ISSN 慈大 2017 feb 呼吸器疾患研究会誌 Jikei Journal of Chest Diseases 豊胸術後にシェーグレン症候群と胸膜肥厚を認めたヒトアジュバント病の 1 例花田豪郎ほか 1 第 90 回研究会記録 2 胸部 CT でスリガラス状陰影

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1 ISSN 慈大 2017 feb 呼吸器疾患研究会誌 Jikei Journal of Chest Diseases 豊胸術後にシェーグレン症候群と胸膜肥厚を認めたヒトアジュバント病の 1 例花田豪郎ほか 1 第 90 回研究会記録 2 胸部 CT でスリガラス状陰影を呈した左肺腫瘍の 1 切除例米山果織ほか 3 肺がんの新しい薬物療法免疫チェックポイント阻害薬滝口裕一 4 第 91 回研究会記録 10 共催 : 慈大呼吸器疾患研究会エーザイ株式会社 Jikei University Chest Diseases Research Association 慈大呼吸器疾患研究会ホームページ

2 90 1 A case of Sjögren's syndrome with pleural thickening associated with breast augmentation as a part of autoimmune syndrome induced by adjuvants. 1) 1) 1) 1) 1) 1) 1) 1) 1) 1) 2) 3) 1) 1) 2) 3) / CT fine crackles KL U/ml SP-D 113 ng/ml SP-A 92 ng/ml Homogeneous Speckled PR3-ANCA SS-A non- UIP COPD GOLD stage II LABA Vol.29 No

3 第 90 回慈大呼吸器疾患研究会記録 :30 20: :30 18:35 18:35 18: :40 19: :20 20: :20 共催 : 慈大呼吸器疾患研究会, エーザイ株式会社 Vol.29 No

4 91 CT CT GGO Pulmonary solitary capillary hemangioma:psch CT S8 GGO CT 1.5cm Pulmonary capillary hemangiomatosis:pch PSCH PSCH CT PCH 10 Key words 3 Vol.29 No

5 91 A new drug therapy for advanced lung cancer implication of immune checkpoint inhibitors Abstract Although molecular targeted therapy has significantly improving survival data in the treatment of advanced non-small cell carcinoma, the strategy is unable to cure the disease partly because of the emerging resistance mechanisms. A newly developed therapy taking advantage of immune checkpoint inhibitors raises a hope that advanced melanoma would be cured with the agents. The strategy is now extended to the field of non-small cell lung cancer, renal cell cancer and head & neck cancer. The present article reviews the current status and future directions of this new therapeutic modality. 1. epidermal growth factor receptor EGFR anaplastic lymphoma kinase ALKpoint mutation, deletion, translocation oncogene addiction EGFR ALK tyrosine-kinase inhibitor TKI progression free survival PFS 1, 2 EGFR ALK EGFR-TKI ALK-TKI ROS-1 RET BRAF TKI TKI TKI 1 TKI overall survival OS EGFR ALK TKI EG- FR-TKI EGFR- T790M 1 gefitinib, erlotinib 2 afatinib EGFR- TKI 3 EGFR-TKI osimertinib T790M EGFR 3 EGFR- TKI re-biopsy EGFR-T790M osimertinib re-biopsy Vol.29 No

6 T790M osimertinib 1 ALK-TKI TKI ALK ALK-TKI TKI ALK-TKI TKI re-biopsy re-biopsy Re-biopsy free- DNA TKI PFS EGFR gefitinib carboplatin + pemetrexed II 4 gefitinib 2 cisplatin + docetaxel 3 gefitinib II PFS III gefitinib gefitinib OS 2.2 autocrine paracrine VEGF HGF FGF EGFR erlotinib erlotinib bevacizumab II 5 PFS TKI III bevacizumab ramcirumab erlotinib 2.3 CSC EMT CSC CSC EMT 5 Vol.29 No

7 CSC EMT metformin mtor CSC EMT 6-8 CSC EMT 2.4 epigenome HDAC 3. DNA DNA neoantigen APC MHC-I/ CD8 T CTL APC B7 CTL CD28 CTL CTLA-4 B7 CD28 CTL MHC-I/ PD-L1 PD-L2 CTL PD-1 CTL T Treg 9 CTLA-4 PD-1 PD-L1 Treg CTLA-4 CTLA-4 Treg CTLA-4 ipilimumab PFS 10 PD-1 nivolumab ipilimumab nivolumab 11 pooled analysis ipilimumab IL IL-2 ipilimumab nivolumab PD-1 PD-L1 14 PD-1 JAK1 JAK2 interferon B2M MHC-I Vol.29 No

8 NSCLC NSCLC PD-1 NSCLC docetaxel docetaxel nivolumab CheckMate OS nivolumab docetaxel OS PFS NSCLC docetaxel nivolumab Check- Mate OS nivolumab responder nivolumab PD-1 pembrolizumab NSCLC nivolumab 3.3 III nivolumab 4. 1 ESMO position paper 18 nivolumab ipilimumab e PD % NSCLC % NSCLC PD-1 pembrolizumab PFS OS nivolumab PFS Pembrolizumab PD-L1 nivolumab 7 Vol.29 No

9 5.2 OS PFS co-primary endpoints nivolumab ipilimumab 11 NSCLC nivolumab EGFR-TKI PD-L1 EGFR-TKI nivolumab EGFR-TKI nivolumab ipilimumab II ipilimumab nivolumab OS EGFR NSCLC NSCLC nivolumab 17 pembrolizumab 21 docetaxel subset EGFR docetaxel ipilimumab nivolumab EGFR 22 ALK 5.4 PD-L1 mutational load PD-L Maemondo M, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362: , Mitsudomi T, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11: , Tan DS, et al. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in J Thorac Oncol 11: , Sugawara S, et al. Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/ TCOG0902. Ann Oncol 26: , Seto T, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol 15: , Sharma SV, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141:69-80, Kurimoto R, et al. Drug resistance originating from a TGF-beta/FGF-2-driven epithelial-to-mesenchymal transition and its reversion in human lung adenocarcinoma cell lines harboring an EGFR mutation. Int J Oncol 48: , Ang YL, et al. Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. Onco Targets Ther 9: , Vol.29 No

10 : , Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363: , Larkin J, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 373:23-34, Schadendorf D, et al. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 33: , Atkins MB, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and J Clin Oncol 17: , Algazi AP, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer Zaretsky JM, et al. Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma. N Engl J Med 375: , Brahmer J, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373: , Borghaei H, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373: , Champiat S, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol 27: , Nishino M, et al. Incidence of Programmed Cell Death 1 Inhibitor-Related Pneumonitis in Patients With Advanced Cancer: A Systematic Review and Meta-analysis. JAMA Oncol Weber JS, et al. Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 17: , Herbst RS, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387: , Hellmann MD, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. ASCO. Chicago; p. suppl; abstr Hatogai K, et al. Comprehensive immunohistochemical analysis of tumor microenvironment immune status in esophageal squamous cell carcinoma. Oncotarget Key words: Immune check point inhibitor, molecular targeted therapy 9 Vol.29 No

11 第 91 回慈大呼吸器疾患研究会記録 :30 20: :30 18:35 18:35 18:40 18:40 19:20 CT :20 20:20 20:20 共催 : 慈大呼吸器疾患研究会, エーザイ株式会社 Vol.29 No

12 慈大呼吸器疾患研究会ホームページ慈大呼吸器疾患研究会 ( 印 : 編集委員 ) article@jcdra.org 慈大呼吸器疾患研究会誌第 29 巻第 1 号慈大呼吸器疾患研究会

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TP T-13i AST ALT ALP Y CTP LOH CHE CRP 8.7 id 0.4 mg/d 21 AWL 131U/L 257 LU/L 12 111/L 234 11J/L 344 IU/L 0.30 mid No K a BUN ORE UA 142 meq/1 4.3 meqa 108 meqa 15.8 met! 0.71 mg/di 5.0 mg/d CEA 5_5 n8/m1