Masugi, Yohei

写真a

Affiliation

School of Medicine, Division of Diagnostic Pathology (Shinanomachi)

Position

Assistant Professor/Senior Assistant Professor

External Links

Career 【 Display / hide

  • 2004.04
    -
    2006.03

    Keio University Hospital, 初期臨床研修医

  • 2006.04
    -
    2010.03

    Keio University, Graduate School of Medicine, 医学研究科博士課程 病理系病理学

  • 2010.04
    -
    2016.03

    Keio University School of Medicine, Department of Pathology, Instructor

  • 2010.04
    -
    2016.03

    Keio University Hospital, Diagnostic Pathology

  • 2015.04
    -
    2017.01

    Dana-Farber Cancer Institute, and Harvard Medical School, Medical Oncology, Research fellow

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Academic Background 【 Display / hide

  • 1998.04
    -
    2004.03

    Keio University School of Medicine

    University, Graduated

  • 2006.04
    -
    2010.03

    Keio University Graduate School, 医学研究科, 病理系病理学

    Graduate School, Withdrawal after completion of doctoral course requirements, Doctoral course

Academic Degrees 【 Display / hide

  • 博士・医学, 慶應義塾大学大学院, 2010.06

Licenses and Qualifications 【 Display / hide

  • 死体解剖資格, 2008.12

  • 日本病理学会病理専門医, 2010.07

  • 病理専門医研究指導医, 2016.04

 

Books 【 Display / hide

  • 膵癌取扱い規約(第7版)

    日本膵臓学会, 2016.07

  • Classification of Pancreatic Carcinoma (Fourth English Edition)

    2017.07

  • 腫瘍病理鑑別診断アトラス大腸癌

    眞杉 洋平,向井 万起男, 2011

    Scope: 病理診断報告書に必要な記載,  Contact page: 283-290

  • 腫瘍病理鑑別診断アトラス肝癌

    眞杉 洋平,坂元 亨宇, 文光堂, 2010

    Scope: 肝細胞癌の多中心性発生と肝内転移,  Contact page: 185-189

Papers 【 Display / hide

  • Three distinct stroma types in human pancreatic cancer identified by image analysis of fibroblast subpopulations and collagen

    Ogawa Y., Masugi Y., Abe T., Yamazaki K., Ueno A., Fujii-Nishimura Y., Hori S., Yagi H., Abe Y., Kitago M., Sakamoto M.

    Clinical Cancer Research (Clinical Cancer Research)  27 ( 1 ) 107 - 119 2021.01

    ISSN  10780432

     View Summary

    Purpose: Cancer-associated fibroblasts have emerged to be highly heterogenous and can play multifaceted roles in dictating pancreatic ductal adenocarcinoma (PDAC) progression, immunosuppression, and therapeutic response, highlighting the need for a deeper understanding of stromal heterogeneity between patients and even within a single tumor. We hypothesized that image analysis of fibroblast subpopulations and collagen in PDAC tissues might guide stroma-based patient stratification to predict clinical outcomes and tumor characteristics. Experimental Design: A novel multiplex IHC-based image analysis system was established to digitally differentiate fibroblast subpopulations. Using whole-tissue slides from 215 treatment-nave PDACs, we performed concurrent quantification of principal fibroblast subpopulations and collagen and defined three stroma types: collagen-rich stroma, fibroblast activation protein a (FAP)dominant fibroblast-rich stroma, and a smooth muscle actin (ACTA2)-dominant fibroblast-rich stroma. These stroma types were assessed for the associations with cancer-specific survival by multivariable Cox regression analyses and with clinicopathologic factors, including CD8þ cell density. Results: FAP-dominant fibroblasts and ACTA2-dominant fibroblasts represented the principal distinct fibroblast subpopulations in tumor stroma. Stroma types were associated with patient survival, SMAD4 status, and transcriptome signatures. Compared with FAP-dominant fibroblast-rich stroma, collagen-rich stroma correlated with prolonged survival [HR, 0.57; 95% confidence interval (CI), 0.33–0.99], while ACTA2-dominant fibroblast-rich stroma exhibited poorer prognosis (HR, 1.65; 95% CI, 1.06–2.58). FAP-dominant fibroblast-rich stroma was additionally characterized by restricted CD8þ cell infiltrates and intense neutrophil infiltration. Conclusions: This study identified three distinct stroma types differentially associated with survival, immunity, and molecular features, thereby underscoring the importance of stromal heterogeneity in subtyping pancreatic cancers and supporting the development of antistromal therapies.

  • Characterization of spatial distribution of tumor-infiltrating CD8<sup>+</sup> T cells refines their prognostic utility for pancreatic cancer survival

    Masugi Y., Abe T., Ueno A., Fujii-Nishimura Y., Ojima H., Endo Y., Fujita Y., Kitago M., Shinoda M., Kitagawa Y., Sakamoto M.

    Modern Pathology (Modern Pathology)  32 ( 10 ) 1495 - 1507 2019.10

    ISSN  08933952

     View Summary

    The abundance of cytotoxic T-cell infiltrates has important implications for patient outcome and therapeutic design for pancreatic ductal adenocarcinoma. However, intratumoral heterogeneity remains a challenge to understanding the complex immune microenvironment. We hypothesized that characterizing CD8+ cell distribution within pancreatic adenocarcinoma tissues might refine the prognostic value of tumor-infiltrating CD8+ lymphocytes. Using multiplex immunohistochemistry-based image analysis on whole-tissue sections of 214 pancreatic ductal adenocarcinomas, we measured CD8+ cell densities in the tumor center, the tumor margin, and the whole tumor, along with the proximity of CD8+ cells to carcinoma cells. Multivariable Cox regression analysis was performed to assess the associations of CD8+ cell densities with pancreatic cancer-specific survival, adjusting for clinicopathologic and immune-related features, including tumor expressions of TP53, SMAD4, and the programmed cell death 1 ligand 1 (CD274, PD-L1) and the extent of tertiary lymphoid structures. There was substantial heterogeneity in CD8+ cell density, with the mean density in the tumor center less than half that in the tumor margin. Tumor CD274 expression and extensive tertiary lymphoid structures were appeared to be associated with higher CD8+ cell density in the tumor margin (P = 0.037 and P = 0.005, respectively), but not with that in the tumor center (P > 0.50). The association of higher CD8+ cell density with prolonged survival was significant for the whole tumor (Ptrend = 0.009); however, the association was stronger for the tumor center (Ptrend = 0.002) and insignificant for the tumor margin (Ptrend = 0.07). Tumor cell–CD8+ cell distance correlated strongly with CD8+ cell density, whereas the density of CD8+ cells proximate to cancer cells exhibited no prognostic association. In conclusion, spatial computational analysis on pancreatic ductal adenocarcinoma reveals the prognostic validity of CD8+ cell density in the tumor center, where CD8+ cell infiltration is ununiformly restricted, likely suggesting pro-tumorigenic roles of the immunosuppressive tumor microenvironment of pancreatic cancer.

  • OATP1B3 expression is strongly associated with Wnt/beta-catenin signalling and represents the transporter of gadoxetic acid in hepatocellular carcinoma

    Ueno, A., Masugi, Y., Yamazaki, K., Komuta, M., Effendi, K., Tanami, Y., Tsujikawa, H., Tanimoto, A., Okuda, S., Itano, O., Kitagawa, Y., Kuribayashi, S. and Sakamoto, M.

    J Hepatol 61 ( 5 ) 1080 - 7 2014.11

    ISSN  0168-8278

     View Summary

    BACKGROUND & AIMS: In the current era of emerging molecular targeted drugs, it is necessary to identify before treatment the specific subclass to which a tumour belongs. Gadoxetic acid is a liver-specific contrast agent that is preferentially taken up by hepatocytes. Therefore, gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) should provide precise molecular information about hepatocellular carcinomas (HCCs). The aim of this study was to investigate the transporters of gadoxetic acid in HCC comprehensively and to analyse the molecular regulatory mechanism of such transporters. METHODS: Expression levels of transporters, transcriptional factors and Wnt target genes in clinical samples were examined by quantitative real-time reverse transcription polymerase chain reaction and immunohistochemistry. LiCl treatment of the HCC cell line KYN-2 was conducted in vitro to assess the effects of Wnt signalling activity. RESULTS: Comprehensive analyses of transporter mRNAs and protein expressions revealed that the organic anion transporting polypeptide 1B3 (OATP1B3) had the strongest correlation with tumour enhancement in hepatobiliary-phase images of EOB-MRI. Association analysis with OATP1B3 expression revealed significant correlation with the expression of Wnt/beta-catenin target genes. Further, LiCl treatment induced OATP1B3 mRNA expression in KYN-2 cells, indicating a strong association between OATP1B3 expression and Wnt/beta-catenin signalling. The sensitivity and specificity to predict Wnt/beta-catenin-activated HCC using tumour enhancement in EOB-MRI were 78.9% and 81.7%, respectively. CONCLUSIONS: OATP1B3 was confirmed as the most important transporter mediating HCC enhancement in EOB-MRI. OATP1B3 expression showed a strong association with the expression of Wnt/beta-catenin target genes, therefore, OATP1B3-upregulated HCC likely represents a specific subclass of Wnt/beta-catenin-activated HCC.

  • Tumour CD274 (PD-L1) expression and T cells in colorectal cancer

    Masugi, Y., Nishihara, R., Yang, J., Mima, K., da Silva, A., Shi, Y., Inamura, K., Cao, Y., Song, M., Nowak, J. A., Liao, X., Nosho, K., Chan, A. T., Giannakis, M., Bass, A. J., Hodi, F. S., Freeman, G. J., Rodig, S., Fuchs, C. S., Qian, Z. R. and Ogino, S.

    Gut  2016.05

    ISSN  0017-5749

     View Summary

    Evidence suggests that CD274 (programmed death-ligand 1, B7-H1) immune checkpoint ligand repress antitumour immunity through its interaction with the PDCD1 (programmed cell death 1, PD-1) receptor of T lymphocytes in various tumours. We hypothesised that tumour CD274 expression levels might be inversely associated with T-cell densities in colorectal carcinoma tissue.|We evaluated tumour CD274 expression by immunohistochemistry in 823 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. We conducted multivariable ordinal logistic regression analyses to examine the association of tumour CD274 expression with CD3(+), CD8(+), CD45RO (PTPRC)(+) or FOXP3(+) cell density in tumour tissue, controlling for potential confounders including tumour status of microsatellite instability (MSI), CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level and KRAS, BRAF and PIK3CA mutations.|CD274 expression in tumour cells or stromal cells (including immune cells) was detected in 731 (89%) or 44 (5%) cases, respectively. Tumour CD274 expression level correlated inversely with FOXP3(+) cell density in colorectal cancer tissue (outcome) (ptrend=0.0002). For a unit increase in outcome quartile categories, multivariable OR in the highest (vs lowest) CD274 expression score was 0.22 (95% CI 0.10 to 0.47). Tumour CD274 expression was inversely associated with MSI-high status (p=0.001). CD274 expression was not significantly associated with CD3(+), CD8(+) or CD45RO(+) cell density, pathological lymphocytic reactions or patient survival prognosis.|Tumour CD274 expression is inversely associated with FOXP3(+) cell density in colorectal cancer tissue, suggesting a possible influence of CD274-expressing carcinoma cells on regulatory T cells in the tumour microenvironment.

  • Aspirin Use and Colorectal Cancer Survival According to Tumor CD274 (Programmed Cell Death 1 Ligand 1) Expression Status

    Hamada, T., Cao, Y., Qian, Z. R., Masugi, Y., Nowak, J. A., Yang, J., Song, M., Mima, K., Kosumi, K., Liu, L., Shi, Y., da Silva, A., Gu, M., Li, W., Keum, N., Zhang, X., Wu, K., Meyerhardt, J. A., Giovannucci, E. L., Giannakis, M., Rodig, S. J., Freeman, G. J., Nevo, D., Wang, M., Chan, A. T., Fuchs, C. S., Nishihara, R. and Ogino, S.

    J Clin Oncol 35 ( 16 ) 1836 - 1844 2017.06

    ISSN  0732-183

     View Summary

    Purpose Blockade of the programmed cell death 1 (PDCD1, PD-1) immune checkpoint pathway can improve clinical outcomes in various malignancies. Evidence suggests that aspirin (a widely used nonsteroidal anti-inflammatory drug) not only prolongs colorectal cancer survival, but can also activate T cell-mediated antitumor immunity and synergize with immunotherapy through inhibition of prostaglandin E2 production. We hypothesized that the survival benefit associated with aspirin might be stronger in colorectal carcinoma with a lower CD274 (PDCD1 ligand 1, PD-L1) expression level that resulted in lower signaling of the immune checkpoint pathway. Patients and Methods Using data from 617 patients with rectal and colon cancer in the Nurses' Health Study and the Health Professionals Follow-Up Study, we examined the association of postdiagnosis aspirin use with patient survival in strata of tumor CD274 expression status measured by immunohistochemistry. We used multivariable Cox proportional hazards regression models to control for potential confounders, including disease stage, microsatellite instability status, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation, cyclooxygenase-2 (PTGS2), and CDX2 expression, and KRAS, BRAF, and PIK3CA mutations. Results The association of postdiagnosis aspirin use with colorectal cancer-specific survival differed by CD274 expression status ( Pinteraction < .001); compared with aspirin nonusers; multivariable-adjusted hazard ratios for regular aspirin users were 0.16 (95% CI, 0.06 to 0.41) in patients with low CD274 and 1.01 (95% CI, 0.61 to 1.67) in patients with high CD274. This differential association seemed consistent in patients with microsatellite-stable or PIK3CA wild-type disease and in strata of PTGS2 expression, CDX2 expression, tumor-infiltrating lymphocytes, or prediagnosis aspirin use status. Conclusion The association of aspirin use with colorectal cancer survival is stronger in patients with CD274-low tumors than CD274-high tumors. Our findings suggest a differential antitumor effect of aspirin according to immune checkpoint status.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

  • Corrigendum to ‟On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity” [Redox Biol. 41 (2021) 101926] (Redox Biology (2021) 41, (S2213231721000744), (10.1016/j.redox.2021.101926))

    Honda K., Hishiki T., Yamamoto S., Yamamoto T., Miura N., Kubo A., Itoh M., Chen W.Y., Takano M., Yoshikawa T., Kasamatsu T., Sonoda S., Yoshizawa H., Nakamura S., Itai Y., Shiota M., Koike D., Naya M., Hayakawa N., Naito Y., Matsuura T., Iwaisako K., Masui T., Uemoto S., Nagashima K., Hashimoto Y., Sakuma T., Matsubara O., Huang W., Ida T., Akaike T., Masugi Y., Sakamoto M., Kato T., Ino Y., Yoshida H., Tsuda H., Hiraoka N., Kabe Y., Suematsu M.

    Redox Biology (Redox Biology)  44   102028 2021.08

    ISSN  22132317

     View Summary

    The authors regret that there are 3 grammatical typos in the abstract published. Below please find the corrected abstract: Chemosensitivity to cisplatin derivatives varies among individual patients with intractable malignancies including ovarian cancer, while how to unlock the resistance remain unknown. Ovarian cancer tissues were collected after the debulking surgery in discovery- (n = 135) and validation- (n = 47) cohorts, to be analyzed with high-throughput automated immunohistochemistry which identified cystathionine γ-lyase (CSE) as an independent marker distinguishing non-responders from responders to post-operative platinum-based chemotherapy. We aimed to identify CSE-derived metabolites responsible for chemoresistant mechanisms: gold-nanoparticle (AuN)-based surface-enhanced Raman spectroscopy (SERS) was used to enhance electromagnetic fields which enabled to visualize multiple sulfur-containing metabolites through detecting scattering light from Au–S vibration two-dimensionally. Clear cell carcinoma (CCC) which turned out less sensitive to cisplatin than serous adenocarcinoma was classified into two groups by the intensities of SERS intensities at 480 cm-1; patients with greater intensities displayed the shorter overall survival after the debulking surgery. The SERS signals were eliminated by topically applied monobromobimane that breaks sulfane-sulfur bonds of polysulfides to result in formation of sulfide dibimane which was detected at 580 cm-1, manifesting the presence of polysulfides in cancer tissues. CCC-derived cancer cell lines in culture were resistant against cisplatin, but treatment with ambroxol, an expectorant degrading polysulfides, renders the cells CDDP-susceptible. Co-administration of ambroxol with cisplatin significantly suppressed growth of cancer xenografts in nude mice. Furthermore, polysulfides, but neither glutathione nor hypotaurine, attenuated cisplatin-induced disturbance of DNA supercoiling. Polysulfide detection by on-tissue SERS thus enables to predict prognosis of cisplatin-based chemotherapy. The current findings suggest polysulfide degradation as a stratagem unlocking cisplatin chemoresistance. The authors would like to apologise for any inconvenience caused.

  • 【膵案取扱いに関する新たな知見と基準】 膵癌治療効果に関する病理組織学的判定基準

    眞杉 洋平,内田 克典

    病理と臨床 (文光堂)  34   832 - 837 2016

    Introduction and explanation (commerce magazine), Joint Work

  • 肝細胞癌の病理学的多様性

    坂元 亨宇,相島 慎一,中島 収,眞杉 洋平

    The Liver Cancer Journal (メディカルビュー社)  7   13 - 22 2015

    Introduction and explanation (commerce magazine), Joint Work

  • 【肝癌のトピックス】 早期肝癌診断と肝癌バイオマーカー

    眞杉 洋平,坂元 亨宇

    病理と臨床 (文光堂)  32   1331 - 1337 2015

    Introduction and explanation (commerce magazine), Joint Work

  • 【肝がん】 Molecular classification

    眞杉 洋平,坂元 亨宇

    診断と治療のABC (最新医学社)  103   30 - 31 2015

    Introduction and explanation (commerce magazine), Joint Work

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 膵がんの線維形成性間質不均一の臨床病理学的意義およびその形状に係る分子機構の解明

    2020.04
    -
    2024.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 眞杉 洋平, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • Subclassification of tumor-immune microenvironment of pancreatic cancer by digital image analysis

    2018.04
    -
    2020.03

    Grant-in-Aid for Scientific Research, Yohei Masugi, Research grant, Principal Investigator

     View Summary

    多重染色技術を用いた画像解析により、組織内T細胞・癌細胞の空間分布を定量・可視化し、膵癌微小環境が腫瘍中心と辺縁で免疫学的ならびに臨床病理学的に大きく異なることを見出した。

  • 膵癌組織の高精細デジタル画像解析による免疫抑制性腫瘍微小環境のサブクラス分類

    2018.04
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    2020.03

    Keio Gijuku Academic Development Fund, No Setting, Principal Investigator

  • 分子病理疫学的手法による消化器癌の発生原因の解明

    2015.04
    -
    2016.03

    Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research, No Setting, Principal Investigator

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     免疫療法をはじめとする新規治療薬の開発、がん治療の多様化が進むとともに、個別化医療の実現に向けた臓器がんの診断・治療・予防が求められる時代となりつつある。一方でがんはヘテロな集団であり、がんの多様性はゲノム・エピゲノム異常の蓄積だけでなく、がん発育過程における環境(例えば、運動や食事習慣、炎症、アスピリンやサプリメント服用、常在バクテリア等)に大いに左右されることも明らかとなっている。申請者は、2015年4月1日~2016年3月31日の期間、ダナファーバー癌研究所ならびにハーバード医学大学院(米国、ボストン)の分子病理疫学研究室に留学し、多様な組み合わせの分子異常や環境因子が、代表的な消化器がん(大腸癌・膵癌)サブタイプとどのように関わっているのかを大規模前向きコホートを用いて解析した。申請者が中心となって明らかにしたのは、以下の6項目である。
    (1)免疫療法のターゲット分子CD274 (PD-L1)の発現レベルは、大腸癌組織内の制御性T細胞マーカーFOXP3陽性リンパ球密度と逆相関する。これは大腸癌の中には、自身に対する免疫反応を抑制する機構として、代表的な免疫抑制機構PDCD1パスウェイと制御性Tリンパ球を使う2つの異なるサブタイプがあることを示唆する(Gut 2016)。
    (2)アスピリンは大腸癌の発生を予防するだけでなく、術後の予後改善効果があることが知られている。我々は、アスピリンの日常的使用はCD274low大腸癌の予後を改善する一方で、CD274high大腸癌の予後改善には効果がないことを明らかにした(J Clin Oncol 2017)。
    (3)CD274のファミリー分子PDCD1LG2(PD-L2)の発現レベルが、大腸癌に対するCrohn’s-like lymphoid reactionという特異な抗腫瘍免疫反応の程度と逆相関することを示した(論文投稿中)。
    (4)オートファジーマーカーSQSTM1を用いて、大腸癌のオートファジーレベルとT細胞反応の関連を検討したところ、オートファジーレベルの高い大腸癌では制御性Tリンパ球の腫瘍内密度が高いことを示した(Oncoimmunol 2017)。
    (5)カルシウム摂取が大腸癌の発生率を下げるという疫学的データがある。我々の研究により、カルシウム摂取はカルシウムレセプターであるcalcium sensing receptor (CASR)陽性大腸癌の発生率低下に関わっているが、CASR陰性大腸癌の発生には寄与しないことが明らかとなった(論文投稿準備中)。
    (6)膵臓癌の代表的な4ドライバー遺伝子KRAS, CDKN2A, TP53, SMAD4が予後に与える影響を検討したところ、KRASにおけるある特定のmutation Xが独立した予後不良因子であることを発見した(論文投稿準備中)。

  • 膵癌における弧在性浸潤の分子機構:弧在性癌細胞に発現する分子の同定および機能解析

    2012.04
    -
    2015.03

    Research grant, Principal Investigator

     View Summary

    弧在性浸潤癌細胞に強発現する分子としてインテグリン4ならびにSMAD3を同定し、これらの分子が膵癌における上皮間葉移行を制御することを見出した。

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Awards 【 Display / hide

  • 平成29年度日本病理学会学術奨励賞

    2018, 日本病理学会

  • 日本病理学会秋期特別総会 優秀演題賞

    2014.11

 

Courses Taught 【 Display / hide

  • GENERAL PATHOLOGY

    2021

  • DISEASES OF ORGAN SYSTEMS

    2021

  • DISEASES OF ORGAN SYSTEMS

    2020

  • GENERAL PATHOLOGY

    2020

  • GENERAL PATHOLOGY

    2019

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Courses Previously Taught 【 Display / hide

  • 病理診断学

    慶應義塾大学, 2019, Major subject

  • Diagnostic Pathology

    Keio University, 2018

  • Pathology

    Keio University, 2018, Full academic year

  • Pathology

    Keio University, 2018, Full academic year

  • Diagnostic Pathology

    Keio University, 2017

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Social Activities 【 Display / hide

Memberships in Academic Societies 【 Display / hide

  • Japanese Society of Pathology, 

    2006
    -
    Present
  • Japanese Cancer Association, 

    2009.07
    -
    Present
  • Japan Pancreas Society, 

    2008.07
    -
    Present
  • United States and Canadian Academy of Pathology, 

    2018.07
    -
    Present
  • American Association for Cancer Research, 

    2013.01
    -
    Present

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Committee Experiences 【 Display / hide

  • 2014.09
    -
    Present

    膵癌取扱い規約検討委員, 日本膵臓学会

  • 2014
    -
    Present

    日本病理学会学術評議員, 日本病理学会