Masugi, Yohei

写真a

Affiliation

School of Medicine, Division of Diagnostic Pathology （Shinanomachi）

Position

Assistant Professor/Senior Assistant Professor

External Links
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Career 【 Display / hide 】

  • 2004.04
    -
    2006.03

    Keio University Hospital, 初期臨床研修医

  • 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

  • 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

  • 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

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Academic Background 【 Display / hide 】

  • 1998.04
    -
    2004.03

    Keio University School of Medicine

    University, Graduated

  • 1998.04
    -
    2004.03

    Keio University School of Medicine

  • 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

  • 2006.04
    -
    2010.03

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

  • 2006.04
    -
    2010.03

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

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Academic Degrees 【 Display / hide 】

  • 博士・医学, 慶應義塾大学大学院, 2010.06

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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

  • 日本病理学会病理専門医研修指導医, 2016.04

  • 日本膵臓学会認定指導医, 2019.12

  • 細胞診専門医, 2021.01

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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

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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

    Joint Work,  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+ 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

    Joint Work,  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.

  • The Desmoplastic Stroma of Pancreatic Cancer: Multilayered Levels of Heterogeneity, Clinical Significance, and Therapeutic Opportunities

    Masugi Y.

    Cancers （Cancers)  14 （ 13 ）  2022.07

    Single Work, Lead author,  ISSN  20726694

    　View Summary

    Pancreatic cancer remains one of the most lethal malignancies and is becoming a dramatically increasing cause of cancer-related mortality worldwide. Abundant desmoplastic stroma is a histological hallmark of pancreatic ductal adenocarcinoma. Emerging evidence suggests a promising therapeutic effect of several stroma-modifying therapies that target desmoplastic stromal elements in the pancreatic cancer microenvironment. The evidence also unveils multifaceted roles of cancer-associated fibroblasts (CAFs) in manipulating pancreatic cancer progression, immunity, and chemotherapeutic response. Current state-of-the-art technologies, including single-cell transcriptomics and multiplexed tissue imaging techniques, have provided a more profound knowledge of CAF heterogeneity in real-world specimens from pancreatic cancer patients, as well as in genetically engineered mouse models. In this review, we describe recent advances in the understanding of the molecular pathology bases of pancreatic cancer desmoplastic stroma at multilayered levels of heterogeneity, namely, (1) variations in cellular and non-cellular members, including CAF subtypes and extracellular matrix (ECM) proteins; (2) geographical heterogeneity in relation to cell–cell interactions and signaling pathways at niche levels and spatial heterogeneity at locoregional levels or organ levels; and (3) intertumoral stromal heterogeneity at individual levels. This review further discusses the clinicopathological significance of desmoplastic stroma and the potential opportunities for stroma-targeted therapies against this lethal malignancy.

  • Keio Uterus Transplantation Research: From Basic Research toward Future Clinical Application

    Kisu I., Banno K., Matoba Y., Yamada Y., Emoto K., Masugi Y., Matsubara K., Obara H., Aoki D.

    The Keio journal of medicine （The Keio journal of medicine)  71 （ 2 ） 33 - 43 2022.06

    ISSN  0022-9717

    　View Summary

    Uterus transplantation (UTx) is now a potential option to allow women with uterine factor infertility to give birth. However, UTx is still at an experimental stage, and basic animal studies, including in non-human primates, are needed for the accumulation of data prior to clinical application. Considering that UTx may provide new hope to Japanese women, we launched UTx research in 2009 and have since accumulated a large archive of results in the UTx research field. Furthermore, we have carried out various activities aimed at the implementation of clinical applications of UTx in Japan while clarifying the ethical and social issues involved. Currently, the clinical application of UTx in Japan is just around the corner, and it is expected that UTx research will develop further in the future. Herein, we summarize our basic experiences using non-human primates and our activities with the goal of future clinical applications.

  • Midazolam exhibits antitumour and anti-inflammatory effects in a mouse model of pancreatic ductal adenocarcinoma

    Oshima Y., Sano M., Kajiwara I., Ichimaru Y., Itaya T., Kuramochi T., Hayashi E., Kim J., Kitajima O., Masugi Y., Masamune A., Ijichi H., Ishii Y., Suzuki T.

    British Journal of Anaesthesia （British Journal of Anaesthesia)  128 （ 4 ） 679 - 690 2022.04

    ISSN  00070912

    　View Summary

    Background: Anaesthesia and perioperative management contribute to long-term outcomes of patients with cancer, including pancreatic ductal adenocarcinoma. We assessed the antitumour, anti-inflammatory, and analgesic effects of midazolam on LSL-KrasG12D/+;Trp53flox/flox;Pdx-1cre/+ transgenic mice with pancreatic ductal adenocarcinoma. Methods: Six-week-old transgenic mice were administered midazolam 30 mg kg−1 day−1 p.o. (n=13); midazolam 30 mg kg−1 day−1 with 1-(2-chlorophenyl)-N-methyl-N(1-methylpropyl)-3-isoquinoline carboxamide (PK11195) 3 mg kg−1 day−1 i.p., a peripheral benzodiazepine receptor antagonist (n=10); or vehicle (water; n=14) until the humane endpoint. Cancer-associated pain was evaluated using hunching score and mouse grimace scale. Tumour stage and immuno-inflammatory status were determined histopathologically. Anti-proliferative and apoptotic potentials of midazolam were investigated using mouse pancreatic ductal adenocarcinoma cell lines. Results: Midazolam significantly inhibited tumour size and proliferative index of Ki-67 and cyclins in pancreatic ductal adenocarcinoma, which was blocked by administration of PK11195. Local myeloperoxidase+ tumour-associated neutrophils, arginase-1+ M2-like tumour-associated macrophages, and CD11b+Ly-6G+ polymorphonuclear myeloid-derived suppressor cells were reduced by midazolam, which was antagonised by administration of PK11195. Hunching and mouse grimace scale were improved by midazolam, whereas the scores increased with midazolam+PK11195 treatment. Plasma pro-inflammatory cytokines, such as interleukin-6 and CC chemokine ligand (CCL)2, CCL3, and CCL5, were reduced by midazolam, whereas these cytokines increased with PK11195. Midazolam inhibited pancreatic ductal adenocarcinoma proliferation through downregulation of cyclins and cyclin-dependent kinases and induced apoptosis in vitro. Conclusions: These results suggest that midazolam inhibits pancreatic ductal adenocarcinoma proliferation and local infiltration of tumour-associated neutrophils, tumour-associated macrophages, and polymorphonuclear myeloid-derived suppressor cells, thereby inhibiting pancreatic ductal adenocarcinoma progression.

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

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Reviews, Commentaries, etc. 【 Display / hide 】

  • Three Distinct Stroma Types in Human Pancreatic Cancer Identified by Image Analysis of Fibroblast Subpopulations and Collagen—Response

    Masugi Y., Abe T., Yamazaki K., Ueno A., Sakamoto M.

    Clinical Cancer Research (Clinical Cancer Research)  28 ( 2 ) 427 2022.01

    ISSN  10780432

  • 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 - 102028 2021.08

    Other, Joint Work,  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

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), 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

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), 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

    Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media), 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
    -
    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

    　View Summary

    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

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Courses Taught 【 Display / hide 】

  • DISEASES OF ORGAN SYSTEMS

    2022

  • GENERAL PATHOLOGY

    2021

  • DISEASES OF ORGAN SYSTEMS

    2021

  • GENERAL PATHOLOGY

    2020

  • DISEASES OF ORGAN SYSTEMS

    2020

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Courses Previously Taught 【 Display / hide 】

  • 病理診断学

    慶應義塾大学

    2019.04
    -
    2020.03

  • Pathology

    Keio University

    2018.04
    -
    2019.03
    , 

    Full academic year

  • Diagnostic Pathology

    Keio University

    2018.04
    -
    2019.03

  • Pathology

    Keio University

    2018.04
    -
    2019.03
    , 

    Full academic year

  • Pathology

    Keio University

    2017.04
    -
    2018.03
    , 

    Full academic year

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Social Activities 【 Display / hide 】

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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

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