Identification of resistant clone for the chemotherapy of hepatocellular carcinoma using cell free DNA
Project/Area Number |
21K07950
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 53010:Gastroenterology-related
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Research Institution | Kindai University |
Principal Investigator |
工藤 正俊 近畿大学, 医学部, 教授 (10298953)
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Co-Investigator(Kenkyū-buntansha) |
西田 直生志 近畿大学, 医学部, 教授 (60281755)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Project Status |
Granted (Fiscal Year 2022)
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Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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Keywords | 肝細胞癌 / 免疫チェックポイント阻害剤 / セルフリーDNA / 腫瘍微小免疫環境 / 無再発生存期間 / アジュバント療法 / 化学療法 / cell free DNA / 遺伝子変異 / ゲノム診断 |
Outline of Research at the Start |
肝細胞癌(肝癌)薬物療法の進歩により、顕著な抗腫瘍反応が認められる例が増えている。しかし、腫瘍の縮小後に再増悪する例も多い。これらは、腫瘍細胞のゲノム変化による耐性変異獲得の結果と予想できる。そこで、腫瘍由来と考えられる血中のcell free DNA(cfDNA)の遺伝子変化を、同一例で経時的に解析し、癌関連遺伝子変異の分子系統樹を作成することにより、薬物療法への反応時から増悪時への移行期に生じるゲノム変化を同定して薬剤耐性クローンのゲノムの特徴を解析する。
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Outline of Annual Research Achievements |
肝細胞癌(肝癌)の治療後に免疫チェックポイント阻害剤(ICI)が投与された例を用い、再発予防と関連する免疫関連分子の解析を行った。32例に関し、免疫染色(IHC)にて評価した腫瘍免疫微小環境(TME)とICI投与下での再発の関連を解析した。免疫染色による腫瘍免疫環境(TME)の解析にはb-カテニン、GS、PD-1、PD-L1、CD8、とFoxp3を用い、腫瘍ゲノムの解析にはThermo FischerのTML assayにより、409の癌関連遺伝子変異、コピー数変化(CNV)、tumor mutation load (TML)を解析した。またRosheのCAPP-Seqにより血漿からctDNA検出を検出し、mlあたりvariant alleleが10コピー以上検出された場合をMRD陽性と判定した。 b-カテニンとGSの染色結果より肝癌をb-catenin経路活性化群、非活性化群、TME状態により4群(hot型、exhausted型、cold型、Treg型)に分類した。ICI投与による術後無再発生存期間(RFS)はb-カテニン経路非活性化群で活性化群より有意に長く(p=0.0191)、またhot/exhausted型はcold/Treg型に比較して有意に長かった(p<0.0001)。次に肝癌コホートでb-カテニン活性化に関わるCNVに注目した。b-カテニンにより活性化される転写因子TCF3, 4、およびMYCのlocusにCNVのある例はない例と比べて再発例が多く、PD-1抗体投与下での根治術後のRFSが有意に短いという結果が得られた。腫瘍組織のTMBとPD-1投与下での再発に関しては、再発例と無再発例でTMB量に差がなく、またRFSにも差がなかった。MRDに関しては、この症例数では有意差はないものの、根治術後にMRD陽性例ではRFSが短い傾向にあった。
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
本研究計画では、肝癌根治術後のアジュバント療法としての免疫チェックポイント阻害剤を使用中に腫瘍が再発した例での遺伝子変異の特徴、チロシンキナーゼ阻害剤による腫瘍反応後に再増悪を来した例の遺伝子変異の特徴を、血中circulating tumor DNA(ctDNA)を用いて解析することを目的としている。今回は前年度の成果から、さらに癌関連遺伝子変異、コピー数変化(CNV)、tumor mutation load (TML)をより詳細に解析した。今回の肝癌コホートではβカテニン遺伝子の変異例が1例、APC変異例が2例しかなかったため、βカテニン経路活性化変異に加え、βカテニンにより活性化される転写因子TCF3, 4、およびMYCのcopy number gain (CNG)に注目した。興味深いことに、これらのlocusにCNVのある例はない例と比べて再発例が多く、PD-1抗体投与下での根治術後のRFSが有意に短いという結果が得られた。また、症例背景に関して血中AFP値との関連を見たところ、術後でもAFPが8ng/ml以上の例では全例MRD陽性であり、血中AFP値が5未満の例でも約半数がMRD陽性となっていた。すなわち、肝癌術後に腫瘍マーカーが低下しても、約半数残存腫瘍がある可能性が示唆された。上記の成果より、本研究は概ね順調の進展していると言える。
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Strategy for Future Research Activity |
今後は、より長期間のフォローによりイベント数が増えてから再解析する予定である。また、研究計画に基づき、チロシンキナーゼ阻害剤(TKI)における耐性変異クローンを同定する目的で、TKI投与により、腫瘍縮小が得られた症例中、治療前に手術あるいは腫瘍生検によるパラフィン包埋組織が利用可能な例を対象として、治療前の腫瘍組織の遺伝子異常をOncomine Tumor Mutation Load Assayにて、治療開始後、及び腫瘍の再増悪時のcfDNA の遺伝子変異をAVENIO ctDNA Surveillance panel にて解析する。
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Report
(2 results)
Research Products
(56 results)
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[Journal Article] Impact of body mass index in patients receiving atezolizumab plus bevacizumab for hepatocellular carcinoma.2023
Author(s)
Vithayathil M, D'Alessio A, Fulgenzi CAM, Nishida N, Schonlein M, von Felden J, Schulze K, Wege H, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, et al.
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Journal Title
Hepatology international
Volume: ー
Issue: 4
Pages: 904-914
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients2023
Author(s)
Rimini M, Persano M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa J, Salani F, Lonardi S, Piscaglia F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Schirripa M, Montes M, Vivaldi C, Solda C, Hiraoka A, Sho T, Niizeki T, Nishida N, et al.
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Journal Title
Journal of cancer research and clinical oncology
Volume: ー
Issue: 10
Pages: 7565-7577
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis?2023
Author(s)
Rimini M, Persano M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Yoo C, Lonardi S, Piscaglia F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Pressiani T, Montes M, Vivaldi C, Solda C, Hiraoka A, Sho T, Niizeki T, Nishida N, et al.
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Journal Title
Targeted oncology
Volume: 18 (2)
Issue: 2
Pages: 221-233
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab.2023
Author(s)
Persano M, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa Ramos J, Masi G, Yoo C, Lonardi S, Stefanini B, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Montes M, Vivaldi C, Solda C, Hiraoka A, Sho T, Niizeki T, Nishida N, et al.
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Journal Title
Oncology
Volume: ー
Issue: 5
Pages: 283-291
DOI
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[Journal Article] Outcomes of beta blocker use in advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.2023
Author(s)
Wu YL, van Hyfte G, Ozbek U, Reincke M, Gampa A, Mohamed YI, Nishida N, Wietharn B, Amara S, Lee PC, Scheiner B, Balcar L, Pinter M, Vogel A, Weinmann A, Saeed A, Pillai A, Rimassa L, Naqash AR, Muzaffar M, Huang YH, Kaseb AO, Kudo M, Pinato DJ, Ang C.
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Journal Title
Frontiers in oncology
Volume: 13
Pages: 128569-1128569
DOI
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[Journal Article] Successful initial tofacitinib treatment for acute severe ulcerative colitis with steroid resistance: a case series.2023
Author(s)
Komeda Y, Kono M, Kashida H, Tribonias G, Masaki S, Takada R, Nagai T, Hagiwara S, Nishida N, Takenaka M, Honjo H, Matsui S, Tsuji N, Kudo M.
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Journal Title
Annals of gastroenterology
Volume: 35 (1)
Pages: 97-102
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study.2022
Author(s)
Talbot T, D'Alessio A, Pinter M, Balcar L, Scheiner B, Marron TU, Jun T, Dharmapuri S, Ang C, Saeed A, Hildebrand H, Muzaffar M, Fulgenzi CAM, Amara S, Naqash AR, Gampa A, Pillai A, Wang Y, Khan U, Lee PC, Huang YH, Bengsch B, Bettinger D, Mohamed YI, Kaseb A, Pressiani T, Nishida N, Kudo M, et al.
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Journal Title
Liver international
Volume: 43(3)
Issue: 3
Pages: 695-707
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Clinical outcomes with atezolizumab plus bevacizumab or lenvatinib in patients with hepatocellular carcinoma: a multicenter real-world study.2022
Author(s)
Persano M, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Rimassa L, Presa J, Masi G, Yoo C, Lonardi S, Tovoli F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Pressiani T, Kawaguchi T, Montes M, Vivaldi C, Solda C, Piscaglia F, Hiraoka A, Sho T, Nishida N, et al.
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Journal Title
Journal of cancer research and clinical oncology
Volume: ー
Issue: 9
Pages: 5591-5602
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratios as Prognostic Biomarkers in Unresectable Hepatocellular Carcinoma Treated with Atezolizumab plus Bevacizumab.2022
Author(s)
Wu YL, Fulgenzi CAM, D'Alessio A, Cheon J, Nishida N, Saeed A, Wietharn B, Cammarota A, Pressiani T, Personeni N, Pinter M, Scheiner B, Balcar L, Huang YH, Phen S, Naqash AR, Vivaldi C, Salani F, Masi G, Bettinger D, Vogel A, Schonlein M, von Felden J, Schulze K, Wege H, Galle PR, Kudo M, et al
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Journal Title
Cancers
Volume: 14(23)
Issue: 23
Pages: 5834-5834
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population.2022
Author(s)
Casadei-Gardini A, Rimini M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Rimassa L, Presa J, Masi G, Yoo C, Lonardi S, Tovoli F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Pressiani T, Montes M, Vivaldi C, Solda C, Piscaglia F, Hiraoka A, Nishida N, et al.
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Journal Title
European journal of cancer
Volume: 180
Pages: 9-20
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Reproducible safety and efficacy of atezolizumab plus bevacizumab for HCC in clinical practice: Results of the AB-real study2022
Author(s)
Fulgenzi CAM, Cheon J, D'Alessio A, Nishida N, Ang C, Marron TU, Wu L, Saeed A, Wietharn B, Cammarota A, Pressiani T, Personeni N, Pinter M, Scheiner B, Balcar L, Napolitano A, Huang YH, Phen S, Naqash AR, Vivaldi C, Salani F, Masi G, Bettinger D, Vogel A, Schonlein M, von Felden J, Schulze K, Kudo M, et al.
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Journal Title
European journal of cancer
Volume: 175
Pages: 204-213
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Impact of older age in patients receiving atezolizumab and bevacizumab for hepatocellular carcinoma.2022
Author(s)
Vithayathil M, D'Alessio A, Fulgenzi CAM, Nishida N, Schonlein M, von Felden J, Schulze K, Wege H, Saeed A, Wietharn B, Hildebrand H, Wu L, Ang C, Marron TU, Weinmann A, Galle PR, Bettinger D, Bengsch B, Vogel A, Balcar L, Scheiner B, Lee PC, Huang YH, Amara S, Muzaffar M, Naqash AR, Cammarota A, Kudo M, et al.
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Journal Title
Liver international
Volume: 42(11)
Issue: 11
Pages: 2538-2547
DOI
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Peer Reviewed / Int'l Joint Research
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[Journal Article] Progression from early to advanced stage of immune-related cholangitis.2022
Author(s)
Hagiwara S, Yoshida T, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Cishina H, Komeda Y, Yoshida A, Hayashi H, Nakagawa K, Kudo M.
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Journal Title
Hepatology research
Volume: 52(10)
Issue: 10
Pages: 888-892
DOI
Related Report
Peer Reviewed
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[Journal Article] Clinical implication of immune checkpoint inhibitor on the chronic hepatitis B virus infection2022
Author(s)
Hagiwara S, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Chishina H, Komeda Y, Yoshida A, Hayashi H, Nakagawa K, Kudo M.
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Journal Title
Hepatology Research
Volume: 52 (9)
Issue: 9
Pages: 754-761
DOI
Related Report
Peer Reviewed
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[Journal Article] Validation of the easy-to-use lenvatinib prognostic index to predict prognosis in advanced hepatocellular carcinoma patients treated with lenvatinib.2022
Author(s)
Rimini M, Kang W, Burgio V, Persano M, Aoki T, Shimose S, Tada T, Kumada T, Sho T, Lai E, Celsa C, Campani C, Tonnini M, Tamburini E, Hiraoka A, Takaguchi K, Nishida N, Iwamoto H, Itobayashi E, Tsuji K, Sakamoto N, Ishikawa T, Toyoda H, Kudo M, et al.
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Journal Title
Hepatology research
Volume: 52(12)
Issue: 12
Pages: 1050-1059
DOI
Related Report
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[Journal Article] Patterns and outcomes of subsequent therapy after immune checkpoint inhibitor discontinuation in HCC2022
Author(s)
Sharma R, Pillai A, Marron TU, Fessas P, Saeed A, Jun T, Dharmapuri S, Szafron D, Naqash AR, Gampa A, Wang Y, Khan U, Muzaffar M, Lee CJ, Lee PC, Bulumulle A, Paul S, Bettinger D, Hildebrand H, Yehia M, Pressiani T, Kaseb A, Huang YH, Ang C, Kudo M, Nishida N, Personeni N, Rimassa L, Pinato DJ.
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Journal Title
Hepatology communications
Volume: 6(7)
Issue: 7
Pages: 1776-1785
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[Journal Article] Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study.2022
Author(s)
Marinelli B, Kim E, D'Alessio A, Cedillo M, Sinha I, Debnath N, Kudo M, Nishida N, Saeed A, Hildebrand H, Kaseb AO, Abugabal YI, Pillai A, Huang YH, Khan U, Muzaffar M, Naqash AR, Patel R, Fischman A, Bishay V, Bettinger D, Sung M, Ang C, Schwartz M, Pinato DJ, Marron T.
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Journal Title
Journal for immunotherapy of cancer
Volume: 10(6)
Issue: 6
Pages: e004205-e004205
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[Journal Article] .Value of artificial intelligence with novel tumor tracking technology in the diagnosis of gastric submucosal tumors by contrast-enhanced harmonic endoscopic ultrasonography.2022
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Tanaka H, Kamata K, Ishihara R, Handa H, Otsuka Y, Yoshida A, Yoshikawa T, Ishikawa R, Okamoto A, Yamazaki T, Nakai A, Omoto S, Minaga K, Yamao K, Takenaka M, Watanabe T, Nishida N, Kudo M.
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Journal Title
Journal of gastroenterology and hepatology
Volume: 37(5)
Issue: 5
Pages: 841-846
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[Journal Article] Role of phlebotomy in the treatment of liver damage related to erythropoietic porphyria.2022
Author(s)
Hagiwara S, Nishida N, Ida H, Ueshima K, Minami Y, Takita M, Aoki T, Morita M, Chishina H, Komeda Y, Yoshida A, Park AM, Sato M, Kawada A, Nakano H, Nakagawa H, Kudo M.
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Journal Title
Scientific reports
Volume: 12(1)
Issue: 1
Pages: 6100-6100
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[Journal Article] Clinicopathological analysis of hepatic immune-related adverse events in comparison with autoimmune hepatitis and graft-versus host disease2021
Author(s)
Satoru Hagiwara, Tomohiro Watanabe, Masatoshi Kudo, Kosuke Minaga, Yoriaki Komeda, Ken Kamata, Masatomo Kimura, Hidetoshi Hayashi, Kazuhiko Nakagawa, Kazuomi Ueshima, Yasunori Minami, Tomoko Aoki, Masahiro Takita, Masahiro Morita, Hirokazu Cishina, Hiroshi Ida, Ah-Mee Park, Naoshi Nishida
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Journal Title
Scientific Reports
Volume: 11
Issue: 1
Pages: 9242-9242
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[Journal Article] Immunological Microenvironment Predicts the Survival of the Patients with Hepatocellular Carcinoma Treated with Anti-PD-1 Antibody.2021
Author(s)
Masahiro Morita, Naoshi Nishida, Kazuko Sakai, Tomoko Aoki, Hirokazu Chishina, Masahiro Takita, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima, Kazuto Nishio, Yukari Kobayashi, Kazuhiro Kakimi, Masatoshi Kudo
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Journal Title
Liver cancer
Volume: 10
Issue: 4
Pages: 380-393
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[Journal Article] Higher enhancement intrahepatic nodules on the Hepatobiliary Phase of Gd-EOB-DTPA-enhanced MRI as a Poor Responsive Marker of Anti-PD-1 / PD-L1 Monotherapy for Unresectable Hepatocellular Carcinoma.2021
Author(s)
Aoki T, Nishida N, Ueshima K, Morita M, Chishina H, Takita M, Hagiwara S, Ida H, Minami Y, Yamada A, Sofue K, Tsurusaki M, Kudo M.
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Journal Title
Liver cancer
Volume: 10
Issue: 6
Pages: 615-628
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[Journal Article] Early Antibiotic Exposure Is Not Detrimental to Therapeutic Effect from Immunotherapy in Hepatocellular Carcinoma.2021
Author(s)
Petros Fessas, Muntaha Naeem, Matthias Pinter, Thomas U Marron, David Szafron, Lorenz Balcar, Anwaar Saeed, Tomi Jun, Sirish Dharmapuri, Naoshi Nishida, et al
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Journal Title
Liver Cancer
Volume: 10
Issue: 6
Pages: 583-592
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[Journal Article] Accumulation of Genetic and Epigenetic Alterations in the Background Liver and Emergence of Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease.2021
Author(s)
Satoru Hagiwara, Naoshi Nishida, Kazuomi Ueshima, Yasunori Minami, Yoriaki Komeda, Tomoko Aoki, Masahiro Takita, Masahiro Morita, Hirokazu Chishina, Akihiro Yoshida, Hiroshi Ida, Masatoshi Kudo
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Journal Title
Cells
Volume: 10
Issue: 11
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[Journal Article] Objective Response Predicts Survival in Advanced Hepatocellular Carcinoma treated with Systemic Therapies.2021
Author(s)
Masatoshi Kudo, Robert Montal, Richard S Finn, Florian Castet, Kazuomi Ueshima, Naoshi Nishida, Philipp K Haber, Youyou Hu, Yasutaka Chiba, Myron Schwartz, Tim Meyer, Riccardo Lencioni, Josep M Llovet
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Journal Title
Clinical cancer research
Volume: Online ahead of print
Issue: 16
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[Journal Article] The Systemic Inflammatory Response Identifies Patients with Adverse Clinical Outcome from Immunotherapy in Hepatocellular Carcinoma.2021
Author(s)
Ambreen Muhammed, Claudia Angela Maria Fulgenzi, Sirish Dharmapuri, Matthias Pinter, Lorenz Balcar, Bernhard Scheiner, Thomas U Marron, Tomi Jun,, Naoshi Nishida, et al.
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Journal Title
Cancers
Volume: 14
Issue: 1
Pages: 186-186
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[Presentation] 複合免疫療法時代におけるイメージングバイオマーカーとしてのEOB-MRIの役割2022
Author(s)
青木智子, 西田直生志, 上嶋一臣, 盛田真弘, 千品寛和, 田北雅弘, 南康範, 依田広, 祖父江慶太郎, 鶴崎正勝, 工藤正俊
Organizer
第58回日本肝癌研究会; パネルディスカッション8 肝癌におけるPrecision Oncology
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[Presentation] 複合免疫療法時代におけるhyper progressive disease (HPD)2022
Author(s)
青木智子, 西田直生志, 上嶋一臣, 盛田真弘, 千品寛和, 田北雅弘, 南康範, 萩原智, 依田広, 鶴崎正勝, 工藤正俊
Organizer
第58回日本肝癌研究会 パネルディスカッション5; 肝癌免疫療法の治療向上を目指して
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[Presentation] Final Results of Adjuvant Nivolumab for Hepatocellular Carcinoma (HCC) after Surgical Resection (SR) or Radiofrequency Ablation (RFA) (NIVOLVE): A Phase 2 Prospective Multicenter Single Arm Trial and Exploratory Biomarker Analysis.2022
Author(s)
Masatoshi Kudo, Kazuomi Ueshima, Shin Nakahira, Naoshi Nishida, Hiroshi Ida, Yasunori Minami, Takuya Nakai, Hiroshi Wada, Shoji Kubo, Kazuyoshi Ohkawa, Asahiro Morishita, Takeo Nomi, Koji Ishida, et al.
Organizer
ASCO Gastrointestinal Cancers Symposium (ASCO-GI)
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[Presentation] Gd-EOB-DTPA-enhanced MRI肝細胞相で高信号の肝細胞癌は PD-1/PD-L1療法への一次耐性を反映し効果不良である2021
Author(s)
青木 智子, 西田 直生志, 上嶋 一臣, 盛田 真弘, 千品 寛和, 田北 雅弘, 南 康範, 萩原 智, 依田 広, 祖父江 慶太郎, 鶴崎 正勝, 工藤 正俊
Organizer
消化器病学会週間 JDDW 2021
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