TOGASHI Yosuke

Researcher Information

Degree

• MD, PhD

J-Global ID

• 201501014921095500

Research Interests

• 呼吸器内科   皮膚腫瘍   Gastrointestinal cancer   Lung cancer   Cancer immunology   Genome biology   Tumor biology   

Research Areas

• Life sciences / Immunology
• Life sciences / Genomics
• Life sciences / Tumor biology
• Life sciences / Gastroenterology
• Life sciences / Respiratory medicine

Academic & Professional Experience

• 2021/06 - Today  Chiba UniversityGraduate School of Medicine客員教授
• 2021/04 - Today  岡山大学学術研究院医歯薬学域教授
• 2019/09 - 2021/03  Chiba Cancer CenterDivision Head
• 2016/04 - 2019/08  National Cancer CenterDivision of Cancer ImmunologyResearcher
• 2017/04 - 2018/03  JSPS Research Fellowship for Young Scientists (PD)
• 2015/04 - 2016/03  Kindai UniversityDepartment of Genome BiologyAssistant Professor
• 2014/04 - 2015/03  JSPS Research Fellowship for Young Scientists (DC2)
• 2011/04 - 2012/03  Kyoto University集学的がん診療学講座Assistant Professor

Education

• 2012/04 - 2015/03  Kindai University, PhD  Faculty of Medicine
• 2000/04 - 2006/03  Kyoto University  Faculty of Medicine  医学科

Association Memberships

• 日本肺癌学会   AACR   日本癌免疫学会   THE JAPANESE SOCIETY FOR IMMUNOLOGY   日本臨床腫瘍学会   THE JAPANESE CANCER ASSOCIATION   THE JAPANESE RESPIRATORY SOCIETY   THE JAPANESE SOCIETY OF INTERNAL MEDICINE   

Published Papers

• CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling.

  Yuto Naoi; Takao Morinaga; Joji Nagasaki; Ryo Ariyasu; Youki Ueda; Kazuo Yamashita; Wenhao Zhou; Shusuke Kawashima; Katsushige Kawase; Akiko Honobe-Tabuchi; Takehiro Ohnuma; Tatsuyoshi Kawamura; Yoshiyasu Umeda; Yu Kawahara; Yasuhiro Nakamura; Yukiko Kiniwa; Osamu Yamasaki; Satoshi Fukushima; Masahito Kawazu; Yutaka Suzuki; Hiroyoshi Nishikawa; Toyoyuki Hanazawa; Mizuo Ando; Takashi Inozume; Yosuke Togashi

  Cancer research 2024/04 

  T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.
• Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade

  Hidetoshi Hayashi; Kenji Chamoto; Ryusuke Hatae; Takashi Kurosaki; Yosuke Togashi; Kazuya Fukuoka; Megumi Goto; Yasutaka Chiba; Shuta Tomida; Takayo Ota; Koji Haratani; Takayuki Takahama; Junko Tanizaki; Takeshi Yoshida; Tsutomu Iwasa; Kaoru Tanaka; Masayuki Takeda; Tomoko Hirano; Hironori Yoshida; Hiroaki Ozasa; Yuichi Sakamori; Kazuko Sakai; Keiko Higuchi; Hitoshi Uga; Chihiro Suminaka; Toyohiro Hirai; Kazuto Nishio; Kazuhiko Nakagawa; Tasuku Honjo

  Journal of Clinical Investigation American Society for Clinical Investigation 134 (7) 2024/04 [Refereed]
  
• Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment.

  Wenhao Zhou; Shusuke Kawashima; Takamasa Ishino; Katsushige Kawase; Youki Ueda; Kazuo Yamashita; Tomofumi Watanabe; Masahito Kawazu; Hiromichi Dansako; Yutaka Suzuki; Hiroyoshi Nishikawa; Takashi Inozume; Joji Nagasaki; Yosuke Togashi

  Cell reports 43 (2) 113797 - 113797 2024/02 [Refereed]
   

  Immune checkpoint inhibitors exert clinical efficacy against various types of cancer through reinvigoration of exhausted CD8+ T cells that attack cancer cells directly in the tumor microenvironment (TME). Using single-cell sequencing and mouse models, we show that CXCL13, highly expressed in tumor-infiltrating exhausted CD8+ T cells, induces CD4+ follicular helper T (TFH) cell infiltration, contributing to anti-tumor immunity. Furthermore, a part of the TFH cells in the TME exhibits cytotoxicity and directly attacks major histocompatibility complex-II-expressing tumors. TFH-like cytotoxic CD4+ T cells have high LAG-3/BLIMP1 and low TCF1 expression without self-renewal ability, whereas non-cytotoxic TFH cells express low LAG-3/BLIMP1 and high TCF1 with self-renewal ability, closely resembling the relationship between terminally differentiated and stem-like progenitor exhaustion in CD8+ T cells, respectively. Our findings provide deep insights into TFH-like CD4+ T cell exhaustion with helper progenitor and cytotoxic differentiated functions, mediating anti-tumor immunity orchestrally with CD8+ T cells.
• Hepatitis C virus NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes.

  Hiromichi Dansako; Masanori Ikeda; Yasuo Ariumi; Yosuke Togashi; Nobuyuki Kato

  The FEBS journal 2023/10 [Refereed]
   

  During the replication of viral genomes, RNA viruses produce double-stranded RNA (dsRNA), through the activity of their RNA-dependent RNA polymerases (RdRps) as viral replication intermediates. Recognition of viral dsRNA by host pattern recognition receptors - such as retinoic acid-induced gene-I (RIG-I)-like receptors and Toll-like receptor 3 - triggers the production of interferon (IFN)-β via the activation of IFN regulatory factor (IRF)-3. It has been proposed that, during the replication of viral genomes, each of RIG-I and melanoma differentiation-associated gene 5 (MDA5) form homodimers for the efficient activation of a downstream signalling pathway in host cells. We previously reported that, in the non-neoplastic human hepatocyte line PH5CH8, the RdRp NS5B derived from hepatitis C virus (HCV) could induce IFN-β expression by its RdRp activity without the actual replication of viral genomes. However, the exact mechanism by which HCV NS5B produced IFN-β remained unknown. In the present study, we first showed that NS5B derived from another Flaviviridae family member, GB virus B (GBV-B), also possessed the ability to induce IFN-β in PH5CH8 cells. Similarly, HCV NS5B, but not its G317V mutant, which lacks RdRp activity, induced the dimerization of MDA5 and subsequently the activation of IRF-3. Interestingly, immunofluorescence analysis showed that HCV NS5B produced dsRNA. Like HCV NS5B, GBV-B NS5B also triggered the production of dsRNA and subsequently the dimerization of MDA5. Taken together, our results show that HCV NS5B triggers an MDA5-mediated innate immune response by producing dsRNA without the replication of viral genomes in human hepatocytes.
• Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors.

  Hideki Ikeda; Joji Nagasaki; Daiki Shimizu; Yuki Katsuya; Hidehito Horinouchi; Yukio Hosomi; Etsuko Tanji; Takekazu Iwata; Makiko Itami; Masahito Kawazu; Yuichiro Ohe; Takuji Suzuki; Yosuke Togashi

  JTO clinical and research reports 4 (10) 100573 - 100573 2023/10 [Refereed]
   

  INTRODUCTION: Unresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs). METHODS: We analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II-expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo. RESULTS: We found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti-programmed cell death protein 1 monoclonal antibody. CONCLUSIONS: Half of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs.
• Low frequency of intracranial progression in advanced NSCLC patients treated with cancer immunotherapies.

  Naoya Kemmotsu; Kiichiro Ninomiya; Kei Kunimasa; Takamasa Ishino; Joji Nagasaki; Yoshihiro Otani; Hiroyuki Michiue; Eiki Ichihara; Kadoaki Ohashi; Takako Inoue; Motohiro Tamiya; Kazuko Sakai; Youki Ueda; Hiromichi Dansako; Kazuto Nishio; Katsuyuki Kiura; Isao Date; Yosuke Togashi

  International journal of cancer 2023/08 [Refereed]
   

  Intracranial metastases are common in nonsmall-cell lung cancer (NSCLC) patients, whose prognosis is very poor. In addition, intracranial progression is common during systemic treatments due to the inability to penetrate central nervous system (CNS) barriers, whereas the intracranial effects of cancer immunotherapies remain unclear. We analyzed clinical data to evaluate the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies compared with those treated without PD-1 blockade therapies, and found that the frequency of intracranial progression in advanced NSCLC patients treated with PD-1 blockade therapies was significantly lower than that in patients treated with cytotoxic chemotherapies. In murine models, intracranial rechallenged tumors after initial rejection by PD-1 blockade were suppressed. Accordingly, long-lived memory precursor effector T cells and antigen-specific T cells were increased by PD-1 blockade in intracranial lesions. However, intracranial rechallenged different tumors are not suppressed. Our results indicate that cancer immunotherapies can prevent intracranial progression, maintaining long-term effects intracranially as well as systemically. If intracranial recurrence occurs during the treatment with PD-1 blockade therapies, aggressive local therapies could be worthwhile.
• Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models.

  Naoya Kemmotsu; Li Zhu; Joji Nagasaki; Yoshihiro Otani; Youki Ueda; Hiromichi Dansako; Yue Fang; Isao Date; Yosuke Togashi

  Cancer science 114 (10) 3848 - 3856 2023/07 [Refereed]
   

  Hydrogen peroxide (H2 O2 ) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H2 O2 and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H2 O2 on antitumor immunity remain unclear. To investigate the effects of H2 O2 , especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H2 O2 mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H2 O2 /RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H2 O2 or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor-draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H2 O2 /RT combination group. In addition, analyses of tumor-infiltrating lymphocytes showed that the number of CD8+ (cluster of differentiation 8) T cells and the frequency of IFN-γ+ (interferon gamma) CD8+ T cells were higher in the noninjected/nonirradiated tumors in the H2 O2 /RT group compared to those in the other groups. PD-1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H2 O2 /RT group. Intratumoral injection of H2 O2 combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD-1 blockade. These findings promote the development of H2 O2 /RT therapy combined with cancer immunotherapies, even for advanced cancers.
• High Expression of MHC Class I Overcomes Cancer Immunotherapy Resistance Due to IFNγ Signaling Pathway Defects.

  Katsushige Kawase; Shusuke Kawashima; Joji Nagasaki; Takashi Inozume; Etsuko Tanji; Masahito Kawazu; Toyoyuki Hanazawa; Yosuke Togashi

  Cancer immunology research 11 (7) OF1-OF14 - 908 2023/04 [Refereed]
   

  IFNγ signaling pathway defects are well-known mechanisms of resistance to immune checkpoint inhibitors. However, conflicting data have been reported, and the detailed mechanisms remain unclear. In this study, we have demonstrated that resistance to immune checkpoint inhibitors owing to IFNγ signaling pathway defects may be primarily caused by reduced MHC-I expression rather than by the loss of inhibitory effects on cellular proliferation or decreased chemokine production. In particular, we found that chemokines that recruit effector T cells were mainly produced by immune cells rather than cancer cells in the tumor microenvironment of a mouse model, with defects in IFNγ signaling pathways. Furthermore, we found a response to immune checkpoint inhibitors in a patient with JAK-negative head and neck squamous cell carcinoma whose HLA-I expression level was maintained. In addition, CRISPR screening to identify molecules associated with elevated MHC-I expression independent of IFNγ signaling pathways demonstrated that guanine nucleotide-binding protein subunit gamma 4 (GNG4) maintained MHC-I expression via the NF-κB signaling pathway. Our results indicate that patients with IFNγ signaling pathway defects are not always resistant to immune checkpoint inhibitors and highlight the importance of MHC-I expression among the pathways and the possibility of NF-κB-targeted therapies to overcome such resistance.
• Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity.

  Tomofumi Watanabe; Takamasa Ishino; Youki Ueda; Joji Nagasaki; Takuya Sadahira; Hiromichi Dansako; Motoo Araki; Yosuke Togashi

  Cancer science 114 (5) 1859 - 1870 2023/02 [Refereed]
   

  Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4+ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that only CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.
• Somatic mutations can induce a noninflamed tumour microenvironment via their original gene functions, despite deriving neoantigens.

  Takamasa Ishino; Shusuke Kawashima; Etsuko Tanji; Toshihide Ueno; Youki Ueda; Sadahisa Ogasawara; Kazuhito Sato; Hiroyuki Mano; Soichiro Ishihara; Naoya Kato; Masahito Kawazu; Yosuke Togashi

  British journal of cancer 2023/02 [Refereed]
   

  BACKGROUND: Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME). METHODS: We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets. RESULTS: We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types. CONCLUSIONS: We propose a novel concept of "paradoxical neoantigenic mutations" that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations.
• Tumor-promoting function and regulatory landscape of PD-L2 in B-cell lymphoma.

  Sumito Shingaki; Junji Koya; Mitsuhiro Yuasa; Yuki Saito; Mariko Tabata; Marni B McClure; Seishi Ogawa; Kotoe Katayama; Yosuke Togashi; Seiya Imoto; Yasunori Kogure; Keisuke Kataoka

  Leukemia 37 (2) 492 - 496 2022/12 [Refereed]
  
• Resistance to immune checkpoint inhibitors and the tumor microenvironment.

  Shusuke Kawashima; Yosuke Togashi

  Experimental dermatology 2022/11 [Refereed][Invited]
   

  Immune checkpoint inhibitors (ICIs) have contributed significantly to the treatment of various types of cancer, including skin cancer. However, not all patients respond; some patients do not respond at all (primary resistance), while others experience recurrence after the initial response (acquired resistance). Therefore, overcoming ICI resistance is an urgent priority. Numerous ICI resistance mechanisms have been reported. They are seemingly quite complex, varying from patient to patient. However, most involve T-cell activation processes, especially in the tumor microenvironment (TME). ICIs exert their effects in the TME by reactivating suppressed T cells through inhibition of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1). Thus, this review focuses on the resistance mechanisms based on the T-cell activation process. Here, we classify the main mechanisms of ICI resistance into three categories based on (1) antigen recognition, (2) T-cell migration and infiltration, and (3) effector functions of T cells. By identifying and understanding these resistance mechanisms individually, including unknown mechanisms, we seek to contribute to the development of novel treatments to overcome ICI resistance.
• A variety of 'exhausted' T cells in the tumor microenvironment.

  Joji Nagasaki; Yosuke Togashi

  International immunology 34 (11) 563 - 570 2022/10 [Refereed][Invited]
   

  In T cell biology, 'exhaustion' was initially described as a hyporesponsive state in CD8 + T cells during chronic infections. Recently, exhaustion has been recognized as a T-cell dysfunctional state in the tumor microenvironment (TME). The term 'exhaustion' is used mainly to refer to effector T cells with a reduced capacity to secrete cytokines and an increased expression of inhibitory receptors. The upregulation of exhaustion-related inhibitory receptors, including programmed cell death protein 1 (PD-1), in such T cells has been associated with the development of tumors, prompting the development of immune checkpoint inhibitors. In addition to CD8 + T cells, CD4 + T cells, including the regulatory T (Treg) cell subset, perform a wide variety of functions within the adaptive immune system. Upregulation of the same inhibitory receptors that are associated with CD8 + T-cell exhaustion has also been identified in CD4 + T cells in chronic infections and cancers, suggesting a similar CD4 + T-cell exhaustion phenotype. For instance, high expression of PD-1 has been observed in Treg cells in the TME, and such Treg cells can play an important role in the resistance to PD-1 blockade therapies. Furthermore, recent progress in single-cell RNA sequencing has shown that CD4 + T cells with cytotoxic activity are also vulnerable to exhaustion. In this review, we will discuss novel insights into various exhausted T-cell subsets, which could reveal novel therapeutic targets and strategies to induce a robust antitumor immune response.
• Mechanisms of resistance to immune checkpoint inhibitors.

  Joji Nagasaki; Takamasa Ishino; Yosuke Togashi

  Cancer science 113 (10) 3303 - 3312 2022/10 [Refereed][Invited]
   

  Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.
• Mixed response to cancer immunotherapy is driven by intratumor heterogeneity and differential inter-lesion immune infiltration

  Takao Morinaga; Takashi Inozume; Masahito Kawazu; Youki Ueda; Nicolas Sax; Kazuo Yamashita; Shusuke Kawashima; Joji Nagasaki; Toshihide Ueno; Jason Lin; Yuuki Ohara; Takeshi Kuwata; Hiroki Yukami; Akihito Kawazoe; Kohei Shitara; Akiko Honobe-Tabuchi; Takehiro Ohnuma; Tatsuyoshi Kawamura; Yoshiyasu Umeda; Yu Kawahara; Yasuhiro Nakamura; Yukiko Kiniwa; Ayako Morita; Eiki Ichihara; Katsuyuki Kiura; Tomohiro Enokida; Makoto Tahara; Yoshinori Hasegawa; Hiroyuki Mano; Yutaka Suzuki; Hiroyoshi Nishikawa; Yosuke Togashi

  Cancer Research Communications American Association for Cancer Research (AACR) 2 (7) 739 - 753 2022/07 [Refereed]
   

  Abstract Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TILs) demonstrated a significant difference in tumor clonality and TILs’ characteristics, especially exhausted T cell clonotypes, although a close relationship between the tumor cell and T cell clones were observed as a response of an overlapped exhausted T cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to PD-1 blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
• PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes.

  Joji Nagasaki; Takashi Inozume; Nicolas Sax; Ryo Ariyasu; Masakazu Ishikawa; Kazuo Yamashita; Masahito Kawazu; Toshihide Ueno; Takuma Irie; Etsuko Tanji; Takao Morinaga; Akiko Honobe; Takehiro Ohnuma; Mitsuru Yoshino; Takekazu Iwata; Katsushige Kawase; Keita Sasaki; Toyoyuki Hanazawa; Vitaly Kochin; Tatsuyoshi Kawamura; Hiroyuki Matsue; Masayuki Hino; Hiroyuki Mano; Yutaka Suzuki; Hiroyoshi Nishikawa; Yosuke Togashi

  Cell reports 38 (5) 110331 - 110331 2022/02 [Refereed]
   

  PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.
• Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.

  Shogo Kumagai; Shohei Koyama; Kota Itahashi; Tokiyoshi Tanegashima; Yi-Tzu Lin; Yosuke Togashi; Takahiro Kamada; Takuma Irie; Genki Okumura; Hidetoshi Kono; Daisuke Ito; Rika Fujii; Sho Watanabe; Atsuo Sai; Shota Fukuoka; Eri Sugiyama; Go Watanabe; Takuya Owari; Hitomi Nishinakamura; Daisuke Sugiyama; Yuka Maeda; Akihito Kawazoe; Hiroki Yukami; Keigo Chida; Yuuki Ohara; Tatsuya Yoshida; Yuki Shinno; Yuki Takeyasu; Masayuki Shirasawa; Kenta Nakama; Keiju Aokage; Jun Suzuki; Genichiro Ishii; Takeshi Kuwata; Naoya Sakamoto; Masahito Kawazu; Toshihide Ueno; Taisuke Mori; Naoya Yamazaki; Masahiro Tsuboi; Yasushi Yatabe; Takahiro Kinoshita; Toshihiko Doi; Kohei Shitara; Hiroyuki Mano; Hiroyoshi Nishikawa

  Cancer cell 40 (2) 201 - 218 2022/01 [Refereed]
   

  The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
• Preoperative Chemoradiotherapy Plus Nivolumab Before Surgery in Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer Patients.

  Hideaki Bando; Yuichiro Tsukada; Koji Inamori; Yosuke Togashi; Shohei Koyama; Daisuke Kotani; Shota Fukuoka; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Akinobu Taketomi; Mamoru Uemura; Takeshi Kato; Makoto Fukui; Masashi Wakabayashi; Naoki Nakamura; Motohiro Kojima; Hiroshi Kawachi; Richard Kirsch; Tsutomu Yoshida; Yutaka Suzuki; Akihiro Sato; Hiroyoshi Nishikawa; Masaaki Ito; Takayuki Yoshino

  Clinical cancer research : an official journal of the American Association for Cancer Research 28 (6) 1136 - 1146 2022/01 [Refereed]
   

  BACKGROUND: Preoperative chemoradiotherapy (CRT) and surgical resection are standard treatment for locally advanced rectal cancer (LARC). Combining immune-checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. METHODS: In phase I, we investigated the feasibility of sequentially-combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. RESULTS: Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathological complete response (pCR) was centrally confirmed in 30% (11/37; 90% CI, 18 %-44%) and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30) (p=0.004, Fisher's exact test) were observed in those with PD-L1 tumor proportion score {greater than or equal to}1% and <1%, respectively; immunohistochemical staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15) (p=0.003, Fisher's exact test) were observed for CD8+-T cell / effector regulatory-T cell (CD8/eTreg) ratios of {greater than or equal to} 2.5 and < 2.5, respectively, in tumor-infiltrating lymphocytes. CONCLUSIONS: CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.
• Programmed Death-Ligand 1-Rich Premetastatic Niche in Adjuvant Chemotherapy.

  Hiromasa Yamamoto; Yosuke Togashi

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 17 (1) 10 - 12 2022/01 [Refereed][Invited]
  
• Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer.

  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 [Refereed]
   

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

  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 [Refereed]
   

  [Figure: see text].
• TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment.

  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 [Refereed]
   

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

  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 162 (3) 799 - 812 2021/10 [Refereed]
   

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

  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 2021/09 [Refereed]
   

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

  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) 2021/05 [Refereed]
   

  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.
• Aging, cancer, and antitumor immunity.

  Hideki Ikeda; Yosuke Togashi

  International journal of clinical oncology 2021/03 [Refereed][Invited]
   

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

  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 2021/03 [Refereed]
   

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

  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 2021/01 [Refereed]
   

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

  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 2021/01 [Refereed]
   

  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.).
• Heterogeneity in congenital melanocytic nevi contributes to multicentric melanomagenesis.

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

  Journal of dermatological science 100 (3) 217 - 219 2020/12 [Refereed]
  
• The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies.

  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 [Refereed]
   

  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.
• 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.

  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 6 (12) 1931 - 1938 2020/10 [Refereed]
   

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

  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 2020/09 [Refereed]
   

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

  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 2020/09 [Refereed]
   

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

  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 26 (22) 5887 - 5894 2020/07 [Refereed]
   

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

  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 2020/07 [Refereed]
   

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

  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 2020/07 [Refereed]
   

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

  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 2020/06 [Refereed]
   

  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.
• 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.

  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 2020/04 [Refereed]
   

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

  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 2020/04 [Refereed]
   

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

  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) 2020/01 [Refereed]
   

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

  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 AMER ASSOC CANCER RESEARCH 18 (12) 1535-7163 2019/12 [Refereed]
  
• Clinical and immune profiling for cancer of unknown primary site.

  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 BMJ 7 (1) 251  2019/09 [Refereed]
  
• Selective inhibition of low-affinity memory CD8⁺ T cells by corticosteroids.

  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 0022-1007 2019/09 [Refereed]
   

  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.
• 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.

  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 0022-202X 2019/07 [Refereed]
   

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

  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 1078-0432 2019/05 [Refereed]
  
• PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer.

  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 0027-8424 2019/04 [Refereed]
   

  PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA-CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1- eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.
• 非小細胞肺癌において上皮成長因子受容体が変異活性化すると細胞外シグナル調節キナーゼを介して主要組織適合遺伝子複合体クラスIの発現が下方制御される(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)

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

  Cancer Science John Wiley & Sons Australia, Ltd 110 (1) 52 - 60 1347-9032 2019/01 

  非小細胞肺癌の細胞株や患者由来検体を実験材料とし、上皮成長因子受容体(EGFR)チロシンキナーゼ阻害薬(TKI)がMHCクラスIの発現に及ぼす影響について調査した。EGFR遺伝子にT790M二次的突然変異などの変異がある細胞株を適切なEGFR-TKIで処理するとMHCクラスIのmRNA/蛋白質発現は亢進した。細胞外シグナル調節キナーゼ(ERK)キナーゼであるMEKの阻害薬で処理した場合もMHCクラスI発現が亢進したことから、EGFR活性化に応答してみられるMHCクラスI発現の下方制御はMEK-ERK経路が媒介していることが示唆された。EGFR-TKI治療を施行したEGFR変異非小細胞肺癌患者から得た検体の免疫組織化学解析からも、疾患進行後においては、リン酸化EGFRやリン酸化ERKの下方制御が、MHC-Iの上方制御、CD8+浸潤T細胞の増加、およびPD-1リガンド1発現亢進と関連していることが明らかになった。これらの結果から、非小細胞癌においてEGFRが変異活性化するとMEK-ERK経路を通じてMHCクラスI発現が阻害され、免疫療法に不応となるのに寄与することが示唆された。
• Regulatory T cells in cancer immunosuppression - implications for anticancer therapy.

  Togashi Y; Shitara K; Nishikawa H

  Nature reviews. Clinical oncology NATURE PORTFOLIO 16 (6) 356 - 371 1759-4774 2019/01 [Refereed]
   

  Regulatory T (T-reg) cells, an immunosuppressive subset of CD4(+) T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, T-reg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in T-reg cells and/or that influence T-reg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in T-reg cells, but the effects of ICIs on T-reg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of T-reg cells, whereas cytotoxic T lymphocyte antigen 4 (CTL A-4) inhibitors might deplete these cells. Thus, although manipulation of T-reg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of T-reg cells in cancer, which can hopefully be used to develop T-reg cell-targeted therapies and facilitate immune precision medicine.
• 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.

  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 1347-9032 2019/01 [Refereed]
   

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

  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 [Refereed]
   

  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.
• Clinicopathological features of 22C3 PD-L1 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

  Gastric Cancer Springer Tokyo 1 - 8 1436-3305 2018/06 [Refereed]
   

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

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

  https://jitc.biomedcentral.com 36 (5) 0732-183X 2018/02 [Refereed]
  
• Suppression from beyond the grave

  Yosuke Togashi; Hiroyoshi Nishikawa

  NATURE IMMUNOLOGY NATURE PUBLISHING GROUP 18 (12) 1285 - 1286 1529-2908 2017/12 [Refereed]
   

  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.
• 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

  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 OXFORD UNIV PRESS 28 (7) 1532 - 1539 0923-7534 2017/07 [Refereed]
   

  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 >= 1% or <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 >= 10% and >= 50%. The proportion of tumors with a PD-L1 level of >= 10% or >= 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.
• Clinical significance of Akt2 in advanced pancreatic cancer treated with erlotinib

  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 SPANDIDOS PUBL LTD 50 (6) 2049 - 2058 1019-6439 2017/06 [Refereed]
   

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

  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 BIOMED CENTRAL LTD 17 (1) 281  1471-2407 2017/04 [Refereed]
   

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

  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 AMER ASSOC CANCER RESEARCH 16 (2) 357 - 364 1535-7163 2017/02 [Refereed]
   

  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.
• 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

  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 WILEY-BLACKWELL 56 (1) 106 - 117 0899-1987 2017/01 [Refereed]
   

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

  Yosuke Togashi; Hiroyoshi Nishikawa

  EMERGING CONCEPTS TARGETING IMMUNE CHECKPOINTS IN CANCER AND AUTOIMMUNITY SPRINGER INTERNATIONAL PUBLISHING AG 410 3 - 27 0070-217X 2017 [Refereed]
   

  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.
• 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

  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 John Wiley and Sons Inc. 56 (1) 106 - 117 1098-2744 2017/01 [Refereed]
   

  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. © 2016 Wiley Periodicals, Inc.
• MEK inhibitors against MET-amplified non-small cell lung cancer

  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 SPANDIDOS PUBL LTD 49 (6) 2236 - 2244 1019-6439 2016/12 [Refereed]
   

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

  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 WILEY-BLACKWELL 107 (11) 1667 - 1676 1347-9032 2016/11 [Refereed]
   

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

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

  LUNG CANCER ELSEVIER IRELAND LTD 101 11 - 15 0169-5002 2016/11 [Refereed]
   

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

  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 AMER ASSOC CANCER RESEARCH 15 (8) 1988 - 1997 1535-7163 2016/08 [Refereed]
   

  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.
• 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?

  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 WILEY-BLACKWELL 107 (8) 1134 - 1140 1347-9032 2016/08 [Refereed]
   

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

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

  CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH 22 (14) 3663 - 3671 1078-0432 2016/07 [Refereed]
   

  Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-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.
• EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs

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

  CLINICAL CANCER RESEARCH AMER ASSOC CANCER RESEARCH 21 (23) 5305 - 5313 1078-0432 2015/12 [Refereed]
   

  Purpose: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Experimental Design: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (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 > 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.
• Clinicopathological and Genetic Differences Between Low-Grade and High-Grade Colorectal Mucinous Adenocarcinomas

  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 WILEY-BLACKWELL 121 (24) 4359 - 4368 0008-543X 2015/12 [Refereed]
   

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

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

  LUNG CANCER ELSEVIER IRELAND LTD 90 (3) 590 - 597 0169-5002 2015/12 [Refereed]
   

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

  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 SPRINGER 76 (5) 989 - 996 0344-5704 2015/11 [Refereed]
   

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

  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 OXFORD UNIV PRESS 26 (8) 1800 - 1801 0923-7534 2015/08 [Refereed]
  
• EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition

  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 SPANDIDOS PUBL LTD 47 (2) 499 - 505 1019-6439 2015/08 [Refereed]
   

  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.
• [Kinase inhibitors and their resistance].

  Togashi Y; Nishio K

  Nihon rinsho. Japanese journal of clinical medicine 73 (8) 1323 - 1329 0047-1852 2015/08 [Refereed]
  
• Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study

  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 WILEY-BLACKWELL 106 (7) 883 - 890 1347-9032 2015/07 [Refereed]
   

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

  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 PUBLIC LIBRARY SCIENCE 10 (5) e0121891  1932-6203 2015/05 [Refereed]
   

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

  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 ELSEVIER IRELAND LTD 88 (1) 16 - 23 0169-5002 2015/04 [Refereed]
   

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

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

  ANTICANCER RESEARCH INT INST ANTICANCER RESEARCH 35 (4) 2005 - 2008 0250-7005 2015/04 [Refereed]
   

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

  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 SPANDIDOS PUBL LTD 46 (3) 1025 - 1030 1019-6439 2015/03 [Refereed]
   

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

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

  BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ACADEMIC PRESS INC ELSEVIER SCIENCE 458 (1) 52 - 56 0006-291X 2015/02 [Refereed]
   

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

  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 NATURE PUBLISHING GROUP 34 (2) 199 - 208 0950-9232 2015/01 [Refereed]
   

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

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

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 10 (1) 116 - 125 1556-0864 2015/01 [Refereed]
   

  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 (>= Gr2 RP) and worse than grade 3 (>= Gr3 RP) were significantly higher in ILD(+) than ILD(-) (1 year >= Gr2 RP rate, 55.0% versus 13.3%; p < 0.001 and 1year >= Gr3 RP rate 10.0% versus 1.5%; p = 0.020). Multivariate analysis also indicated that ILD(+) was a risk factor for >= Gr2 and >= 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.
• Inhibition of beta-Catenin Enhances the Anticancer Effect of Irreversible EGFR-TKI in EGFR-Mutated Non-small-cell Lung Cancer with a T790M Mutation

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

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 10 (1) 93 - 101 1556-0864 2015/01 [Refereed]
   

  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.
• 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; Kiyotaka Okuno; Masatoshi Kudo; Kazuto Nishio

  CANCER LETTERS ELSEVIER IRELAND LTD 356 (2) 819 - 827 0304-3835 2015/01 [Refereed]
   

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

  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 SPRINGER INTERNATIONAL PUBLISHING AG 4 7  2193-1801 2015/01 [Refereed]
   

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

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

  INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 54 (3) 325 - 331 0918-2918 2015 [Refereed]
   

  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.
• MEK Inhibitor for Gastric Cancer with MEK1 Gene Mutations

  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 AMER ASSOC CANCER RESEARCH 13 (12) 3098 - 3106 1535-7163 2014/12 [Refereed]
   

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

  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 SPANDIDOS PUBL LTD 45 (4) 1430 - 1436 1019-6439 2014/10 [Refereed]
   

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

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

  ONCOTARGET IMPACT JOURNALS LLC 5 (16) 7040 - 7050 1949-2553 2014/08 [Refereed]
   

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

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

  SPRINGERPLUS SPRINGER INTERNATIONAL PUBLISHING AG 3 417  2193-1801 2014/08 [Refereed]
   

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

  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 IMPACT JOURNALS LLC 5 (9) 2588 - 2595 1949-2553 2014/05 [Refereed]
   

  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.
• 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; Akihiko Ito; Masatoshi Kudo; Kazuto Nishio

  MOLECULAR CANCER BIOMED CENTRAL LTD 13 126  1476-4598 2014/05 [Refereed]
   

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

  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 IMPACT JOURNALS LLC 5 (10) 2962 - 2973 1949-2553 2014/05 [Refereed]
   

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

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

  PLOS ONE PUBLIC LIBRARY SCIENCE 9 (4) e94772  1932-6203 2014/04 [Refereed]
   

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

  Yosuke Togashi; Hidetoshi Hayashi; Kazuhiko Nakagawa; Kazuto Nishio

  DRUG DESIGN DEVELOPMENT AND THERAPY DOVE MEDICAL PRESS LTD 8 1037 - 1046 1177-8881 2014 [Refereed]
   

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

  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 ADIS INT LTD 52 (7) 593 - 609 0312-5963 2013/07 [Refereed]
   

  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 > T, 2677G > T/A, 3435C > T), ABCG2 (421C > A), and CYP3A5 (6986A > 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 < 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 < 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.
• Continuous morphine infusion for end-stage lung cancer patients

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

  ONCOLOGY LETTERS SPANDIDOS PUBL LTD 5 (3) 972 - 974 1792-1074 2013/03 [Refereed]
   

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

  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 1792-1074 2013/02 [Refereed]
   

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

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

  Oncology 84 (4) 214 - 8 0030-2414 2013 [Refereed]
   

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

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

  MEDICAL ONCOLOGY HUMANA PRESS INC 29 (5) 3169 - 3175 1357-0560 2012/12 [Refereed]
   

  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 < 0.0001), and tumors without vascular-poor area (P < 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 > 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.
• 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

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

  MEDICAL ONCOLOGY HUMANA PRESS INC 29 (3) 1614 - 1621 1357-0560 2012/09 [Refereed]
   

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

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

  CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 13 (5) 385 - 390 1525-7304 2012/09 [Refereed]
   

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

  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 SPRINGER 70 (3) 399 - 405 0344-5704 2012/09 [Refereed]
   

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

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

  CIRCULATION LIPPINCOTT WILLIAMS & WILKINS 126 (13) E195 - E197 0009-7322 2012/09 [Refereed]
  
• Successful erlotinib rechallenge for leptomeningeal metastases of lung adenocarcinoma after erlotinib-induced interstitial lung disease: A case report and review of the literature

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

  LUNG CANCER ELSEVIER IRELAND LTD 77 (2) 464 - 468 0169-5002 2012/08 [Refereed]
   

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

  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 SPRINGER 70 (2) 271 - 276 0344-5704 2012/08 [Refereed]
   

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

  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 SPANDIDOS PUBL LTD 41 (1) 24 - 30 1019-6439 2012/07 [Refereed]
   

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

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

  CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 13 (4) 304 - 311 1525-7304 2012/07 [Refereed]
   

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

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

  CANCER SCIENCE WILEY-BLACKWELL 103 (6) 1065 - 1070 1347-9032 2012/06 [Refereed]
   

  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)
• 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

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

  MEDICAL ONCOLOGY HUMANA PRESS INC 29 (1) 185 - 192 1357-0560 2012/03 [Refereed]
   

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

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

  LUNG CANCER ELSEVIER IRELAND LTD 74 (1) 98 - 102 0169-5002 2011/10 [Refereed]
   

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

  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 SPRINGER 68 (4) 1089 - 1092 0344-5704 2011/10 [Refereed]
   

  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.
• 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

  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 SPANDIDOS PUBL LTD 26 (4) 795 - 803 1021-335X 2011/10 [Refereed]
   

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

  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 CIG MEDIA GROUP, LP 12 (5) 307 - 312 1525-7304 2011/09 [Refereed]
   

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

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

  INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY SPRINGER TOKYO 16 (4) 444 - 446 1341-9625 2011/08 [Refereed]
   

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

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

  JOURNAL OF CLINICAL ONCOLOGY AMER SOC CLINICAL ONCOLOGY 29 (16) E465 - E467 0732-183X 2011/06 [Refereed]
  
• Two Cases of Cancer-associated Retinopathy Combined with Small-cell Lung Cancer

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

  JAPANESE JOURNAL OF CLINICAL ONCOLOGY OXFORD UNIV PRESS 41 (5) 669 - 673 0368-2811 2011/05 [Refereed]
   

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

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

  JAPANESE JOURNAL OF CLINICAL ONCOLOGY OXFORD UNIV PRESS 41 (4) 582 - 585 0368-2811 2011/04 [Refereed]
   

  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.
• 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

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

  MEDICAL ONCOLOGY HUMANA PRESS INC 28 (1) 351 - 356 1357-0560 2011/03 [Refereed]
   

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

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

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 6 (3) 641 - 642 1556-0864 2011/03 [Refereed]
  
• Association between brain natriuretic peptide and distant metastases in advanced non-small cell lung cancer patients

  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 SPANDIDOS PUBL LTD 2 (2) 253 - 256 1792-1074 2011/03 [Refereed]
   

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

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

  ONCOLOGY LETTERS SPANDIDOS PUBL LTD 2 (2) 383 - 387 1792-1074 2011/03 [Refereed]
   

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

  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 SPRINGER 67 (2) 325 - 330 0344-5704 2011/02 [Refereed]
   

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

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

  CANCER WILEY-BLACKWELL PUBLISHING, INC 117 (4) 819 - 825 0008-543X 2011/02 [Refereed]
   

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

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

  ONCOLOGY REPORTS SPANDIDOS PUBL LTD 25 (2) 377 - 382 1021-335X 2011/02 [Refereed]
   

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

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

  CLINICAL LUNG CANCER CIG MEDIA GROUP, LP 12 (1) 56 - 61 1525-7304 2011/01 [Refereed]
   

  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 < 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 > 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.
• Infectious background of febrile advanced lung cancer patients who received chemotherapy

  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 SPANDIDOS PUBL LTD 1 (5) 849 - 853 1792-1074 2010/09 [Refereed]
   

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

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

  TOHOKU JOURNAL OF EXPERIMENTAL MEDICINE TOHOKU UNIV MEDICAL PRESS 222 (1) 51 - 53 0040-8727 2010/09 [Refereed]
   

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

  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 LIPPINCOTT WILLIAMS & WILKINS 5 (7) 950 - 955 1556-0864 2010/07 [Refereed]
   

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

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

  JOURNAL OF THORACIC ONCOLOGY LIPPINCOTT WILLIAMS & WILKINS 5 (6) 924 - 925 1556-0864 2010/06 [Refereed]
  
• 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

  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 LIPPINCOTT WILLIAMS & WILKINS 5 (5) 601 - 605 1556-0864 2010/05 [Refereed]
   

  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.
• 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.

  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 1662-6575 2010/04 [Refereed]
   

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

  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 1662-6575 2010/03 [Refereed]
   

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

  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 KARGER 79 (5-6) 355 - 362 0030-2414 2010 [Refereed]
   

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

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

  [Rinsho ketsueki] The Japanese journal of clinical hematology (一社)日本血液学会-東京事務局 49 (8) 664 - 667 0485-1439 2008/08 [Refereed]
   

  症例はLoeys-Dietz症候群(LDS)の54歳男性で、易疲労を主訴とした。患者の長男はLDSで、父と弟にLDSの疑いがある。入院時血液検査にて、芽球の存在、白血球の増加、ヘモグロビン及び血小板の減少を認め、骨髄検査にて芽球(peroxidase染色及びesterase染色陽性)を認めた。また、染色体検査にてt(11;19)(q23;p13.1)を認め、PT-PCRにてMLL遺伝子異常を認めた。以上より、11q23(MLL)異常を有する急性骨髄性白血病(M4)と診断し、idarubicinとcytarabineの寛解導入を開始し、完全寛解を得た。その後、寛解後療法を3クール行った。なお、LDSと悪性腫瘍の合併の報告は本例が最初である。
• 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 (一財)住友病院 (35) 45 - 50 0285-8177 2008/07 

  症例は85歳,女性.50歳頃から家族性高コレステロール血症の診断にて治療を開始,75歳時には解離性大動脈瘤を認め保存的に経過観察されていた.数日前より全身の紫斑に気付き当院受診し,大動脈瘤に起因する慢性播種性血管内凝固症候群(DIC)と診断された.動脈瘤に対する手術は困難であったため,蛋白分解酵素阻害薬であるメシル酸カモスタットと抗線溶薬であるトラネキサム酸とを併用したところ,DICはコントロールでき外来通院可能となった.本症例は家族性高コレステロール血症に合併しており,高度の動脈硬化のため動脈瘤内に多量の血栓を形成し慢性DICを呈したものと考えられた.大血管病変に起因する慢性DICに対する治療は標準化されておらず,適切な治療を確立するためにも今後多数例での前向きの検討が望まれる.(著者抄録)
• A Japanese family of typical loeys-dietz syndrome with a TGFBR2 mutation

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

  INTERNAL MEDICINE JAPAN SOC INTERNAL MEDICINE 46 (24) 1995 - 2000 0918-2918 2007 [Refereed]
   

  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.

Books etc

• 「特集」免疫チェックポイント : 阻害薬の"耐性"に挑む : がん免疫サイクルから見出す戦略

  冨樫, 庸介 羊土社 2022/10 9784758125604 p2550-2676

Conference Activities & Talks

• Treg細胞の活性化CTLA-4非依存性免疫抑制によるCTLA-4遮断の不安定な抗腫瘍効果(Disturbed anti-tumor effect of CTLA-4 blockade by activated CTLA-4-independent immunosuppression of Treg cells)

  渡部 智文; 石野 貴雅; 上田 優輝; 長崎 譲慈; 河田 達志; 定平 卓也; 岩田 健宏; 片山 聡; 枝村 康平; 小林 泰之; 團迫 浩方; 荒木 元朗; 冨樫 庸介

  西日本泌尿器科学会総会抄録集  2023/11  (一社)西日本泌尿器科学会
  
• Treg細胞の活性化CTLA-4非依存性免疫抑制によるCTLA-4遮断の不安定な抗腫瘍効果(Disturbed anti-tumor effect of CTLA-4 blockade by activated CTLA-4-independent immunosuppression of Treg cells)

  渡部 智文; 石野 貴雅; 上田 優輝; 長崎 譲慈; 河田 達志; 定平 卓也; 岩田 健宏; 片山 聡; 枝村 康平; 小林 泰之; 團迫 浩方; 荒木 元朗; 冨樫 庸介

  西日本泌尿器科学会総会抄録集  2023/11  (一社)西日本泌尿器科学会
  
• CTLA-4の単純な阻害はTreg細胞のCTLA-4以外の免疫抑制機構の活性化を引き起こす(Anti-tumor effects of CTLA-4 blockade are distrubed by activated CTLA-4-independent immunosuppression of Treg cells)

  渡部 智文; 石野 貴雅; 上田 優輝; 長崎 譲慈; 丸山 雄樹; 河田 達志; 定平 卓也; 岩田 健宏; 片山 聡; 西村 慎吾; 枝村 康平; 小林 知子; 小林 泰之; 團迫 浩方; 荒木 元朗; 冨樫 庸介

  日本癌学会総会記事  2023/09  (一社)日本癌学会
  
• プレシジョンがん免疫療法の開発に向けた研究

  猪爪 隆史; 川島 秀介; 松澤 高光; 松江 弘之; 田渕 亜希子; 大沼 毅紘; 川村 龍吉; 島田 眞路; 冨樫 庸介

  日本皮膚科学会雑誌  2022/10  (公社)日本皮膚科学会
  
• 中型先天性色素性母斑とそこから生じた悪性黒色腫における遺伝子変異状況の比較

  保延 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  2022/10  (公社)日本皮膚科学会
  
• その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neontigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

  石野 貴雅; 上野 敏秀; 上田 優輝; 間野 博行; 石原 聡一郎; 加藤 直也; 河津 正人; 冨樫 庸介

  日本癌学会総会記事  2022/09  (一社)日本癌学会
  
• その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neoantigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

  石野 貴雅; 上野 敏秀; 上田 優輝; 間野 博行; 石原 聡一郎; 加藤 直也; 河津 正人; 冨樫 庸介

  日本癌学会総会記事  2022/09  (一社)日本癌学会
  
• 腫瘍微小環境の1細胞解析(Single-cell analyses for the tumor microenvironment)

  冨樫 庸介

  日本癌学会総会記事  2022/09  (一社)日本癌学会
  
• 腫瘍微小環境における制御性T細胞に特徴的な代謝学的チェックポイントの同定(Identification of a distinctive metabolic checkpoint of regulatory T cells in the tumor microenvironment)

  熊谷 尚悟; 小山 正平; 板橋 耕太; 冨樫 庸介; 吉田 達哉; 石井 源一郎; 河津 正人; 山崎 直也; 坪井 正博; 谷田部 恭; 木下 敬弘; 土井 俊彦; 設楽 絋平; 間野 博行; 西川 博嘉

  日本癌学会総会記事  2022/09  (一社)日本癌学会
  
• がん免疫療法の現状の課題と今後の期待

  冨樫 庸介

  日本がん免疫学会総会プログラム・抄録集  2022/06  日本がん免疫学会
  
• B細胞性リンパ腫におけるPD-L2の生物学的機能と調節機序の解析(Dissecting biological function and regulation of PD-L2 in B-cell lymphoma)

  新垣 清登; 古屋 淳史; 湯淺 光博; 斎藤 優樹; 田畑 真梨子; Marni McClure; 片山 琴絵; 冨樫 庸介; 井元 清哉; 木暮 泰寛; 片岡 圭亮

  日本リンパ網内系学会会誌  2022/06  (一社)日本リンパ網内系学会
  
• がん免疫療法のバイオマーカー

  冨樫 庸介

  日本臨床細胞学会雑誌  2022/05  (公社)日本臨床細胞学会
  
• 消化器癌における免疫治療と分子標的治療の基礎研究と臨床 腫瘍微小環境から考えるがん免疫療法

  冨樫 庸介

  日本消化器病学会雑誌  2022/03  (一財)日本消化器病学会
  
• Precision Medicine of Cancer Immunotherapy

  Yosuke Togashi

  CANCER SCIENCE  2022/02  WILEY
  
• Technology for analyses in cancer immunology

  Yosuke Togashi

  CANCER SCIENCE  2022/02  WILEY
  
• 大腸癌周術期治療の臨床開発と将来展望 進行直腸癌に対する化学放射線療法と免疫チェックポイント阻害剤を用いた術前治療

  塚田 祐一郎; 坂東 英明; 稲守 宏冶; 冨樫 庸介; 結城 敏志; 小松 嘉人; 本間 重紀; 武冨 紹信; 植村 守; 加藤 健志; 若林 将史; 佐藤 暁洋; 西川 博嘉; 伊藤 雅昭; 吉野 孝之

  日本癌治療学会学術集会抄録集  2021/10  (一社)日本癌治療学会
  
• 胸部腫瘍(非小細胞肺癌を除く)に対する複合免疫療法を考える(Mechanisms and Application of Immune Checkpoint Inhibitors Against Thoracic Malignancies Other than NSCLC)

  冨樫 庸介

  肺癌  2021/10  (NPO)日本肺癌学会
  
• がん免疫とは何か 解析手法の基礎

  冨樫 庸介

  日本癌学会総会記事  2021/09  (一社)日本癌学会
  
• 変革する病理学:形態診断から普遍的研究プラットフォームへ がん免疫療法の個別化医療を目指して

  冨樫 庸介

  日本癌学会総会記事  2021/09  (一社)日本癌学会
  
• がん免疫療法の個別化医療を目指して

  冨樫 庸介

  日本癌学会総会記事  2021/09  (一社)日本癌学会
  
• Efficacy predictors of preoperative CRT and consolidation nivolumab in patients with locally advanced rectal cancer

  Koji Inamori; Yosuke Togashi; Hideaki Bando; Yuichiro Tsukada; Shota Fukuoka; Ayako Suzuki; Yutaka Suzuki; Daisuke Kotani; Motohiro Kojima; Makoto Fukui; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Akinobu Taketomi; Mamoru Uemura; Takeshi Kato; Masaaki Ito; Hiroyoshi Nishikawa; Takayuki Yoshino

  ANNALS OF ONCOLOGY  2021/07  ELSEVIER
  
• 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  2021/05  日本がん免疫学会
  
• 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  2021/05  日本がん免疫学会
  
• 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  2021/05  日本がん免疫学会
  
• 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  2021/05  (公社)日本皮膚科学会
  
• Translational research of VOLTAGE-A: Efficacy predictors of preoperative chemoradiotherapy and consolidation nivolumab in patients with both microsatellite stable and microsatellite instability-high locally advanced rectal cancer

  Koji Inamori; Yosuke Togashi; Hideaki Bando; Yuichiro Tsukada; Shota Fukuoka; Ayako Suzuki; Yutaka Suzuki; Daisuke Kotani; Motohiro Kojima; Makoto Fukui; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Akinobu Taketomi; Mamoru Uemura; Takeshi Kato; Masaaki Ito; Hiroyoshi Nishikawa; Takayuki Yoshino

  JOURNAL OF CLINICAL ONCOLOGY  2021/01  LIPPINCOTT WILLIAMS & WILKINS
  
• 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  2020/12  (一社)日本泌尿器科学会総会事務局
  
• 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  2020/12  (一社)日本泌尿器科学会総会事務局
  
• 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  2020/10  (一社)日本癌学会
  
• 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  2020/10  西日本泌尿器科学会
  
• 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  2020/10  (一社)日本癌学会
  
• 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  2020/08  (一社)日本呼吸器学会
  
• Translational research of voltage-A1: Efficacy predictors of preoperative chemoradiotherapy and subsequent nivolumab monotherapy in patients with microsatellite-stable locally advanced rectal cancer.

  Koji Inamori; Yosuke Togashi; Hideaki Bando; Yuichiro Tsukada; Ayako Suzuki; Yutaka Suzuki; Daisuke Kotani; Shota Fukuoka; Motohiro Kojima; Makoto Fukui; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Mamoru Uemura; Takeshi Kato; Masaaki Ito; Hiroyoshi Nishikawa; Takayuki Yoshino

  JOURNAL OF CLINICAL ONCOLOGY  2020/05  LIPPINCOTT WILLIAMS & WILKINS
  
• Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.

  Satoshi Yuki; Hideaki Bando; Yuichiro Tsukada; Koji Inamori; Yoshito Komatsu; Shigenori Homma; Mamoru Uemura; Takeshi Kato; Daisuke Kotani; Shota Fukuoka; Naoki Nakamura; Makoto Fukui; Masashi Wakabayashi; Motohiro Kojima; Yosuke Togashi; Akihiro Sato; Hiroyoshi Nishikawa; Masaaki Ito; Takayuki Yoshino

  JOURNAL OF CLINICAL ONCOLOGY  2020/05  LIPPINCOTT WILLIAMS & WILKINS
  
• 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  2019/11  (NPO)日本肺癌学会
  
• EGFR-TKIによる腫瘍微小環境の免疫状態の変化  [Not invited]

  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  2019/11  (NPO)日本肺癌学会
  
• Novel biomarkers for immunotherapies The role of soluble immune-checkpoint factors in advanced NSCLC(和訳中)  [Not invited]

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

  肺癌  2019/11  (NPO)日本肺癌学会
  
• A novel regulatory T Cell-Targeted Immunotherapy by targeting their crucial signal by HSP90 inhibitors

  Ayaka Tsuge; Yosuke Togashi; Kohei Shitara; Hiroyoshi Nishikawa

  JOURNAL FOR IMMUNOTHERAPY OF CANCER  2019/11  BMC
  
• 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)  [Not invited]

  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  2019/09  日本癌学会
  
• 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)  [Not invited]

  冨樫 庸介

  日本癌学会総会記事  2019/09  日本癌学会
  
• 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  [Not invited]

  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  2019/07
• 『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?  [Not invited]

  冨樫 庸介

  日本がん免疫学会総会プログラム・抄録集  2019/07
• 腫瘍に発現するPD-L2の免疫抑制機能について  [Not invited]

  種子島 時祥; 冨樫 庸介; 江藤 正俊; 西川 博嘉

  腎癌研究会会報  2019/07
• Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.

  Takayuki Yoshino; Hideaki Bando; Yuichiro Tsukada; Koji Inamori; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Mamoru Uemura; Takeshi Kato; Daisuke Kotani; Shota Fukuoka; Takeshi Sasaki; Yuji Nishizawa; Naoki Nakamura; Masashi Wakabayashi; Motohiro Kojima; Yosuke Togashi; Akihiro Sato; Hiroyoshi Nishikawa; Masaaki Ito

  JOURNAL OF CLINICAL ONCOLOGY  2019/05  AMER SOC CLINICAL ONCOLOGY
  
• The secondary immune selection is the dominant mechanism for acquired resistance against adoptive cell therapy  [Not invited]

  Takahiro Kamada; Yosuke Togashi; Yoshihiro Ohue; Hiroyoshi Nishikawa

  AACR Annual Meeting 2019  2019/03
• The association of genomic features and immunosuppression in gastric cancer.  [Not invited]

  Shogo Kumagai; Yosuke Togashi; Kohei Shitara; Takahiro Kinoshita; Katsuya Tsuchihara; Hiroyoshi Nishikawa

  AACR Annual Meeting 2019  2019/03
• An Open Label Phase I Study to Evaluate the Safety and Efficacy of OBP-301 With Pembrolizumab in Patients With Advanced Solid Tumors (EPOC1505)  [Not invited]

  Takashi Kojima; Toshiyoshi Fujiwara; Yasuhiro Shirakawa; Keisuke Hori; Hiromi Ono; Masako Nakamoto; Hiromi Hasegawa; Nami Hirano; Masashi Wakabayashi; Shogo Nomura; Yosuke Togashi; Hiroyoshi Nishikawa; Akihiro Sato; Atsushi Ohtsu; Toshihiko Doi

  AACR Annual Meeting 2019  2019/03
• Translational Research for Predictive Biomarkers in Cancer Immunotherapy

  Yosuke Togashi

  CANCER SCIENCE  2018/12  WILEY
  
• Immunotherapy targeting effector Treg cells via heat shock protein 90  [Not invited]

  Ayaka Tsuge; Yosuke Togashi; Hiroyoshi Nishikawa

  日本免疫学会学術集会  2018/12
• 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―  [Not invited]

  冨樫庸介

  日本肺癌学会総会号  2018/10
• 悪性胸膜中皮腫における腫瘍内浸潤リンパ球の検討  [Not invited]

  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

  日本肺癌学会総会号  2018/10
• 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  [Not invited]

  冨樫 庸介

  肺癌  2018/10
• 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)  [Not invited]

  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  2018/09
• 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)  [Not invited]

  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  2018/09
• 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)  [Not invited]

  冨樫 庸介

  日本癌学会総会記事  2018/09
• 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  [Not invited]

  冨樫庸介; 稲守宏治; 福岡聖大; 杉山大介; 伊藤雅昭; 西川博嘉

  がん免疫学会総会  2018/08
• 腫瘍免疫における制御性T細胞の役割  [Not invited]

  Yosuke Togashi

  がん免疫学会総会  2018/08
• Innate control of antitumor immunity by cancer cells  [Not invited]

  Yosuke Togashi; Eri Sugiyama; Yoshiko Takeuchi; Masahiro Tsuboi; Hiroyoshi Nishikawa

  Sixth JCA-AACR Special Joint Conference on the Latest Advances in Lung Cancer Research  2018/07
• Basic and Translational Research in Cancer Immunology  [Not invited]

  Yosuke Togashi

  日本臨床腫瘍学会学術集会  2018/07
• Clinicopathological, genomic and immunological features of hyperprogressive disease during PD-1 blockade in gastric cancer patients.  [Not invited]

  Togashi Yosuke; Kamada Takahiro; Sasaki Akinori; Nakamura Yoshiaki; Fukuoka Shota; Tada Yasuko

  JOURNAL OF CLINICAL ONCOLOGY  2018/05
• Association of gut microbiome with immune status and clinical response in solid tumor patients who received on anti-PD-1 therapies.  [Not invited]

  Fukuoka Shota; Daisuke Motooka; Togashi Yosuke; Sugiyama Eri; Udagawa Hibiki; Kirita Keisuke

  JOURNAL OF CLINICAL ONCOLOGY  2018/05
• Regulatory T cells as a target in anticancer immunotherapy  [Invited]

  Yosuke Togashi

  7th Japan-Taiwan Oncology Phase I Conference 2018  2018/05
• Translational Research of Cancer Immunology in Gastric Cancer  [Invited]

  Yosuke Togashi

  胃癌学会総会  2018/03
• Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer.  [Not invited]

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

  JOURNAL OF CLINICAL ONCOLOGY  2018/02
• Innate control of antitumor immunity by cancer cells  [Invited]

  Yosuke Togashi

  The 33th Nagoya International Cancer Treatment Symposium  2018/02
• 呼吸器・消化器分野における腫瘍免疫のトランスレーショナルリサーチ  [Not invited]

  冨樫庸介

  日本気管食道科学会認定気管食道科専門医大会テキスト  2018
• 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  [Not invited]

  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  2017/09
• 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  [Not invited]

  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)  2017
• 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  [Not invited]

  竹内美子; 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; 西川博嘉

  日本肺癌学会総会号  2016/11
• 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  [Not invited]

  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

  日本肺癌学会総会号  2016/11
• 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  [Not invited]

  千葉眞人; 冨樫庸介; 光冨徹哉; 西尾和人

  日本肺癌学会総会号  2016/11
• 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  [Not invited]

  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  2016/10
• 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  [Not invited]

  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  2016/10
• 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  [Not invited]

  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  2016/10
• 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  [Not invited]

  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  2016/10
• 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  [Not invited]

  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(Web)  2016/04
• 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  [Not invited]

  冨樫庸介; 水内寛; 林秀敏; 林秀敏; 小林祥久; 中川和彦; 光冨徹哉; 西尾和人

  日本肺癌学会総会号  2015/10
• EGFR exon18変異肺癌の頻度と各世代EGFR‐TKIに対する奏効率の違い  [Not invited]

  小林祥久; 冨樫庸介; 谷田部恭; 水内寛; 水内寛; 朴将哲; 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

  日本肺癌学会総会号  2015/10
• 非小細胞肺がんにおけるDDR2変異の機能解析  [Not invited]

  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  2015/10
• EGFR exon18変異肺癌の治療戦略 afatinibとneratinibに対する高感受性  [Not invited]

  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  2015/10
• 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  [Not invited]

  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)  2015/08
• 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  [Not invited]

  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

  日本肺癌学会総会号  2014/10
• 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  [Not invited]

  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; VELASCO Marco A de; 坂井和子; 藤田至彦; 冨田秀太; 加藤元一; 中川和彦; 西尾和人

  日本肺癌学会総会号  2014/10
• 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  [Not invited]

  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

  日本肺癌学会総会号  2014/10
• 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)  [Not invited]

  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  2014/09
• 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)  [Not invited]

  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  2014/09
• 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  [Not invited]

  冨樫庸介; 曽我部俊介; 加藤寛章; 寺嶋雅人; 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)  2014
• 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  [Not invited]

  柳原一広; 金永学; 真砂勝康; 冨樫庸介; 阪森優一; 平林正孝; 二階堂純一

  日本肺癌学会総会号  2013/10
• 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  [Not invited]

  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

  日本肺癌学会総会号  2013/10
• 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  [Not invited]

  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

  日本肺癌学会総会号  2013/10
• 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  [Not invited]

  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  2013/06
• 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  [Not invited]

  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

  Jpn J Radiol  2013/02
• 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  [Not invited]

  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)  2013
• 肺小細胞癌に合併した傍腫瘍性Guillain‐Barre症候群の一例  [Not invited]

  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  2012/12
• 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  [Not invited]

  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  2012/10
• 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  [Not invited]

  白波瀬浩幸; 城戸貴之; 松田耕一郎; 羽賀博典; 金永学; 真砂勝泰; 冨樫庸介; 三嶋理晃

  日本呼吸器学会誌  2012/03
• 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  [Not invited]

  福土将秀; 池見泰明; 冨樫庸介; 真砂勝泰; 金永学; 三嶋理晃; 桂敏也

  臨床薬理  2011/10
• 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  [Not invited]

  冨樫庸介; 真砂勝泰; 阪森優一; 金永学; 三嶋理晃

  肺癌  2011/10
• 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  [Not invited]

  冨樫庸介; 真砂勝泰; 福土将秀; 奥田千幸; 阪森優一; 金永学; 桂敏也; 三嶋理晃

  肺癌  2011/10
• 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  [Not invited]

  阪森優一; 金永学; 奥田千幸; 冨樫庸介; 真砂勝泰; 三尾直士; 三嶋理晃

  肺癌  2011/10
• 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)  [Not invited]

  金永学; 平林正孝; 冨樫庸介; 平野勝也; 富井啓介; 真砂勝泰; 金田俊彦; 吉松昭和; 大塚浩二郎; 三尾直士; 冨岡洋海; 鈴木雄二郎; 三嶋理晃

  肺癌  2011/10
• 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  [Not invited]

  藤本大智; 冨樫庸介; 真砂勝泰; 阪森優一; 金永学; 三嶋理晃; 福土将秀; 桂敏也

  肺癌  2011/10
• 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  [Not invited]

  金永学; 冨樫庸介; 奥田千幸; 阪森優一; 真砂勝泰; 三嶋理晃

  肺癌  2011/10
• 間質性肺炎合併肺小細胞癌患者の予後の検討  [Not invited]

  奥田千幸; 冨樫庸介; 真砂勝泰; 半田知宏; 谷澤公伸; 阪森優一; 金永学; 三嶋理晃

  肺癌  2011/10
• 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  [Not invited]

  奥田千幸; 金永学; 冨樫庸介; 真砂勝泰; 阪森優一; 三尾直士; 三嶋理晃

  肺癌  2011/04
• Gefitinibとerlotinibの毒性の違い  [Not invited]

  冨樫庸介; 真砂勝泰; 阪森優一; 金永学; 三尾直士; 三嶋理晃

  肺癌  2011/04
• Pemetrexed投与による肝障害の検討  [Not invited]

  阪森優一; 金永学; 奥田千幸; 冨樫庸介; 真砂勝泰; 三尾直士; 三嶋理晃

  肺癌  2011/04
• 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  [Not invited]

  冨樫庸介; 真砂勝泰; 福土政秀; 金永学; 三尾直士; 桂敏也; 乾賢一; 三嶋理晃

  日本呼吸器学会雑誌  2011/03
• 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  [Not invited]

  福土将秀; 池見泰明; 寺田智祐; 桂敏也; 乾賢一; 冨樫庸介; 真砂勝泰; 金永学; 三尾直士; 三嶋理晃

  臨床薬理  2010/11
• 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  [Not invited]

  真砂勝泰; 冨樫庸介; 金永学; 阪森優一; 三尾直士; 三嶋理晃

  肺癌  2010/10
• 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  [Not invited]

  冨樫庸介; 真砂勝泰; 金永学; 阪森優一; 三尾直士; 三嶋理晃

  肺癌  2010/10
• 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  [Not invited]

  冨樫庸介; 真砂勝泰; 久保武; 金永学; 阪森優一; 三尾直士; 富樫かおり; 三嶋理晃

  肺癌  2010/10
• 進行非小細胞肺癌透析症例におけるerlotinibの血中薬物動態  [Not invited]

  冨樫庸介; 真砂勝寛; 入佐薫; 金永学; 三尾直士; 三嶋理晃; 福土将秀; 寺田智祐; 乾賢一

  肺癌  2010/02
• 甲状腺乳頭癌の上皮成長因子受容体遺伝子変異  [Not invited]

  入佐薫; 真砂勝泰; 阪森優一; 冨樫庸介; 金永学; 三尾直士; 三嶋理晃

  肺癌  2010/02
• 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  [Not invited]

  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  2009/05

MISC

• 免疫チェックポイント阻害薬の耐性機序—Mechanisms of resistance to immune checkpoint inhibitors

  長﨑 譲慈; 冨樫 庸介  腫瘍内科 = Clinical oncology / 腫瘍内科編集委員会 編  32-  (5)  568  -574  2023/11
• Translational Research in Cancer Immunotherapies

  Nishi Tatsuya; Togashi Yosuke  Haigan  62-  (5)  363  -370  2022/10
• 【免疫チェックポイント阻害薬の"耐性"に挑む がん免疫サイクルから見出す戦略】抗腫瘍免疫応答におけるT細胞活性化プロセスとがん免疫療法の耐性メカニズム

  冨樫 庸介  実験医学  40-  (16)  2550  -2556  2022/10
• 【免疫チェックポイント阻害薬の"耐性"に挑む がん免疫サイクルから見出す戦略】免疫チェックポイント阻害薬治療によるクローン進化

  石野 貴雅; 冨樫 庸介  実験医学  40-  (16)  2587  -2592  2022/10
• プレシジョンがん免疫療法の開発に向けた研究

  猪爪 隆史; 川島 秀介; 松澤 高光; 松江 弘之; 田渕 亜希子; 大沼 毅紘; 川村 龍吉; 島田 眞路; 冨樫 庸介  日本皮膚科学会雑誌  132-  (11)  2543  -2543  2022/10
• その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neoantigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

  石野 貴雅; 上野 敏秀; 上田 優輝; 間野 博行; 石原 聡一郎; 加藤 直也; 河津 正人; 冨樫 庸介  日本癌学会総会記事  81回-  P  -2171  2022/09
• その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neontigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

  石野 貴雅; 上野 敏秀; 上田 優輝; 間野 博行; 石原 聡一郎; 加藤 直也; 河津 正人; 冨樫 庸介  日本癌学会総会記事  81回-  E  -2052  2022/09
• 腫瘍微小環境におけるクローン進展

  上田 優輝; 冨樫 庸介  癌と化学療法  49-  (9)  907  -913  2022/09
• 腫瘍微小環境における制御性T細胞に特徴的な代謝学的チェックポイントの同定(Identification of a distinctive metabolic checkpoint of regulatory T cells in the tumor microenvironment)

  熊谷 尚悟; 小山 正平; 板橋 耕太; 冨樫 庸介; 吉田 達哉; 石井 源一郎; 河津 正人; 山崎 直也; 坪井 正博; 谷田部 恭; 木下 敬弘; 土井 俊彦; 設楽 絋平; 間野 博行; 西川 博嘉  日本癌学会総会記事  81回-  CES1  -3  2022/09
• 腫瘍微小環境の1細胞解析(Single-cell analyses for the tumor microenvironment)

  冨樫 庸介  日本癌学会総会記事  81回-  IS8  -4  2022/09
• その機能がnon-inflamedな腫瘍微小環境を誘導し得る逆説的なネオ抗原の存在(Paradoxical neoantigens; neoantigens can paradoxically induce a non-inflamed tumor microenvironment via gene functions.)

  石野 貴雅; 上野 敏秀; 上田 優輝; 間野 博行; 石原 聡一郎; 加藤 直也; 河津 正人; 冨樫 庸介  日本癌学会総会記事  81回-  P  -2171  2022/09
• 【疲弊T細胞】腫瘍微小環境における疲弊T細胞

  冨樫 庸介  臨床免疫・アレルギー科  78-  (2)  127  -134  2022/08
• 免疫チェックポイント阻害薬 がん免疫療法を少し深く考えてみませんか?

  冨樫 庸介  癌の臨床  66-  (3)  129  -136  2022/07
• 【がん免疫療法の展望:免疫チェックポイント阻害薬の併用療法に中心に】がん免疫併用療法のあり方 がんの免疫チェックポイント阻害薬への抵抗性獲得のメカニズムと、その克服の手段としての併用療法の現状

  石野 貴雅; 冨樫 庸介  腫瘍内科  30-  (1)  59  -66  2022/07
• 【悪性黒色腫の最前線】免疫チェックポイント阻害薬への耐性機構

  川島 秀介; 冨樫 庸介  皮膚科  2-  (1)  18  -25  2022/07
• B細胞性リンパ腫におけるPD-L2の生物学的機能と調節機序の解析(Dissecting biological function and regulation of PD-L2 in B-cell lymphoma)

  新垣 清登; 古屋 淳史; 湯淺 光博; 斎藤 優樹; 田畑 真梨子; Marni McClure; 片山 琴絵; 冨樫 庸介; 井元 清哉; 木暮 泰寛; 片岡 圭亮  日本リンパ網内系学会会誌  62-  89  -89  2022/06
• がん免疫療法の現状の課題と今後の期待

  冨樫 庸介  日本がん免疫学会総会プログラム・抄録集  26回-  67  -67  2022/06
• がん免疫療法のバイオマーカー

  冨樫 庸介  日本臨床細胞学会雑誌  61-  (Suppl.1)  98  -98  2022/05
• 【腫瘍免疫-免疫ネットワークから考える基礎と臨床】ネットワークの各因子と、その因子を応用or標的とした基礎研究の現在と可能性 がん微小環境TME内の免疫ネットワーク解明の研究手段 フローサイトメトリー、マスサイトメトリーを用いた腫瘍微小環境の病態解明

  長崎 譲慈; 冨樫 庸介  医学のあゆみ  281-  (5)  422  -427  2022/04
• 【腫瘍免疫-免疫ネットワークから考える基礎と臨床】ネットワークの各因子と、その因子を応用or標的とした基礎研究の現在と可能性 がん微小環境TME内の免疫ネットワーク解明の研究手段 フローサイトメトリー、マスサイトメトリーを用いた腫瘍微小環境の病態解明

  長崎 譲慈; 冨樫 庸介  医学のあゆみ  281-  (5)  422  -427  2022/04
• 消化器癌における免疫治療と分子標的治療の基礎研究と臨床 腫瘍微小環境から考えるがん免疫療法

  冨樫 庸介  日本消化器病学会雑誌  119-  (臨増総会)  A40  -A40  2022/03
• 消化器癌における免疫治療と分子標的治療の基礎研究と臨床 腫瘍微小環境から考えるがん免疫療法

  冨樫 庸介  日本消化器病学会雑誌  119-  (臨増総会)  A40  -A40  2022/03
• Technology for analyses in cancer immunology

  Yosuke Togashi  CANCER SCIENCE  113-  2022/02
• Precision Medicine of Cancer Immunotherapy

  Yosuke Togashi  CANCER SCIENCE  113-  1249  -1249  2022/02
• 【がん免疫療法研究の進歩】免疫チェックポイント阻害薬によるがん免疫応答の制御 シングルセル解析を用いた腫瘍微小環境の解明

  上田 優輝; 冨樫 庸介  腫瘍内科  29-  (2)  150  -156  2022/02
• 【がん免疫療法研究の進歩】免疫チェックポイント阻害薬によるがん免疫応答の制御 シングルセル解析を用いた腫瘍微小環境の解明

  上田 優輝; 冨樫 庸介  腫瘍内科  29-  (2)  150  -156  2022/02
• TIGIT/CD155axisは炎症性腫瘍微小環境を伴うメラノーマ患者のICI耐性化に関与する

  猪爪隆史; 川島秀介; 田渕亜希子; 川村龍吉; 大沼毅紘; 福島聡; 松江弘之; 冨樫庸介  西日本皮膚科  84-  (6)  2022
• 腫瘍浸潤B細胞の本態解明とその治療応用

  冨樫 庸介  上原記念生命科学財団研究報告集  36-  1  -5  2022
• 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  岡山医学会雑誌  133-  (3)  151  -157  2021/12
• Cancer-immunotherapy biomarkers in the tumor microenvironment

  Togashi Yosuke  Okayama Igakkai Zasshi (Journal of Okayama Medical Association)  133-  (3)  151  -157  2021/12
• 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
• 大腸癌周術期治療の臨床開発と将来展望 進行直腸癌に対する化学放射線療法と免疫チェックポイント阻害剤を用いた術前治療

  塚田 祐一郎; 坂東 英明; 稲守 宏冶; 冨樫 庸介; 結城 敏志; 小松 嘉人; 本間 重紀; 武冨 紹信; 植村 守; 加藤 健志; 若林 将史; 佐藤 暁洋; 西川 博嘉; 伊藤 雅昭; 吉野 孝之  日本癌治療学会学術集会抄録集  59回-  SY2  -4  2021/10
• 胸部腫瘍(非小細胞肺癌を除く)に対する複合免疫療法を考える(Mechanisms and Application of Immune Checkpoint Inhibitors Against Thoracic Malignancies Other than NSCLC)

  冨樫 庸介  肺癌  61-  (6)  474  -474  2021/10
• 胸部腫瘍(非小細胞肺癌を除く)に対する複合免疫療法を考える(Mechanisms and Application of Immune Checkpoint Inhibitors Against Thoracic Malignancies Other than NSCLC)

  冨樫 庸介  肺癌  61-  (6)  474  -474  2021/10
• 大腸癌周術期治療の臨床開発と将来展望 進行直腸癌に対する化学放射線療法と免疫チェックポイント阻害剤を用いた術前治療

  塚田 祐一郎; 坂東 英明; 稲守 宏冶; 冨樫 庸介; 結城 敏志; 小松 嘉人; 本間 重紀; 武冨 紹信; 植村 守; 加藤 健志; 若林 将史; 佐藤 暁洋; 西川 博嘉; 伊藤 雅昭; 吉野 孝之  日本癌治療学会学術集会抄録集  59回-  SY2  -4  2021/10
• 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
• がん免疫療法の個別化医療を目指して

  冨樫 庸介  日本癌学会総会記事  80回-  [IS10  -3]  2021/09
• 変革する病理学:形態診断から普遍的研究プラットフォームへ がん免疫療法の個別化医療を目指して

  冨樫 庸介  日本癌学会総会記事  80回-  [S10  -3]  2021/09
• がん免疫とは何か 解析手法の基礎

  冨樫 庸介  日本癌学会総会記事  80回-  [IC3]  -[IC3]  2021/09
• がん免疫療法の個別化医療を目指して

  冨樫 庸介  日本癌学会総会記事  80回-  [IS10  -3]  2021/09
• 変革する病理学:形態診断から普遍的研究プラットフォームへ がん免疫療法の個別化医療を目指して

  冨樫 庸介  日本癌学会総会記事  80回-  [S10  -3]  2021/09
• 【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  2021/08
• Efficacy predictors of preoperative CRT and consolidation nivolumab in patients with locally advanced rectal cancer

  Koji Inamori; Yosuke Togashi; Hideaki Bando; Yuichiro Tsukada; Shota Fukuoka; Ayako Suzuki; Yutaka Suzuki; Daisuke Kotani; Motohiro Kojima; Makoto Fukui; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Akinobu Taketomi; Mamoru Uemura; Takeshi Kato; Masaaki Ito; Hiroyoshi Nishikawa; Takayuki Yoshino  ANNALS OF ONCOLOGY  32-  S343  -S343  2021/07
• 【がん免疫療法の新展開】免疫チェックポイント阻害剤の耐性メカニズムを考える

  冨樫 庸介  日本皮膚悪性腫瘍学会学術大会プログラム・抄録集  37回-  77  -77  2021/06
• 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  2021/05
• 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  2021/05
• 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  2021/05
• 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  2021/05
• 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  2021/05
• 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  2021/04
• Translational Research using Clinical Samples in Cancer Immunology

  Yosuke Togashi  CANCER SCIENCE  112-  206  -206  2021/02
• Translational research of VOLTAGE-A: Efficacy predictors of preoperative chemoradiotherapy and consolidation nivolumab in patients with both microsatellite stable and microsatellite instability-high locally advanced rectal cancer

  Koji Inamori; Yosuke Togashi; Hideaki Bando; Yuichiro Tsukada; Shota Fukuoka; Ayako Suzuki; Yutaka Suzuki; Daisuke Kotani; Motohiro Kojima; Makoto Fukui; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Akinobu Taketomi; Mamoru Uemura; Takeshi Kato; Masaaki Ito; Hiroyoshi Nishikawa; Takayuki Yoshino  JOURNAL OF CLINICAL ONCOLOGY  39-  (3)  2021/01
• 【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  2021/01
• 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
• 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
• 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
• 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
• 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
• 【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  2020/09
• 【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  2020/09
• 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  2020/08
• 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  2020/08
• 【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  2020/07
• Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable and microsatellite instability-high locally advanced rectal cancer.

  Satoshi Yuki; Hideaki Bando; Yuichiro Tsukada; Koji Inamori; Yoshito Komatsu; Shigenori Homma; Mamoru Uemura; Takeshi Kato; Daisuke Kotani; Shota Fukuoka; Naoki Nakamura; Makoto Fukui; Masashi Wakabayashi; Motohiro Kojima; Yosuke Togashi; Akihiro Sato; Hiroyoshi Nishikawa; Masaaki Ito; Takayuki Yoshino  JOURNAL OF CLINICAL ONCOLOGY  38-  (15)  2020/05
• Translational research of voltage-A1: Efficacy predictors of preoperative chemoradiotherapy and subsequent nivolumab monotherapy in patients with microsatellite-stable locally advanced rectal cancer.

  Koji Inamori; Yosuke Togashi; Hideaki Bando; Yuichiro Tsukada; Ayako Suzuki; Yutaka Suzuki; Daisuke Kotani; Shota Fukuoka; Motohiro Kojima; Makoto Fukui; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Mamoru Uemura; Takeshi Kato; Masaaki Ito; Hiroyoshi Nishikawa; Takayuki Yoshino  JOURNAL OF CLINICAL ONCOLOGY  38-  (15)  2020/05
• 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  2020/02
• 異所性に存在する腫瘍ネオ抗原特異的T細胞クローンの同定方法の開発—Identification of Ectopic Neoantigen-Specific T Cell Clones—2019年度研究奨励金受領報告

  冨樫 庸介  東京生化学研究会助成研究報告集  35-  231  -234  2020
• 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  (50)  14  -14  2020
• 【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
• 【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
• A novel regulatory T Cell-Targeted Immunotherapy by targeting their crucial signal by HSP90 inhibitors

  Ayaka Tsuge; Yosuke Togashi; Kohei Shitara; Hiroyoshi Nishikawa  JOURNAL FOR IMMUNOTHERAPY OF CANCER  7-  2019/11
• 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
• 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
• 【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  2019/09
• 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  2019/09
• 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  2019/09
• 【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  2019/09
• Early safety from an open label Phase I study to evaluate the safety and efficacy of a telomerase-specific oncolytic adenovirus (OBP-301) with pembrolizumab in patients with advanced solid tumors. (EPOC1505)

  Takashi Kojima; Toshiyoshi Fujiwara; Yasuhiro Shirakawa; Keisuke Hori; Hiromi Ono; Masako Nakamoto; Nami Hirano; Masashi Wakabayashi; Shogo Nomura; Yosuke Togashi; Hiroyoshi Nishikawa; Akihiro Sato; Atushi Ohtsu; Toshihiko Doi  CANCER RESEARCH  79-  (13)  2019/07
• 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  2019/07
• 『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  2019/07
• 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  2019/07
• TENERGY: Multicenter phase II study of atezolizumab monotherapy following definitive chemoradiotherapy with 5-FU plus cisplatin in patients with locally advanced esophageal squamous cell carcinoma.

  Hideaki Bando; Daisuke Kotani; Takahiro Tsushima; Hiroki Hara; Shigenori Kadowaki; Ken Kato; Keisho Chin; Kensei Yamaguchi; Shun-ichiro Kageyama; Hidehiro Hojo; Masashi Wakabayashi; Miki Fukutani; Yosuke Togashi; Nozomu Fuse; Hiroyoshi Nishikawa; Takashi Kojima  JOURNAL OF CLINICAL ONCOLOGY  37-  (15)  2019/05
• Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).

  Shota Fukuoka; Hiroki Hara; Naoki Takahashi; Takashi Kojima; Akihito Kawazoe; Masako Asayama; Takako Yoshii; Daisuke Kotani; Hitomi Tamura; Yuichi Mikamoto; Ayako Sugama; Masashi Wakabayashi; Shogo Nomura; Akihiro Sato; Yosuke Togashi; Hiroyoshi Nishikawa; Kohei Shitara  JOURNAL OF CLINICAL ONCOLOGY  37-  (15)  2019/05
• Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.

  Takayuki Yoshino; Hideaki Bando; Yuichiro Tsukada; Koji Inamori; Satoshi Yuki; Yoshito Komatsu; Shigenori Homma; Mamoru Uemura; Takeshi Kato; Daisuke Kotani; Shota Fukuoka; Takeshi Sasaki; Yuji Nishizawa; Naoki Nakamura; Masashi Wakabayashi; Motohiro Kojima; Yosuke Togashi; Akihiro Sato; Hiroyoshi Nishikawa; Masaaki Ito  JOURNAL OF CLINICAL ONCOLOGY  37-  (15)  2019/05
• 気管食道領域の薬物療法・周術期治療 : 腫瘍免疫のトランスレーショナルリサーチ

  冨樫 庸介  専門医通信  (57)  17  -21  2018/12
• Translational Research for Predictive Biomarkers in Cancer Immunotherapy

  Yosuke Togashi  CANCER SCIENCE  109-  1225  -1225  2018/12
• 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
• 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
• 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  2018/09
• 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  2018/09
• 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  2018/09
• 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  2018/08
• 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?—特集 免疫チェックポイント療法の新潮流

  冨樫 庸介  医薬ジャーナル = Medicine and drug journal  54-  (8)  83  -87  2018/08
• 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  2018/07
• 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  2018/07
• 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  2018/06
• An open label phase I study to evaluate the safety and efficacy of OBP-301 with pembrolizumab in patients with advanced solid tumors.

  Takashi Kojima; Toshiyoshi Fujiwara; Yasuhiro Shirakawa; Hiromi Ono; Masako Nakamoto; Hiromi Hasegawa; Nami Hirano; Masashi Wakabayashi; Shogo Nomura; Yosuke Togashi; Hiroyoshi Nishikawa; Akihiro Sato; Atsushi Ohtsu; Toshihiko Doi  JOURNAL OF CLINICAL ONCOLOGY  36-  (15)  2018/05
• Clinicopathological, genomic and immunological features of hyperprogressive disease during PD-1 blockade in gastric cancer patients.

  Yosuke Togashi; Takahiro Kamada; Akinori Sasaki; Yoshiaki Nakamura; Shota Fukuoka; Yasuko Tada; Akihito Kawazoe; Kohei Shitara; Hiroyoshi Nishikawa  JOURNAL OF CLINICAL ONCOLOGY  36-  (15)  2018/05
• 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)  2018/05
• VOLTAGE: Multicenter phase 1b/II study of nivolumab monotherapy and subsequent radical surgery after preoperative chemoradiotherapy with capecitabine in patients with locally advanced rectal cancer.

  Yuichiro Tsukada; Hideaki Bando; Koji Inamori; Shota Fukuoka; Takeshi Sasaki; Yuji Nishizawa; Daisuke Kotani; Motohiro Kojima; Yosuke Togashi; Naoki Nakamura; Tetsuo Akimoto; Yoshito Komatsu; Satoshi Yuki; Shigenori Homma; Yutaka Hatanaka; Yoshihiro Matsuno; Akihiro Sato; Hiroyoshi Nishikawa; Masaaki Ito  JOURNAL OF CLINICAL ONCOLOGY  36-  (4)  2018/02
• 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—Novel Concept of Regulatory T cells in Cancer Immunology

  冨樫 庸介  SGH cancer research reports = SGHがん研究報告  29-  74  -76  2018
• 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
• 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
• The liquid biopsy: Its present and future

  Kazuto Nishio; Yosuke Togashi; Kazuko Sakai  Japanese Journal of Lung Cancer  57-  (6)  733  -738  2017/11
• 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
• 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
• 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  2017/09
• 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  2017/06
• 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-  2017/05
• 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-  2017/05
• 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-  2017/05
• 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
• 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  2017/01
• 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

  寺嶋雅人; 冨樫庸介; 佐藤克明; 水内寛; 坂井和子; 須田健一; 中村雄; 坂野恵里; 林秀敏; デベラスコ 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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  2016/07
• 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-  2016/07
• 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-  2016/07
• 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  2016/04
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• EGFR exon18変異肺癌の頻度と各世代EGFR-TKIに対する奏効率の違い

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

  小林 祥久; 冨樫 庸介; 谷田部 恭; 水内 寛; 朴 将哲; 近藤 千晶; 須田 健一; 富沢 健二; 樋田 豊明; 西尾 和人; 光冨 徹哉  日本癌学会総会記事  74回-  E  -1176  2015/10
• 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
• 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  2015/09
• EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs

  Yoshihisa Kobayashi; Yosuke Togashi; Yasushi Yatabe; Hiroshi Mizuuchi; Park Jangchul; Chiaki Kondo; Masaki Shimoji; Katsuaki Sato; Kenichi Suda; Kenji Tomizawa; Toshiki Takemoto; Toyoaki Hida; Kazuto Nishio; Tetsuya Mitsudomi  JOURNAL OF THORACIC ONCOLOGY  10-  (9)  S177  -S178  2015/09
• 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  2015/09
• 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  2015/09
• 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  2015/08
• 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  2015/08
• 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-  2015/08
• 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-  2015/08
• 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-  2015/08
• 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  2015/08
• 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
• 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  2015/01
• 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
• 【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
• 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
• 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
• 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
• 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
• 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
• 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
• 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  2014/09
• 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  2014/09
• 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  2014/09
• 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  2014/08
• 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  2014/04
• 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  2014/02
• 【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  2014/02
• 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
• PHASE II STUDY OF BEVACIZUMAB AND ERLOTINIB IN PATIENTS WITH NON-SQUAMOUS NON-SMALL LUNG CANCER THAT IS REFRACTORY OR RELAPSED AFTER 1-2 PREVIOUS TREATMENT (BEST STUDY)

  Kazuhiro Yanagihara; Shiro Tanaka; Miyuki N. Niimi; Katsuhiro Masago; Yosuke Togashi; Hiroki Nagai; Young Hak Kim; Junichi Nikaidou; Masataka Hirabayashi  JOURNAL OF THORACIC ONCOLOGY  8-  S560  -S560  2013/11
• 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
• 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
• 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

  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  [Refereed]
  
• 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
• 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
• 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
• 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  2013/04
• 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  2013/02
• 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
• 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
• 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
• 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
• 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  2012/08
• 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  2012/03
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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  2011/06
• 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)  2011/05
• 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  2011/04
• 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  2011/04
• 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  2011/04
• 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  2011/03
• 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
• 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
• 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
• 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
• 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  2010/07
• 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  2010/02
• 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  2010/02
• 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
• 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  2009/05

Awards & Honors

• 2023/10 アステラス病態代謝研究会 最優秀理事長賞
  
• 2023/04 がんと代謝研究会 第５回がんと代謝研究会若手の会最優秀賞
  
• 2022/12 MSD生命科学財団 がん領域研究助成医学奨励賞最優秀賞
   

  受賞者: 冨樫庸介
• 2022/06 宇部興産学術振興財団 第62回渡辺記念特別奨励賞
   

  受賞者: 冨樫庸介
• 2021/12 日本免疫学会 日本免疫学会若手免疫学研究支援事業
   

  受賞者: 冨樫庸介
• 2020/10 日本癌学会 日本癌学会奨励賞
   

  受賞者: 冨樫庸介
• 2020/02 日本癌学会 第1回日本癌学会若手の会最優秀口演賞
   

  受賞者: 冨樫庸介
• 2018 The Naito Foundation Best Poster Award
   

  受賞者: 冨樫庸介
• 2015 ESMO ESMO Asia Travel Grant
   

  受賞者: 冨樫庸介
• 2015 Kindai University Medical Science Award
   

  受賞者: 冨樫庸介
• 2011 Kyoto University Hospital Nice Teacher Award
   

  受賞者: 冨樫庸介
• 2010 Kyoto University Hospital Nice Teacher Award
   

  受賞者: 冨樫庸介

Research Grants & Projects

• 時空間マルチサンプリング検体の単一細胞解析によるヒト免疫療法の基盤となる免疫記憶の解明

  AMED：CREST

  Date (from‐to) : 2022/10 -2028/03
• 腫瘍微小環境のゲノム異常とクローン性造血の関係解明

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2023/09 -2027/03 

  Author : 冨樫 庸介
• Roles of cancer extracellular vesicles in hijacking macrophages and metastatic niche formation

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

  Date (from‐to) : 2023/04 -2026/03 

  Author : 江口 傑徳; 河合 穂高; 高橋 賢; 冨樫 庸介; 岡元 邦彰
• Elucidation of Tumor Microenvironment Network Regulated by Fibrinolysis Inhibitory Factor and Its Therapeutic Application

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

  Date (from‐to) : 2023/04 -2026/03 

  Author : 伊達 慶一; 豊岡 伸一; 諏澤 憲; 山本 寛斉; 枝園 和彦; 冨田 秀太; 冨樫 庸介
• 非小細胞肺癌に対するPD-1経路阻害薬の継続と休止に関するランダム化比較第III相試験

  AMED：革新的がん医療実用化研究事業

  Date (from‐to) : 2023/11 -2026/03
• 患者血液検体を用いたミトコンドリア異常と免疫チェックポイント阻害薬の治療効果との関連について明らかにする後方視的研究

  AMED：次世代がん医療加速化研究事業

  Date (from‐to) : 2023/10 -2026/03
• 時空間的ミトコンドリア免疫代謝異常の解明とその制御による新規治療開発

  AMED：次世代がん医療加速化研究事業

  Date (from‐to) : 2023/10 -2026/03
• マトリセルラータンパク質阻害によるがん微小環境の破壊と抗腫瘍効果の検討

  日本学術振興会：科学研究費助成事業 基盤研究(B)

  Date (from‐to) : 2022/04 -2026/03 

  Author : 豊岡 伸一; 冨田 秀太; 枝園 和彦; 山本 寛斉; 岡崎 幹生; 阪口 政清; 冨樫 庸介; 諏澤 憲
• Comprehensive elucidation of molecular pathogenesis based on genetic abnormalities in malignant lymphoma

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

  Date (from‐to) : 2021/07 -2026/03 

  Author : 片岡 圭亮; 木暮 泰寛; 冨樫 庸介

   

  悪性リンパ腫は、びまん性大細胞型B細胞リンパ腫（DLBCL）や、成人T細胞白血病リンパ腫（ATL）、節外性NK/T細胞リンパ腫（ENKTL）などを含む不均一な疾患である。近年、リンパ腫においても遺伝子異常の全体像が解明され、様々な新規異常が同定されてきた。しかし、多くの異常の生物学的意義、特に、その分子機構や生体内でリンパ腫発症に果たす役割、微小環境に与える変化は不明のままである。本研究では、申請者が同定した異常を中心に、リンパ腫で認められる遺伝子異常の詳細な分子機構・生体内における役割・微小環境に与える変化を解明するために、A．申請者の遺伝子解析研究で同定された異常の分子機能の解明・疾患動物モデルの解析、B．生体内CRISPRスクリーニングによるリンパ腫発症に寄与する遺伝子異常の高効率な検証、C. CRISPR制御部位スクリーニングによるB細胞リンパ腫特異的PD-L2発現制御機構の解明、D．単一細胞マルチオミクス解析のマウスリンパ腫モデルへの応用とリンパ腫微小環境の解明、E．ヒト検体由来の網羅的遺伝子解析データを用いた臨床応用の可能性の探索、を実施した。 本年度は、項目Aでは、ATLでアイソフォーム特異的に変異が認められるCICのアイソフォーム特異的欠失マウスの構築・解析を行い、CIC-L欠失により、ATLの起源細胞である制御性T細胞が増加することを明らかにした（Y Kogure, 2022 Blood）。項目Bでは、DLBCLで認められる異常も対象として生体内CRISPRスクリーニングを実施し、様々な造血器腫瘍の発症・進展に関与する遺伝子を同定した。項目Cでは、PD-L2発現制御に関わる転写因子をCRISPRスクリーニングにより探索した結果、7個の転写抑制因子および2個の転写促進因子を同定した。項目Dでは、単一細胞マルチオミクス解析のマウスモデルへの応用を実現した。
• Clarification of the mechanism for endogenous retrovirus to get involved in the antitumor immunity response

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

  Date (from‐to) : 2022/06 -2025/03 

  Author : 豊岡 伸一; 冨樫 庸介; 本田 知之; 冨田 秀太; 山本 寛斉; 諏澤 憲; 枝園 和彦
• Analysis of tumor antigen recognition of T cell accumulated in the underlying liver of hepatocellular carcinoma

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

  Date (from‐to) : 2022/04 -2025/03 

  Author : 小笠原 定久; 冨樫 庸介
• 免疫チェックポイント阻害剤の課題克服を目指した腫瘍特異的T細胞の解析

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2022/04 -2025/03 

  Author : 猪爪 隆史; 冨樫 庸介
• 腫瘍微小環境のミトコンドリア異常に基づく新規バイオマーカー及び治療開発

  AMED：革新的がん医療実用化研究事業

  Date (from‐to) : 2022/04 -2025/03
• Spatiotemporal T-cell differentiation dynamics in the tumor "peripheral" environment

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

  Date (from‐to) : 2022/06 -2024/03 

  Author : 冨樫 庸介; 宝田 剛志
• CAR-T細胞を薬剤送達システムとして活用したがん標的治療法の開発

  AMED：次世代がん医療加速化研究事業

  Date (from‐to) : 2022/06 -2024/03
• 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

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2021/04 -2024/03 

  Author : 盛永 敬郎; 猪爪 隆史; 冨樫 庸介

   

  免疫チェックポイント阻害薬(ICB)は、PD-1など免疫チェックポイント分子によって免疫応答が不活性化(疲弊)している腫瘍特異的T細胞を再活性化して、治療効果を発揮する。ICBは悪性黒色腫への効果が証明されているが、まったく無効な症例もあり、ICBで活性化できないT細胞の分子機構解明は急務である。我々は以前に、悪性黒色腫患者検体の腫瘍浸潤T細胞のシングルセルシークエンス(scRNA-seq)から、腫瘍特異的T細胞に既知の免疫チェックポイント分子以上に高発現する分子として、複数の接着因子を見いだしており、本研究は①これら接着因子の腫瘍特異的T細胞における発現機序を解明し、②抗腫瘍免疫応答における機能と結合リガンドを明らかにし、③臨床検体を用いて既存のICB治療効果も含め臨床病理学的に検討することで、接着因子を標的とした新規ICB治療法開発を目指すものである。 2021年度は①の分子機構について、そのシグナル経路を明らかにし、阻害薬でこれを抑制できることを確認した。また②については、当該分子の過剰発現が免疫応答に与える影響をin vitro実験で明らかにした。③についても臨床検体を集めて解析に着手している。これらの実験に附随して、本年度はPD-1阻害療法が疲弊T細胞に与える影響に関する共著論文を発表したほか、がん細胞自体の進化が免疫療法に影響しうるといった研究成果の論文発表を準備しており、目標としている新規ICB治療法開発の基礎的な知見を積み重ねている。
• 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

  日本学術振興会：科学研究費助成事業 基盤研究(C)

  Date (from‐to) : 2021/04 -2024/03 

  Author : 花澤 豊行; 猪爪 隆史; 冨樫 庸介

   

  鼻副鼻腔を原発とする粘膜型悪性黒色腫は、皮膚型の悪性黒色腫に比較すると予後が悪く、手術と放射線治療を有効に組み合わせることで、比較的良好な局所制御率を達成しているものの、遠隔転移が多いため極めて予後不良な疾患である。また、悪性黒色腫に効果があるとされる重粒子線治療単独での局所制御は高いものの、やはり遠隔転移が多いことが課題である。更に免疫チェックポイント阻害薬は、悪性黒色腫に対して一定の効果が示されているが、その効果は15％程度であり、有効な化学療法が存在しない現況から遠隔転移を如何に制御できるかは喫緊の課題である。本研究においては、粘膜型悪性黒色腫に対する免疫チェックポイント阻害薬の抗腫瘍免疫応答のメカニズムを明らかにすることが目的である。そこで、まずは鼻副鼻腔を原発とする粘膜型悪性黒色腫の免疫状態を解析するために、貴重な臨床検体を用いて、患者由来の悪性黒色腫細胞株およびオルガノイドとそのペアの腫瘍浸潤リンパ球を樹立して、腫瘍微小環境を再現する系の作製を試みた。腫瘍浸潤リンパ球の樹立には成功したものの、粘膜型悪性黒色腫細胞株の樹立に関してはさまざまな細胞が多数混在しているためやや難渋している。しかし、樹立した腫瘍浸潤リンパ球と臨床検体処理直後のTumor digestを共培養することで、IFN-γが産生されていることが確認でき、Tumor digestに含まれる粘膜型悪性黒色腫細胞を樹立した腫瘍浸潤リンパ球が認識できていることが確認できた。
• 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

  AMED：次世代がん医療創生研究事業

  Date (from‐to) : 2021/06 -2023/03
• Analysis of PD-1+ tumor-infiltrating T cells according to cancer antigen hierarchy

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

  Date (from‐to) : 2020/04 -2023/03 

  Author : 冨樫 庸介; 盛永 敬郎

   

  抗PD-1/PD-L1抗体はT細胞を活性化し抗腫瘍効果を発揮している。特に体細胞変異由来のネオ抗原は強い免疫応答を起こすことができるため、それらを認識しているエフェクターT細胞が重要である。申請者は肺癌の臨床検体から腫瘍浸潤T細胞のPD-1発現のバランスが抗PD-1/PDL1抗体の効果・耐性に関与することを明らかにした。本研究はさらに発展させ、ネオ抗原や共通抗原といった認識するがん抗原の階層性に基づくT細胞のPD-1発現といった表現型や機能の違いを明らかにし、より効果の高い治療や正確なバイオマーカー、個別化細胞療法の基盤データを得ることを目指す。 前年度に腫瘍細胞と反応するPD-1陽性CD8陽性エフェクターT細胞と制御性T細胞を含むCD4陽性T細胞を同定した。さらにシングルシークエンスを加速させるために共同で機器を購入したうえで詳細を解析したところ、CD4陽性T細胞に関してはPD-1の発現に加えて、他のマーカーも発現しており、1部では細胞傷害活性も有していた。CD4陽性T細胞の細胞傷害活性に関わる転写因子に関してもシングルセルシークエンスデータを解析したところ、CD8陽性T細胞で報告のある転写因子を同定できた。今後の同定した転写因子の機能への影響を検証する予定である。また制御性T細胞のPD-1発現機序として、乳酸代謝が関わることを明らかにした。 抗原性の観点でも制御性T細胞の解析を行ったが、今までに見つかっていない異常ペプチドを質量分析から同定しており、反応するT細胞に関して今後検証していく予定である。
• 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

  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）

  Date (from‐to) : 2021 -2022/03
• 腫瘍微小周辺環境における特異的分子に基づいた新規治療開発

  AMED：橋渡し研究シーズA

  Date (from‐to) : 2022
• 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

  JST：創発的研究支援事業

  Date (from‐to) : 2021/04
• Novel immunoediting mechanisms via somatic mutations

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

  Date (from‐to) : 2019/06 -2021/03 

  Author : Togashi Yosuke

   

  Cancer cells with high tumor mutation burden (TMB) can have a more malignant phenotype, but strong antitumor immunity can be also induced by high TMB. Here, we have found that a fraction of patients has non-inflamed tumor microenvironment despite high TMB due to some signaling pathways related to the malignant phenotype and we could validate several pathways using mouse models. From these findings, novel immunoediting mechanisms via somatic mutations is proposed, and we should consider not only just simple TMB but also the quality.
• 異所性に存在する腫瘍ネオ抗原特異的T 細胞クローンの同定方法の開発

  東京生化学研究会：研究奨励金

  Date (from‐to) : 2020 -2021 

  Author : 冨樫庸介
• 腫瘍浸潤PD-1陽性制御性T細胞は「疲弊状態」にある

  第一三共生命科学研究振興財団：研究助成

  Date (from‐to) : 2020 -2021 

  Author : 冨樫庸介
• 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

  AMED：革新がん医療実用化研究事業

  Date (from‐to) : 2019 -2021 

  Author : 冨樫庸介
• 腫瘍浸潤B細胞の本態解明とその治療応⽤

  上原記念生命科学財団：研究奨励金

  Date (from‐to) : 2021
• Influence of immune response for tumor evolution

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

  Date (from‐to) : 2017/04 -2020/03 

  Author : 冨樫 庸介

   

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

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

  Date (from‐to) : 2017/04 -2020/03 

  Author : Kubo Shoji

   

  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.
• 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

  三菱財団：三菱財団自然科学助成金

  Date (from‐to) : 2019 -2020 

  Author : 冨樫庸介
• 腫瘍微小環境の「疲弊」CD4陽性T細胞の本態解明

  千里ライフサイエンス振興財団：岸本基金研究助成

  Date (from‐to) : 2020
• 代謝産物が紡ぐがんドライバー遺伝子異常による抗腫瘍免疫応答への影響の解明と治療への応用

  興和生命科学振興財団：

  Date (from‐to) : 2020
• 前がん病変から発がん過程における免疫応答とその逃避機構の解明

  MSD生命科学財団：がん領域研究助成

  Date (from‐to) : 2020
• 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

  公益財団法人がん研究振興財団：がん研究助成金

  Date (from‐to) : 2020
• Gene alterations and anti-tumor immunity

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

  Date (from‐to) : 2017/04 -2019/03 

  Author : Togashi Yosuke; Tsuboi Masahiro; Shitara Kohei

   

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

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

  Date (from‐to) : 2016/04 -2019/03 

  Author : Inozume Takashi; YAGUCHI tomonori; Togashi Yosuke

   

  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.
• 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

  AMED：次世代がん医療創生研究事業

  Date (from‐to) : 2018 -2019 

  Author : 冨樫庸介
• 腎細胞癌におけるPD-L1非依存的免疫逃避機構の解明

  ノバルティス科学振興財団：ノバルティス研究助成

  Date (from‐to) : 2018 -2019 

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

  小林がん学術振興会：小林がん研究助成

  Date (from‐to) : 2018 -2019 

  Author : 冨樫庸介
• 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

  武田科学振興財団：武田科学振興財団（研究助成金・奨励金）

  Date (from‐to) : 2017 -2018 

  Author : 冨樫庸介
• 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

  SGH財団：SGHがん研究助成金

  Date (from‐to) : 2017 -2018 

  Author : 冨樫庸介
• 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

  BMS株式会社：BMS研究助成金

  Date (from‐to) : 2017 -2018 

  Author : 冨樫庸介
• 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

  内藤記念財団：内藤記念科学奨励費・研究助成

  Date (from‐to) : 2017 -2018 

  Author : 冨樫庸介
• Novel biomarkers for EGFR inhibitors in gastroenterological cancers based on CGH analyses

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

  Date (from‐to) : 2015/08 -2017/03 

  Author : Togashi Yosuke

   

  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.
• がんの新規治療標的分子の探索並びに創薬への応用

  日本学術振興会：科学研究費助成事業 特別研究員奨励費

  Date (from‐to) : 2014/04 -2016/03 

  Author : 冨樫 庸介

   

  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。
• 腫瘍局所3次リンパ様構造の本態解明と治療への応用

  安田記念医学財団：若手癌研究助成
• 濾胞性ヘルパーT 細胞の腫瘍免疫における新たな機能の解明

  かなえ医薬振興財団：研究助成金
• IFN-γシグナル異常によるがん免疫療法耐性の本態解明と克服のための新規治療開発

  がん集学的治療研究財団：研究助成金
• 腫瘍浸潤ネオ抗原特異的T 細胞の増殖・長期生存メカニズムの解明とその治療への応用

  持田記念医学薬学振興財団：研究助成金
• 胸腺腫・胸腺癌における抗腫瘍免疫応答の解明

  日本肺癌学会：肺癌研究助成金
• ネオ抗原特異的T細胞に発現する分子の機能解析

  九州大学・生体防御医学研究所：令和2年度共同利用・共同研究
• 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

  武田科学振興財団：研究継続助成金・奨励金

Teaching Experience

PharmacologyPharmacology Okayama University

Social Contribution

• Mechanisms of Cancer Immunotherapy from efficacy to resistance

  Date (from-to) : 2023/03/14

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : JSMO

  Event, Program, Title : JSMO-RISA
• がん免疫療法の歴史と現状、そして未来を展望する

  Date (from-to) : 2023/02/23

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : SGH財団

  Event, Program, Title : 第21回市民公開講座
• 腫瘍免疫

  Date (from-to) : 2023

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : JSMO

  Event, Program, Title : 教育セミナーAセッション
• がん免疫療法ってわかりにくい？

  Date (from-to) : 2022/07/07

  Role : Lecturer

  Sponser, Organizer, Publisher  : 東京がん化学療法研究会

  Event, Program, Title : 第22回臨床腫瘍夏期セミナー
• がんと免疫の戦いの 現場をのぞいてみよう

  Date (from-to) : 2021/08/21

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : 日本免疫学会

  Event, Program, Title : 免疫ふしぎ未来2021
• がん免疫療法を少し深く考えてみませんか?

  Date (from-to) : 2021/07/16

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : 東京がん化学療法研究会

  Event, Program, Title : 第21回臨床腫瘍夏期セミナー
• がん免疫療法のバイオマーカー

  Date (from-to) : 2021/01/23

  Role : Lecturer

  Category : Seminar

  Sponser, Organizer, Publisher  : 日本臨床腫瘍学会

  Event, Program, Title : がん免疫療法エキスパートセミナー
• がん免疫療法はどうやって効いているの？

  Date (from-to) : 2019/07/04-2019/07/05

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : 東京がん化学療法研究会

  Event, Program, Title : 第20回臨床腫瘍夏期セミナー
• 腫瘍免疫を基礎から考える

  Date (from-to) : 2019/04/20

  Role : Lecturer

  Sponser, Organizer, Publisher  : 日本臨床腫瘍学会

  Event, Program, Title : がん免疫療法エキスパートセミナー
• がん免疫療法はどうしてわかりにくいの？

  Date (from-to) : 2018/07/12-2018/07/13

  Role : Lecturer

  Category : Lecture

  Sponser, Organizer, Publisher  : 東京がん化学療法研究会

  Event, Program, Title : 第19回臨床腫瘍夏期セミナー

Other link

researchmap

https://researchmap.jp/j-ytogashi