatic melanoma lesions. After a 12-month period of successful tumor suppression by anti-PD-1 antibody therapy, one lesion started to grow again. We resected both lesions and examined the tumor cells and tumor-infiltrating lymphocytes. The shrinking lesion consisted of necrotic tissue and macrophages, and the enlarged lesion consisted of both necrotic tissue and viable tumor cells. The tumor cells completely lost major histocompatibility complex class I expression, but it was restored upon retroviral transduction of the normal β2-microglobulin gene. When we checked the tumor-specific reactivity of tumor-infiltrating lymphocytes derived from the relapsing lesion, we found that these tumor-infiltrating lymphocytes failed to recognize the native tumor cells derived from the lesion, but strongly recognized the major histocompatibility complex class-I-recovered cells by β2-microglobulin transduction. Our report emphasizes the limitations of T-cell-based immunotherapy and highlights the importance of developing alternative strategies for such cases.

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  • Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. Reviewed

    Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D, Kinoshita F, Akiba J, Kashiwagi E, Takeuchi A, Irie T, Tatsugami K, Hoshino T, Eto M, Nishikawa H

    Clinical cancer research : an official journal of the American Association for Cancer Research   25 ( 15 )   4808 - 4819   2019.5

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  • PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Reviewed

    Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, Morikawa H, Kawazoe A, Kinoshita T, Shitara K, Sakaguchi S, Nishikawa H

    Proceedings of the National Academy of Sciences of the United States of America   116 ( 20 )   9999 - 10008   2019.4

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  • Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer. Reviewed International journal

    Satomi Watanabe, Hidetoshi Hayashi, Koji Haratani, Shigeki Shimizu, Junko Tanizaki, Kazuko Sakai, Hisato Kawakami, Kimio Yonesaka, Junji Tsurutani, Yosuke Togashi, Kazuto Nishio, Akihiko Ito, Kazuhiko Nakagawa

    Cancer science   110 ( 1 )   52 - 60   2019.1

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    The efficacy of programmed cell death-1 (PD-1) blockade in patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC-I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC-I expression in NSCLC cell lines. Appropriate EGFR-TKIs increased MHC-I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also increased MHC-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK-ERK pathway mediates the down-regulation of MHC-I expression in response to EGFR activation. Immunohistochemical analysis of EGFR-mutated NSCLC specimens obtained before and after EGFR-TKI treatment also revealed down-regulation of phosphorylated forms of EGFR and ERK in association with up-regulation of MHC-I, an increased number of infiltrating CD8+ T cells, and increased PD-1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC-I expression through the MEK-ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR-MEK-ERK signaling in and the immune response to EGFR-mutated NSCLC. .

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  • Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Reviewed

    Togashi Y, Shitara K, Nishikawa H

    Nature reviews. Clinical oncology   16 ( 6 )   356 - 371   2019.1

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  • Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8+ T cells in the tumor microenvironment. Reviewed International journal

    Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K

    Journal for immunotherapy of cancer   6 ( 1 )   106 - 106   2018.10

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    BACKGROUND: Several studies have established a correlation between the VEGF-VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers. METHODS: We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry. RESULTS: Within the tumor microenvironment, both PD-L1 expression and CD8+ T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA-FOXP3highCD4+ cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8+ T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2+ eTreg cell proliferation, and this effect could be inhibited by RAM. CONCLUSIONS: This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade.

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  • Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein–Barr virus status, and cancer genome alterations in metastatic gastric cancer Reviewed

    Akihito Kawazoe, Kohei Shitara, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Atsushi Ohtsu, Atsushi Ochiai, Yosuke Togashi, Hiroyoshi Nishikawa, Toshihiko Doi, Takeshi Kuwata

    Gastric Cancer   1 - 8   2018.6

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    Background: Recently, the U.S. Food and Drug Administration approved pembrolizumab for patients (pts) with PD-L1-positive metastatic gastric cancer (MGC) based on 22C3 immunohistochemistry (IHC) assay. However, little is known about detailed clinicopathological features of 22C3 PD-L1 expression in MGC. Patients and methods: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression (22C3) on tumor cell (TC) or immune cell (IC) and mismatch repair (MMR) were analyzed by IHC. Epstein–Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) and cancer genome alterations were evaluated by IHC or next-generation sequencing. Results: A total of 225 pts were analyzed in this study. PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P &lt
    0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P &lt
    0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor. Conclusions: 22C3 PD-L1 expression in MGC was associated with distinct clinicopathological features, but was not a prognostic factor.

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  • Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer. Reviewed

    Togashi Yosuke, Tada Yasuko, Kotani Daisuke, Kawazoe Akihito, Doi Toshihiko, Nishikawa Hiroyoshi

    https://jitc.biomedcentral.com   36 ( 5 )   2018.2

  • Suppression from beyond the grave Reviewed

    Yosuke Togashi, Hiroyoshi Nishikawa

    NATURE IMMUNOLOGY   18 ( 12 )   1285 - 1286   2017.12

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    Adenosine produced by apoptotic regulatory T cells (T-reg cells) has a more important immunosuppressive role in the tumor microenvironment than that of live Treg cells. This discovery raises the possibility of novel strategies for cancer immunotherapy.

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  • Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment Reviewed

    K. Haratani, H. Hayashi, T. Tanaka, H. Kaneda, Y. Togashi, K. Sakai, K. Hayashi, S. Tomida, Y. Chiba, K. Yonesaka, Y. Nonagase, T. Takahama, J. Tanizaki, K. Tanaka, T. Yoshida, K. Tanimura, M. Takeda, H. Yoshioka, T. Ishida, T. Mitsudomi, K. Nishio, K. Nakagawa

    ANNALS OF ONCOLOGY   28 ( 7 )   1532 - 1539   2017.7

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    Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
    Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
    Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of &gt;= 1% or &lt;1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of &gt;= 10% and &gt;= 50%. The proportion of tumors with a PD-L1 level of &gt;= 10% or &gt;= 50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8(+) TIL density and nonsynonymous mutation burden.
    Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

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  • Clinical significance of Akt2 in advanced pancreatic cancer treated with erlotinib Reviewed

    Eri Banno, Yosuke Togashi, Marco A. De Velasco, Takuro Mizukami, Yu Nakamura, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

    INTERNATIONAL JOURNAL OF ONCOLOGY   50 ( 6 )   2049 - 2058   2017.6

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    Akt2 is an isoform of Akt, and an association between Akt2 and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been suggested in pancreatic cancer (PC) in vitro. In this study, we investigated the association between Akt2 expression as evaluated using immunohistochemistry and the outcome of patients with advanced PC who had received treatment with erlotinib (an EGFR-TKI). Although the difference was not significant, patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with erlotinib plus gemcitabine than those with low expression levels (P=0.16 and 0.19, respectively). In vitro, an Akt2-amplified PC cell line and Akt2-overexpressed cell lines exhibited resistance to anti-EGFR therapies, including erlotinib, but combined treatment with BYL719 (a PI3K inhibitor) cancelled this resistance. Our findings suggest that Akt2 might be associated with the resistance to anti-EGFR therapies, especially the use of erlotinib against PC, and that this resistance can be overcome by combined treatment with a PI3K inhibitor. Akt2 expression could become a predictive biomarker for erlotinib resistance in PC.

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  • Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A Reviewed

    Masato Chiba, Yosuke Togashi, Eri Bannno, Yoshihisa Kobayashi, Yu Nakamura, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

    BMC CANCER   17 ( 1 )   281   2017.4

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    Background: Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second-or third-generation EGFR-TKIs.
    Methods: Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated.
    Results: Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second-and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone.
    Conclusions: Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.

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  • Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer Reviewed

    Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi

    MOLECULAR CANCER THERAPEUTICS   16 ( 2 )   357 - 364   2017.2

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    Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with firstgeneration TKIs (1G-TKI). However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib. Afatinib-resistant clones were separately established through N-ethylN-nitrosourea (ENU) mutagenesis and exposure to fixed concentrations of afatinib. Rebiopsy samples from patients whose tumors acquired resistance to afatinib were analyzed. Afatinibresistant cells with Del19, L858R, or G719A developed T790M, whereas those with Del18 acquired novel L792F mutation. ENU mutagenesis screening established 84 afatinib-resistant clones. All Del19 clones and most of the other clones acquired only T790M. However, C797S occurred in subsets of L858R, G719A, and Del18 clones. In addition, subsets of Del18 clones acquired L792F. C797S-acquired cells were sensitive to 1G erlotinib. L792F demonstrated intermediate resistance between T790M and C797S to both 1G-and 3G-TKIs, whereas L792F was the least resistant to 2G-TKIs, particularly dacomitinib. Chronic exposure of Del18-L792F cells to dacomitinib induced additional T790M. T790M was detected in one of four clinical samples. In conclusion, L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells particularly using a low dose of afatinib, and these minor mutations appear to exhibit sensitivity to dacomitinib and erlotinib, respectively. These secondary mutations should be tested in clinical practice.

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  • Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies Reviewed International journal

    Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

    Molecular Carcinogenesis   56 ( 1 )   106 - 117   2017.1

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    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of &gt
    5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.

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  • Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies Reviewed

    Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

    MOLECULAR CARCINOGENESIS   56 ( 1 )   106 - 117   2017.1

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    Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. (c) 2016 Wiley Periodicals, Inc.

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  • Regulatory T Cells: Molecular and Cellular Basis for Immunoregulation Reviewed

    Yosuke Togashi, Hiroyoshi Nishikawa

    EMERGING CONCEPTS TARGETING IMMUNE CHECKPOINTS IN CANCER AND AUTOIMMUNITY   410   3 - 27   2017

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    CD4(+) regulatory T cells (Tregs) are a highly immune-suppressive subset of CD4(+) T cells, characterized by expression of the master regulatory transcription factor FOXP3. Tregs are proven to play central roles in the maintenance of self-tolerance in healthy individuals. Tregs are involved in maintaining immune homeostasis: they protect hosts from developing autoimmune diseases and allergy, whereas in malignancies, they promote tumor progression by suppressing anti-tumor immunity. Elucidating factors influencing Treg homeostasis and function have important implications for understanding disease pathogenesis and identifying therapeutic opportunities. Thus, the manipulating Tregs for up-or down-regulation of their suppressive function is a new therapeutic strategy for treating various diseases including autoimmune disorders and cancer. This review will focus on recent advances in how Tregs integrate extracellular and intracellular signals to control their survival and stability. Deeper mechanistic understanding of disease-specific Treg development, maintenance, and function could make disease-specific Treg-targeted therapy more effective, resulting in an increase of efficacy and decrease of side effects related to manipulating Tregs.

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  • MEK inhibitors against MET-amplified non-small cell lung cancer Reviewed

    Masato Chiba, Yosuke Togashi, Shuta Tomida, Hiroshi Mizuuchi, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasc, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

    INTERNATIONAL JOURNAL OF ONCOLOGY   49 ( 6 )   2236 - 2244   2016.12

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    Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFRmutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

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  • FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib Reviewed

    Masaaki Hibi, Hiroyasu Kaneda, Junko Tanizaki, Kazuko Sakai, Yosuke Togashi, Masato Terashima, Marco Antonio De Velasco, Yoshihiko Fujita, Eri Banno, Yu Nakamura, Masayuki Takeda, Akihiko Ito, Tetsuya Mitsudomi, Kazuhiko Nakagawa, Isamu Okamoto, Kazuto Nishio

    CANCER SCIENCE   107 ( 11 )   1667 - 1676   2016.11

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    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.

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  • Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation Reviewed

    Junko Tanizaki, Eri Banno, Yosuke Togashi, Hidetoshi Hayashi, Kazuko Sakai, Masayuki Takeda, Hiroyasu Kaneda, Kazuto Nishio, Kazuhiko Nakagawa

    LUNG CANCER   101   11 - 15   2016.11

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    Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

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  • Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor? Reviewed

    Eri Banno, Yosuke Togashi, Yu Nakamura, Masato Chiba, Yoshihisa Kobayashi, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

    CANCER SCIENCE   107 ( 8 )   1134 - 1140   2016.8

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    Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKI), and their sensitivities to various EGFR-TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR-TKI were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations.

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  • Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC Reviewed

    Yu Nakamura, Yosuke Togashi, Hirokazu Nakahara, Shuta Tomida, Eri Banno, Masato Terashima, Hidetoshi Hayashi, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Takatsugu Okegawa, Kikuo Nutahara, Suguru Hamada, Kazuto Nishio

    MOLECULAR CANCER THERAPEUTICS   15 ( 8 )   1988 - 1997   2016.8

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    The prognosis for patients with advanced esophageal or head-and-neck squamous cell carcinoma (ESCC or HNSCC) remains poor, and the identification of additional oncogenes and their inhibitors is needed. In this study, we evaluated the sensitivities of several ESCC and HNSCC cell lines to HER inhibitors (cetuximab, erlotinib, and afatinib) in vitro and found two cell lines that were hypersensitive to afatinib. Sequence analyses for the afatinib-targeted HER family genes in the two cell lines revealed that one cell line had a previously reported activating EGFR L861Q mutation, whereas the other had an HER4 G1109C mutation of unknown function. No amplification of HER family genes was found in either of the two cell lines. The phosphorylation level of HER4 was elevated in the HER4 G1109C mutation-overexpressed HEK293 cell line, and the mutation had a transforming potential and exhibited tumorigenicity in an NIH3T3 cell line, indicating that this HER4 mutation was an activating oncogenic mutation. Afatinib dramatically reduced the phosphorylation level of EGFR or HER4 and induced apoptosis in the two cell lines. In vivo, tumor growth was also dramatically decreased by afatinib. In a database, the frequencies of HER family gene mutations in ESCC or HNSCC ranged from 0% to 5%. In particular, HER4 mutations have been found relatively frequently in HNSCC. Considering the addiction of cancer cells to activating oncogenic EGFR or HER4 mutations for proliferation, HNSCC or ESCC with such oncogenic mutations might be suitable for targeted therapy with afatinib. (C) 2016 AACR.

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

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

    CLINICAL CANCER RESEARCH   22 ( 14 )   3663 - 3671   2016.7

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    Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets.
    Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro.
    Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-overex-pressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor.
    Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. (C) 2016 AACR.

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  • EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs Reviewed

    Yoshihisa Kobayashi, Yosuke Togashi, Yasushi Yatabe, Hiroshi Mizuuchi, Park Jangchul, Chiaki Kondo, Masaki Shimoji, Katsuaki Sato, Kenichi Suda, Kenji Tomizawa, Toshiki Takemoto, Toyoaki Hida, Kazuto Nishio, Tetsuya Mitsudomi

    CLINICAL CANCER RESEARCH   21 ( 23 )   5305 - 5313   2015.12

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    Purpose: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18.
    Experimental Design: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC(90)s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined.
    Results: Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC(90)s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by &gt; 11-50-fold), whereas IC(90)s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (similar to 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature.
    Conclusions: Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. (C) 2015 AACR.

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  • MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor Reviewed

    Yosuke Togashi, Hiroshi Mizuuchi, Shuta Tomida, Masato Terashima, Hidetoshi Hayashi, Kazuto Nishio, Tetsuya Mitsudomi

    LUNG CANCER   90 ( 3 )   590 - 597   2015.12

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    Background: MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3% of all lung adenocarcinomas. Patients with lung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported. The CRISPR/Cas9 system is a recently developed genome-engineering tool that can easily and rapidly cause small insertions or deletions.
    Materials and methods: We created an in vitro model for MET exon 14 deletion using the CRISPR/Cas9 system and the HEK293 cell line. The phenotype, which included MET inhibitor sensitivity, was then investigated in vitro. Additionally, MET splice site mutations were analyzed in several cancers included in The Cancer Genome Atlas (TCGA) dataset.
    Results: An HEK293 cell line with a MET exon 14 deletion was easily and rapidly created; this cell line had a higher MET protein expression level, enhanced MET phosphoiylation, and prolonged MET activation. In addition, a direct comparison of phenotypes using this system demonstrated enhanced cellular growth, colony formation, and MET inhibitor sensitivity. In the TCGA dataset, lung adenocarcinomas had the highest incidence of MET exon 14 deletions, while other cancers rarely carried such mutations. Approximately 10% of the lung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion.
    Conclusions: These findings suggested that this system may be useful for experiments requiring the creation of specific mutations, and the present experimental findings encourage the development of MET-targeted therapy against lung cancer carrying the MET exon 14 deletion. (c) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • Clinicopathological and Genetic Differences Between Low-Grade and High-Grade Colorectal Mucinous Adenocarcinomas Reviewed

    Yasumasa Yoshioka, Yosuke Togashi, Takaaki Chikugo, Akihiro Kogita, Masataka Taguri, Masato Terashima, Takuro Mizukami, Hidetoshi Hayashi, Kazuko Sakai, Marco A. de Velasco, Shuta Tomida, Yoshihiko Fujita, Tadao Tokoro, Akihiko Ito, Kiyotaka Okuno, Kazuto Nishio

    CANCER   121 ( 24 )   4359 - 4368   2015.12

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    BACKGROUND: Although colorectal mucinous adenocarcinomas (MCs) are conventionally regarded as exhibiting high-grade differentiation, they can be divided by differentiation into 2 groups according to the glandular appearance: low-grade mucinous adenocarcinoma (low-MC) and high-grade mucinous adenocarcinoma (high-MC). METHODS: Patients with colorectal cancer (CRC) who underwent surgical resection between 2000 and 2012 were enrolled in this study. Among the cases with MC, the clinicopathological and genetic differences between low-MC and high-MC were investigated with next-generation sequencing. RESULTS: A total of 1373 patients with CRC were analyzed. Forty patients (2.9%) had MC, and 13 patients had high-MC. Patients with MC had significantly shorter disease-free survival (DFS) and overall survival (OS) periods than those with nonmucinous carcinoma. When low-MC patients and high-MC patients were compared, those with high-MC had significantly shorter DFS and OS periods than those with low-MC. Multivariate analyses revealed that high-MC was significantly associated with both shorter DFS and shorter OS, but low-MC was not. A genome analysis revealed that low-MC had a considerably larger number of mutations than high-MC, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and adenomatous polyposis coli mutations were particularly frequently found in low-MC. In contrast, SMAD family member 4 (SMAD4) mutations were frequently found in high-MC. CONCLUSIONS: High-MC is an independent prognostic factor in CRC (but low-MC is not), and it is genetically different from other CRCs, including low-MC. Both the clinicopathological differences and the genetic differences suggest that low-MC and high-MC should be distinguished in clinical settings. (C) 2015 American Cancer Society.

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  • Urinary kidney injury molecule-1 and monocyte chemotactic protein-1 are noninvasive biomarkers of cisplatin-induced nephrotoxicity in lung cancer patients Reviewed

    Haruka Shinke, Satohiro Masuda, Yousuke Togashi, Yasuaki Ikemi, Aiko Ozawa, Tomoko Sato, Young Hak Kim, Michiaki Mishima, Takaharu Ichimura, Joseph V. Bonventre, Kazuo Matsubara

    CANCER CHEMOTHERAPY AND PHARMACOLOGY   76 ( 5 )   989 - 996   2015.11

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    Acute kidney injury (AKI) is a common and serious adverse effect of cisplatin-based chemotherapy. However, traditional markers of kidney function, such as serum creatinine, are suboptimal, because they are not sensitive measures of proximal tubular injury. We aimed to determine whether the new urinary biomarkers such as kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and neutrophil gelatinase-associated lipocalin (NGAL) could detect cisplatin-induced AKI in lung cancer patients in comparison with the conventional urinary proteins such as N-acetyl-beta-d-glucosaminidase (NAG) and beta 2-microglobulin.
    We measured KIM-1, MCP-1, NGAL, NAG, and beta 2-microglobulin concentrations in urine samples from 11 lung cancer patients, which were collected the day before cisplatin administration and on days 3, 7, and 14. Subsequently, we evaluated these biomarkers by comparing their concentrations in 30 AKI positive (+) and 12 AKI negative (-) samples and performing receiver operating characteristic (ROC) curve analyses.
    The urinary levels normalized with urine creatinine of KIM-1 and MCP-1, but not NGAL, NAG, and beta 2-microglobulin in AKI (+) samples were significantly higher than those in AKI (-) samples. In addition, ROC curve analyses revealed that KIM-1 and MCP-1, but not NGAL, could detect AKI with high accuracy (area under the curve [AUC] = 0.858, 0.850, and 0.608, respectively). The combination of KIM-1 and MCP-1 outperformed either biomarker alone (AUC = 0.871).
    Urinary KIM-1 and MCP-1, either alone or in combination, may represent biomarkers of cisplatin-induced AKI in lung cancer patients.

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  • An activating ALK gene mutation in ALK IHC-positive/FISH-negative nonsmall-cell lung cancer Reviewed

    Y. Togashi, H. Mizuuchi, Y. Kobayashi, H. Hayashi, M. Terashima, K. Sakai, E. Banno, T. Mizukami, Y. Nakamura, M. A. de Velasco, Y. Fujita, S. Tomida, T. Mitsudomi, K. Nishio

    ANNALS OF ONCOLOGY   26 ( 8 )   1800 - 1801   2015.8

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  • [Kinase inhibitors and their resistance]. Reviewed

    Togashi Y, Nishio K

    Nihon rinsho. Japanese journal of clinical medicine   73 ( 8 )   1323 - 1329   2015.8

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  • EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition Reviewed

    Takuro Mizukami, Yosuke Togashi, Shunsuke Sogabe, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

    INTERNATIONAL JOURNAL OF ONCOLOGY   47 ( 2 )   499 - 505   2015.8

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    Since the prognosis of unresectable advanced gastric cancer remains poor, novel therapeutic strategies are needed. Somatic MEKI gene mutations have been reported as oncogenic activating mutations in gastric cancer, and MEK inhibitors can be effective against such gastric cancers. In the present study, however, activated EGFR and HER2 signals after treatment with a MEK inhibitor (trametinib) were found in a MEK1-mutated gastric cancer cell line (OCUM-1 cell line) using a phospho-receptor tyrosine kinase array. The phosphorylation of EGFR and HER2 reactivated ERK1/2, which had been inhibited by trametinib, and EGF stimulation led to resistance to trametinib in this cell line. Lapatinib, an EGFR and an HER2 inhibitor, reversed the activation of ERK1/2 by inhibiting the phosphorylation of EGFR and HER2 and cancelled the resistance. The combination of trametinib and lapatinib synergistically inhibited the cell growth of the OCUM-1 cell line and strongly induced apoptosis by inhibiting the activated EGFR and HER2 signals. These results suggest that the EGFR and HER2 signals play a salvage role and are related to resistance to MEK inhibitors in MEK1-mutated gastric cancer. Moreover, combination therapy with trametinib and lapatinib can exhibit a synergistic effect and may contribute to overcoming the resistance to MEK inhibitors.

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  • Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study Reviewed

    Hiroki Yamaue, Takuya Tsunoda, Masaji Tani, Motoki Miyazawa, Kenji Yamao, Nobumasa Mizuno, Takuji Okusaka, Hideki Ueno, Narikazu Boku, Akira Fukutomi, Hiroshi Ishii, Shinichi Ohkawa, Masayuki Furukawa, Hiroyuki Maguchi, Masafumi Ikeda, Yosuke Togashi, Kazuto Nishio, Yasuo Ohashi

    CANCER SCIENCE   106 ( 7 )   883 - 890   2015.7

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    Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide+gemcitabine) or Placebo group (placebo+gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n=100; Placebo group, n=53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36months (95% CI, 7.46-10.18) for the Active group and 8.54months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.
    Phase II/III trial of elpamotide was performed to evaluate the clinical effect for advanced pancreatic cancer. Despite the lack of benefit in OS, sub-group analysis suggested that the patients with severe ISR might have better survival.

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  • Extended RAS and BRAF Mutation Analysis Using Next-Generation Sequencing Reviewed

    Kazuko Sakai, Junji Tsurutani, Takeharu Yamanaka, Azusa Yoneshige, Akihiko Ito, Yosuke Togashi, Marco A. De Velasco, Masato Terashima, Yoshihiko Fujita, Shuta Tomida, Takao Tamura, Kazuhiko Nakagawa, Kazuto Nishio

    PLOS ONE   10 ( 5 )   e0121891   2015.5

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    Somatic mutations in KRAS, NRAS, and BRAF genes are related to resistance to anti-EGFR antibodies in colorectal cancer. We have established an extended RAS and BRAF mutation assay using a next-generation sequencer to analyze these mutations. Multiplexed deep sequencing was performed to detect somatic mutations within KRAS, NRAS, and BRAF, including minor mutated components. We first validated the technical performance of the multiplexed deep sequencing using 10 normal DNA and 20 formalin-fixed, paraffin-embedded (FFPE) tumor samples. To demonstrate the potential clinical utility of our assay, we profiled 100 FFPE tumor samples and 15 plasma samples obtained from colorectal cancer patients. We used a variant calling approach based on a Poisson distribution. The distribution of the mutation-positive population was hypothesized to follow a Poisson distribution, and a mutation-positive status was defined as a value greater than the significance level of the error rate (alpha = 2 x 10(-5)). The cut-off value was determined to be the average error rate plus 7 standard deviations. Mutation analysis of 100 clinical FFPE tumor specimens was performed without any invalid cases. Mutations were detected at a frequency of 59% (59/100). KRAS mutation concordance between this assay and Scorpion-ARMS was 92% (92/100). DNA obtained from 15 plasma samples was also analyzed. KRAS and BRAF mutations were identified in both the plasma and tissue samples of 6 patients. The genetic screening assay using next-generation sequencer was validated for the detection of clinically relevant RAS and BRAF mutations using FFPE and liquid samples.

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  • Chronic nicotine exposure mediates resistance to EGFR-TKI in EGFR-mutated lung cancer via an EGFR signal Reviewed

    Yosuke Togashi, Hidetoshi Hayashi, Kunio Okamoto, Soichi Fumita, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

    LUNG CANCER   88 ( 1 )   16 - 23   2015.4

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    Background: Some of patients with non-small cell lung cancer (NSCLC) harboring somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) show poor responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment. Cigarette smoking is the strongest documented risk factor for the development of lung cancer. Nicotine, while not carcinogenic by itself, has been shown to induce proliferation, angiogenesis, and the epithelial-mesenchymal transition; these effects might be associated with EGFR-TKI resistance.
    Materials and methods: PC-9 and 11-18 cell lines (EGFR-mutated NSCLC cell lines) were cultured with 1 mu M nicotine for 3 months and were designated as PC-9/N and 11-18/N cell lines, respectively. The sensitivities of these cell lines to EGFR-TKI were then tested in vitro. Moreover, the association between the smoking status and the progression-free survival (PFS) period was investigated in patients with EGFR-mutated NSCLC who were treated with gefitinib.
    Results: The PC-9/N and 11-18/N cell lines were resistant to EGFR-TKI, compared with controls. The phosphorylation of EGFR in these cell lines was reduced by EGFR-TKI to a smaller extent than that observed in controls, and a higher concentration of EGFR-TKI was capable of further decreasing the phosphorylation. Clinically, smoking history was an independent predictor of a poor PFS period on gefitinib treatment.
    Conclusions: Chronic nicotine exposure because of cigarette smoking mediates resistance to EGFR-TKI via an EGFR signal. Smoking cessation is of great importance, while resistance may be overcome through the administration of high-dose EGFR-TKI. (c) 2015 Elsevier Ireland Ltd. All rights reserved.

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  • Afatinib is Especially Effective Against Non-small Cell Lung Cancer Carrying an EGFR Exon 19 Deletion Reviewed

    Eri Banno, Yosuke Togashi, Yoshihisa Kobayashi, Hidetoshi Hayashi, Tetsuya Mitsudomi, Kazuto Nishio

    ANTICANCER RESEARCH   35 ( 4 )   2005 - 2008   2015.4

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    Background: A recent pooled analysis of the LUX-LUNG3 and LUX-LUNG6 trials suggested that afatinib (an irreversible epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)) is especially effective against non-small cell lung cancer (NSCLC) carrying an EGFR exon 19 deletion. Materials and Methods: Stable viral transfectant HEK293 cell lines carrying an exon 19 deletion (HEK293/19 del) or exon 21 L858R mutation (HEK293/L858R)) were created and their drug sensitivities to AG1478 (a reversible EGFR-TKI) and afatinib were examined using an MTT assay. Western blot analyses were performed to estimate the phosphorylation of EGFR. Results: In the HEK293/19 del, the 50% inhibitory concentration (IC50) of afatinib was significantly lower than that in the HEK293/L858R. In addition, afatinib inhibited the phosphorylation of EGFR to a greater degree in the HEK293/19 del than in the HEK293/L858R. Conclusion: Our experimental findings suggest that afatinib is especially effective against NSCLC carrying an EGFR exon 19 deletion.

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  • Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer Reviewed

    Akihiro Kogita, Yosuke Togashi, Hidetoshi Hayashi, Eri Banno, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuhiko Nakagawa, Kazuto Nishio

    INTERNATIONAL JOURNAL OF ONCOLOGY   46 ( 3 )   1025 - 1030   2015.3

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    Non-small cell lung cancer (NSCLC) carrying echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements is hypersensitive to ALK inhibitors, including crizotinib and alectinib. Crizotinib was initially designed as a MET inhibitor, whereas alectinib is a selective ALK inhibitor. The MET signal, which is inhibited by crizotinib but not by alectinib, is dysregulated in many human cancers. However, the role of the MET signal in ALK-positive NSCLC remains unclear. In this study, we found that hepatocyte growth factor (HGF), ligand of MET, mediated the resistance to alectinib, but not to crizotinib, via the MET signal in ALK-positive NSCLC cell lines (H3122 and H2228 cell lines). In addition, alectinib activated the MET signal even in the absence of HGF and the inhibition of the MET signal enhanced the efficacy of alectinib. These findings suggest that activated MET acts as a salvage signal in ALK-positive NSCLC. This novel role of the MET signal in ALK-positive NSCLC may pave the way for further clinical trials examining MET inhibitors.

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  • Inter- and intra-tumor profiling of multi-regional colon cancer and metastasis Reviewed

    Akihiro Kogita, Yasumasa Yoshioka, Kazuko Sakai, Yosuke Togashi, Shunsuke Sogabe, Takuya Nakai, Kiyotaka Okuno, Kazuto Nishio

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   458 ( 1 )   52 - 56   2015.2

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    Intra- and inter-tumor heterogeneity may hinder personalized molecular-target treatment that depends on the somatic mutation profiles. We performed mutation profiling of formalin-fixed paraffin embedded tumors of multi-regional colon cancer and characterized the consequences of intra- and inter-tumor heterogeneity and metastasis using targeted re-sequencing.
    We performed targeted re-sequencing on multiple spatially separated samples obtained from multi-regional primary colon carcinoma and associated metastatic sites in two patients using nextgeneration sequencing. In Patient 1 with four primary tumors (P1-1, P1-2, P1-3, and P1-4) and one liver metastasis (H1), mutually exclusive pattern of mutations was observed in four primary tumors. Mutations in primary tumors were identified in three regions; KARS (G13D) and APC (R876*) in P1-2, TP53 (A161S) in P1-3, and KRAS (G12D), PIK3CA (Q546R), and ERBB4 (T272A) in P1-4. Similar combinatorial mutations were observed between P1-4 and H1. The ERBB4 (T272A) mutation observed in P1-4, however, disappeared in H1. In Patient 2 with two primary tumors (P2-1 and P2-2) and one liver metastasis (H2), mutually exclusive pattern of mutations were observed in two primary tumors. We identified mutations; KRAS (G12V), SMAD4 (N129K, R445*, and G508D), TP53 (R175H), and FGFR3 (R805W) in P2-1, and NRAS (Q61K) and FBXW7 (R425C) in P2-2. Similar combinatorial mutations were observed between P2-1 and H2. The SMAD4 (N129K and G508D) mutations observed in P2-1, however, were nor detected in H2. These results suggested that different clones existed in primary tumors and metastatic tumor in Patient 1 and 2 likely originated from P1-4 and P2-1, respectively.
    In conclusion, we detected the muti-clonalities between intra- and inter-tumors based on mutational profiling in multi-regional colon cancer using next-generation sequencing. Primary region from which metastasis originated could be speculated by mutation profile. Characterization of inter- and inter-tumor heterogeneity can lead to underestimation of the tumor genomics landscape and treatment strategy of personal medicine. (C) 2015 Published by Elsevier Inc.

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  • Impact of Pretreatment Interstitial Lung Disease on Radiation Pneumonitis and Survival after Stereotactic Body Radiation Therapy for Lung Cancer Reviewed

    Nami Ueki, Yukinori Matsuo, Yosuke Togashi, Takeshi Kubo, Keiko Shibuya, Yusuke Iizuka, Takashi Mizowaki, Kaori Togashi, Michiaki Mishima, Masahiro Hiraoka

    JOURNAL OF THORACIC ONCOLOGY   10 ( 1 )   116 - 125   2015.1

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    Introduction: To investigate the impact of pre-existing radiological interstitial lung disease (ILD) findings on the incidence of radiation pneumonitis (RP) and clinical outcomes after stereotactic body radiation therapy (SBRT) for stage I non-small-cell lung cancer.
    Methods: We included 157 consecutive patients who underwent SBRT alone for stage I non-small-cell lung cancer and whose pretreatment lung computed tomography images were available for retrospective review. The pretreatment computed tomography images were evaluated retrospectively for the presence of ILD. The incidence of RP, overall survival (OS) rate, and the incidence of disease progression and local progression were evaluated between patients with ILD (ILD[+]) and without ILD (ILD[-]).
    Results: Pre-existing ILD was identified in 20 patients. The median follow-up period was 39.5 months. The incidences of RP worse than grade 2 (&gt;= Gr2 RP) and worse than grade 3 (&gt;= Gr3 RP) were significantly higher in ILD(+) than ILD(-) (1 year &gt;= Gr2 RP rate, 55.0% versus 13.3%; p &lt; 0.001 and 1year &gt;= Gr3 RP rate 10.0% versus 1.5%; p = 0.020). Multivariate analysis also indicated that ILD(+) was a risk factor for &gt;= Gr2 and &gt;= Gr3 RP, and the volume of the irradiated lung. The OS rate tended to be worse in ILD(+) than ILD(-) (3-year OS, 53.8% versus 70.8%; p = 0.28). No difference was observed in the disease progression or local progression rates.
    Conclusions: Pre-existing ILD was a significant risk factor for symptomatic and severe RP. Prescreening for ILD findings is important for determining the radiation pneumonitis risk when planning SBRT.

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  • The OCT4 pseudogene POU5F1B is amplified and promotes an aggressive phenotype in gastric cancer Reviewed

    H. Hayashi, T. Arao, Y. Togashi, H. Kato, Y. Fujita, M. A. De Velasco, H. Kimura, K. Matsumoto, K. Tanaka, I. Okamoto, A. Ito, Y. Yamada, K. Nakagawa, K. Nishio

    ONCOGENE   34 ( 2 )   199 - 208   2015.1

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    POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.

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  • Performance of a novel KRAS mutation assay for formalin-fixed paraffin embedded tissues of colorectal cancer Reviewed

    Kazuko Sakai, Azusa Yoneshige, Akihiko Ito, Yoji Ueda, Satoshi Kondo, Hitoshi Nobumasa, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Marco A. De Velasco, Shuta Tomida, Kazuto Nishio

    SPRINGERPLUS   4   7   2015.1

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    We compared the performance of the 3D-Gene (R) mutation assay (3D-Gene (R) KRAS mutation assay kit) with the Scorpion-ARMS (therascreen (R) KRAS RGQ PCR Kit) and Luminex (MEBGEN (TM) KRAS kit) assays for the detection of KRAS mutations in formalin-fixed, paraffin-embedded tissue samples from 150 patients diagnosed with colorectal cancer. DNA was extracted from the paraffin-embedded tissue samples with or without macrodissection under hematoxylin and eosin staining and the KRAS mutation status was independently determined using these assays. Discordant results were re-analyzed by Sanger sequencing. Mutation detection analysis was successfully performed in all 150 specimens using the 3D-Gene (R) mutation assay without an invalid case. The concordance rate between the 3D-Gene (R) mutation assay and Scorpion-ARMS or Luminex was 98.7% (148/150). KRAS mutations were detected at a frequency of 35.3% (53/150) in colorectal cancer specimens. Three discrepant cases were found between the three assays. Overall, our results demonstrate a high concordance rate of between the 3D-Gene (R) mutation assay and the two existing in-vitro diagnostics kits. All three assays proved to be validated methods for detecting clinically significant KRAS mutations in paraffin-embedded tissue samples.

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  • Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer Reviewed

    Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Kiyotaka Okuno, Masatoshi Kudo, Kazuto Nishio

    CANCER LETTERS   356 ( 2 )   819 - 827   2015.1

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    We previously reported that activin produces a signal with a tumor suppressive role in pancreatic cancer (PC). Here, the association between plasma activin A and survival in patients with advanced PC was investigated. Contrary to our expectations, however, patients with high plasma activin A levels had a significantly shorter survival period than those with low levels (median survival, 314 days vs. 482 days, P = 0.034). The cellular growth of the MIA PaCa-2 cell line was greatly enhanced by activin A via non-SMAD pathways. The cellular growth and colony formation of an INHBA (beta subunit of inhibin)overexpressed cell line were also enhanced. In a xenograft study, INHBA-overexpressed cells tended to result in a larger tumor volume, compared with a control. The bodyweights of mice inoculated with INHBA-overexpressed cells decreased dramatically, and these mice all died at an early stage, suggesting the occurrence of activin-induced cachexia. Our findings indicated that the activin signal can promote cancer progression in a subset of PC and might be involved in cachexia. The activin signal might be a novel target for the treatment of PC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

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  • Inhibition of beta-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non-small-cell Lung Cancer with a T790M Mutation Reviewed

    Yosuke Togashi, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

    JOURNAL OF THORACIC ONCOLOGY   10 ( 1 )   93 - 101   2015.1

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    Introduction: Patients with non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations) generally respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). beta-Catenin is a key component of the Wnt/beta-Catenin signal and is an important oncogene that is involved in the pathogenesis and progression of malignant tumors, especially cancer stem cells.
    Methods and Results: We found that EGFR-mutated NSCLC cell lines exhibited a high expression level of beta-Catenin, compared with cell lines with the wild-type EGFR gene, and XAV939 (a beta-Catenin inhibitor) enhanced the sensitivities to EGFR-TKI in EGFR-mutated NSCLC cell lines. In EGFR-mutated NSCLC cell lines with the acquired resistance threonine-to-methionine mutation in codon 790 (T790M) mutation, XAV939 enhanced the sensitivity of the cells to an irreversible EGFR-TKI but not a reversible EGFR-TKI. The combination of XAV939 and EGFR-TKIs strongly inhibited the beta-Catenin signal and strongly decreased the phosphorylation of EGFR, compared with the use of EGFR-TKIs alone, suggesting an interaction between EGFR and the beta-Catenin signal. The stem cell-like properties of the EGFR-mutated cell line carrying the T790M mutation were inhibited by XAV939 and BIBW2992 (an irreversible EGFR-TKI). Furthermore, the stem cell-like properties were strongly inhibited by a combination of both the agents. A xenograft study demonstrated that beta-Catenin knockdown enhanced the antitumor effect of BIBW2992 in the EGFR-mutated NSCLC cell line carrying the T790M mutation.
    Conclusion: Our findings indicate that beta-Catenin might be a novel therapeutic target in EGFR-mutated NSCLC carrying the T790M mutation.

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  • Multiple Primary Malignancies in Patients with Non-Small Cell Lung Cancer Reviewed

    Shiro Fujita, Katsuhiro Masago, Jumpei Takeshita, Yosuke Togashi, Akito Hata, Reiko Kaji, Masaki Kokubo, Nobuyuki Katakami

    INTERNAL MEDICINE   54 ( 3 )   325 - 331   2015

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    Objective Information regarding multiple primary malignancies is important, as it has the potential to clarify etiological factors and may indicate the need to refine patient follow-up to include screening for associated malignancies. Upper aerodigestive tract cancer often develops in patients with smoking-related lung cancer; however, little is known about the frequencies or types of other primary malignancies in patients with non-small cell lung cancer (NSCLC) without a history of smoking.
    Methods We retrospectively evaluated the records of patients examined and/or treated for NSCLC at the Institute of Biomedical Research and Innovation between January 2007 and June 2012. Patients In total, 938 patients, including 599 men (never-smoker/ever-smoker: 35/564) and 339 women (never-smoker/ever-smoker: 236/103), were analyzed.
    Results Among the 209 patients (22.3%) with multiple primary malignancies, 151 had a history of smoking and 58 were never-smokers. The most common cancers were gastric (43 cases), colorectal (33 cases), and prostate (29 cases) cancer. Smoking-related cancer was more common in current smokers and ex-smokers for both men and women. Among women with NSCLC, never-smokers were more likely to have thyroid cancer than those with a history of smoking (5.1% vs. 0%, p= 0.021).
    Conclusion In this study, several differences in malignancies were observed between never-smokers and patients with a history of smoking. Thyroid cancer and NSCLC co-existed in some women without a history of smoking, implicating predisposing factors other than tobacco smoke in the onset of these cancers.

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  • MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations Reviewed

    Shunsuke Sogabe, Yosuke Togashi, Hiroaki Kato, Akihiro Kogita, Takuro Mizukami, Yoichi Sakamoto, Eri Banno, Masato Terashima, Hidetoshi Hayashi, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takushi Yasuda, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuto Nishio

    MOLECULAR CANCER THERAPEUTICS   13 ( 12 )   3098 - 3106   2014.12

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    The prognosis for patients with unresectable advanced or recurrent gastric cancer remains poor. The identification of additional oncogenes with influences similar to those of epidermal growth factor receptor gene mutations, upon which the growth of cancer cells is dependent, is needed. In this study, we evaluated sensitivity to MEK inhibitors (GSK1120212 and PD0325901) in several gastric cancer cell lines in vitro and found three poorly differentiated gastric cancer cell lines that were hypersensitive to the inhibitors. The sequence analyses in these three cell lines revealed that one cell line had a novel MEK1 mutation, while the other two had previously reported KRAS and MEK1 mutations, respectively; the gene statuses of the other resistant cell lines were all wild-type. Experiments using MEK1 expression vectors demonstrated that the MEK1 mutations induced the phosphorylation of ERK1/2 and had a transforming potential, enhancing the tumorigenicity. The MEK inhibitor dramatically reduced the phosphorylation of ERK1/2 and induced apoptosis in the cell lines with MEK1 mutations. In vivo, tumor growth was also dramatically decreased by an inhibitor. One of the 46 gastric cancer clinical samples that were examined had a MEK1 mutation; this tumor had a poorly differentiated histology. Considering the addiction of cancer cells to active MEK1 mutations for proliferation, gastric cancer with such oncogenic MEK1 mutations might be suitable for targeted therapy with MEK inhibitors. (C)2014 AACR.

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  • Hypoxia induces resistance to ALK inhibitors in the H3122 non-small cell lung cancer cell line with an ALK rearrangement via epithelial-mesenchymal transition Reviewed

    Akihiro Kogita, Yosuke Togashi, Hidetoshi Hayashi, Shunsuke Sogabe, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Yoshifumi Takeyama, Kiyotaka Okuno, Kazuhiko Nakagawa, Kazuto Nishio

    INTERNATIONAL JOURNAL OF ONCOLOGY   45 ( 4 )   1430 - 1436   2014.10

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    Patients with non-small cell lung cancer (NSCLC) with echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangements generally respond to ALK inhibitors such as crizotinib. However, some patients with EML4-ALK rearrangements respond poorly to crizotinib. Hypoxia is involved in the resistance to chemotherapeutic treatments in several cancers, and we investigated the association between the responses to ALK inhibitors and hypoxia. Sensitivity of the H3122 NSCLC cell line (EML4-ALK rearrangement) to ALK inhibitors (crizotinib or alectinib) was investigated during a normoxic or hypoxic state using an MTT assay. We found that the cell line was resistant to the inhibitors during hypoxia. Hypoxia mediated morphologic changes, including cell scattering and the elongation of the cell shape, that are characteristic of the epithelial-mesenchymal transition (EMT). A migration assay demonstrated that the number of migrating cells increased significantly during hypoxia, compared with during normoxia. Regarding EMT-related molecules, the expressions of slug, vimentin, and fibronectin were increased while that of E-cadherin was decreased by hypoxia. In addition, hypoxia inducible factor 1A-knockdown cancelled the hypoxia-induced EMT and resistance. Our findings indicate that hypoxia induces resistance to ALK inhibitors in NSCLC with an EML4-ALK rearrangement via the EMT.

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  • KIAA1199 interacts with glycogen phosphorylase kinase beta-subunit (PHKB) to promote glycogen breakdown and cancer cell survival Reviewed

    Masato Terashima, Yoshihiko Fujita, Yosuke Togashi, Kazuko Sakai, Marco A. De Velasco, Shuta Tomida, Kazuto Nishio

    ONCOTARGET   5 ( 16 )   7040 - 7050   2014.8

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    The KIAA1199 gene was first discovered to be associated with non-syndromic hearing loss. Recently, several reports have shown that the up-regulation of KIAA1199 is associated with cancer cell migration or invasion and a poor prognosis. These findings indicate that KIAA1199 may be a novel target for cancer therapy. Therefore, we explored in detail the function of KIAA1199 in cancer cells. In this study, we investigated the interaction of KIAA1199 protein with intracellular proteins in cancer cells. To this end, we expressed KIAA1199-MBP fusion protein and performed a pull-down assay. In addition, KIAA1199-overexpressing cancer cell lines were constructed using a retroviral vector and were used for further experiments. A pull-down analysis showed that the glycogen phosphorylase kinase beta-subunit (PHKB) interacted with the C-terminal region of KIAA1199 protein. Furthermore, we observed the interaction of KIAA1199 with glycogen phosphorylase brain form (PYGB) under serum-free conditions. The interaction promoted glycogen breakdown and cancer cell survival. Our findings indicate that KIAA1199 plays an important role in glycogen breakdown and cancer cell survival and that it may represent a novel target for cancer therapy.

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  • Synergistic antitumor effects of S-1 with eribulin in vitro and in vivo for triple-negative breast cancer cell lines Reviewed

    Masato Terashima, Kazuko Sakai, Yosuke Togashi, Hidetoshi Hayashi, Marco A. De Velasco, Junji Tsurutani, Kazuto Nishio

    SPRINGERPLUS   3   417   2014.8

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    Triple-negative breast cancer (TNBC) is associated with a higher incidence of recurrence and distant metastasis and a poor prognosis, whereas effective treatment strategies remain to be established. Finding an effective treatment for TNBC has become imperative. We examined the effect of the combination of S-1 (or 5-FU in an in vitro study) and eribulin in TNBC cell lines. The in vitro effect of the combination was examined in four TNBC cell lines (MDA-MB-231, MDA-MB-468, BT-549 and MX-1) using a combination index and isobolograms. In addition, we assessed the effect of the combination in an MDA-MB-231 tumor xenograft model. A synergistic effect was observed in three TNBC cell lines (MDA-MB-231, MDA-MB-468, and MX-1), and in an in vivo study, the combination of S-1 and eribulin resulted in significantly higher antitumor effects compared with S-1 or eribulin alone. 5-FU induced epithelial-mesenchymal transition (EMT) change in the TNCB cell line, as supported by the decreased expression of epithelial marker and the increased expression of mesenchymal markers. Meanwhile, TGF-beta induced EMT changes in a TNBC cell line and decreased the sensitivity to 5-FU. This result suggests that 5-FU-induced EMT changes reduce the sensitivity to 5-FU. In contrast, eribulin induced a mesenchymal-epithelial transition (MET) in a TNBC cell line. The EMT phenotype induced by 5-FU was also canceled by eribulin. We demonstrate that the combination of S-1 (5-FU) and eribulin exerts a synergistic effect for TNBC cell lines through MET-induction by eribulin. Therefore, this combination therapy may be a potential treatment option for TNBC.

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  • Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production Reviewed

    Yosuke Togashi, Tokuzo Arao, Hiroaki Kato, Kazuko Matsumoto, Masato Terashima, Hidetoshi Hayashi, Marco A. de Velasco, Yoshihiko Fujita, Hideharu Kimura, Takushi Yasuda, Hitoshi Shiozaki, Kazuto Nishio

    ONCOTARGET   5 ( 10 )   2962 - 2973   2014.5

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    Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC). The oral cancer overexpressed 1 (ORAOV1) gene has been identified within this region, but its detailed biological function in human ESCC remains largely unclear. In our clinical samples of stage III ESCC, ORAOV1 amplification was observed in 49 of 94 cases (53%). ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus. Patients with ORAOV1 amplification tended to have a shorter survival period, although the difference was not significant. To investigate the function of ORAOV1, we created ORAOV1-overexpressed ESCC cell lines that exhibited increased cellular proliferation and colony formation, compared with in vitro controls. In vivo, ORAOV1-overexpressed cells exhibited a significantly increased tumorigenicity and a significantly larger tumor volume and poorer differentiation than controls. The peptide mass fingerprinting technique demonstrated that ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is associated with proline metabolism and reactive oxygen species (ROS) production. Then, ORAOV1-overexpressed cell lines were resistant to stress treatment, which was cancelled by PYCR-knockdown. In addition, the ORAOV1-overexpressed cell line had a higher intracellular proline concentration and a lower ROS level. Our findings indicate that the ORAOV1 gene is frequently amplified in ESCC, enhances tumorigenicity and tumor growth, and is associated with a poorly differentiated tumor histology via proline metabolism and ROS production. ORAOV1 could be a novel target for the treatment of ESCC.

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  • Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer Reviewed

    Yosuke Togashi, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Yoshihiko Fujita, Yasuo Kodera, Kazuko Sakai, Shuta Tomida, Masayuki Kitano, Akihiko Ito, Masatoshi Kudo, Kazuto Nishio

    MOLECULAR CANCER   13   126   2014.5

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    Background: Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear.
    Methods and results: We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21(CIP1/WAF1) in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene.
    Conclusion: We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.

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  • Biomarkers of reactive resistance and early disease progression during chemotherapy plus bevacizumab treatment for colorectal carcinoma Reviewed

    Hidetoshi Hayashi, Tokuzo Arao, Kazuko Matsumoto, Hideharu Kimura, Yosuke Togashi, Yoshinori Hirashima, Yosuke Horita, Satoru Iwasa, Natsuko Tsuda Okita, Yoshitaka Honma, Atsuo Takashima, Ken Kato, Tetsuya Hamaguchi, Yasuhiro Shimada, Kazuhiko Nakagawa, Kazuto Nishio, Yasuhide Yamada

    ONCOTARGET   5 ( 9 )   2588 - 2595   2014.5

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    Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.

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  • Melanoma Transition Is Frequently Accompanied by a Loss of Cytoglobin Expression in Melanocytes: A Novel Expression Site of Cytoglobin Reviewed

    Yoshihiko Fujita, Satoshi Koinuma, Marco A. De Velasco, Jan Bolz, Yosuke Togashi, Masato Terashima, Hidetoshi Hayashi, Takuya Matsuo, Kazuto Nishio

    PLOS ONE   9 ( 4 )   e94772   2014.4

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    The tissue distribution and function of hemoglobin or myoglobin are well known; however, a newly found cytoglobin (CYGB), which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2'-, 7'-dichlorofluorescein diacetate (DCFH-DA), an indicator of reactive oxygen species (ROS), revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition.

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  • Clinical utility of erlotinib for the treatment of non-small-cell lung cancer in Japanese patients: current evidence Reviewed

    Yosuke Togashi, Hidetoshi Hayashi, Kazuhiko Nakagawa, Kazuto Nishio

    DRUG DESIGN DEVELOPMENT AND THERAPY   8   1037 - 1046   2014

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    Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood-brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted.

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  • Population Pharmacokinetics/Pharmacodynamics of Erlotinib and Pharmacogenomic Analysis of Plasma and Cerebrospinal Fluid Drug Concentrations in Japanese Patients with Non-Small Cell Lung Cancer Reviewed

    Masahide Fukudo, Yasuaki Ikemi, Yosuke Togashi, Katsuhiro Masago, Young Hak Kim, Tadashi Mio, Tomohiro Terada, Satoshi Teramukai, Michiaki Mishima, Ken-ichi Inui, Toshiya Katsura

    CLINICAL PHARMACOKINETICS   52 ( 7 )   593 - 609   2013.7

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    Erlotinib shows large inter-patient pharmacokinetic variability, but the impact of early drug exposure and genetic variations on the clinical outcomes of erlotinib remains fully investigated. The primary objective of this study was to clarify the population pharmacokinetics/pharmacodynamics of erlotinib in Japanese patients with non-small cell lung cancer (NSCLC). The secondary objective was to identify genetic determinant(s) for the cerebrospinal fluid (CSF) permeability of erlotinib and its active metabolite OSI-420.
    A total of 88 patients treated with erlotinib (150 mg/day) were enrolled, and CSF samples were available from 23 of these patients with leptomeningeal metastases. Plasma and CSF concentrations of erlotinib and OSI-420 were measured by high-performance liquid chromatography with UV detection. Population pharmacokinetic analysis was performed with the nonlinear mixed-effects modelling program NONMEM. Germline mutations including ABCB1 (1236C &gt; T, 2677G &gt; T/A, 3435C &gt; T), ABCG2 (421C &gt; A), and CYP3A5 (6986A &gt; G) polymorphisms, as well as somatic EGFR activating mutations if available, were examined. Early exposure to erlotinib and its safety/efficacy relationship were evaluated.
    The apparent clearance of erlotinib and OSI-420 were significantly decreased by 24 and 35 % in patients with the ABCG2 421A allele, respectively (p &lt; 0.001), while ABCB1 and CYP3A5 polymorphisms did not affect their apparent clearance. The ABCG2 421A allele was significantly associated with increased CSF penetration for both erlotinib and OSI-420 (p &lt; 0.05). Furthermore, the incidence of grade a parts per thousand yen2 diarrhea was significantly higher in patients harboring this mutant allele (p = 0.035). A multivariate logistic regression model showed that erlotinib trough (C-0) levels on day 8 were an independent risk factor for the development of grade a parts per thousand yen2 diarrhea (p = 0.037) and skin rash (p = 0.031). Interstitial lung disease (ILD)-like events occurred in 3 patients (3.4 %), and the median value of erlotinib C-0 levels adjacent to these events was approximately 3 times higher than that in patients who did not develop ILD (3253 versus 1107 ng/mL; p = 0.014). The objective response rate in the EGFR wild-type group was marginally higher in patients achieving higher erlotinib C-0 levels (a parts per thousand yen1711 ng/mL) than that in patients having lower erlotinib C-0 levels (38 versus 5 %; p = 0.058), whereas no greater response was observed in the higher group (67 %) versus the lower group (77 %) within EGFR mutation-positive patients (p = 0.62).
    ABCG2 can influence the apparent clearance of erlotinib and OSI-420, and their CSF permeabilities in patients with NSCLC. Our preliminary findings indicate that early exposure to erlotinib may be associated with the development of adverse events and that increased erlotinib exposure may be relevant to the antitumor effects in EGFR wild-type patients while having less of an impact on the tumor response in EGFR mutation-positive patients.

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  • Continuous morphine infusion for end-stage lung cancer patients Reviewed

    Young Hak Kim, Chiyuki Okuda, Yuichi Sakamori, Katsuhiro Masago, Yosuke Togashi, Michiaki Mishima

    ONCOLOGY LETTERS   5 ( 3 )   972 - 974   2013.3

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    End-stage cancer patients frequently receive continuous morphine infusion (CMI) to alleviate the various symptoms associated with cancer progression or adverse events; however, there have been a limited number of studies concerning such patients. We conducted a retrospective analysis of 79 end-stage lung cancer patients who received CMI at the Kyoto University Hospital, Kyoto, Japan between 2008 and 2010. Thirty-one patients (39%) received CMI intravenously and 48 (61%) received it subcutaneously. The patients were divided into four groups based on the indications for CMI: group A (uncontrolled pain; n=9), group B (dyspnea; n=44), group C (both dyspnea and pain; n=13) and group D (an inability to take oral medicine; n=13). The median maximum dose of morphine in groups A-D was 60.0, 25.0, 50.0 and 15.0 mg/day, respectively. The median survival time from the start of CMI was 4 days (range 0-136). In our limited experience, pain, dyspnea and the inability to take oral medicine were identified as indications for CMI in end-stage lung cancer patients, with dyspnea being the major indication for CMI. Patients in group B (dyspnea) required a lower dose of morphine for alleviation compared with those in groups A (uncontrolled pain) and C (both dyspnea and pain). The survival time from the initiation of CMI was markedly shorter in patients with dyspnea (groups B and C) than in patients without dyspnea (group A). Further studies are required to facilitate the effective and appropriate use of CMI in end-stage lung cancer patients. Dyspnea was the major indication for CMI in end-stage lung cancer patients, and the survival time was extensively limited in such patients.

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  • Pneumocystis jiroveci pneumonia and colonization in patients with advanced lung cancer. Reviewed International journal

    Yosuke Togashi, Katsuhiro Masago, Yutaka Ito, Yuichi Sakamori, Chiyuki Okuda, Akiko Fukuhara, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

    Oncology letters   5 ( 2 )   601 - 604   2013.2

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    Pneumocystis jiroveci pneumonia (PCP) has long been recognized as a cause of mortality in immuno-compromised populations, including those with advanced lung cancer. Although Pneumocystis colonization has only recently been described due to the development of more sensitive molecular techniques, including polymerase chain reaction (PCR), it is unknown whether Pneumocystis colonization leads to the development of PCP. In the present study, we aimed to determine the prevalence of Pneumocystis colonization in advanced lung cancer patients. Furthermore, the association between PCP and Pneumocystis colonization was also investigated. Advanced lung cancer patients with no indication of PCP were evaluated to determine the prevalence of Pneumocystis colonization. We analyzed their oral wash (OW) samples and retrospectively evaluated advanced lung cancer patients with PCP by analyzing their sections of formalin-fixed, paraffin-embedded lung tissues obtained following a diagnosis of lung cancer. Pneumocystis colonization was determined by a PCR test for Pneumocystis jiroveci (P. jiroveci). No P. jiroveci was detected by PCR in the OW samples of 47 advanced lung cancer patients with no indication of PCP, or in the lung tissues of four advanced lung cancer patients with PCP. These results indicate that PCP is not associated with Pneumocystis colonization in advanced lung cancer patients, although this study is limited since this was a cross-sectional and retrospective study.

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  • Effect of the BCL2 gene polymorphism on survival in advanced-stage non-small cell lung cancer patients who received chemotherapy. Reviewed International journal

    Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Hiroki Nagai, Yuichi Sakamori, Chiyuki Okuda, Young Hak Kim, Michiaki Mishima

    Oncology   84 ( 4 )   214 - 8   2013

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    INTRODUCTION: This study aimed to evaluate the association between BCL2 single-nucleotide polymorphisms and survival outcome in advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and sixty-eight patients with advanced NSCLC who were treated with anti-cancer drugs and could be evaluated for therapeutic response between April 2005 and March 2010 at Kyoto University Hospital were enrolled. DNA was extracted from peripheral blood samples. The BCL2 polymorphisms -938 C→A (rs2279115) and +21 A→G (rs1801018) were genotyped using the 5'-nuclease assay. The univariate relationship between each independent clinicopathologic variable and BCL2 genotype was examined using Fisher's exact test. To evaluate risk factors associated with prognosis, a Cox proportional hazards regression model with a step-down procedure was used. RESULTS: The median survival time of patients with the -938 AA and AC genotypes were significantly shorter than those with the -938 CC genotype (p = 0.027 by log-rank test). Based on multivariate analysis, poor performance status [hazard ratio (HR) 2.424, 95% confidence interval (CI) 1.727-3.262; p < 0.0001], non-adenocarcinoma histology (HR 1.512, 95% CI 1.167-1.938; p = 0.0048) and the BCL2 -938 AA + AC genotype (HR 1.219, 95% CI, 1.024-1.456; p = 0.0256) were significant independent prognostic factors for survival. CONCLUSIONS: Polymorphisms in BCL2 may be associated with survival in advanced-stage NSCLC patients who received chemotherapy.

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  • Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma Reviewed

    Yosuke Togashi, Katsuhiro Masago, Takeshi Kubo, Daichi Fujimoto, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Kaori Togashi, Michiaki Mishima

    MEDICAL ONCOLOGY   29 ( 5 )   3169 - 3175   2012.12

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    Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P &lt; 0.0001), and tumors without vascular-poor area (P &lt; 0.0001). Based on a multivariate analysis, presence of EGFR mutations was independently associated with never-smokers (P = 0.0046), lack of vascular-poor area (P = 0.0001), and tumor size &gt; 30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency.

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  • Clinical significance of serum hepatocyte growth factor and epidermal growth factor gene somatic mutations in patients with non-squamous non-small cell lung cancer receiving gefitinib or erlotinib Reviewed

    Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Yuichi Sakamori, Chiyuki Okuda, Young Hak Kim, Tadashi Mio, Michiaki Mishima

    MEDICAL ONCOLOGY   29 ( 3 )   1614 - 1621   2012.9

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    A study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and serum hepatocyte growth factor (HGF) for their associations with response to gefitinib therapy and prognostic impact. An enzyme-linked immunosorbent assay was used to determine levels of HGF in serum from 96 Japanese patients with advanced non-squamous NSCLC. The peptic nucleic acid-locked nucleic acid clamp method was used to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and risk factors associated with prognosis. HGF-positive serum status (hazard ratio, 1.536; 95% confidence interval, 1.042-2.400; P = 0.0295) had a significant and independent negative effect on progression-free survival among patients with wild-type EGFR. We demonstrate that having HGF-positive serum is predictive of a negative response to gefitinib therapy in patients with advanced NSCLC who harbor wild-type EGFR.

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  • Expressions of Insulin-Like Growth Factor Receptor-1 and Insulin-Like Growth Factor Binding Protein 3 in Advanced Non-Small-Cell Lung Cancer Reviewed

    Young Hak Kim, Shinji Sumiyoshi, Seiji Hashimoto, Katsuhiro Masago, Yosuke Togashi, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

    CLINICAL LUNG CANCER   13 ( 5 )   385 - 390   2012.9

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    The insulin-like growth factor (IGF) pathway plays an important role in tumor progression. We examined immunohistochemical expression of both IGF receptor-1 (IGF-1R) and IGF binding protein 3 in 68 patients with advanced non-small-cell lung cancer and found that IGF-1R expression was significantly more frequent in squamous cell carcinoma (100%) than in adenocarcinoma (44%) (P &lt; .001). IGF-1R antibody may be useful in the pathologic diagnosis in non-small-cell lung cancer.
    Background: The insulin-like growth factor (IGF) pathway plays an important role in cell proliferation, differentiation, and apoptosis, and IGF induces those effects mainly through IGF receptor-1 (IGF-1R). The activities of IGF are strictly regulated by a family of IGF binding proteins (IGFBP), especially IGFBP3, a major serum carrier protein for IGF. Patients and Methods: Between January 2006 and February 2009, in our hospital, 191 patients were histologically diagnosed as having non-small-cell lung cancer (NSCLC), and 74 patients were treated by chemotherapy alone. We examined immunohistochemical expression of both IGF-1R and IGFBP3 in 68 patients who were definitively diagnosed as having adenocarcinoma or squamous cell carcinoma among the 74 patients. Results: The clinical characteristics of the included patients were as follows: median age was 68 years (range, 29-86 years); men vs. women, 40 vs. 28; stage III vs. IV, 18 vs. 50; performance status 0-1 vs. 2-4, 58 vs. 10; smoker vs. non-smoker, 44 vs. 24; and squamous cell carcinoma vs. adenocarcinoma, 13 vs. 55. Expression of IGF-1R and IGFBP3 was observed in 37 (54%) and 11 patients (16%), respectively. IGF-1R expression was detected more frequently in patients with squamous cell carcinoma (100%) than in patients with adenocarcinoma (44%) (P &lt; .001), although IGFBP3 expression was not significantly associated with any clinical variables. Among all factors, including IGF-1R and IGFBP3 expression, IGF-1R was significantly associated with response to chemotherapy (P = .028) and performance status was significantly associated with overall survival (P &lt; .001). Conclusions: High sensitivity of IGF-1R to squamous cell carcinoma (100%) in this study and another study encourages the use of IGF-1R antibody in the pathologic diagnosis between squamous cell and non-squamous cell carcinoma when using small biopsy specimens.

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  • Coronary Air Embolism and Cardiogenic Shock During Computed Tomography-Guided Needle Biopsy of the Lung Reviewed

    Tetsuma Kawaji, Hiroki Shiomi, Yosuke Togashi, Daigo Gunji, Masao Imai, Takahiro Doi, Takeshi Kimura

    CIRCULATION   126 ( 13 )   E195 - E197   2012.9

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  • Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer Reviewed

    Yosuke Togashi, Katsuhiro Masago, Satohiro Masuda, Tomoyuki Mizuno, Masahide Fukudo, Yasuaki Ikemi, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Toshiya Katsura, Michiaki Mishima

    CANCER CHEMOTHERAPY AND PHARMACOLOGY   70 ( 3 )   399 - 405   2012.9

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    Several cases have been reported in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) resistant to gefitinib were improved by erlotinib. However, there has been no study in which cerebrospinal fluid (CSF) concentrations of gefitinib and erlotinib are directly compared. Thus, we aimed to compare them.
    We examined 15 Japanese patients with NSCLC and CNS metastases with epidermal growth factor receptor gene mutations who received CSF examinations during epidermal growth factor receptor-tyrosine kinase inhibitors treatment (250 mg daily gefitinib or 150 mg daily erlotinib). Plasma and CSF concentrations were determined using high-performance liquid chromatography with tandem mass spectrometry.
    The concentration and penetration rate of gefitinib (mean +/- A standard deviation) in the CSF were 3.7 +/- A 1.9 ng/mL (8.2 +/- A 4.3 nM) and 1.13 +/- A 0.36 %, respectively. The concentration and penetration rate of erlotinib in the CSF were 28.7 +/- A 16.8 ng/mL (66.9 +/- A 39.0 nM) and 2.77 +/- A 0.45 %, respectively. The CSF concentration and penetration rate of erlotinib were significantly higher than those of gefitinib (P = 0.0008 and &lt; 0.0001, respectively). The CNS response rates of patients with erlotinib treatment were preferentially (but not significantly) higher than those with gefitinib treatment. (1/3 vs. 4/7, respectively). Leptomeningeal metastases in one patient, which were refractory to gefitinib, dramatically responded to erlotinib.
    This study suggested that higher CSF concentration could be achieved with erlotinib and that erlotinib could be more effective for the treatment for CNS metastases, especially leptomeningeal metastases, than gefitinib.

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  • Phase II study of carboplatin and pemetrexed in advanced non-squamous, non-small-cell lung cancer: Kyoto Thoracic Oncology Research Group Trial 0902 Reviewed

    Young Hak Kim, Masataka Hirabayashi, Yosuke Togashi, Katsuya Hirano, Keisuke Tomii, Katsuhiro Masago, Toshihiko Kaneda, Harukazu Yoshimatsu, Koujirou Otsuka, Tadashi Mio, Hiromi Tomioka, Yujiro Suzuki, Michiaki Mishima

    CANCER CHEMOTHERAPY AND PHARMACOLOGY   70 ( 2 )   271 - 276   2012.8

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    Subgroup analyses of randomized studies have consistently shown that pemetrexed is exclusively effective in non-small-cell lung cancer (NSCLC) other than squamous cell carcinoma and the combination of pemetrexed and platinum agents is recommended for first-line chemotherapy in advanced non-squamous NSCLC; however, there have been few prospective studies of a selected population.
    This was a single-arm phase II study of carboplatin and pemetrexed in Japanese patients with chemo-naive advanced non-squamous NSCLC. Patients received six cycles of pemetrexed (500 mg/m(2)) combined with carboplatin (area under the curve: AUC 6) every 3 weeks. Maintenance chemotherapy with pemetrexed was permitted in patients whose disease did not progress after combination chemotherapy. The primary endpoint was the response rate, and secondary endpoints were safety and survival.
    Fifty-one patients were enrolled between November 2009 and March 2011, and 49 patients were evaluable for both safety and efficacy. All but one patient had adenocarcinoma histology. Forty-four (90 %) patients completed four cycles, and 33 (67 %) completed six cycles of chemotherapy. Partial response was achieved in 25 patients (response rate: 51 %) and stable disease in 18 patients (37 %). Median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 24.3 months, respectively. The median PFS and OS were 7.9 months and 24.3 months in patients with epidermal growth factor receptor (EGFR) mutation, and 6.3 months and 21.0 months in patients with EGFR wild type or unknown. There were no statistical differences between EGFR mutants and non-mutants for both PFS (p = 0.09) and OS (p = 0.23). Grade 3/4 neutropenia and thrombocytopenia were observed in 16 (33 %) and 9 (18 %) patients, respectively. Non-hematologic toxicities were generally mild, and there were no treatment-related deaths.
    The combination of carboplatin and pemetrexed was safe and effective in advanced non-squamous NSCLC. Although the sample size was small, our results indicate that pemetrexed is a key drug for advanced non-squamous NSCLC, irrespective of the EGFR mutation status (UMIN-CTR number 000002451).

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  • Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: A case report and review of the literature Reviewed

    Yosuke Togashi, Katsuhiro Masago, Yasuhiro Hamatani, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

    LUNG CANCER   77 ( 2 )   464 - 468   2012.8

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    The most serious adverse reaction associated with treatment with epidermal growth factor receptortyrosine kinase inhibitors (EGFR-TKIs) is drug-induced interstitial lung disease (ILD). Because EGFR-TKIs are key drugs for patients with non-small cell lung cancer who have somatic activating mutations of the epidermal growth factor receptor gene (EGFR mutations), several cases of retreatment with EGFR-TKIs after ILD induced by these drugs have been reported. Here, we present a 68-year-old man with lung adenocarcinoma and leptomeningeal metastases having an EGFR mutation who was retreated with erlotinib after erlotinib-induced ILD. He suffered no ILD recurrence and his leptomeningeal metastases dramatically improved. In addition to the present case, reports of nine patients who were retreated with EGFR-TKIs after ILD were found in the literature. Only one patient had recurrence of ILD (although seven were retreated at a reduced dose of EGFR-TKIs, including the patient with recurrence). In contrast, three patients had no recurrence of ILD even without dose-reduction. These reports suggest that dose-reduction plays a limited role in preventing recurrence. Many patients received corticosteroids during retreatment, but not the one with recurrence of ILD. This may suggest that corticosteroids can prevent recurrence due to their antiinflammatory properties. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

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  • Prognostic Significance of Preexisting Interstitial Lung Disease in Japanese Patients With Small-Cell Lung Cancer Reviewed

    Yosuke Togashi, Katsuhiro Masago, Tomohiro Handa, Kiminobu Tanizawa, Chiyuki Okuda, Yuichi Sakamori, Hiroki Nagai, Young Hak Kim, Michiaki Mishima

    CLINICAL LUNG CANCER   13 ( 4 )   304 - 311   2012.7

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    We retrospectively investigated patients with small-cell lung cancer with or without interstitial lung disease (ILD). Response rates and median progression-free survival of first-line chemotherapy in patients with or without preexisting ILD was not significantly different. However, pneumonitis associated with chemotherapy was significantly increased in patients with preexisting ILD, and preexisting ILD is an independent prognostic factor for poorer survival.
    Background: In Japan, iatrogenic acute exacerbation of interstitial lung disease (ILD) is a serious complication in patients with lung cancer and simultaneous ILD. Results of some reports suggest that patients with ILD and small-cell lung cancer (SCLC) might benefit from chemotherapy, but the influence of ILD on prognosis is unclear. Patients and Methods: Retrospective study of patients with SCLC with or without ILD. Between April 2006 and March 2011, 122 patients with SCLC who were receiving platinum-based combination chemotherapy participated. Results: Twenty-eight patients (23.0%) had ILD at diagnosis. Pneumonitis associated with chemotherapy, including acute exacerbation-ILD was significantly increased in patients with preexisting ILD (8/28 vs. 2/94; P = .0001). In patients receiving chemotherapy alone, response rates and median progression-free survival of first-line chemotherapy in patients with or without preexisting ILD was not significantly different (P = .26; 20/26 vs. 52/60 and P = .089; 4.4 months vs. 5.4 months, respectively). The median overall survival of all patients was 15.5 months, but those without preexisting ILD survived significantly longer (P = .0010; 17.8 months vs. 10.7 months). Multivariate analysis revealed that performance status of 0 or 1 (hazard ratio [HR] 0.19 [95% confidence interval {CI}, 0.10-0.37]; P &lt; .0001) limited disease (HR 0.42 [95% CI, 0.23-0.73]; P = .0017), and no preexisting ILD (HR 0.36 [95% CI, 0.19-0.69]; P = .0027) were significantly associated with longer overall survival. Conclusion: Patients with SCLC and ILD might benefit from chemotherapy, but preexisting ILD is an independent prognostic factor for poorer survival.

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  • Nitric oxide (NO) enhances pemetrexed cytotoxicity via NO-cGMP signaling in lung adenocarcinoma cells in vitro and in vivo Reviewed

    Hiroki Nagai, Hiroyasu Yasuda, Yukimasa Hatachi, Deng Xue, Takahiko Sasaki, Mutsuo Yamaya, Yuichi Sakamori, Yousuke Togashi, Katsuhiro Masago, Isao Ito, Young Hak Kim, Tadashi Mio, Michiaki Mishima

    INTERNATIONAL JOURNAL OF ONCOLOGY   41 ( 1 )   24 - 30   2012.7

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    Pemetrexed (PEM) is a novel, multitargeted, antifolate, antineoplastic agent for the treatment of non-small cell lung cancer and malignant pleural mesothelioma. Additional effects of nitric oxide (NO) donors on the chemosensitivity of cancers have been reported. However, the effects of an NO donor on PEM-induced cytotoxicity remain unknown. In this study, we investigated the effects of the NO donors, NOC-18 on the cytotoxicity in A549 cells in vitro and of nitroglycerin (GTN), on the tumor growth of Lewis lung carcinoma cells in a murine syngraft model treated with PEM. The effects of NO donors on the expression of proteins associated with PEM metabolism, including thymidylate synthase (TS), reduced folate carrier 1 (RFC1), folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH) and multidrug resistance-related protein (MRP)5, and the effects of cyclic guanosine monophosphate (cGMP) signaling on these proteins were examined in A549 cells. Treatment with 100 nM NOC-18 for 3 days significantly enhanced PEM-induced cytotoxicity and increased the expression of RFC1 and FPGS in A549 cells. Treatment with 10 nM 8-bromo-cGMP (8-Br-cGMP) for 3 days also increased the expression of RFC1 and FPGS in A549 cells. 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 mu m) significantly reversed the increase in RFC1 and FPGS expression induced by 100 nM NOC-18 in A549 cells. Combination therapy with GTN and PEM significantly reduced tumor growth compared with PEM alone in the syngraft model. The enhanced antitumor effect of GTN plus PEM was significantly reversed by the concomitant addition of ODQ. These findings suggest that NO donors, such as NOC-18 and GTN, enhance the anticancer effects of PEM by increasing the RFC1 and FPGS expression and stimulating cGMP signaling pathways in cancer cells.

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  • Increase in circulating endothelial progenitor cells predicts response in patients with advanced non-small-cell lung cancer Reviewed

    Yuichi Sakamori, Katsuhiro Masago, Katsuyuki Ohmori, Yosuke Togashi, Hiroki Nagai, Chiyuki Okuda, Young Hak Kim, Satoshi Ichiyama, Michiaki Mishima

    CANCER SCIENCE   103 ( 6 )   1065 - 1070   2012.6

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    Previous reports have shown that circulating endothelial progenitor cells (CEPs) are released in response to cytotoxic chemotherapy. We investigate the relationship between the kinetics of CEPs during one cycle of chemotherapy and the response to cytotoxic chemotherapy and prognostic impacts. Previously untreated patients (n = 38) receiving cytotoxic chemotherapy for non-small-cell lung cancer were included. Blood sampling was carried out on day 1, day 8, and just before the second cycle of chemotherapy. The mononuclear cell fraction was analyzed for CEPs by FACS analysis. We evaluated the relationship between the kinetics of CEPs, each independent clinicopathological variable, the response to chemotherapy, and the risk factors associated with prognosis. On the eighth day after chemotherapy, a significant decrease in CEPs was observed. In contrast, CEP counts before the second cycle of chemotherapy were significantly increased. The high percentage change in CEPs between day 1 and before the second cycle of chemotherapy is an independent predictive factor for response to chemotherapy. However, the change in CEP levels did not predict progression-free survival. These findings indicate that the late release of CEPs is a common phenomenon after chemotherapeutic treatment. The correlation with clinical response to chemotherapy provides further support for the biologic relevance of these cells in patients' prognosis and highlights the potential use of CEPs as therapeutic targets. (Cancer Sci 2012; 103: 10651070)

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  • Significance of pretreatment comorbidities in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitor Reviewed

    Kaoru Irisa, Katsuhiro Masago, Yosuke Togashi, Shiro Fujita, Yukimasa Hatachi, Akiko Fukuhara, Yuichi Sakamori, Yung Hak Kim, Tadashi Mio, Michiaki Mishima

    MEDICAL ONCOLOGY   29 ( 1 )   185 - 192   2012.3

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    A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome.

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  • Clinical significance of epidermal growth factor receptor mutations and insulin-like growth factor 1 and its binding protein 3 in advanced non-squamous non-small cell lung cancer Reviewed

    Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Kaoru Irisa, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

    ONCOLOGY REPORTS   26 ( 4 )   795 - 803   2011.10

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    This study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and two serum markers, serum insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3), for their associations to response to gefitinib therapy and for their prognostic impact. An immunoradiometric assay determined levels of IGF1 and IGFBP3 in serum from 68 patients with advanced non-squamous NSCLC. The peptic nucleic acid locked nucleic acid clamp method determined their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. Having IGF1-positive serum as determined by the 75th percentile and having wild-type EGFR were both independent negative predictive factors for geftinib treatment by multivariate logistic regression model analysis. Both having serum positive for IGF1 as determined by the 25th percentile and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. We demonstrated that having IGF1-positive serum predicts a negative response to gefitinib therapy independent of EGFR mutational status. We also demonstrated that both IGF1-positive serum and wild-type EGFR were independent poor prognostic factors in patients with non-squamous NSCLC who received gefitinib therapy.

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  • Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer Reviewed

    Yosuke Togashi, Katsuhiro Masago, Shiro Fujita, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Michiaki Mishima

    LUNG CANCER   74 ( 1 )   98 - 102   2011.10

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    Purpose: The maximum tolerated dose (MTD) of erlotinib (150 mg) is the approved daily dose. In contrast, the approved daily dose of gefitinib (250 mg) is only one-third of its MID. Significantly different adverse events have been associated with gefitinib and erlotinib.
    Experimental design: A retrospective investigation examining the adverse events and tolerances of 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer (NSCLC) was performed. Adverse events were assessed according to Common Terminology Criteria for Adverse Events version 3.0. To determine tolerance for each agent, failure was defined as dose reduction or discontinuation of the drug due to adverse events, and early failure as dose reduction or discontinuation due to adverse events before the first evaluation of response.
    Results: More adverse events including skin disorders, diarrhea, oral mucositis, asthenic conditions, anorexia, nausea, vomiting, and gastrointestinal bleeding were observed in the erlotinib group. Liver function test abnormalities and pneumonitis did not differ between the two groups. Based on multivariate analysis, failure, early failure, and discontinuation due to adverse events were independently associated with erlotinib use.
    Conclusion: Our data show that 150 mg daily erlotinib was associated with more toxicity and less tolerability than 250 mg daily gefitinib. (C) 2011 Published by Elsevier Ireland Ltd.

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  • Efficacy of increased-dose erlotinib for central nervous system metastases in non-small cell lung cancer patients with epidermal growth factor receptor mutation Reviewed

    Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Yasuhiro Tsuchido, Chiyuki Okuda, Young Hak Kim, Yasuaki Ikemi, Yuichi Sakamori, Tadashi Mio, Toshiya Katsura, Michiaki Mishima

    CANCER CHEMOTHERAPY AND PHARMACOLOGY   68 ( 4 )   1089 - 1092   2011.10

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    Purpose Recent reports indicate that refractory central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) are improved by high-dose gefitinib or erlotinib administration. Wedescribe a Japanese woman with NSCLC and CNS metastases who was resistant to 75 mg daily erlotinib, but the metastases were improved by 150 mg daily erlotinib. We investigated the plasma and CSF concentrations of erlotinib at each dose as well as the correlation between the plasma and CSF concentrations of erlotinib.
    Methods Including this patient, we administered 150 mg erlotinib daily to nine NSCLC patients with CNS metastases and measured the plasma and CSF concentrations just before administration on day 8. The concentrations were determined using high-performance liquid chromatography with ultraviolet detection.
    Results The plasma and CSF concentrations of erlotinib at a dose of 75 mg were 433 and 14 nM, respectively. The plasma and CSF concentrations of erlotinib at a dose of 150 mg were increased to 1,117 and 44 nM, respectively. The mean +/- standard deviation of CSF concentrations and penetration rates were 106 +/- 59 nM and 4.5 +/- 1.5%, respectively. There was a good correlation (R(2) = 0.84) between plasma and CSF concentrations (P = 0.0005).
    Conclusions This study indicates that CSF concentrations of erlotinib depend on its plasma concentration. As seen in this patient, high CSF concentrations of erlotinib can be achieved by high-dose administration, and this finding suggests the efficacy of high-dose administration, especially to refractory CNS metastases of NSCLC patients.

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  • Plasma and Pleural Fluid Pharmacokinetics of Erlotinib and its Active Metabolite OSI-420 in Patients With Non-Small-Cell Lung Cancer With Pleural Effusion Reviewed

    Katsuhiro Masago, Yosuke Togashi, Masahide Fukudo, Tomohiro Terada, Kaoru Irisa, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

    CLINICAL LUNG CANCER   12 ( 5 )   307 - 312   2011.9

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    Background: Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). Patients and Methods: We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. Results: The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. Conclusions: There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects.

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  • Pulmonary embolism due to internal jugular vein thrombosis in a patient with non-small cell lung cancer receiving bevacizumab Reviewed

    Yosuke Togashi, Young Hak Kim, Katsuhiro Masago, Koji Tamai, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

    INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY   16 ( 4 )   444 - 446   2011.8

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    Internal jugular vein thrombosis is much less common than deep venous thrombosis of lower limbs and is generally caused by an indwelling venous catheter or otological infection. Several cases of internal jugular vein thrombosis associated with malignancy have been also reported. Bevacizumab, a monoclonal neutralizing antibody against vascular endothelial growth factor, has shown benefits in the treatment of many types of malignancy and its use is increasing. Serious adverse effects, however, are associated with the use of bevacizumab, including venous thromboembolism. In this article, we present a rare case of non-small cell lung cancer complicated by pulmonary embolism due to internal jugular vein thrombosis associated with bevacizumab.

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  • Good Clinical Response to Erlotinib in a Patient With Anaplastic Thyroid Carcinoma Harboring an Epidermal Growth Factor Somatic Mutation, L858R, in Exon 21 Reviewed

    Katsuhiro Masago, Masako Miura, Yoshiro Toyama, Yosuke Togashi, Michiaki Mishima

    JOURNAL OF CLINICAL ONCOLOGY   29 ( 16 )   E465 - E467   2011.6

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  • Two Cases of Cancer-associated Retinopathy Combined with Small-cell Lung Cancer Reviewed

    Yuichi Sakamori, Young Hak Kim, Chiyuki Okuda, Yosuke Togashi, Daisuke Kinose, Katsuhiro Masago, Tadashi Mio, Akihito Uji, Michiaki Mishima

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   41 ( 5 )   669 - 673   2011.5

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    Cancer-associated retinopathy is a rare paraneoplastic syndrome that is often associated with small-cell lung cancer. It is caused by an autoantibody to the 23 kDa photoreceptor protein, recoverin. A small number of reports have described effective treatment for the disease. We report two cases of cancer-associated retinopathy with small-cell lung cancer whose visual symptom preceded the diagnosis of cancer. Their visual acuity and visual field were slightly improved after steroid and anticancer therapy. Steroid therapy was effective, although the period from visual symptom onset to therapy was comparative longer. When cancer-associated retinopathy is suspected, a comparatively large quantity of steroids and anticancer treatment should be combined immediately.

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  • Long-term Survival in a Patient with Small-cell Lung Cancer Undergoing Hemodialysis Who Received Multiple Courses of Chemotherapy Reviewed

    Yosuke Togashi, Young Hak Kim, Katsuhiro Masago, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

    JAPANESE JOURNAL OF CLINICAL ONCOLOGY   41 ( 4 )   582 - 585   2011.4

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    The prognosis of small-cell lung cancer remains poor and it is speculated that small-cell lung cancer patients with end-stage renal failure undergoing hemodialysis have a poorer prognosis. In this article, we present a Japanese woman with extensive small-cell lung cancer with end-stage renal failure undergoing hemodialysis who received multiple courses of chemotherapy. Although she achieved long-term survival of more than 2 years, the last-line chemotherapy, consisting of irinotecan, induced grade 4 febrile neutropenia and her performance status deteriorated even with a reduced dose according to the analysis of UDP-glucuronosyltransferase 1A1. We also conducted a pharmacokinetic analysis of irinotecan, the resulting values of which were much higher than in previous reports. Although further studies are needed, chemotherapy for small-cell lung cancer patients should not be withheld just because they are undergoing hemodialysis; however, chemotherapy should be performed more carefully because more severe toxicities can occur than expected.

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  • EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy Reviewed

    Young Hak Kim, Katsuhiro Masago, Yosuke Togashi, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

    ONCOLOGY LETTERS   2 ( 2 )   383 - 387   2011.3

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    Somatic mutations of epidermal growth factor receptor (EGFR) are the strongest predictive markers for the response to EGFR-tyrosine kinase inhibitors (TKIs). Patients with EGFR mutations generally receive EGFR-TKI treatment, and their survival has been significantly improved compared with that before the development of EGFR-TKIs. This study aimed to clarify the impact of EGFR mutational status on the survival of patients with non-small cell lung cancer (NSCLC) receiving cytotoxic agents, but not EGFR-TKIs, as their first-line chemotherapy. In addition, we analyzed patients with EGFR mutations to determine whether the timing of EGFR-TKI administration affects overall survival (OS). A total of 83 NSCLC patients with stage IIIB/IV who received chemotherapy alone and whose EGFR mutational status was known were investigated. Univariate and multivariate analysis for OS was performed using parameters such as age, gender, performance status (PS), histology, disease stage, smoking status, EGFR mutational status and administration of a first-line regimen. Among the 52 patients with EGFR mutations who received EGFR-TKIs, OS between those who received EGFR-TKIs as their first-line treatment and after chemotherapy were similar. Among the 83 patients who received cytotoxic agents as their first-line chemotherapy, the multivariate analysis showed OS to be significantly associated with PS (p &lt; 0.001), histology (p=0.039) and EGFR mutational status (p=0.040). OS was almost similar among the 52 patients with EGFR mutations who received EGFR-TKIs in a first- and second-line setting (25.6 vs. 26.8 months, p=0.914). The EGFR mutational status had a significant impact on the survival of NSCLC patients, although these patients did not receive EGFR-TKIs as their first-line chemotherapy. In future randomized trials, even when EGFR-TKIs are not included in experimental regimens, patients may need to be stratified by EGFR mutational status in order that study results be evaluated appropriately.

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  • Association between brain natriuretic peptide and distant metastases in advanced non-small cell lung cancer patients Reviewed

    Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Kaoru Irisa, Yuichi Sakamori, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Young Hak Kim, Tadashi Mio, Michiaki Mishima

    ONCOLOGY LETTERS   2 ( 2 )   253 - 256   2011.3

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    This study aimed to investigate the relationship between clinicopathological factors and plasma brain natriuretic peptide (BNP) levels in non-small cell lung cancer (NSCLC) patients. A total of 133 patients with advanced NSCLC were included in this study. The level of BNP was determined at the time of diagnosis. The BNP plasma concentration was measured using a chemiluminescent enzyme immunoassay kit. The univariate relationship between each independent clinicopathological variable and plasma BNP was examined using the Chi-square test. The survival curves were determined using the Kaplan-Meier method. According to the cut-off value of plasma BNP levels (11.5 and 22.4 pg/ml), plasma BNP negatively correlated with the presence of metastases (Chi-square test, p=0.0374 and p=0.0098, respectively). However, no significant association between patient survival time and plasma BNP levels was found. Reduced plasma BNP levels in advanced NSCLC patients with metastases were noted and the possibility was raised that BNP decreases distant metastases of advanced NSCLC patients.

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  • Successful Treatment with Pemetrexed in a Patient with Mucinous Bronchioloalveolar Carcinoma Long-Term Response Duration with Mild Toxicity Reviewed

    Chiyuki Okuda, Young Hak Kim, Kengo Takeuchi, Yosuke Togashi, Katsuhiro Masago, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

    JOURNAL OF THORACIC ONCOLOGY   6 ( 3 )   641 - 642   2011.3

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  • Clinical significance of the ratio between the alpha 2 plasmin inhibitor-plasmin complex and the thrombin-antithrombin complex in advanced non-small cell lung cancer Reviewed

    Katsuhiro Masago, Shiro Fujita, Tadashi Mio, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Kaoru Irisa, Yuichi Sakamori, Michiaki Mishima

    MEDICAL ONCOLOGY   28 ( 1 )   351 - 356   2011.3

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    The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin-antithrombin complex (TAT), and plasmin-alpha 2-plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future.

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  • Phase I study of the combination of nedaplatin and gemcitabine in previously untreated advanced squamous cell lung cancer Reviewed

    Katsuhiro Masago, Shiro Fujita, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Kaoru Irisa, Hiroki Nagai, Yuichi Sakamori, Yosuke Togashi, Tadashi Mio, Michiaki Mishima

    CANCER CHEMOTHERAPY AND PHARMACOLOGY   67 ( 2 )   325 - 330   2011.2

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    The objectives of this phase I trial were to evaluate the toxicity of the nedaplatin/gemcitabine regimen, determine the maximum tolerated doses (MTDs) of these agents, and observe the anti-tumor effects of this regimen on advanced squamous cell lung cancer.
    Patients with previously untreated advanced squamous cell lung cancer were eligible if they had a performance status of 0 or 1 with adequate organ function. The doses of gemcitabine (days 1 and 8) and nedaplatin (day 8) studied were 800/70, 1,000/80, 1,000/90, and 1,000/100 (mg/m(2)), repeated every 3 weeks.
    Toxicity and response could be assessed in all 13 patients enrolled. The patients included 12 men and one woman with a median age of 69 years (range 57-81 years). Three patients had stage IIIB disease and 10 patients had stage IV disease. The MTDs were reached at 1,000 mg/m(2) gemcitabine and 80 mg/m(2) nedaplatin. The most frequent toxic effects were thrombocytopenia and neutropenia; grade 3 or 4 thrombocytopenia was observed in 23% of patients, and grade 3 or 4 neutropenia was seen in 46% of patients. Non-hematologic toxicities were mild. Grade 3 fatigue, nausea/vomiting, and appetite loss occurred in two patients. The overall response rate was 62%.
    We recommend doses of 800 mg/m(2) gemcitabine and 70 mg/m(2) nedaplatin for phase II study. This combination chemotherapeutic regimen is active and well tolerated.

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  • Association of the transforming growth factor beta 1 promoter polymorphism, C-509T, with smoking status and survival in advanced non-small cell lung cancer Reviewed

    Yosuke Togashi, Katsuhiro Masago, Shiro Fujita, Young Hak Kim, Yuichi Sakamori, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Tadashi Mio, Michiaki Mishima

    ONCOLOGY REPORTS   25 ( 2 )   377 - 382   2011.2

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    Transforming growth factor beta (TGF-beta) signaling can inhibit tumor growth in developing tumors. However, it promotes tumor invasiveness and metastasis in late-stage tumors. A number of TGF-beta gene polymorphisms have been identified that can affect the survival of patients with advanced non-small cell lung cancer (NSCLC). In this study, we investigated the association of the TGF-beta 1 polymorphism, C-509T, with survival in patients with advanced NSCLC. Japanese patients who were treated for unresectable advanced NSCLC between April 2003 and March 2008 at Kyoto University Hospital, were enrolled in this study. Analyses of genotype associations with survival outcomes were performed using statistical tests. The median survival of patients with the TT genotype was shorter, although not significantly, than that of patients with either the CT or CC genotype. Based on both univariable and multivariable analyses, the TGF-B1 polymorphism, C-509T, was not associated with prognosis. In patients with a smoking status of &lt;40 pack-years, the median survival was significantly shorter with the TT genotype than with the CT or CC genotype. Based on univariable analysis, stage IV cancer and the TT genotype had a significant prognostic effect on survival. Based on multivariable analysis, the TT genotype was a significantly independent prognostic factor for survival. There was no association between the TGF-beta 1 polymorphism, C-509T, and survival in patients with advanced NSCLC. In patients with a smoking status of &lt;40 pack-years, however, the TGF-beta 1 polymorphism, C-509T, was significantly associated with the prognosis of advanced NSCLC, and the TT genotype was an independent prognostic factor for poor survival.

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  • Association of Diffuse, Random Pulmonary Metastases, Including Miliary Metastases, With Epidermal Growth Factor Receptor Mutations in Lung Adenocarcinoma Reviewed

    Yosuke Togashi, Katsuhiro Masago, Takeshi Kubo, Yuichi Sakamori, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Tadashi Mio, Kaori Togashi, Michiaki Mishima

    CANCER   117 ( 4 )   819 - 825   2011.2

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    BACKGROUND: Although the association of multiple pulmonary metastases, and particularly miliary metastases, with response to gefitinib treatment in patients with nonsmall cell lung cancer has been reported, the association of miliary pulmonary metastases with epidermal growth factor receptor gene (EGFR) mutations remains unclear. METHODS: The authors retrospectively investigated the association of diffuse, random pulmonary metastases in patients with lung adenocarcinoma. The study included 163 Japanese patients who had unresectable, advanced lung adenocarcinoma diagnosed between April 2003 and March 2010. Computed tomography scans that were obtained at the time of diagnosis were analyzed by 2 investigators. For the purposes of this study, diffuse, random pulmonary metastases were defined as multiple nodules (n = 50; &lt;= 3 cm in greatest dimension) distributed diffusely and randomly throughout the lungs. RESULTS: Of 163 patients, 55 had pulmonary metastases, and EGFR mutations were detected in 22 of those 55 patients. The mutations were identified preferentially among women (P = .15) and were identified significantly among patients who had a smoking history of &lt;10 pack-years (P = .0057). Diffuse, random pulmonary metastases were identified in 11 of 22 patients who had EGFR mutations and in 4 of 33 patients who had the wildtype EGFR (P = .0043). On the basis of multivariate analyses, EGFR mutations were associated independently with a smoking history of &lt;10 pack-years (P = .026) and with diffuse, random pulmonary metastases (P = .012). CONCLUSIONS: When patients with lung adenocarcinomas who had EGFR mutations developed pulmonary metastases, they tended to be diffuse and random, including military metastases. However, such metastases were much less common in patients who had lung adenocarcinomas with wild-type EGFR. Cancer 2011;117:819-25. (C) 2070 American Cancer Society

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  • Clinicopathologic Factors Affecting the Progression-Free Survival of Patients With Advanced Non-Small-Cell Lung Cancer After Gefitinib Therapy Reviewed

    Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Yuichi Sakamori, Tadashi Mio, Michiaki Mishima

    CLINICAL LUNG CANCER   12 ( 1 )   56 - 61   2011.1

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    Background: The aim of this study was to analyze the factors independent of epidermal growth factor (EGFR) gene mutations that affect the progression-free survival (PFS) of patients with advanced non-small-cell lung cancer (NSCLC) after gefitinib therapy. Patients and Methods: Eighty patients with advanced NSCLC between January 2003 and April 2010 at Kyoto University Hospital were analyzed for EGFR somatic mutations and treated with gefitinib. We adopted the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method for determination of EGFR mutation status. To evaluate risk factors associated with PFS, Cox proportional hazards regression model with a step-down procedure was used. Proportional hazards assumptions were checked and satisfied; only those variables with statistically significant results in univariate analysis were included in a multivariate analysis. Results: The median PFS of patients with EGFR mutations were significantly longer than in patients with wild-type EGFR. The median PFS of patients after first-line gefitinib therapy was significantly longer than those who received treatment as a second-line therapy. The median PFS of patients over 75 years of age was significantly longer than in younger patients. Based on multivariate analysis, wild-type EGFR status and age &lt; 75 years were significant and independent negative factors that affect PFS after gefitinib therapy. Conclusion: In this study, we showed the EGFR mutants and age &gt; 75 years were good predictive factors for PFS after gefitinib therapy, suggesting that first-line gefitinib treatment for older patients is efficacious regardless of EGFR mutational status.

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  • Octreotide, a Somatostatin Analogue, in the Treatment of Chylothorax Associated with Idiopathic Fibrosing Mediastinitis Reviewed

    Yosuke Togashi, Young Hak Kim, Ryo Miyahara, Kaoru Irisa, Yuichi Sakamori, Katsuhiro Masago, Tadashi Mio, Hiroshi Date, Michiaki Mishima

    TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE   222 ( 1 )   51 - 53   2010.9

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    Fibrosing mediastinitis (FM) is a rare benign disorder that is characterized by excessive fibrotic reactions in the mediastinum. FM is associated with various diseases, including Histoplasma capsulatum infection and IgG4-related disease, and may compromise the airways, great vessels, and other mediastinal structures. Chylothorax is not a common manifestation of FM, and there is no standard treatment for FM or chylothorax. Recently, however, somatostatin and octreotide, a somatostatin analogue, were successfully used for the treatment of chylothorax due to various causes, and they are considered as putative therapeutic interventions for chylothorax. Here, we present a 28-year-old Japanese man with chylothorax due to idiopathic FM, who was successfully treated with octreotide. The patient visited our hospital because of dyspnea on exertion. On admission, chest computed tomography revealed pericardial effusion, bilateral pleural effusion, and a mass in the mediastinum. The right pleural effusion appeared chylous, with the triglyceride level of 253 mg/dl. The biopsy specimen from the mediastinal mass showed collagenous fibers and fibroblasts with moderate infiltration of lymphocytes. Neither fungi nor bacteria were cultured from the biopsy specimen. Steroid therapy was not effective. The patient was then treated with subcutaneous octreotide (100 mu g three times daily). Five days after starting the treatment, the drained pleural fluid was decreased to similar to 150 ml/day from similar to 1,000 ml/day. The mediastinal mass decreased in size 2 weeks after the initiation of octreotide treatment. After discharge, the patient has received octreotide treatment for 6 months without serious adverse events. We suggest octreotide as a treatment option for FM.

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  • Infectious background of febrile advanced lung cancer patients who received chemotherapy Reviewed

    Katsuhiro Masago, Akiko Fukuhara, Yutaka Ito, Yukimasa Hatachi, Kaoru Irisa, Yuichi Sakamori, Yosuke Togashi, Shiro Fujita, Young Hak Kim, Tadashi Mio, Michiaki Mishima

    ONCOLOGY LETTERS   1 ( 5 )   849 - 853   2010.9

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    The study aimed to determine the diagnostic utility of procalcitonin (PCT) in order to discriminate between infective fever and fever due to inflammation in febrile advanced lung cancer patients treated with cytotoxic chemotherapy. A total of 121 patients with advanced lung cancer, treated with a cytotoxic chemotherapy regimen between September 2007 and September 2008 at Kyoto University Hospital, were recruited. Blood samples were obtained on the first day of the fever. Serum c-reactive protein (CRP) and PCT levels were measured. At least two blood cultures were performed, and sputum was taken for Gram staining and culture. There were 71 episodes in 61 patients in the 12 months of the study, representing 50.4% of our study population. A total of 41 patients (57.7%) were diagnosed with, pneumonia using imaging modalities, 6 (8.5%) with bacteremia using blood culture and 4 (5.6%) with urinary tract infections using urine culture. Among the 41 pneumonia cases, culture from sputum revealed pathologic bacteria in 21 (51.2%) and fungal disease in 14 (34.1%) cases. Among the 71 febrile episodes, serum procalcitonin and CRP were measured in 50 episodes.. Serum procalcitonin-positive patients showed poor outcomes on antibiotics therapy (Fisher's exact test, p=0.042). Furthermore, serum procalcitonin positivity was able to discriminate infective fever from fever due to inflammation (Chi-square test, p=0.001). We showed the causative organisms of febrile advanced lung cancer patients who received cytotoxic chemotherapy, as well as the possibility of PCT to discriminate infective fever from fever due to inflammation.

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  • Cerebrospinal Fluid Concentration of Erlotinib and its Active Metabolite OSI-420 in Patients with Central Nervous System Metastases of Non-small Cell Lung Cancer Reviewed

    Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Tomohiro Terada, Shiro Fujita, Kaoru Irisa, Yuichi Sakamori, Young Hak Kim, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

    JOURNAL OF THORACIC ONCOLOGY   5 ( 7 )   950 - 955   2010.7

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    Background: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420.
    Method: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8.
    Results: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean +/- SD CSF concentrations of erlotinib and OSI-420 were 54 +/- 30 ng/ml and 10.8 +/- 8.2 ng/ml, respectively. The mean +/- SD CSF penetration rates of erlotinib and OSI-420 were 5.1% +/- 1.9% and 5.8% +/- 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC(50)) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene.
    Conclusion: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

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  • A Case of Radiation Recall Pneumonitis Induced by Erlotinib, Which Can be Related to High Plasma Concentration Reviewed

    Yosuke Togashi, Katsuhiro Masago, Michiaki Mishima, Masahide Fukudo, Ken-ichi Inui

    JOURNAL OF THORACIC ONCOLOGY   5 ( 6 )   924 - 925   2010.6

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  • Pharmacokinetics of Erlotinib and Its Active Metabolite OSI-420 in Patients with Non-small Cell Lung Cancer and Chronic Renal Failure Who Are Undergoing Hemodialysis Reviewed

    Yosuke Togashi, Katsuhiro Masago, Masahide Fukudo, Tomohiro Terada, Yasuaki Ikemi, Young Hak Kim, Shiro Fujita, Kaoru Irisa, Yuichi Sakamori, Tadashi Mio, Ken-ichi Inui, Michiaki Mishima

    JOURNAL OF THORACIC ONCOLOGY   5 ( 5 )   601 - 605   2010.5

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    Introduction: Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC).
    Method: We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8.
    Results: In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response.
    Conclusion: Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

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  • Good Clinical Response to Erlotinib in a Non-Small Cell Lung Cancer Patient Harboring Multiple Brain Metastases and a Double Active Somatic Epidermal Growth Factor Gene Mutation. Reviewed International journal

    Katsuhiro Masago, Yosuke Togashi, Masahide Fukudo, Tomohiro Terada, Kaoru Irisa, Yuichi Sakamori, Shiro Fujita, Young Hak Kim, Tadashi Mio, Ken-Ichi Inui, Michiaki Mishima

    Case reports in oncology   3 ( 2 )   98 - 105   2010.4

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    Recently, 2 small molecule kinase inhibitors (TKIs), targeting epidermal growth factor receptor (EGFR), have proven effective in the treatment of non-small cell lung cancer. However, it is unknown whether the EGFR double activating mutation of L858R in exon 21 and the in-frame deletion in exon 19 is a predictor of the effectiveness of EGFR-TKIs. We report for the first time a case of non-small cell lung cancer with central nervous system metastases harboring a rare EGFR double activating mutation who showed a good clinical response to erlotinib, regardless of his poor performance status, as swallowing is not possible. Therefore, we suggest that erlotinib may become a therapeutic choice in cases of central nervous system metastases even with poor performance status.

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  • Outcome of Surgical Treatment for Metastatic Vertebra Bone Tumor in Advanced Lung Cancer. Reviewed International journal

    Akiko Fukuhara, Katsuhiro Masago, Masashi Neo, Shunsuke Fujibayashi, Shiro Fujita, Yukimasa Hatachi, Kaoru Irisa, Yuichi Sakamori, Yosuke Togashi, Young Hak Kim, Tadashi Mio, Michiaki Mishima

    Case reports in oncology   3 ( 1 )   63 - 71   2010.3

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    BACKGROUND: Spinal metastases of patients with advanced stage lung cancer are an important target for palliative therapy, because their incidence is high, and they often cause severe symptoms and worsen the quality of life. Surgery is one of the most effective treatment options, but the indication of surgery is unclear as the procedure is invasive and patients with spinal metastasis have a rather short life expectancy. Furthermore, there have been few studies that have focused on lung cancer with poor prognosis. METHODS: We reviewed all of the cases of lung cancer from January 1999 to July 2007 in the Department of Respiratory Medicine, Kyoto University Hospital, Japan. Thirteen patients with metastatic spinal tumor of lung cancer underwent surgery, and all of them had a poor performance status score (3 or 4). RESULTS: Neurological improvement by at least 1 Frankel grade was seen in 10 of 14 cases (71%). Improvement of the movement capacity was noted in 9 of 14 cases (64%), and pain improvement was noted in 12 of 14 (86%). Median postoperative survival was 5 months (1-25 months). In particular, the group with a good postoperative performance status score (0-2) was shown to have a better median postoperative survival of 13 months. CONCLUSIONS: Surgical treatment for symptomatic metastatic spinal tumor of lung cancer can improve quality of life in a substantially high percentage of patients. Surgery should be considered even if preoperative performance status is poor.

    DOI: 10.1159/000299385

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  • Clinical Significance of Pretreatment C-Reactive Protein in Patients with Advanced Nonsquamous, Non-Small Cell Lung Cancer Who Received Gefitinib Reviewed

    Katsuhiro Masago, Shiro Fujita, Yosuke Togashi, Young Hak Kim, Yukimasa Hatachi, Akiko Fukuhara, Hiroki Nagai, Kaoru Irisa, Yuichi Sakamori, Chiyuki Okuda, Tadashi Mio, Michiaki Mishima

    ONCOLOGY   79 ( 5-6 )   355 - 362   2010

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    Purpose: We examined patients with advanced nonsquamous, non-small cell lung cancer (NSCLC) to evaluate epidermal growth factor receptor (EGFR) mutation status and serum C-reactive protein (CRP) for their associations with response to gefitinib therapy and for prognostic impacts. Methods: Serum levels of CRP from 79 Japanese patients with advanced nonsquamous NSCLC were measured before the start of gefitinib. We used the peptic nucleic acid-locked nucleic acid clamp method to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. Results: Having CRP-positive serum and having wild-type EGFR were both independent negative predictive factors for the response to gefitinib treatment by multivariate logistic regression model analysis. Having CRP-positive serum and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. Conclusions: Having CRP-positive serum predicted a lack of response to gefitinib therapy independent of EGFR mutational status. Both CRP-positive serum and wild-type EGFR were independent poor prognostic factors in patients with nonsquamous NSCLC who received gefitinib therapy. Copyright (C) 2011 S. Karger AG, Basel

    DOI: 10.1159/000323486

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  • [Loeys-Dietz syndrome with acute myeloid leukemia]. Reviewed

    Togashi Y, Sakoda H, Sugahara H, Asagoe K, Matsuzawa Y

    [Rinsho ketsueki] The Japanese journal of clinical hematology   49 ( 8 )   664 - 667   2008.8

  • 大動脈瘤に起因する慢性播種性血管内凝固症候群を呈した家族性高コレステロール血症の1例

    冨樫庸介, 菅原浩之, 平岡久豊, 松澤佑次

    住友病院医学雑誌   ( 35 )   45 - 50   2008.7

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  • A Japanese family of typical loeys-dietz syndrome with a TGFBR2 mutation Reviewed

    Yosuke Togashi, Hiroto Sakoda, Akira Nishimura, Naomichi Matsumoto, Hisatoyo Hiraoka, Yuji Matsuzawa

    INTERNAL MEDICINE   46 ( 24 )   1995 - 2000   2007

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    This report describes a Japanese family with vessel and craniofacial abnormalities. Although the clinical findings of the patient's father fulfilled the diagnostic criteria for Marfan syndrome, arterial tortuosity, aneurysms, hypertelorism and a bifid uvula were noted in both the patient and his father. These findings were compatible with the clinical manifestations that were previously reported in Loeys-Dietz syndrome. A molecular genetic analysis demonstrated a heterozygous missense mutation of the transforming growth factor-beta receptor II gene in both the patient and his father, which thus caused Loeys- Dietz syndrome. This is the first Japanese family case report of typical Loeys- Dietz syndrome.

    DOI: 10.2169/internalmedicine.46.0467

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  • 免疫チェックポイント阻害薬の耐性メカニズムを考える

    川島 秀介, 冨樫 庸介

    Skin Cancer   36 ( 2 )   127 - 132   2021.10

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  • 【がん微小環境に1細胞レベルで挑む 技術革新で見えてきた腫瘍内の細胞と免疫応答の多様性、がん悪性化・治療抵抗性の鍵】(第2章)腫瘍内の免疫・炎症応答多様性とがん微小環境 シングルセル解析から迫る腫瘍微小免疫環境の多様性

    冨樫 庸介, 長崎 譲慈

    実験医学   39 ( 12 )   1904 - 1909   2021.8

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    がん免疫療法の有効性が多くのがん種で証明されたが、その治療効果は不十分である。効果予測バイオマーカーやより有効性の高い治療を求めて、抗腫瘍免疫応答の本質を解明するために腫瘍微小環境の解析がさかんに行われているが、免疫細胞は非常に不均一で多様な集団であり、塊(バルク)での解析では本質に迫ることは難しい。そこで、シングルセルレベルでの解析が必要であるが、タンパク質レベルの解析として抗体に蛍光色素をラベルして解析するフローサイトメトリーを代表に、よりマーカーを増やすために金属をラベルした抗体を用いるマスサイトメトリーも使用され、40分子程度までシングルセルレベルで腫瘍微小環境の解析が可能である。さらに網羅的な遺伝子発現をシングルセルレベルで解析できるようにもなっている。また、抗体やMHCマルチマー、抗原ペプチドにオリゴヌクレオチドをラベルしてシークエンスする技術や、T細胞・B細胞受容体配列、オープンクロマチン領域、ゲノム自体も解析することがシングルセルレベルで可能である。加えて、位置情報もシングルセルレベルに近い形で解析できる技術も登場し、次々と腫瘍微小環境に関する新たな知見が明らかになっている。(著者抄録)

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  • 中型先天性色素性母斑とそこから生じた悪性黒色腫と転移巣における遺伝子変異状況の比較

    田渕 亜希子, 大沼 毅紘, 出口 順啓, 島田 眞路, 川村 龍吉, 坂井 和子, 西尾 和人, 冨樫 庸介, 猪爪 隆史

    日本皮膚科学会雑誌   131 ( 5 )   1417 - 1417   2021.5

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  • CD155/TIGIT axisは免疫チェックポイント阻害剤のinflamed resistanceに関与する

    猪爪 隆史, 川島 秀介, 河津 正人, 池原 譲, 木庭 幸子, 中村 泰大, 梅田 善康, 川崎 朋範, 川村 龍吉, 大沼 毅紘, 保延 亜希子, 冨樫 庸介

    日本がん免疫学会総会プログラム・抄録集   25回   185 - 185   2021.5

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  • 腫瘍局所における代謝機構を介した制御性T細胞の新規PD-1発現機構の解明

    熊谷 尚悟, 鎌田 貴裕, 冨樫 庸介, 小山 正平, 川添 彬人, 河津 正人, 青景 圭樹, 名嘉眞 健太, 吉田 達哉, 山崎 直也, 大江 裕一郎, 坪井 正博, 設樂 紘平, 間野 博行, 西川 博嘉

    日本がん免疫学会総会プログラム・抄録集   25回   92 - 92   2021.5

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  • 中型先天性色素性母斑とそこから生じた悪性黒色腫と転移巣における遺伝子変異状況の比較

    田渕 亜希子, 大沼 毅紘, 出口 順啓, 島田 眞路, 川村 龍吉, 坂井 和子, 西尾 和人, 冨樫 庸介, 猪爪 隆史

    日本皮膚科学会雑誌   131 ( 5 )   1417 - 1417   2021.5

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  • がん治療における腫瘍微小環境の解析 腫瘍微小環境のシングルセル解析

    冨樫 庸介

    日本がん免疫学会総会プログラム・抄録集   25回   74 - 74   2021.5

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  • がんと制御性T細胞

    池田 英樹, 冨樫 庸介

    臨床免疫・アレルギー科   75 ( 4 )   455 - 462   2021.4

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    制御性T細胞(Treg)は、自己に対する免疫応答や過度な免疫応答を制御する自己免疫寛容にかかわる免疫細胞である。また、Tregは抗腫瘍免疫応答を抑制することで腫瘍の進展に寄与しているが、不明な点も多い。Tregの機能分類と抑制メカニズム、腫瘍微小環境におけるTregの役割、Tregと免疫チェックポイント分子阻害剤との関係、Tregを標的とした治療法の開発などについて概説した。

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  • 【先端ゲノム医療とゲノム診療】シングルセルシークエンスのがん臨床研究への応用

    冨樫 庸介, 池田 英樹

    腫瘍内科   27 ( 1 )   7 - 13   2021.1

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  • 腫瘍に発現するPD-L2の免疫抑制機能について

    種子島 時祥, 冨樫 庸介, 東 公一, 入江 拓磨, 木下 史生, 柏木 英志, 武内 在雄, 立神 勝則, 江藤 正俊, 西川 博嘉

    日本泌尿器科学会総会   108回   471 - 471   2020.12

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  • 腫瘍に発現するPD-L2の免疫抑制機能について

    種子島 時祥, 冨樫 庸介, 東 公一, 入江 拓磨, 木下 史生, 柏木 英志, 武内 在雄, 立神 勝則, 江藤 正俊, 西川 博嘉

    日本泌尿器科学会総会   108回   471 - 471   2020.12

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  • 臨床検体を用いた腫瘍免疫のトランスレーショナルリサーチ

    冨樫 庸介

    日本癌学会総会記事   79回   YIA - 9   2020.10

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  • PD-L2による、自発的・治療関連抗腫瘍免疫に対する免疫抑制機能(Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity)

    種子島 時祥, 冨樫 庸介, 江藤 正俊, 西川 博嘉

    西日本泌尿器科   82 ( 増刊 )   138 - 138   2020.10

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  • 臨床検体を用いた腫瘍免疫のトランスレーショナルリサーチ

    冨樫 庸介

    日本癌学会総会記事   79回   YIA - 9   2020.10

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  • 【ゲノム医療時代のがん 分子標的薬と診断薬研究「治療」の選択肢を広げる新しい標的、併用療法、横断的・マルチコンパニオン診断薬、リキッドバイオプシー】(第5章)耐性メカニズムとその克服方法 免疫チェックポイント阻害剤の耐性メカニズム

    冨樫 庸介

    実験医学   38 ( 15 )   2609 - 2616   2020.9

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    免疫チェックポイント阻害剤の有効性が多くのがん種で証明されたが、単剤での効果は50%以下と限定的であることから、その耐性メカニズムの解明が有効性を高めるうえでも重要である。初期耐性に加えて、一度効果がみられたあとに耐性化する獲得耐性も問題となっている。免疫チェックポイント阻害剤は細胞傷害性T細胞を活性化させることで有効性を発揮するため、このT細胞活性化のプロセスが耐性メカニズムを考えるうえでも非常に重要で、それに沿ったような耐性メカニズムがさまざまに報告されている。免疫チェックポイント阻害剤の有効性を高めるためにも、それらを明らかにしたうえで、克服するような新たな治療開発が進められている。(著者抄録)

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  • 【ゲノム医療時代のがん 分子標的薬と診断薬研究「治療」の選択肢を広げる新しい標的、併用療法、横断的・マルチコンパニオン診断薬、リキッドバイオプシー】(第5章)耐性メカニズムとその克服方法 免疫チェックポイント阻害剤の耐性メカニズム

    冨樫 庸介

    実験医学   38 ( 15 )   2609 - 2616   2020.9

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    免疫チェックポイント阻害剤の有効性が多くのがん種で証明されたが、単剤での効果は50%以下と限定的であることから、その耐性メカニズムの解明が有効性を高めるうえでも重要である。初期耐性に加えて、一度効果がみられたあとに耐性化する獲得耐性も問題となっている。免疫チェックポイント阻害剤は細胞傷害性T細胞を活性化させることで有効性を発揮するため、このT細胞活性化のプロセスが耐性メカニズムを考えるうえでも非常に重要で、それに沿ったような耐性メカニズムがさまざまに報告されている。免疫チェックポイント阻害剤の有効性を高めるためにも、それらを明らかにしたうえで、克服するような新たな治療開発が進められている。(著者抄録)

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  • 免疫チェックポイント阻害剤を含む併用療法の実際 免疫チェックポイント阻害剤を含む併用療法におけるバイオマーカー

    冨樫 庸介

    日本呼吸器学会誌   9 ( 増刊 )   24 - 24   2020.8

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  • 免疫チェックポイント阻害剤を含む併用療法の実際 免疫チェックポイント阻害剤を含む併用療法におけるバイオマーカー

    冨樫 庸介

    日本呼吸器学会誌   9 ( 増刊 )   24 - 24   2020.8

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  • 【がん免疫療法におけるバイオマーカーと新規治療アプローチ】バイオマーカー研究の最先端 腫瘍微小環境とがん免疫療法のバイオマーカー

    冨樫 庸介

    腫瘍内科   26 ( 1 )   10 - 17   2020.7

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  • 免疫チェックポイント阻害薬 がん免疫療法はどうやって効くの?

    冨樫 庸介

    癌の臨床   65 ( 1 )   23 - 30   2020.2

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  • 【シングルセルゲノミクス 組織の機能、病態が1細胞レベルで見えてきた!】(第2章)シングルセル解析によるバイオロジー 免疫・がん シングルセルレベルでのT細胞受容体・B細胞受容体解析

    冨樫 庸介

    実験医学   37 ( 20 )   3414 - 3419   2019.12

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    不均一な集団である免疫細胞の解析は、1細胞レベルでCD4やCD8といったlineageマーカーや既知のPD-1などに対するモノクローナル抗体を利用してフローサイトメトリーといった機器でなされてきた。しかしながら、抗体や色素に依存してしまうため、既知の分子でかつ抗体が存在するものに限られ、解析できるマーカー数にも限界がある。T細胞やB細胞は多様な抗原を認識するために遺伝子再構成や体細胞超突然変異という機構でその受容体の多様性を獲得している。一方で、その多様性がゆえにT細胞受容体(T cell receptor:TCR)やB細胞受容体(B cell receptor:BCR)の解析を正確に行うことは難しく、従来は存在する限られたモノクローナル抗体を利用してフローサイトメトリーで解析する方法や、塊(バルク)の検体をシークエンスして受容体のレパートリー(レパトア)から頻度や多様性で論じる方法しかなかった。これらの方法では多様な受容体のα/β鎖や重/軽鎖を正確にペアで解析することや、どういったTCRやBCRをもつ細胞がどのような表現型を呈しているのか?といったことを正確に解析することは難しかった。ところが、最近の技術革新によってシングルセルシークエンスが可能となり、遺伝子発現だけでなくTCRやBCRも1細胞ずつ解析できるようになった。網羅的な遺伝子発現と一緒に解析することによってクローンごとの表現型も詳細に明らかにできるようになっている。将来的にはさまざまな疾患での病態解明や個別化療法・バイオマーカー開発といった「個別化免疫医療」につながる可能性がある。(著者抄録)

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  • 【シングルセルゲノミクス 組織の機能、病態が1細胞レベルで見えてきた!】(第2章)シングルセル解析によるバイオロジー 免疫・がん シングルセルレベルでのT細胞受容体・B細胞受容体解析

    冨樫 庸介

    実験医学   37 ( 20 )   3414 - 3419   2019.12

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    不均一な集団である免疫細胞の解析は、1細胞レベルでCD4やCD8といったlineageマーカーや既知のPD-1などに対するモノクローナル抗体を利用してフローサイトメトリーといった機器でなされてきた。しかしながら、抗体や色素に依存してしまうため、既知の分子でかつ抗体が存在するものに限られ、解析できるマーカー数にも限界がある。T細胞やB細胞は多様な抗原を認識するために遺伝子再構成や体細胞超突然変異という機構でその受容体の多様性を獲得している。一方で、その多様性がゆえにT細胞受容体(T cell receptor:TCR)やB細胞受容体(B cell receptor:BCR)の解析を正確に行うことは難しく、従来は存在する限られたモノクローナル抗体を利用してフローサイトメトリーで解析する方法や、塊(バルク)の検体をシークエンスして受容体のレパートリー(レパトア)から頻度や多様性で論じる方法しかなかった。これらの方法では多様な受容体のα/β鎖や重/軽鎖を正確にペアで解析することや、どういったTCRやBCRをもつ細胞がどのような表現型を呈しているのか?といったことを正確に解析することは難しかった。ところが、最近の技術革新によってシングルセルシークエンスが可能となり、遺伝子発現だけでなくTCRやBCRも1細胞ずつ解析できるようになった。網羅的な遺伝子発現と一緒に解析することによってクローンごとの表現型も詳細に明らかにできるようになっている。将来的にはさまざまな疾患での病態解明や個別化療法・バイオマーカー開発といった「個別化免疫医療」につながる可能性がある。(著者抄録)

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  • 免疫療法の新規バイオマーカー 進行NSCLCにおける可溶性免疫チェックポイント因子の役割(Novel biomarkers for immunotherapies The role of soluble immune-checkpoint factors in advanced NSCLC)

    Hayashi Hidetoshi, 茶本 健司, 冨樫 庸介, 中川 和彦, 本庶 佑

    肺癌   59 ( 6 )   558 - 558   2019.11

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  • EGFR-TKIによる腫瘍微小環境の免疫状態の変化

    多根 健太, 宇田川 響, 桐田 圭輔, 杉山 栄里, 三好 智裕, 青景 圭樹, 後藤 功一, 坪井 正博, 冨樫 庸介, 西川 博嘉

    肺癌   59 ( 6 )   691 - 691   2019.11

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  • 腫瘍に発現するPD-L2の免疫抑制機能について(Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity)

    種子島 時祥, 冨樫 庸介, 東 公一, 江藤 正俊, 西川 博嘉

    日本癌学会総会記事   78回   P - 2082   2019.9

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  • 【がん免疫療法の個別化を支える 新・腫瘍免疫学】第I部 腫瘍免疫応答の基本とその制御メカニズム (第1章)腫瘍免疫応答の正負の調節機構 シングルセル解析技術の腫瘍免疫研究への応用 T細胞の解析を中心に

    冨樫 庸介, 西川 博嘉

    実験医学   37 ( 15 )   2461 - 2467   2019.9

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    がん免疫療法の有効性が多くのがん種で証明されたが、治療効果が限定的であることから抗腫瘍免疫応答の本質に迫るための免疫細胞の解析が注目されている。免疫細胞は不均一な集団であり、塊(バルク)での解析では限界がありシングルセルレベルでの解析が必要である。タンパク質レベルの解析では従来から利用されてきた抗体に蛍光色素をラベルして解析するフローサイトメトリーを代表に、さらにマーカーを増やすために金属をラベルした抗体を用いるマスサイトメトリーも使用され、40分子程度までシングルセルレベルでの解析が可能になっている。また網羅的な遺伝子発現をシングルセルレベルで解析できるようにもなり(シングルセルRNAシークエンス)、最大で10,000遺伝子程度まで解析可能になっている。また、抗体やMHCマルチマーにオリゴヌクレオチドをラベルしてシークエンスする技術や、T細胞・B細胞受容体配列、オープンクロマチン領域も解析することがシングルセルレベルで可能となっている。さらには位置情報も含めた解析技術も登場してきて、次々と新たな知見が明らかになっている。(著者抄録)

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  • 【がん免疫療法の個別化を支える 新・腫瘍免疫学】第I部 腫瘍免疫応答の基本とその制御メカニズム (第1章)腫瘍免疫応答の正負の調節機構 シングルセル解析技術の腫瘍免疫研究への応用 T細胞の解析を中心に

    冨樫 庸介, 西川 博嘉

    実験医学   37 ( 15 )   2461 - 2467   2019.9

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    がん免疫療法の有効性が多くのがん種で証明されたが、治療効果が限定的であることから抗腫瘍免疫応答の本質に迫るための免疫細胞の解析が注目されている。免疫細胞は不均一な集団であり、塊(バルク)での解析では限界がありシングルセルレベルでの解析が必要である。タンパク質レベルの解析では従来から利用されてきた抗体に蛍光色素をラベルして解析するフローサイトメトリーを代表に、さらにマーカーを増やすために金属をラベルした抗体を用いるマスサイトメトリーも使用され、40分子程度までシングルセルレベルでの解析が可能になっている。また網羅的な遺伝子発現をシングルセルレベルで解析できるようにもなり(シングルセルRNAシークエンス)、最大で10,000遺伝子程度まで解析可能になっている。また、抗体やMHCマルチマーにオリゴヌクレオチドをラベルしてシークエンスする技術や、T細胞・B細胞受容体配列、オープンクロマチン領域も解析することがシングルセルレベルで可能となっている。さらには位置情報も含めた解析技術も登場してきて、次々と新たな知見が明らかになっている。(著者抄録)

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  • 一細胞解析によるがん多様性の解明 シングルセル解析による腫瘍免疫研究(Tumor heterogeneity at single-cell resolution Single cell analysis for cancer immunology)

    冨樫 庸介

    日本癌学会総会記事   78回   S6 - 2   2019.9

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  • 腫瘍に発現するPD-L2の免疫抑制機能について

    種子島 時祥, 冨樫 庸介, 江藤 正俊, 西川 博嘉

    腎癌研究会会報   ( 49 )   37 - 37   2019.7

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  • 抗PD-1抗体が著効した進行期メラノーマにおけるTILの機能解析

    猪爪 隆史, 冨樫 庸介, 有安 亮, 谷口 智憲, 河上 裕, 西川 博嘉

    日本がん免疫学会総会プログラム・抄録集   23回   121 - 121   2019.7

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  • 『がん免疫療法実用化の時代』〜あなたが抱く基礎・臨床の課題を皆で考える2019〜 抗がん剤と免疫療法の併用療法の機序をどう思いますか?

    冨樫 庸介

    日本がん免疫学会総会プログラム・抄録集   23回   53 - 53   2019.7

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  • 新規治療薬時代の術後補助療法の考え方 早期がんに対するがん免疫療法 手術療法と組み合わせる試み

    冨樫 庸介

    肺癌   58 ( 6 )   443 - 443   2018.10

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  • 悪性胸膜中皮腫における腫瘍内浸潤リンパ球の検討

    塩田 哲広, 橋本 健太郎, 野原 淳, 石床 学, 渡邉 壽規, 山本 喜啓, 新宅 雅幸, 杉山 栄里, 冨樫 庸介, 西川 博嘉

    肺癌   58 ( 6 )   555 - 555   2018.10

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  • 免疫プロファイリングによる、濾胞性リンパ腫の予後予測(Immune profiling analysis for prediction of outcome in patients with folliclular lymphoma)

    山内 寛彦, 湯田 淳一朗, 藤岡 優樹, 長崎 譲慈, 山崎 美貴, 冨樫 庸介, 南 陽介, 西川 博嘉

    臨床血液   59 ( 9 )   1503 - 1503   2018.9

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  • 肺がん治療の進歩 がん免疫治療のバイオマーカー研究(Advances in treatments for lung cancer Translational Research for Predictive Biomarkers in Cancer Immunotherapy)

    冨樫 庸介

    日本癌学会総会記事   77回   1984 - 1984   2018.9

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  • 脱メチル化阻害薬はMDSにおける腫瘍免疫を増強する(HMAs enhance anti-tumor effects via regulation of tumor immunity in patients with MDS)

    湯田 淳一朗, 板橋 耕太, 冨樫 庸介, 山内 寛彦, 南 陽介, 西川 博嘉

    臨床血液   59 ( 9 )   1588 - 1588   2018.9

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  • 免疫チェックポイント療法の新潮流 4.PD‐L1を標的とする免疫チェックポイント阻害薬~抗PD‐1抗体と同じ?違う?~

    冨樫庸介, 冨樫庸介

    医薬ジャーナル   54 ( 8 )   1831 - 1835   2018.8

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  • 大腸癌における免疫学的な新たな分類と新規がん免疫療法の可能性

    冨樫 庸介, 稲守 宏治, 福岡 聖大, 杉山 大介, 伊藤 雅昭, 西川 博嘉

    日本がん免疫学会総会プログラム・抄録集   22回   83 - 83   2018.7

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  • 腫瘍微小環境と免疫制御 腫瘍免疫における制御性T細胞の役割

    冨樫 庸介

    日本がん免疫学会総会プログラム・抄録集   22回   44 - 44   2018.7

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  • がんは免疫系をいかに抑制するのか 新規がん免疫療法研究開発の「狂騒曲」

    冨樫庸介, 冨樫庸介

    実験医学   36 ( 9 )   1474 - 1482   2018.6

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  • Association of gut microbiome with immune status and clinical response in solid tumor patients who received on anti-PD-1 therapies.

    Shota Fukuoka, Motooka Daisuke, Yosuke Togashi, Eri Sugiyama, Hibiki Udagawa, Keisuke Kirita, Takahiro Kamada, Akihito Kawazoe, Koichi Goto, Toshihiko Doi, Kohei Shitara, Shota Nakamura, Hiroyoshi Nishikawa

    JOURNAL OF CLINICAL ONCOLOGY   36 ( 15 )   2018.5

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    DOI: 10.1200/JCO.2018.36.15_suppl.3011

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  • The Liquid Biopsy: Its Present and Future

    西尾和人, 冨樫庸介, 坂井和子

    肺癌(Web)   57 ( 6 )   733‐738(J‐STAGE) - 738   2017.11

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    血中循環腫瘍細胞、血中遊離DNA、エクソソームなどの、主に血液由来の液性検体はリキッドバイオプシーと総称される。これらを用いた、腫瘍由来DNAの分子異常の検出は、低侵襲であり複数回の実施が可能であるため、治療選択、モニタリング、proof of conceptのために期待される。デジタルPCR、次世代シーケンサーの登場により、高感度、マルチ解析が可能となり、実用化が近づいた。また低頻度変異アレル検出のための技術革新が進行中である。血中遊離DNAは、遺伝子導入、免疫への作用などの生物学的な働きも明らかになりつつあり、これらの知見は癌治療への応用へとつながる。肺癌領域では、血漿サンプルによるEGFR遺伝子変異検査が追加承認され、実用化された。リキッドバイオプシーは、腫瘍不均一性によるバイアスを克服する手段として期待される。今後はリキッドバイオプシーを用いたモニタリングにより、adaptive treatmentへのパラダイムシフトが訪れる。(著者抄録)

    DOI: 10.2482/haigan.57.733

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  • The liquid biopsy: Its present and future

    Kazuto Nishio, Yosuke Togashi, Kazuko Sakai

    Japanese Journal of Lung Cancer   57 ( 6 )   733 - 738   2017.11

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    Cell free DNA, circulating tumor cell, and exosomes are collectively called liquid biopsy. The detection of molecular abnormalities in a liquid biopsy is a low-invasive technique that allows us to perform analyses and monitoring multiple times. Digital polymerase chain reaction and next-generation sequencing have improved the sensitivity and multiplicity of liquid biopsy analyses. Efforts to improve the detection of low-frequency mutation alleles further are now underway. Biological understanding of the cell free DNA with regard to aspects such as gene transfer and immune reactions have led to the development of cancer treatment regimens using liquid biopsies. In the clinical setting of lung cancer patients, serum EGFR mutation kits are available to identify patients indicated for third-generation EGFR-tyrosine kinase inhibitors. Liquid biopsies may eliminate the sampling bias caused by tumor heterogeneity and bring a paradigm shift to the adaptive treatment of lung cancer.

    DOI: 10.2482/haigan.57.733

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    Other Link: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J01244&link_issn=&doc_id=20171127490002&doc_link_id=%2Fec7jaluc%2F2017%2F005706%2F002%2F0733-0738%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fec7jaluc%2F2017%2F005706%2F002%2F0733-0738%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • PD-L1はどのようなタイミングで測定すればよいか? 免疫チェックポイント阻害薬を使用する直前の検体で評価する

    冨樫 庸介, 西川 博嘉

    日本医事新報   ( 4881 )   60 - 61   2017.11

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  • 免疫チェックポイントとがん免疫治療 1.がん免疫における免疫チェックポイントと免疫抑制細胞

    冨樫庸介, 西川博嘉, 西川博嘉

    血液フロンティア   27 ( 11 )   1511 - 1517   2017.10

  • Translational research for predictive biomarkers and novel cancer immunotherapies beyond PD-1/PD-L1 blockade therapies

    Yousuke Togashi

    ANNALS OF ONCOLOGY   28   2017.10

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  • Gene expression and mutation profiling for cancer of unknown primary

    Hidetoshi Hayashi, Shuta Tomida, Yoshihiko Fujita, Yosuke Togashi, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa

    ANNALS OF ONCOLOGY   28   2017.10

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  • まれなEGFR遺伝子変異L861QおよびS768I陽性非小細胞性肺癌に対する最適なEGFR阻害剤の選択

    坂野 恵里, 冨樫 庸介, 中村 雄, 千葉 眞人, 小林 祥久, 林 秀敏, 谷崎 潤子, 寺嶋 雅人, デ・ベラスコ・マルコ A., 坂井 和子, 藤田 至彦, 光冨 徹哉, 西尾 和人

    日本癌学会総会記事   76回   YSA - 4   2017.9

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  • FGFR遺伝子異常を有する肺扁平上皮癌の術後再発生存期間に対する影響とマルチキナーゼ阻害薬に対する感受性

    西尾 和人, 金田 裕靖, 谷崎 潤子, 坂井 和子, 冨樫 庸介, 寺嶋 雅人, デベラスコ・マルコ, 藤田 至彦, 坂野 恵里, 中村 雄, 武田 真幸, 伊藤 彰彦, 光冨 徹哉, 中川 和彦, 岡本 勇

    肺癌   57 ( 3 )   253 - 253   2017.6

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  • Multicenter phase I/II trial of BBI608 and pembrolizumab combination in patients with metastatic colorectal cancer (SCOOP Study): EPOC1503.

    Yasutoshi Kuboki, Akihito Kawazoe, Yoshito Komatsu, Tomohiro Nishina, Eiji Shinozaki, Hiroki Hara, Satoshi Yuki, Miki Fukutani, Natsuko Tsukahara, Hiromi Hasegawa, Nami Hirano, Shogo Nomura, Yosuke Togashi, Hiroyoshi Nishikawa, Akihiro Sato, Atsushi Ohtsu, Takayuki Yoshino

    JOURNAL OF CLINICAL ONCOLOGY   35   2017.5

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    DOI: 10.1200/JCO.2017.35.15_suppl.TPS3623

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  • Clinicopathological features of program death ligand-1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.

    Akihito Kawazoe, Kohei Shitara, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Atsushi Ohtsu, Atsushi Ochiai, Yosuke Togashi, Hiroyoshi Nishikawa, Toshihiko Doi, Takeshi Kuwata

    JOURNAL OF CLINICAL ONCOLOGY   35   2017.5

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    DOI: 10.1200/JCO.2017.35.15_suppl.4040

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  • Regulatory-T cells (Tregs) in tumor infiltrating lymphocytes (TILs) from patients with advanced gastric cancer (AGC) after chemotherapy containing ramucirumab.

    Daisuke Kotani, Yosuke Togashi, Akihito Kawazoe, Toshihiko Doi, Hiroyoshi Nishikawa, Kohei Shitara

    JOURNAL OF CLINICAL ONCOLOGY   35   2017.5

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    DOI: 10.1200/JCO.2017.35.15_suppl.e15570

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  • EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib

    Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Kim, Yosuke Togashi, Yuichi Sesumi, Masaya Nishino, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S1266 - S1267   2017.1

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  • EGFR遺伝子変異陽性非小細胞肺癌におけるEGFR-TKI耐性後T790M変異有無によるニボルマブ治療効果と腫瘍微小免疫環境の後向き検討

    原谷浩司, 林秀敏, 田中妙, 金田裕靖, 冨樫庸介, 坂井和子, 吉岡弘鎮, 光冨徹哉, 西尾和人, 中川和彦

    日本臨床腫瘍学会学術集会(CD-ROM)   15th   2017

  • FGFR遺伝子異常を有する肺扁平上皮癌の術後再発生存期間に対する影響とマルチキナーゼ阻害薬に対する感受性

    西尾和人, 金田裕靖, 谷崎潤子, 坂井和子, 冨樫庸介, 寺嶋雅人, デベラスコ マルコ, 藤田至彦, 坂野恵里, 中村雄, 武田真幸, 伊藤彰彦, 光冨徹哉, 中川和彦, 岡本勇

    肺癌(Web)   57 ( 3 )   2017

  • 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

    寺嶋雅人, 冨樫庸介, 佐藤克明, 水内寛, 坂井和子, 須田健一, 中村雄, 坂野恵里, 林秀敏, デベラスコ マルコ, 藤田至彦, 冨田秀太, 光冨徹哉, 西尾和人, 寺嶋雅人

    近畿大学医学雑誌   41 ( 3-4 )   20A - 20A   2016.12

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  • 稀なEGFR遺伝子の耐性二次変異(L747S、D761Y、T854A)における各種EGFR-TKIの感受性

    千葉 眞人, 冨樫 庸介, 光冨 徹哉, 西尾 和人

    肺癌   56 ( 6 )   514 - 514   2016.11

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  • アファチニブ獲得耐性機序としてのEGFR二次変異T790M、L792F、C797Sの特徴

    小林 祥久, 東 公一, 永井 宏樹, 金 永学, 冨樫 庸介, 瀬角 裕一, 西野 将矢, 西平 守道, 佐藤 克明, 千葉 眞人, 下治 正樹, 富沢 健二, 武本 智樹, 西尾 和人, 光冨 徹哉

    肺癌   56 ( 6 )   532 - 532   2016.11

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  • アファチニブ獲得耐性機序としてのEGFR二次変異T790M、L792F、C797Sの特徴

    小林 祥久, 東 公一, 永井 宏樹, 金 永学, 冨樫 庸介, 瀬角 裕一, 西野 将矢, 西平 守道, 佐藤 克明, 千葉 眞人, 下治 正樹, 富沢 健二, 武本 智樹, 西尾 和人, 光冨 徹哉

    肺癌   56 ( 6 )   532 - 532   2016.11

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  • 稀なEGFR遺伝子の耐性二次変異(L747S、D761Y、T854A)における各種EGFR-TKIの感受性

    千葉 眞人, 冨樫 庸介, 光冨 徹哉, 西尾 和人

    肺癌   56 ( 6 )   514 - 514   2016.11

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  • EGFR遺伝子変異陽性非小細胞肺癌で細胞障害性Tリンパ球浸潤が減少する分子学的機序

    竹内 美子, 冨樫 庸介, 杉山 栄里, 木島 貴志, 熊ノ郷 淳, 新谷 康, 奥村 明之進, 青景 圭樹, 菱田 智之, 石井 源一郎, 坪井 正博, 西川 博嘉

    肺癌   56 ( 6 )   529 - 529   2016.11

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  • PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討

    倉 由吏恵, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受

    日本癌学会総会記事   75回   E - 1029   2016.10

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  • DDR2 E655K変異タンパク質はユビキチン-プロテアソーム系による分解を受け機能が喪失する

    寺嶋 雅人, 冨樫 庸介, 坂井 和子, 中村 雄, 坂野 恵里, デベラスコ・マルコ, 藤田 至彦, 西尾 和人

    日本癌学会総会記事   75回   P - 3047   2016.10

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  • 頭頸部または食道扁平上皮癌に対するアファチニブの効果 頭頸部扁平上皮癌における活性型発癌性HER4遺伝子変異

    中村 雄, 冨樫 庸介, 寺嶋 雅人, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 桶川 隆嗣, 濱田 傑, 西尾 和人

    日本癌学会総会記事   75回   P - 2296   2016.10

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  • PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる

    デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受

    日本癌学会総会記事   75回   E - 1073   2016.10

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  • PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討

    倉 由吏恵, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受

    日本癌学会総会記事   75回   E - 1029   2016.10

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  • Tumor-educated plateletsによるliquid biopsyの可能性

    冨樫 庸介

    がん分子標的治療   14 ( 3 )   357,273 - 274   2016.10

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  • DDR2 E655K変異タンパク質はユビキチン-プロテアソーム系による分解を受け機能が喪失する

    寺嶋 雅人, 冨樫 庸介, 坂井 和子, 中村 雄, 坂野 恵里, デベラスコ・マルコ, 藤田 至彦, 西尾 和人

    日本癌学会総会記事   75回   P - 3047   2016.10

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  • 頭頸部または食道扁平上皮癌に対するアファチニブの効果 頭頸部扁平上皮癌における活性型発癌性HER4遺伝子変異

    中村 雄, 冨樫 庸介, 寺嶋 雅人, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 桶川 隆嗣, 濱田 傑, 西尾 和人

    日本癌学会総会記事   75回   P - 2296   2016.10

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  • PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる

    デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受

    日本癌学会総会記事   75回   E - 1073   2016.10

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  • Analysis of noncoding RNA expression in a mouse model of PTEN-deficient prostate cancer

    Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yuji Hatanaka, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-954

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  • 世代別(第1,2,3)EGFR‐TKIの耐性化機構

    冨樫庸介, 西尾和人

    がん分子標的治療   14 ( 2 )   237 - 243   2016.7

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    上皮成長因子受容体(EGFR)遺伝子の活性型変異(exon 19欠失変異もしくはexon 21 L858R変異など)を有する非小細胞肺がん(NSCLC)ではEGFRチロシンキナーゼ阻害薬(TKI)が著効する。しかしながら、大多数はいずれ耐性化してしまい、その機序としては2次変異としてゲートキーパー変異であるexon 20のT790M変異が50%程度関与する。そこで、T790M変異を有する場合でも阻害できる第2・3世代EGFR-TKIが開発されてきた。第2世代EGFR-TKIは、T790M変異を有する場合の臨床効果は限定的であるが、ほかのヒト上皮成長因子受容体(HER)ファミリーを阻害できる効果や稀な変異(exon 18変異、S768I変異、L861Q変異)への効果が期待されている。第3世代EGFR-TKIは、T790M変異を有する場合でも有効性が証明されているが、新たな耐性変異であるC797S変異がすでに報告されている。それぞれのEGFR-TKIの特徴を理解することで、より効果的な使い分け、すなわち「EGFR遺伝子変異肺がんの個別化医療」が可能となるであろう。(著者抄録)

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  • Alternative splicing is a frequent event in mouse PTEN-deficient prostate cancer

    Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura

    CANCER RESEARCH   76   2016.7

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    DOI: 10.1158/1538-7445.AM2016-2014

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  • 大腸粘液癌の分化度による臨床病理学的・分子生物学的な相違

    吉岡 康多, 冨樫 庸介, 筑後 孝章, 小北 晃弘, 寺嶋 雅人, 水上 拓郎, 坂井 和子, 所 忠男, 肥田 仁一, 西尾 和人, 奥野 清隆

    日本外科学会定期学術集会抄録集   116回   OP - 5   2016.4

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  • Afatinib activity against head-and-neck or esophageal squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in head-and-neck squamous cell carcinoma

    Y. Togashi, Y. Nakamura, S. Tomida, H. Hayashi, M. A. de Velasco, K. Sakai, Y. Fujita, S. Hamada, K. Nishio

    ANNALS OF ONCOLOGY   26   97 - 97   2015.12

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  • An activating ALK gene mutation in ALK IHC-positive/FISH-negative non-small cell lung cancer

    Yosuke Togashi, Hiroshi Mizuuchi, Kazuko Sakai, Eri Banno, Hidetoshi Hayashi, Marco de Velasco, Yoshihiko Fujita, Shuta Tomida, Tetsuya Mitsudomi, Kazuto Nishio

    ANNALS OF ONCOLOGY   26   73 - 73   2015.11

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  • EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition

    Takuro Mizukami, Yosuke Togashi, Shunsuke Sogabe, Marco A. de Velasco, Kazuko Sakai, Yoshihiro Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

    ANNALS OF ONCOLOGY   26   129 - 129   2015.11

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  • Comparison of various EGFR tyrosine kinase inhibitors (TKIs) for tumors with exon 18 mutations of the EGFR gene

    Tetsuya Mitsudomi, Yoshihisa Kobayashi, Yosuke Togashi, Hiroshi Mizuuchi, Kenichi Suda, Kazuto NIshio

    ANNALS OF ONCOLOGY   26   83 - 83   2015.11

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  • Integrative algorithm to determine the metastatic carcinoma tissue of origin using next generation sequencing (NGS)

    Hidetoshi Hayashi, Shuta Tomida, Yosuke Togashi, Kazuko Sakai, Yoshihiko Fujita, Junji Tsurutani, Issei Kurahashi, Takayasu Kurata, Kazuhiko Nakagawa, Kazuto Nishio

    ANNALS OF ONCOLOGY   26   86 - 86   2015.11

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  • 非小細胞肺がんにおけるDDR2変異の機能解析

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

    日本癌学会総会記事   74回   P - 2223   2015.10

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  • 非小細胞肺がんにおけるDDR2変異の機能解析

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

    日本癌学会総会記事   74回   P - 2223   2015.10

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  • EGFR exon18変異肺癌の頻度と各世代EGFR-TKIに対する奏効率の違い

    小林 祥久, 冨樫 庸介, 谷田部 恭, 水内 寛, 朴 将哲, 近藤 千晶, 下治 正樹, 佐藤 克明, 須田 健一, 富沢 健二, 武本 智樹, 樋田 豊明, 西尾 和人, 光冨 徹哉

    肺癌   55 ( 5 )   454 - 454   2015.10

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  • Kinases and lung cacer 非小細胞肺癌における受容体チロシンキナーゼ遺伝子変異の探索と機能解析・問題点

    冨樫 庸介, 水内 寛, 林 秀敏, 小林 祥久, 中川 和彦, 光冨 徹哉, 西尾 和人

    肺癌   55 ( 5 )   367 - 367   2015.10

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  • EGFR exon18変異肺癌の治療戦略 afatinibとneratinibに対する高感受性

    小林 祥久, 冨樫 庸介, 谷田部 恭, 水内 寛, 朴 将哲, 近藤 千晶, 須田 健一, 富沢 健二, 樋田 豊明, 西尾 和人, 光冨 徹哉

    日本癌学会総会記事   74回   E - 1176   2015.10

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  • EGFR exon18変異肺癌の治療戦略 afatinibとneratinibに対する高感受性

    小林 祥久, 冨樫 庸介, 谷田部 恭, 水内 寛, 朴 将哲, 近藤 千晶, 須田 健一, 富沢 健二, 樋田 豊明, 西尾 和人, 光冨 徹哉

    日本癌学会総会記事   74回   E - 1176   2015.10

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  • Fibroblast growth factor 9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

    T. Mizukami, Y. Togashi, E. Banno, M. Terashima, M. A. De Velasco, K. Sakai, H. Hayashi, Y. Fujita, S. Tomida, T. Eguchi Nakajima, N. Boku, A. Ito, K. Nakagawa, K. Nishio

    EUROPEAN JOURNAL OF CANCER   51   S46 - S46   2015.9

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  • Receptor tyrosine kinase mutations in non-small cell lung cancer

    H. Hayashi, Y. Togashi, M. Terashima, K. Sakai, H. Mizuuchi, Y. Kobayashi, K. Suda, K. Nakagawa, K. Nishio, T. Mitsudomi

    EUROPEAN JOURNAL OF CANCER   51   S601 - S601   2015.9

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  • Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinoma

    Y. Togashi, Y. Yoshioka, T. Chikugo, M. Terashima, T. Mizukami, H. Hayashi, K. Sakai, M. De Velasco, S. Tomida, Y. Fujita, K. Okuno, K. Nishio

    EUROPEAN JOURNAL OF CANCER   51   S390 - S390   2015.9

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  • EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs

    Yoshihisa Kobayashi, Yosuke Togashi, Yasushi Yatabe, Hiroshi Mizuuchi, Park Jangchul, Chiaki Kondo, Masaki Shimoji, Katsuaki Sato, Kenichi Suda, Kenji Tomizawa, Toshiki Takemoto, Toyoaki Hida, Kazuto Nishio, Tetsuya Mitsudomi

    JOURNAL OF THORACIC ONCOLOGY   10 ( 9 )   S177 - S178   2015.9

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  • 活性型ALK遺伝子変異を有するALK免疫染色陽性/FISH陰性のまれな肺腫瘍

    冨樫 庸介, 寺嶋 雅人, 坂井 和子, 林 秀敏, 西尾 和人, 水内 寛, 小林 祥久, 光冨 徹哉

    肺癌   55 ( 4 )   304 - 304   2015.8

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  • Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer

    Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-3402

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  • 固形がんの分子標的薬 II.各論 がん分子標的治療の臨床 キナーゼ阻害剤とその耐性化機構

    冨樫庸介, 西尾和人

    日本臨床   73 ( 8 )   1323 - 1329   2015.8

  • 固形がんの分子標的薬 II.各論 がん分子標的治療の臨床 PI3K/mTORシグナル系と分子標的治療

    西尾和人, 坂井和子, 冨樫庸介

    日本臨床   73 ( 8 )   1315 - 1322   2015.8

  • FGF9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

    Takuro Mizukami, Yosuke Togashi, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-5456

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  • Melanoma transition is frequently accompanied by a loss of cytoglobin, a putative tumor suppressor, in melanocytes

    Yoshihiko Fujita, Satoshi Koinuma, Marco De Velasco, Bolz Jan, Yosuke Togashi, Masato Terashima, Hidetoshi Hayashi, Takuya Matsuo, Kazuto Nishio

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-4958

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  • 診断の進歩 シークエンス技術の発展と肺癌のdriver oncogene

    冨樫 庸介, 西尾 和人

    Annual Review呼吸器   2015   133 - 140   2015.1

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    肺癌は全癌の中で世界的に最も頻度の高い死亡原因である.従来進行肺癌は非常に予後不良であったが,driver oncogeneであるepidermal growth factor receptor(EGFR)遺伝子変異やanaplastic lymphoma kinase(ALK)融合遺伝子が発見され,それぞれEGFRチロシンキナーゼ阻害剤(EGFR-TKI),ALK阻害剤といった分子標的薬の登場により予後も改善しつつある.またシークエンス技術の発展,次世代シークエンサーが登場したことで,がんの全ゲノム解読が実現可能となり,これまで明らかにされていなかった新しいがん関連遺伝子の発見が急激な勢いで進んでいる.肺癌領域でもROS1,RET,NTRK1遺伝子といった新たなdriver oncogeneが治療標的分子として次々と発見され,今後はさらに治療標的に基づく個別化治療が進んでいくと考えられる.(著者抄録)

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  • 活性型ALK遺伝子変異を有するALK免疫染色陽性/FISH陰性のまれな肺腫瘍

    冨樫庸介, 寺嶋雅人, 坂井和子, 林秀敏, 西尾和人, 水内寛, 小林祥久, 光冨徹哉

    肺癌(Web)   55 ( 4 )   2015

  • 【コンパニオン診断の進展2014-2015-個別化医療を進めるために-】 個別化医療の実現に向けて 分子標的治療の実用化とコンパニオン診断

    西尾 和人, 坂井 和子, 富樫 庸介

    臨床病理レビュー   ( 153 )   23 - 27   2014.11

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    次世代シークエンサーを用いた遺伝子解析の臨床応用が進んでいる。全ゲノム、エクソーム解析により、新規標的分子が同定され、発見された標的分子に対する治療法の開発も行われている。一方、ターゲッテドシークエンシングの診断薬としての応用がすすめられている。本技術をマルチ診断薬として開発することは、がん治療、特に、分子標的薬のコンパニオン診断の実用化にとり重要であり、個別化医療に直結する。(著者抄録)

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  • 新技術の呼吸器への応用を考える ゲノム解析技術と呼吸器

    冨樫庸介, 西尾和人

    Lung Perspect   22 ( 4 )   401 - 407   2014.11

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    ゲノム解析技術は「速く大量に」を目標に技術革新が進み、今日の次世代シークエンサー(NGS)が発展してきた。NGSの配列決定速度の向上は目覚ましく、低価格化も進み、さまざまな分野で革新的な成果を収めつつある。呼吸器分野においては、特に腫瘍分野で肺癌の新たな治療標的となりうる変異や融合遺伝子が次々に発見されている。呼吸器に関わる感染症分野、さらにはマイクロバイオームの分野でもその利用が進んでいる。また、クリニカルシークエンスというNGSの臨床現場への応用が始まりつつあり、今後は臨床現場での新たな検査のツールとなることが期待されている。(著者抄録)

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  • 新規ALK阻害剤であるアレクチニブはMET阻害剤との併用で効果が高まる

    冨樫 庸介, 林 秀敏, 寺嶋 雅人, 坂井 和子, 藤田 至彦, 冨田 秀太, 中川 和彦, 西尾 和人

    肺癌   54 ( 5 )   403 - 403   2014.10

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  • 喫煙によるニコチン曝露はEGFR遺伝子変異陽性肺がんにおいてEGFR-TKIの耐性因子である

    林 秀敏, 冨樫 庸介, 岡本 邦男, 田中 妙, 文田 壮一, 新谷 亮多, 清川 寛文, 坂本 洋一, 寺嶋 雅人, de Velasco Marco A, 坂井 和子, 藤田 至彦, 冨田 秀太, 加藤 元一, 中川 和彦, 西尾 和人

    肺癌   54 ( 5 )   626 - 626   2014.10

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  • 低酸素はALK融合遺伝子を有するH3122肺癌細胞株のALK阻害剤に対する耐性化を誘導する

    冨樫 庸介, 林 秀敏, 寺嶋 雅人, 坂井 和子, 藤田 至彦, 冨田 秀太, 中川 和彦, 西尾 和人

    肺癌   54 ( 5 )   470 - 470   2014.10

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  • MEK INHIBITORS ARE EFFECTIVE AGAINST GASTRIC CANCER CELL LINES WITH ONCOGENIC MEK1 GENE MUTATIONS

    Yosuke Togashi, Shunsuke Sogabe, Hiroaki Kato, Masato Terashima, Hidetoshi Hayashi, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takushi Yasuda, Kazuto Nishio

    ANNALS OF ONCOLOGY   25   2014.10

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    DOI: 10.1093/annonc/mdu435.90

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  • Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

    Yosuke Togashi, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Yoshihiko Fujita, Yasuo Kodera, Kazuko Sakai, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-5271

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  • CHRONIC NICOTINE EXPOSURE MEDIATES RESISTANCE TO EGFR-TKI IN EGFR-MUTATED LUNG CANCER VIA EGFR SIGNAL

    Hidetoshi Hayashi, Yosuke Togashi, Kunio Okamoto, Soichi Fumita, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

    ANNALS OF ONCOLOGY   25   2014.10

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    DOI: 10.1093/annonc/mdu435.122

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  • メラノサイトからメラノーマへの移行は、しばしばがん抑制因子であるサイトグロビンの発現低下を伴う(Cytoglobin, a putative tumor suppressor, is frequently lost in melanocyte during melanoma transition)

    藤田 至彦, 鯉沼 聡, デベラスコ・マルコ, ボルツ・ヤン, 富樫 庸介, 寺嶋 雅人, 林 秀敏, 松尾 拓哉, 西尾 和人

    日本癌学会総会記事   73回   P - 3066   2014.9

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  • MEK遺伝子変異を有する胃がんに対するMEK阻害剤の有効性(MEK inhibitor for gastric cancer with MEK1 gene mutations)

    冨樫 庸介, 加藤 寛章, 林 秀敏, 寺嶋 雅人, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 冨田 秀太, 安田 卓司, 西尾 和人

    日本癌学会総会記事   73回   P - 2349   2014.9

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  • KIAA1199はグリコーゲンホスホリラーゼキナーゼβサブユニットと結合してグリコーゲンの分解さらには細胞生存を亢進する(KIAA1199 interacts with PHKB and promotes glycogen breakdown and cancer cell survival)

    寺嶋 雅人, 藤田 至彦, 冨樫 庸介, 坂井 和子, 冨田 秀太, 西尾 和人

    日本癌学会総会記事   73回   P - 2211   2014.9

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  • 次世代シークエンサーによるがんゲノム解析

    冨樫庸介, 西尾和人

    月刊呼吸器内科   26 ( 2 )   141 - 146   2014.8

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  • 免疫チェックポイント阻害療法のバイオマーカー

    冨樫庸介, 西尾和人

    がん分子標的治療   12 ( 1 )   76 - 79   2014.4

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    T細胞における免疫チェックポイント分子は、自己に対する免疫反応を調整する重要なメカニズムである。腫瘍組織がこのメカニズムを利用することで、免疫監視機構から逃避している特性が明らかになってきた。そのような分子を標的とした治療法が免疫チェックポイント阻害療法であるが、特に近年CTLA-4分子やPD-1分子に対する抗体治療の有効性が報告されている。これらの治療は過剰な免疫反応による有害事象を高頻度で誘発する一方で、長期生存する症例も報告されているため、そのような患者を選択するためのバイオマーカーが求められている。(著者抄録)

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  • 個別化治療のためのバイオマーカー

    冨樫庸介, 西尾和人

    日本臨床   72   697 - 700   2014.2

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  • 【最新がん薬物療法学-がん薬物療法の最新知見-】 個別化治療のためのバイオマーカー

    冨樫 庸介, 西尾 和人

    日本臨床   72 ( 増刊2 最新がん薬物療法学 )   697 - 700   2014.2

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  • MEK1遺伝子変異を有する胃がん細胞株に対するMEK阻害剤の有効性と臨床サンプルの検討

    冨樫庸介, 曽我部俊介, 加藤寛章, 寺嶋雅人, 林秀敏, 林秀敏, 坂井和子, 藤田至彦, 冨田秀太, 安田卓志, 西尾和人

    日本臨床腫瘍学会学術集会(CD-ROM)   12th   2014

  • ORAOV1 IS AMPLIFIED IN ESOPHAGEAL SQUAMOUS CELL CANCER AND RELATED TO TUMOR GROWTH AND POORLY DIFFERENTIATED TUMOR

    Y. Togashi, T. Arao, H. Kato, K. Matsumoto, M. Terashima, H. Hayashi, Y. Fujita, T. Yasuda, H. Shiozaki, K. Nishio

    ANNALS OF ONCOLOGY   24   2013.11

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    DOI: 10.1093/annonc/mdt459.131

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  • 間質性疾患の画像所見を有する患者における体幹部定位放射線治療 Reviewed

    植木 奈美, 松尾 幸憲, 冨樫 庸介, 久保 武, 澁谷 景子, 飯塚 裕介, 平岡 真寛

    肺癌   53 ( 5 )   554 - 554   2013.10

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  • 非小細胞肺癌(非扁平上皮癌)に対する2次・3次治療としてのエルロチニブ/ベバシズマブ併用療法・第II相試験

    YANAGIHARA KAZUHIRO, KIN EIGAKU, MASAGO KATSUYASU, TOGASHI YOSUKE, SAKAMORI YUICHI, HIRABAYASHI MASATAKA, NIKAIDO JUN'ICHI

    日本肺癌学会総会号   53 ( 5 )   678 - 678   2013.10

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  • NGSによる極微量検体を用いたmultiplex mutation analysisの最適化(Optimization of multiplex mutation analysis based on minimum amount of lung cancer specimen)

    冨田 秀太, 坂井 和子, 藤田 至彦, 寺嶋 雅人, 富樫 庸介, デベラスコ・マルコ, 光冨 徹哉, 中川 和彦, 西尾 和人

    日本癌学会総会記事   72回   458 - 458   2013.10

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  • 肺癌生物像に基づいた、新しい肺癌治療の戦略 EGFR遺伝子変異を有する肺癌においてβカテニンを阻害することでEGFR-TKIの効果が増強する

    冨樫 庸介, 林 秀敏, 寺嶋 雅人, 藤田 至彦, 坂井 和子, 冨田 秀太, 中川 和彦, 西尾 和人

    肺癌   53 ( 5 )   397 - 397   2013.10

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  • 乳がん 研究編 乳がんのバイオマーカー

    冨樫庸介, 西尾和人

    Clinician   60 ( 10 )   889 - 894   2013.10

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  • がん患者のバイオマーカー―分子標的戦略 肺がんの発症機構と診断・治療戦略

    冨樫庸介, 西尾和人

    Cefiro   ( 17 )   12 - 17   2013.4

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  • 肺癌定位放射線治療における金マーカー留置の初期経験

    中村 清直, 植木 奈美, 松尾 幸憲, 飯塚 裕介, 宮城 健, 溝脇 尚志, 平岡 真寛, 冨樫 庸介

    Japanese Journal of Radiology   31 ( Suppl.I )   57 - 57   2013.2

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  • シスプラチンによる腎障害を反映する尿中バイオマーカーとしてのkidney injury molecule‐1およびmonocyte chemotactic protein‐1

    SHINKE HARUKA, IKEMI YASUAKI, TATEHARA MASAMI, MATSUBARA KAZUO, TOGASHI YOSUKE, KIN EIGAKU, MISHIMA MICHIAKI, MASUDA SATOHIRO

    日本薬学会年会要旨集(CD-ROM)   133rd   ROMBUNNO.29P-PM02S   2013

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  • 食道扁平上皮癌で高頻度に増幅しているORAOV1遺伝子は腫瘍増大と低分化な組織型に関与している

    冨樫庸介, 荒尾徳三, 加藤寛章, 松本和子, 寺嶋雅人, 林秀敏, 藤田至彦, 安田卓司, 塩崎均, 西尾和人

    日本臨床腫瘍学会学術集会(CD-ROM)   11th   2013

  • ペプチド療法の臨床試験におけるバイオマーカーの探索

    西尾和人, 冨樫庸介, 中川和彦, 山上裕機, 大橋靖雄

    日本がん免疫学会総会プログラム・抄録集   17th   2013

  • 肺小細胞癌に合併した傍腫瘍性Guillain-Barre症候群の一例

    中奥 由里子, 菱澤 美貴, 藤本 大智, 冨樫 庸介, 奥田 千幸, 真砂 勝泰, 植村 健吾, 猪原 匡史, 岡 伸幸, 三嶋 理晃, 高橋 良輔

    末梢神経   23 ( 2 )   349 - 350   2012.12

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  • 進行期非小細胞癌による癌性胸水に対するベバシズマブ包含化学療法の有効性

    藤本 大智, 真砂 勝泰, 冨樫 庸介, 奥田 千幸, 阪森 優一, 金 永学, 三嶋 理晃

    肺癌   52 ( 5 )   698 - 698   2012.10

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  • 肺がん分子標的薬の個別化医療―基礎と臨床 新たな肺癌の治療標的分子

    冨樫庸介, 西尾和人

    月刊メディカル・サイエンス・ダイジェスト   38 ( 9 )   384 - 387   2012.8

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    肺癌は全癌の中で世界的に最も頻度の高い死亡原因である。従来進行肺癌は非常に予後不良であったが、近年ではEGFR-TKIといった分子標的薬の登場により予後も改善しつつある。さらにALKやROS1、RET遺伝子といった有望な新たな治療標的分子も発見され、今後はさらに治療標的に基づく個別化治療が進んでいくと考えられる。本稿では肺癌の新たな治療標的分子・分子標的薬をまとめるとともに、米国での腫瘍組織バンキングや次世代シークエンサーも含めた今後の展望についても言及した。(著者抄録)

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  • EGFR遺伝子変異検査に供する細胞診検体保存方法に関する検討

    SHIRAHASE HIROYUKI, KIDO TAKAYUKI, MATSUDA KOICHIRO, HAGA HIRONORI, KIN EIGAKU, MASAGO KATSUYASU, TOGASHI YOSUKE, MISHIMA MICHIAKI

    日本呼吸器学会誌   1 ( 増刊 )   238 - 238   2012.3

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  • Monocyte Chemotactic Protein‐1(MCP‐1)の薬剤性腎障害を反映する尿中バイオマーカーとしての有用性評価

    SHINKE HARUKA, NAKAGAWA SHUNSAKU, IKEMI YASUAKI, KATSURA TOSHIYA, TOGASHI YOSUKE, KIN EIGAKU, MISHIMA MICHIAKI, ICHIMURA RYUJI, BONVENTRE JOSEPH V, MASUDA SATOHIRO

    臨床薬理   42 ( Supplement )   S240   2011.10

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  • 進行非小細胞肺癌患者におけるEGFR遺伝子変異と全身性炎症反応との関係

    TOGASHI YOSUKE, MASAGO KATSUYASU, SAKAMORI YUICHI, KIN EIGAKU, MISHIMA MICHIAKI

    肺癌   51 ( 5 )   510 - 510   2011.10

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  • 間質性肺炎合併肺小細胞癌患者の予後の検討

    OKUDA CHIYUKI, TOGASHI YOSUKE, MASAGO KATSUYASU, HANDA TOMOHIRO, TANIZAWA KIMINOBU, SAKAMORI YUICHI, KIN EIGAKU, MISHIMA MICHIAKI

    肺癌   51 ( 5 )   403 - 403   2011.10

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  • 京大病院呼吸器内科病棟で塩酸モルヒネ持続注射が用いられた終末期肺癌患者のレトロスペクティブ解析

    KIN EIGAKU, TOGASHI YOSUKE, OKUDA CHIYUKI, SAKAMORI YUICHI, MASAGO KATSUYASU, MISHIMA MICHIAKI

    肺癌   51 ( 5 )   408 - 408   2011.10

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  • エルロチニブの母集団薬物動態と副作用に関する薬理ゲノム解析

    FUKUDO MASAHIDE, IKEMI YASUAKI, TOGASHI YOSUKE, MASAGO KATSUYASU, KIN EIGAKU, MISHIMA MICHIAKI, KATSURA TOSHIYA

    臨床薬理   42 ( Suppl. )   S229 - S229   2011.10

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  • T790Mを有するgefitinib耐性非小細胞肺癌に対してerlotinibを使用しその濃度を測定した2症例

    FUJIMOTO MASATOMO, TOGASHI YOSUKE, MASAGO KATSUYASU, SAKAMORI YUICHI, KIN EIGAKU, MISHIMA MICHIAKI, FUKUDO MASAHIDE, KATSURA TOSHIYA

    肺癌   51 ( 5 )   569 - 569   2011.10

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  • 中枢神経転移を有する非小細胞肺癌患者におけるerlotinibの血清と髄液濃度の相関関係の検討

    TOGASHI YOSUKE, MASAGO KATSUYASU, FUKUDO MASAHIDE, OKUDA KAZUYUKI, SAKAMORI YUICHI, KANENAGA MANABU, KATSURA TOSHIYA, MISHIMA MICHIAKI

    肺癌   51 ( 5 )   364 - 364   2011.10

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  • 2nd line以降の既治療非小細胞肺癌に対するベバシズマブ併用療法の臨床的検討

    SAKAMORI YUICHI, KIN EIGAKU, OKUDA CHIYUKI, TOGASHI YOSUKE, MASAGO KATSUYASU, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   51 ( 5 )   563 - 563   2011.10

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  • 扁平上皮癌を除く進行非小細胞肺癌に対するCBDCA+PEM併用療法の第II相試験(KTORG0902)

    KIN EIGAKU, HIRABAYASHI MASATAKA, TOGASHI YOSUKE, HIRANO KATSUYA, TOMII KEISUKE, MASAGO KATSUYASU, KANEDA TOSHIHIKO, YOSHIMATSU AKIKAZU, OTSUKA KOJIRO, MIO TADASHI, TOMIOKA HIROMI, SUZUKI YUJIRO, MISHIMA MICHIAKI

    肺癌   51 ( 5 )   397 - 397   2011.10

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  • PROGNOSTIC SIGNIFICANCE OF SYSTEMIC INFLAMMATORY RESPONSE AND EPIDERMAL GROWTH FACTOR RECEPTOR GENE STATUS IN PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER

    Yosuke Togashi, Katsuhiro Masago, Yuichi Sakamori, Young Hak Kim, Michiaki Mishima

    JOURNAL OF THORACIC ONCOLOGY   6 ( 6 )   S1012 - S1013   2011.6

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  • Population pharmacokinetics and pharmacogenomics of erlotinib: Effect of drug exposure on treatment outcomes in Japanese patients with non-small cell lung cancer.

    M. Fukudo, Y. Ikemi, Y. Togashi, K. Masago, Y. H. Kim, T. Mio, M. Mishima, K. Inui, T. Katsura

    JOURNAL OF CLINICAL ONCOLOGY   29 ( 15 )   2011.5

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    Web of Science

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  • Pemetrexedが長期にわたり有効であった粘液産生型気管支肺胞上皮癌の1例

    OKUDA CHIYUKI, KIN EIGAKU, TOGASHI YOSUKE, MASAGO KATSUYASU, SAKAMORI YUICHI, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   51 ( 2 )   146 - 146   2011.4

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    J-GLOBAL

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  • Gefitinibとerlotinibの毒性の違い

    TOGASHI YOSUKE, MASAGO KATSUYASU, SAKAMORI YUICHI, KIN EIGAKU, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   51 ( 2 )   141 - 141   2011.4

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  • Pemetrexed投与による肝障害の検討

    SAKAMORI YUICHI, KIN EIGAKU, OKUDA CHIYUKI, TOGASHI YOSUKE, MASAGO KATSUYASU, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   51 ( 2 )   141 - 142   2011.4

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  • 中枢神経転移を有する非小細胞肺癌患者におけるerlotinibの血清と髄液濃度の相関関係の検討

    TOGASHI YOSUKE, MASAGO KATSUYASU, FUKUTSUCHI MASAHIDE, KIN EIGAKU, MIO TADASHI, KATSURA TOSHIYA, INUI KEN'ICHI, MISHIMA MICHIAKI

    日本呼吸器学会雑誌   49 ( 増刊 )   131 - 131   2011.3

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  • 非小細胞肺癌患者におけるエルロチニブの体内動態と副作用に関する母集団解析

    FUKUDO MASAHIDE, IKEMI YASUAKI, TERADA TOMOHIRO, KATSURA TOSHIYA, INUI KEN'ICHI, TOGASHI YOSUKE, MASAGO KATSUYASU, KIN EIGAKU, MIO TADASHI, MISHIMA MICHIAKI

    臨床薬理   41 ( Suppl. )   S228 - S228   2010.11

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  • ランダムパターンを呈する彌慢性肺内転移とEGFR遺伝子変異との関連性についての検討

    TOGASHI YOSUKE, MASAGO KATSUYASU, KUBO TAKESHI, KIN EIGAKU, SAKAMORI YUICHI, MIO TADASHI, TOGASHI KAORI, MISHIMA MICHIAKI

    肺癌   50 ( 5 )   527 - 527   2010.10

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  • 進行非小細胞肺癌悪性胸水貯留例におけるエルロチニブ及び代謝産物の薬物動態

    MASAGO KATSUYASU, TOGASHI YOSUKE, KIN EIGAKU, SAKAMORI YUICHI, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   50 ( 5 )   712 - 712   2010.10

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  • EGFR遺伝子変異陽性非小細胞肺癌の中枢神経系転移に対するEGFRチロシンキナーゼ阻害剤の有効性の検討

    TOGASHI YOSUKE, MASAGO KATSUYASU, KIN EIGAKU, SAKAMORI YUICHI, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   50 ( 5 )   536 - 536   2010.10

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  • バンコマイシンが奏効せず,リネゾリドが有効であったMRSA肺炎の検討

    重松三知夫, 冨樫庸介, 今村拓也, 佐竹範夫

    住友病院医学雑誌   ( 37 )   64 - 64   2010.7

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  • 甲状腺乳頭癌の上皮成長因子受容体遺伝子変異

    IRISA KAORU, MASAGO KATSUYASU, SAKAMORI YUICHI, TOGASHI YOSUKE, KIN EIGAKU, MIO TADASHI, MISHIMA MICHIAKI

    肺癌   50 ( 1 )   95 - 96   2010.2

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  • 進行非小細胞肺癌透析症例におけるerlotinibの血中薬物動態

    TOGASHI YOSUKE, MASAGO MASAHIRO, IRISA KAORU, KIN EIGAKU, MIO TADASHI, MISHIMA MICHIAKI, FUKUDO MASAHIDE, TERADA TOMOHIRO, INUI KEN'ICHI

    肺癌   50 ( 1 )   96 - 97   2010.2

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  • CLINICAL PHARMACOKINETICS OF ERLOTINIB AND ITS ACTIVE METABOLITE OSI-420 IN PATIENTS WITH NON-SMALL CELL LUNG CANCER

    Fukudo Masahide, Togashi Yosuke, Masago Katsuhiro, Terada Tomohiro, Katsura Toshiya, Kim Young Hak, Mio Tadashi, Mishima Michiaki, Inui Ken-ichi

    Abstracts of JSSX meeting   25 ( 0 )   107 - 107   2010

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    Language:Japanese   Publisher:The Japanese Society for the Study of Xenobiotics  

    DOI: 10.14896/jssxmeeting.25.0.107.0

    CiNii Article

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  • バンコマイシンが奏効せずにリネゾリドが有効であったMRSA肺炎の検討

    冨樫 庸介, 重松 三知夫, 今村 拓也, 佐竹 範夫

    日本呼吸器学会雑誌   47 ( 増刊 )   293 - 293   2009.5

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Presentations

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Awards

  • 日本免疫学会若手免疫学研究支援事業

    2021.12   日本免疫学会  

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  • 日本癌学会奨励賞

    2020.10   日本癌学会  

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  • 第1回日本癌学会若手の会最優秀口演賞

    2020.2   日本癌学会  

    冨樫庸介

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  • Best Poster Award

    2018   The Naito Foundation  

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  • ESMO Asia Travel Grant

    2015   ESMO  

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  • Medical Science Award

    2015   Kindai University  

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  • Nice Teacher Award

    2011   Kyoto University Hospital  

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  • Nice Teacher Award

    2010   Kyoto University Hospital  

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Research Projects

  • NAFLD/NASH肝癌における免疫応答の解明

    2022

    小野医学研究財団  研究奨学助成金 

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  • 悪性リンパ腫における遺伝子異常を基盤とした発症機構・分子病態の統合的解明

    Grant number:21H05051  2021.07 - 2026.03

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

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    Authorship:Coinvestigator(s) 

    Grant amount:\186680000 ( Direct expense: \143600000 、 Indirect expense:\43080000 )

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  • ゲノム異常を有する腫瘍浸潤リンパ球の1細胞解析方法の開発とその臨床的意義の解明

    2021.06 - 2023.03

    AMED  次世代がん医療創生研究事業 

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  • 悪性黒色腫の腫瘍特異的疲弊T細胞に発現する新規接着因子の機能解析と臨床応用

    Grant number:21K08314  2021.04 - 2024.03

    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)

    盛永 敬郎, 猪爪 隆史, 冨樫 庸介

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    Authorship:Coinvestigator(s) 

    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • 鼻副鼻腔原発の粘膜型悪性黒色腫の免疫ゲノム解析および重粒子線の影響解明

    Grant number:21K09625  2021.04 - 2024.03

    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)

    花澤 豊行, 猪爪 隆史, 冨樫 庸介

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    Authorship:Coinvestigator(s) 

    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

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  • 抗腫瘍免疫応答に重要な真のネオ抗原の同定と発がんとの関係解明

    2021.04

    JST  創発的研究支援事業 

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  • COPDの病態解明・新規治療開発のための空間解析を含むマルチオミックスデータベース構築

    2021 - 2022.03

    AMED  ゲノム医療実現バイオバンク利活用プログラム(次世代医療基盤を支えるゲノム・オミックス解析) 

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  • Analysis of PD-1+ tumor-infiltrating T cells according to cancer antigen hierarchy

    Grant number:20H03694  2020.04 - 2023.03

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

    冨樫 庸介, 盛永 敬郎

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    Grant amount:\17810000 ( Direct expense: \13700000 、 Indirect expense:\4110000 )

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  • HLA class I/class IIとがん免疫療法の効果と耐性への影響の解明と新たな治療開発

    2020

    公益財団法人がん研究振興財団  がん研究助成金 

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  • 体細胞変異に伴う抗腫瘍免疫応答に対する新たな免疫編集機構の解析

    Grant number:19K22574  2019.06 - 2021.03

    日本学術振興会  科学研究費助成事業 挑戦的研究(萌芽)  挑戦的研究(萌芽)

    冨樫 庸介

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    Grant amount:\6500000 ( Direct expense: \5000000 、 Indirect expense:\1500000 )

    非小細胞肺癌、大腸癌の臨床検体を用いて、体細胞変異数が異常に多いにも関わらず、免疫応答が起きていないような症例の存在を明らかにした。そういった症例について、体細胞変異からネオ抗原を予測し、予測上位のペプチドと患者リンパ球を用いてアッセイした。ELISPOTではそのような症例でも抗原特異的T細胞の存在が確認され、ネオ抗原は存在するにも関わらず、特異的T細胞が浸潤できていないような状況が想定された。遺伝子発現を解析するとそういった症例では抗原提示細胞に関わる遺伝子発現が低下しており、逆にがんの悪性化に関わるシグナルの遺伝子発現が上昇していた。
    またマウスモデルで変異を誘導した腫瘍株はマウスに拒絶されたが(株1)、さらに変異を誘導すると再びマウスに生着することを確認した(株2)。免疫不全マウスでは親株と株1、株2で生着や増殖に差は見られず、この現象には何らかの免疫環境が関与していると考えられた。これらの株について変異解析を行ったところ、親株<株1<株2と体細胞変異数が多かった。一方で、発現解析からは臨床検体同様に腫瘍の悪性化に関わるシグナルが複数関与していることを明らかにした。これらシグナルの阻害剤を使用した際に再生着した株2の成長が抑制され、この効果は他の株や免疫不全マウスでは見られず、株2でこのシグナルが免疫系に作用し免疫応答が抑制されていることが示唆された。
    以上より、体細胞変異・ネオ抗原に対する抗腫瘍免疫応答を腫瘍側の悪性化に関わるシグナルが抑制するような新たな免疫編集機構の存在が示唆された。

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  • シングルセルシークエンスによるネオ抗原特異的T細胞の時空間的解析から治療標的・バイオマーカーへの応用

    2019 - 2021

    AMED  革新がん医療実用化研究事業 

    冨樫庸介

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  • ネオ抗原特異的腫瘍浸潤T細胞に発現する接着因子の腫瘍免疫における役割

    2019 - 2020

    三菱財団  三菱財団自然科学助成金 

    冨樫庸介

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  • T細胞受容体認識エピトープによる腫瘍浸潤Tリンパ球の次世代解析方法の開発

    2018 - 2019

    AMED  次世代がん医療創生研究事業 

    冨樫庸介

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    Authorship:Principal investigator  Grant type:Competitive

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  • 免疫チェックポイント阻害剤によるHyperprogressive diseaseの病態解明

    2018 - 2019

    小林がん学術振興会  小林がん研究助成 

    冨樫庸介

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  • 腎細胞癌におけるPD-L1非依存的免疫逃避機構の解明

    2018 - 2019

    ノバルティス科学振興財団  ノバルティス研究助成 

    冨樫庸介

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  • Influence of immune response for tumor evolution

    Grant number:17J09900  2017.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows  Grant-in-Aid for JSPS Fellows

    冨樫 庸介

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    Grant amount:\4030000 ( Direct expense: \3100000 、 Indirect expense:\930000 )

    腫瘍に対する免疫応答が、がんの進化・腫瘍不均一性に与える影響、すなわち腫瘍のゲノムを編集し悪性化や治療の耐性化に寄与するかどうかを明らかにする目的で、まず活性化したT細胞と腫瘍細胞株とを共培養した場合に上昇してくる遺伝子について解析を行った。共培養の系では特徴的な遺伝子群がコントロールに比較して腫瘍側で上昇しており、その遺伝子群は変異の誘導などにも関わっている可能性が考えられた。カラムを用いて共培養しても同様の結果が得あれらたため、液性因子に注目した。活性化したT細胞が分泌する液性因子としてはインターフェロンγやTNFα、IL-2などが有名であり、それぞれ中和抗体を用いてブロックしたところ、その遺伝子群の発現上昇はインターフェロンγ抗体により阻害された。そこでマウスモデルを用いてB16細胞株のgp100というがん抗原に対して特異的なTCRを持つpMEL-1マウスを使用してこの遺伝子群の上昇を解析したところ、野生型マウスに比べてpMEL-1マウスのほうがこれら遺伝子群の上昇が認められ、さらにインターフェロンγノックアウトマウスとpMEL-1マウスをかけあわせて同様の実験を行ったところ、遺伝子群の上昇がキャンセルされた。今後実際にこれら遺伝子群を強制発現もしくはノックダウンした場合に腫瘍細胞の遺伝子異常にどのような影響を与えるかを解析する予定である。
    また実際の臨床検体の解析でもこれら遺伝子群と免疫応答に関わる遺伝子群の発現状況が正の相関を認め、TCGAといった公共データベースでも同様の傾向が見られた。

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  • Studies of treatment and carcinogenesis for intrahepatic cholangiocarcinoma by genomic and immunological analysis

    Grant number:17K10674  2017.04 - 2020.03

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

    Kubo Shoji

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

    The gene analysis of occupational cholangiocarcinoma revealed a high mutation burden and a unique trinucleotide mutation signature and multicentric carcinogenesis. By immunohistochemical analysis, cholangiocarcinoma cells and massive invasion of immune cells including cytotoxic T cells were positive for PD-1 and PD-L1. The combined positive score was 10% to 90%, which was extremely higher than non-occupational cholangiocarcinoma. These findings indicate that occupational cholangiocarcinoma has characteristic immune response such as a high mutation burden, cancer immune cells positive for PD-1 and PD-L1, massive invasion of immune cells, which suggests the usefulness of immune checkpoint inhibitors.

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  • Gene alterations and anti-tumor immunity

    Grant number:17K18388  2017.04 - 2019.03

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

    Togashi Yosuke, Tsuboi Masahiro, Shitara Kohei

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    We investigated immunological phenotypes in tumor microenvironment (TME) of EGFR-mutated lung adenocarcinomas, to which cancer immunotherapy is largely ineffective. While EGFR-mutated lung adenocarcinomas had non-inflamed tumor micronenvironment, CD4+ effector regulatory T cells (Tregs), that are highly infiltrated. The EGFR signal plays an important role in this unique tumor micronenvironment and an EGFR signal inhibitor improved the immune status, and combination with immunotherapy provided better anti-tumor effects compared with either of single treatment.
    Furthermore, we investigated gene signature related to Treg-infiltration, showing a specific gene signature. We further analyze this relationship.

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  • 腫瘍免疫における制御性T細胞の新たな概念とその制御に基づいた治療応用

    2017 - 2018

    SGH財団  SGHがん研究助成金 

    冨樫庸介

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  • がん抗原の階層性検討による抗腫瘍免疫応答の本体解明

    2017 - 2018

    武田科学振興財団  武田科学振興財団(研究助成金・奨励金) 

    冨樫庸介

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  • 1細胞レベルのRNAシークエンシング技術のがん免疫への応用

    2017 - 2018

    BMS株式会社  BMS研究助成金 

    冨樫庸介

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  • がん免疫における新たなTregの概念とその制御に基づく治療への応用

    2017 - 2018

    内藤記念財団  内藤記念科学奨励費・研究助成 

    冨樫庸介

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  • Identification of novel immunecheckpoints and development of methods to inhibit them

    Grant number:16K10148  2016.04 - 2019.03

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

    Inozume Takashi, YAGUCHI tomonori, Togashi Yosuke

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

    In this study we have shown (1) and (2) as below, in the in vitro experiment using human melanoma tumor infiltrating lymphocytes that are thought to play central role in tumor rejection, and, in the in vivo tumor-treatment model using a humanizes mouse model.
    (1) PD-1, TIGIT, and LAG3 are selectively expressed by tumor-infiltrating, tumor-specific T cells, and cooperatively suppress T cell function (2) Co-blockade for their signals by the blocking antibodies synergistically activate the tumor specific T cells.

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  • Novel biomarkers for EGFR inhibitors in gastroenterological cancers based on CGH analyses

    Grant number:15H06754  2015.08 - 2017.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up  Grant-in-Aid for Research Activity Start-up

    Togashi Yosuke

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    Grant amount:\2990000 ( Direct expense: \2300000 、 Indirect expense:\690000 )

    The CGH analysis has shown that FGF9, MAP3K10, and AKT2 genes can be related to the resistance to EGFR inhibitors. Using overexpressing cell lines, the resistance has been demonstrated in FGF9 and AKT2 genes, which can be cancelled by FGFR and PI3K inhibitors, respectively, but not in MAP3K10 gene.
    In clinical samples, FGF9 amplification was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS. In addition, the difference was not significant, pancreatic cancer patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with an EGFR inhibitor than those with low expression levels.

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  • がんの新規治療標的分子の探索並びに創薬への応用

    Grant number:14J12493  2014.04 - 2016.03

    日本学術振興会  科学研究費助成事業 特別研究員奨励費  特別研究員奨励費

    冨樫 庸介

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    Grant amount:\2200000 ( Direct expense: \2200000 )

    我々は膵癌細胞株のarray-CGH法を用いた解析の結果からアクチビン受容体であるアクチビンA受容体type IBの欠損を同定した。そこで膵癌におけるアクチビンシグナルについての研究を行い、治療標的なり得るかを検証した。
    まず受容体非欠損株ではアクチビンAによる刺激で増殖が抑制されること、さらにshRNAによりその受容体をノックダウンしたところ、アクチビンによる増殖抑制シグナルがキャンセルされ、癌の進展に関わっていることを証明した。また膵癌の生検サンプルでは29例中6例で受容体が欠損していた。
    一方で膵癌患者の血清のアクチビンA濃度をELISAで測定したところ、予想と反してアクチビンA濃度が高い群が予後不良であった。さらにMIA PaCa-2という膵癌細胞株はアクチビンAにより極端に増殖が亢進した。アクチビンによる増殖抑制効果と増殖促進効果の違いを調べるために代表的な下流シグナルを検証したところ、MIA PaCa-2はSMADシグナルに加えて非SMADシグナルのPI3KやJNKシグナルが活性化しており、増殖が抑制される細胞株では非SMADシグナルは活性化されていなかったことを見出した。アクチビンAのサブユニットであるINHBAを強制発現した細胞株を作成したところMIA PaCa-2については増殖が亢進した。さらにINHBA強制発現株を移植したマウスはコントロールに比較して体重が極端に減少し、予後が極めて不良であった。解剖したところ筋組織の委縮が著明でアクチビンによる悪液質の影響が考えられた。
    膵癌におけるアクチビンシグナルは一部では癌抑制的に作用するが一部では癌促進的にも作用し、さらに悪液質へ関与することが示唆された。そういった群ではアクチビンシグナルが治療標的となり得、抗体療法といった実際の治療についての検証も計画している。

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