免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用改写了很多恶性肿瘤的治疗策略,成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”,在“松开刹车”后会带来一系列的全身性毒副反应,其中部分可能为危重和难...免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用改写了很多恶性肿瘤的治疗策略,成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”,在“松开刹车”后会带来一系列的全身性毒副反应,其中部分可能为危重和难治性,甚至具有潜在致死性。本文对免疫相关不良事件(immune-related adverse effects,irAEs)相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总,包括欧洲肿瘤内科学会年会(European Society for Medical Oncology,ESMO)、美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)/美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)、肿瘤免疫治疗学会(Society for Immunotherapy of Cancer,SITC)和中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)指南,并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后,对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充,重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况,包括抗白介素6(interleukin 6,IL-6)阻断、抗CD20单抗、抗肿瘤坏死因子α(tumor necrosis factor-α,TNFα)单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白(antithymocyte globulin,ATG).本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑,并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则,建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的,不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此,建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。展开更多
恶性肿瘤的免疫治疗是当前肿瘤研究和治疗领域的热点,免疫检查点分子程序性死亡受体-1(programmed cell death receptor-1,PD-1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen 4,CTLA-4)相关信号通路的激活...恶性肿瘤的免疫治疗是当前肿瘤研究和治疗领域的热点,免疫检查点分子程序性死亡受体-1(programmed cell death receptor-1,PD-1)和细胞毒性T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen 4,CTLA-4)相关信号通路的激活可以抑制T淋巴细胞活化,肿瘤细胞通过激活该信号通路实现免疫逃逸。免疫检查点抑制剂(immuno-checkpoint inhibitors,ICIs)通过抑制该信号通路,活化T淋巴细胞发挥机体对肿瘤细胞的清除。因此,ICIs的相关毒性包括免疫相关的不良事件(immune-related adverse effects,irAEs)。消化系统如胃肠道、肝脏作为人体重要的消化吸收器官、代谢解毒器官,同时也是重要的免疫相关器官,是irAEs的常见受累系统。本文将分别对ICIs的肝脏、胃肠道不良反应的发生率、临床表现、诊断和处理分别进行阐述。展开更多
免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)已成功应用于多种恶性肿瘤治疗,其中程序化细胞死亡蛋白(programmed death 1,PD-1)/程序化细胞死亡配体-1(programmed death ligand 1,PD-L1)抑制剂近年来开始用于非小细胞肺癌中...免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)已成功应用于多种恶性肿瘤治疗,其中程序化细胞死亡蛋白(programmed death 1,PD-1)/程序化细胞死亡配体-1(programmed death ligand 1,PD-L1)抑制剂近年来开始用于非小细胞肺癌中。目前认为PD-1/PD-L1抑制剂具有较小的副作用,并不会增加感染风险。但目前出现了免疫治疗相关不良事件(immune-related adverse events,irAEs)使用糖皮质激素和免疫抑制剂后出现机会性感染,及未出现irAEs的情况下发生潜伏/慢性感染重新激活的病案报道,使得免疫检查点抑制剂相关感染开始受到重视。本文将针对PD-1/PD-L1抑制剂相关感染的现有临床数据、可能机制及诊治建议进行叙述。展开更多
Background:Hepatocholangiocarcinoma(H-ChC)has the clinicopathological features of both hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)and is a more aggressive subtype of primary hepatic carcinom...Background:Hepatocholangiocarcinoma(H-ChC)has the clinicopathological features of both hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)and is a more aggressive subtype of primary hepatic carcinoma than HCC or iCCA.Methods:We sequenced 91,112 single-cell transcriptomes from 16 human samples to elucidate the molecular mechanisms underlying the coexistence of HCC and iCCA components in H-ChC.Results:We observed two molecular subtypes of H-ChC at the whole-transcriptome level(CHP and CIP),where a metabolically active tumour cell subpopulation enriched in CHP was characterized by a cellular pre-differentiation property.To define the heterogeneity of tumours and their associated microenvironments,we observe greater tumour diversity in H-ChC than HCC and iCCA.H-ChC exhibits weaker immune cell infiltration and greater CD8+exhausted T cell(Tex)dysfunction than HCC and iCCA.Then we defined two broad cell states of 6,852 CD8+Tex cells:GZMK+CD8+Tex cells and terminal CD8+Tex cells.GZMK+CD8+Tex cells exhibited higher infiltration of after treatment in H-ChC,the effector scores and expression of the immune checkpoints of them greatly increased after immunotherapy,which indicated that H-ChC might be more sensitive than HCC or iCCA to immunotherapy.Conclusions:In this paper,H-ChC was explored,hoping to contribute to the study of mixed tumours in other cancers.展开更多
Gallbladder carcinoma(GBC)is a highly malignant tumor of the digestive system,and the 5-year survival rate of stage IVb is only 2%(1).For unresectable GBC,although the guidelines published by the National Comprehensiv...Gallbladder carcinoma(GBC)is a highly malignant tumor of the digestive system,and the 5-year survival rate of stage IVb is only 2%(1).For unresectable GBC,although the guidelines published by the National Comprehensive Cancer Network(NCCN)in 2019 recommended radiotherapy combined with chemotherapy as the first-line treatment,no promising prognosis has been reported(2).Conversion therapy refers to the achievement of long-term survival by radical surgery in some patients with advanced cancer on the premise that systemic therapy will be effective(3,4).Herein,we reported the case of a 61-year-old male patient with stage IVb GBC who was diagnosed with multiple abdominal,retroperitoneal,mediastinal,and bilateral hilar lymph nodes.The results of follow-up showed that the patient achieved a disease-free survival(DFS)of 11.3 months and overall survival(OS)of 18.1 months after conversion therapy.展开更多
Background Small cell lung cancer(SCLC)is a highly malignant and aggressive neuroendocrine tumor.With the rise of immunotherapy,it has provided a new direction for SCLC.However,due to the lack of prognostic biomarkers...Background Small cell lung cancer(SCLC)is a highly malignant and aggressive neuroendocrine tumor.With the rise of immunotherapy,it has provided a new direction for SCLC.However,due to the lack of prognostic biomarkers,the median overall survival of SCLC is still to be improved.This study aimed to explore novel biomarkers and tumor-infiltrating immune cell characteristics that may serve as potential diagnostic and prognostic markers in SCLC.Methods Gene expression profiles from patients with SCLC were downloaded from the Gene Expression Omnibus(GEO)database,and tumor microenvironment(TME)infiltration profile data were obtained using CIBERSORT.The robust rank aggregation(RRA)method was utilized to integrate three SCLC microarray datasets downloaded from the GEO database and identify robust differentially expressed genes(DEGs)between normal and tumor tissue samples.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were performed to explore the functions of the robust DEGs.Subsequently,protein-protein interaction networks and key modules were constructed by Cytoscape,and hub genes were selected from the whole network using the plugin cytoHubba.Survival analysis of hub genes was performed by Kaplan-Meier plotter in 18 patients with extensive-stage SCLC.Results A total of 312 robust DEGs,including 55 upregulated and 257 downregulated genes,were screened from 129 SCLC tissue samples and 44 normal tissue samples.GO and KEGG enrichment analyses revealed that the robust DEGs were predominantly involved in human T-cell leukemia virus 1 infection,focal adhesion,complement and coagulation cascades,tumor necrosis factor(TNF)signaling pathway,and ECM-receptor interaction,which are closely associated with the development and progression of SCLC.Subsequently,three DEGs modules and six hub genes(ITGA10,DUSP12,PTGS2,FOS,TGFBR2,and ICAM1)were identified through screening with the Cytoscape plugins MCODE and cytoHubba,respectively.Immune cell infiltration analysis by the CIBERSORT algorithm revealed that resting memory CD4+T cells were the predominant infiltrating immune cells in SCLC.In addition,Kaplan-Meier plotter revealed that the gene prostaglandin-endoperoxide synthase 2(PTGS2)was a potential prognostic biomarker of SCLC.Conclusions Hub genes and tumor-infiltrating immune cells may be the molecular mechanisms underlying the development of SCLC,and this finding could contribute to the formulation of individualized immunotherapy strategies for SCLC.展开更多
文摘免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)的应用改写了很多恶性肿瘤的治疗策略,成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”,在“松开刹车”后会带来一系列的全身性毒副反应,其中部分可能为危重和难治性,甚至具有潜在致死性。本文对免疫相关不良事件(immune-related adverse effects,irAEs)相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总,包括欧洲肿瘤内科学会年会(European Society for Medical Oncology,ESMO)、美国国立综合癌症网络(National Comprehensive Cancer Network,NCCN)/美国临床肿瘤学会(American Society of Clinical Oncology,ASCO)、肿瘤免疫治疗学会(Society for Immunotherapy of Cancer,SITC)和中国临床肿瘤学会(Chinese Society of Clinical Oncology,CSCO)指南,并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后,对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充,重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况,包括抗白介素6(interleukin 6,IL-6)阻断、抗CD20单抗、抗肿瘤坏死因子α(tumor necrosis factor-α,TNFα)单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白(antithymocyte globulin,ATG).本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑,并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则,建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的,不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此,建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。
文摘免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)已成功应用于多种恶性肿瘤治疗,其中程序化细胞死亡蛋白(programmed death 1,PD-1)/程序化细胞死亡配体-1(programmed death ligand 1,PD-L1)抑制剂近年来开始用于非小细胞肺癌中。目前认为PD-1/PD-L1抑制剂具有较小的副作用,并不会增加感染风险。但目前出现了免疫治疗相关不良事件(immune-related adverse events,irAEs)使用糖皮质激素和免疫抑制剂后出现机会性感染,及未出现irAEs的情况下发生潜伏/慢性感染重新激活的病案报道,使得免疫检查点抑制剂相关感染开始受到重视。本文将针对PD-1/PD-L1抑制剂相关感染的现有临床数据、可能机制及诊治建议进行叙述。
基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-061 and 2021-1-I2M-003)CSCO-hengrui Cancer Research Fund(Y-HR2019-0239)+4 种基金CSCO-MSD Cancer Research Fund(Y-MSDZD2021-0213)National Ten-thousand Talent Program(to J.L.)Young Scientists Fund of the National Natural Science Foundation of China(82303720)Beijing Natural Science Foundation(7234381)Fundamental Research Funds for the Central Universities(3332023011 to J.L.).
文摘Background:Hepatocholangiocarcinoma(H-ChC)has the clinicopathological features of both hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA)and is a more aggressive subtype of primary hepatic carcinoma than HCC or iCCA.Methods:We sequenced 91,112 single-cell transcriptomes from 16 human samples to elucidate the molecular mechanisms underlying the coexistence of HCC and iCCA components in H-ChC.Results:We observed two molecular subtypes of H-ChC at the whole-transcriptome level(CHP and CIP),where a metabolically active tumour cell subpopulation enriched in CHP was characterized by a cellular pre-differentiation property.To define the heterogeneity of tumours and their associated microenvironments,we observe greater tumour diversity in H-ChC than HCC and iCCA.H-ChC exhibits weaker immune cell infiltration and greater CD8+exhausted T cell(Tex)dysfunction than HCC and iCCA.Then we defined two broad cell states of 6,852 CD8+Tex cells:GZMK+CD8+Tex cells and terminal CD8+Tex cells.GZMK+CD8+Tex cells exhibited higher infiltration of after treatment in H-ChC,the effector scores and expression of the immune checkpoints of them greatly increased after immunotherapy,which indicated that H-ChC might be more sensitive than HCC or iCCA to immunotherapy.Conclusions:In this paper,H-ChC was explored,hoping to contribute to the study of mixed tumours in other cancers.
文摘Gallbladder carcinoma(GBC)is a highly malignant tumor of the digestive system,and the 5-year survival rate of stage IVb is only 2%(1).For unresectable GBC,although the guidelines published by the National Comprehensive Cancer Network(NCCN)in 2019 recommended radiotherapy combined with chemotherapy as the first-line treatment,no promising prognosis has been reported(2).Conversion therapy refers to the achievement of long-term survival by radical surgery in some patients with advanced cancer on the premise that systemic therapy will be effective(3,4).Herein,we reported the case of a 61-year-old male patient with stage IVb GBC who was diagnosed with multiple abdominal,retroperitoneal,mediastinal,and bilateral hilar lymph nodes.The results of follow-up showed that the patient achieved a disease-free survival(DFS)of 11.3 months and overall survival(OS)of 18.1 months after conversion therapy.
文摘Background Small cell lung cancer(SCLC)is a highly malignant and aggressive neuroendocrine tumor.With the rise of immunotherapy,it has provided a new direction for SCLC.However,due to the lack of prognostic biomarkers,the median overall survival of SCLC is still to be improved.This study aimed to explore novel biomarkers and tumor-infiltrating immune cell characteristics that may serve as potential diagnostic and prognostic markers in SCLC.Methods Gene expression profiles from patients with SCLC were downloaded from the Gene Expression Omnibus(GEO)database,and tumor microenvironment(TME)infiltration profile data were obtained using CIBERSORT.The robust rank aggregation(RRA)method was utilized to integrate three SCLC microarray datasets downloaded from the GEO database and identify robust differentially expressed genes(DEGs)between normal and tumor tissue samples.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analyses were performed to explore the functions of the robust DEGs.Subsequently,protein-protein interaction networks and key modules were constructed by Cytoscape,and hub genes were selected from the whole network using the plugin cytoHubba.Survival analysis of hub genes was performed by Kaplan-Meier plotter in 18 patients with extensive-stage SCLC.Results A total of 312 robust DEGs,including 55 upregulated and 257 downregulated genes,were screened from 129 SCLC tissue samples and 44 normal tissue samples.GO and KEGG enrichment analyses revealed that the robust DEGs were predominantly involved in human T-cell leukemia virus 1 infection,focal adhesion,complement and coagulation cascades,tumor necrosis factor(TNF)signaling pathway,and ECM-receptor interaction,which are closely associated with the development and progression of SCLC.Subsequently,three DEGs modules and six hub genes(ITGA10,DUSP12,PTGS2,FOS,TGFBR2,and ICAM1)were identified through screening with the Cytoscape plugins MCODE and cytoHubba,respectively.Immune cell infiltration analysis by the CIBERSORT algorithm revealed that resting memory CD4+T cells were the predominant infiltrating immune cells in SCLC.In addition,Kaplan-Meier plotter revealed that the gene prostaglandin-endoperoxide synthase 2(PTGS2)was a potential prognostic biomarker of SCLC.Conclusions Hub genes and tumor-infiltrating immune cells may be the molecular mechanisms underlying the development of SCLC,and this finding could contribute to the formulation of individualized immunotherapy strategies for SCLC.
