免疫检查点抑制剂相关毒副作用管理之激素的使用

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)通过激活机体的肿瘤免疫杀灭肿瘤细胞,给肿瘤患者的治疗带来新的希望。然而也可引起一系列以免疫损伤为基础的免疫检查点抑制剂相关毒副反应(immune-related adverse events,irAEs).糖皮质激素是治疗这类毒副反应的基础,而在具体治疗irAEs时,其用法、用量、疗程又与治疗经典的自身免疫性疾病有所不同。同时,大剂量的糖皮质激素的长期使用可能引起严重的不良反应,本文对激素的作用机制、剂量剂型、毒副作用及管理等方面进行详细描述,为肿瘤医生在临床实践中应用激素提供参考和建议。

免疫检查点抑制剂相关心脏不良反应的临床诊治建议

恶性肿瘤的免疫治疗已经成为肿瘤研究和治疗领域的热点,给晚期肿瘤患者带来了新的希望。免疫检查点分子程序性死亡蛋白-1和细胞毒性T淋巴细胞相关抗原4相关信号通路的激活可以抑制T淋巴细胞活化,从而阻断炎症反应。肿瘤细胞通过激活免疫检查点分子相关的信号通路实现免疫逃逸。而免疫检查点抑制剂能够唤醒T淋巴细胞,增强机体对肿瘤细胞的清除。但是免疫检查点抑制剂的作用并非肿瘤细胞特异,在杀灭肿瘤细胞的同时,会引起包括心血管系统在内的多系统副作用。我们将总结相关的心脏副反应并对如何防治给予建议。

免疫检查点抑制剂相关肺炎的临床诊治建议

免疫检查点抑制剂在肿瘤中的使用给晚期肿瘤患者带来了新的希望。然而,由免疫检查点抑制剂激活的免疫系统,其中主要是T细胞免疫,可能攻击人体正常组织器官导致相应的免疫毒性反应产生,在肺部可引起免疫检查点抑制剂相关肺炎。这是一类不同于已知肺部间质性肺炎的疾病,如处理不当,有潜在的致命风险。我们将对免疫检查点抑制剂相关肺炎的诊断和治疗给予建议。

免疫检查点抑制剂相关内分泌不良反应的临床诊治建议

免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)作为一类新型抗肿瘤药物,已经在多种恶性肿瘤治疗中表现出显著的疗效。由于ICIs特定的作用目标和机制,可引起自身免疫和炎症效应,称为免疫相关不良反应(immune-related adverse effects,irAEs)。与传统疗法的不良反应机制不同,irAEs表现隐匿且不固定,有些严重不良反应将迫使患者中止治疗,甚至影响患者生存。因此,随着ICIs在临床上的广泛应用,临床医生需要充分认识此类药物治疗可能产生的不良反应以及合理的治疗策略,以提高接受ICIs治疗患者的生存率和治疗效果。本文将对ICIs引起的内分泌系统不良反应的发生率、临床表现、诊断和处理分别进行阐述。

危重及难治性免疫检查点抑制剂相关毒性反应诊治建议及探索

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。

非小细胞肺癌围手术期免疫治疗相关不良反应管理的临床诊疗建议

背景与目的肺癌围手术期治疗(术前新辅助治疗及术后辅助治疗)作为手术的重要辅助手段,已成为非小细胞肺癌(non-small cell lung cancer,NSCLC)全程管理中越来越重要的环节。近年来,小规模临床研究发现免疫新辅助治疗主要病理缓解率明显提升,甚至达到完全病理缓解,有望成为NSCLC治疗的重要组成部分。然而,免疫新辅助治疗带来疗效和生存获益,同时,其相关严重不良反应(延误手术、丧失手术机会、死亡等)备受关注。本诊疗建议目的是针对免疫检查点抑制剂相关不良反应(immune-related adverse event,irAE)形成适合国内医疗现状的诊疗方案。方法本文由胸外科专家、肿瘤学专家、胸内科专家以及irAE相关科室专家(消化内科、呼吸内科、心血管内科、感染内科、血液内科、内分泌科、风湿免疫科、神经内科、皮肤科和急诊科)共同完成本诊疗意见的制定工作。专家充分参考irAE指南、胸外科公开发表的大型临床研究数据以及国内医生的临床实战经验和公开发表个案,多学科反复讨论,形成针对围手术期免疫治疗相关不良反应的诊疗建议。结果本诊疗意见涵盖irAE相关的预防、评估、检查、治疗和监测全过程,以便全面、有效的指导临床工作。结论围手术期irAE管理是肺癌免疫围手术期治疗的重要组成部分,随着免疫围手术期治疗的不断发展,未来需要更多的研究,以优化围手术irAE的诊疗。

免疫检查点抑制剂相关血液毒性处理的临床诊疗建议

免疫检查点抑制剂能够重新激活免疫系统,启动肿瘤杀伤,而T细胞过度激活导致各种免疫相关不良反应。血液系统不良反应报道少见,主要表现为单系或多系血细胞减少,包括自身免疫性溶血性贫血、免疫性血小板减少症、中性粒细胞减少症,严重时表现为再生障碍性贫血,甚至可能致命,如噬血细胞淋巴组织细胞增多症。我们将总结免疫检查点抑制剂相关血液不良反应的临床特点,并对诊断和治疗给予建议。

免疫检查点抑制剂相关消化系统不良反应的临床诊治建议

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。

肿瘤靶向治疗和免疫治疗——眼科系统毒性反应的诊治

靶向治疗和免疫治疗给晚期肿瘤患者带来了希望。但是治疗过程中的药物毒副作用也随着药物的普及而逐渐展现出来。其中眼部的毒副反应常被患者和医生忽视。眼部的不良反应包括从眼睑、睫毛、结膜、角膜、葡萄膜、视网膜、视神经和眼眶等,可累及眼部的所有组织。本文就靶向治疗和免疫治疗相关的眼部毒副作用的诊断和治疗给予相应的描述和建议。

免疫检查点抑制剂风湿性毒副反应诊治建议

近年来,免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)已成为肿瘤治疗的突破性进展之一。但随着ICIs的广泛应用,这类药物所导致的免疫相关副反应(immune-related adverse events,irAEs)也逐渐引起人们的重视。研究发现,irAEs几乎可影响到人体的各个器官。本文主要针对ICIs在风湿方面毒副反应的临床特点展开综述,并且总结了具有基础风湿病的患者在使用ICIs后的免疫相关副反应,最后对这类副反应的治疗进行了探讨。

免疫检查点抑制剂相关皮肤不良反应诊治建议

免疫检查点抑制剂已应用于多种恶性肿瘤的治疗。免疫检查点抑制剂会引起免疫相关不良反应,其中皮肤不良反应是常见的不良反应之一。皮肤不良反应最常表现为斑丘疹和瘙痒。严重的皮肤不良反应包括Stevens-Johnson综合征、中毒性表皮坏死松解症等。本文综合各个免疫治疗相关不良反应管理指南、皮肤不良反应个案报道及综述,并结合临床实践,提出了免疫相关皮肤不良反应的诊治建议。

免疫检查点抑制剂相关感染诊治建议

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。

Purification and characterization of alkaline chitinase from Paenibacillus pasadenensis CS0611

An extracellular chitinase produced by Paenibacillus pasadenensis CS0611was purified by ammoniumsulfate precipitation,HiTrap DEAE FF and HiLoad26/600Superdex200pg column chromatography.The apparent molecular mass determined by sodium dodecyl sulfate polyacrylamide gelelectrophoresis was69kDa.The optimum pH and optimum temperature of the chitinase were5.0and50°C,respectively.The enzyme showed high stability at alkaline pH values and temperaturesbelow40°C.Additionally,the metal ions Mn2+,Mg2+,and Co2+inhibited activity of the chitinase.Thechitinase was active on colloidal chitin with an apparent Km of4.41mg/mL and Vmax of1.08mg/min.Substrate spectrum analysis indicated that the chitinase reacted preferentially with the glucosidicbond between GlcNAc‐GlcNAc.The enzymatic hydrolysate was analyzed by high‐performance liquidchromatography and thin layer chromatography,and clearly showed that a subunit of(GlcNAc)2was the main hydrolysis product.

Hypoxia-induced ROS aggravate tumor progression through HIF-1α-SERPINE1 signaling in glioblastoma

Hypoxia,as an important hallmark of the tumor microenvironment,is a major cause of oxidative stress and plays a central role in various malignant tumors,including glioblastoma.Elevated reactive oxygen species(ROS)in a hypoxic microenvironment promote glioblastoma progression;however,the underlying mechanism has not been clarified.Herein,we found that hypoxia promoted ROS production,and the proliferation,migration,and invasion of glioblastoma cells,while this promotion was restrained by ROS scavengers N-acetyl-L-cysteine(NAC)and diphenyleneiodonium chloride(DPI).Hypoxia-induced ROS activated hypoxia-inducible factor-1α(HIF-1α)signaling,which enhanced cell migration and invasion by epithelial-mesenchymal transition(EMT).Furthermore,the induction of serine protease inhibitor family E member 1(SERPINE1)was ROS-dependent under hypoxia,and HIF-1αmediated SERPINE1 increase induced by ROS via binding to the SERPINE1 promoter region,thereby facilitating glioblastoma migration and invasion.Taken together,our data revealed that hypoxia-induced ROS reinforce the hypoxic adaptation of glioblastoma by driving the HIF-1α-SERPINE1 signaling pathway,and that targeting ROS may be a promising therapeutic strategy for glioblastoma.

Extraordinary thermal conductivity of polyvinyl alcohol composite by aligning densified carbon fiber via magnetic field

Thermal interface materials(TIMs)with high through-plane thermal conductivity are urgently desired to avoid overheating of high-power density electronics.Introducing and aligning fillers in polymer matrixes via magnetic field is a promising method to improve the thermal conductivity of the polymer.However,either the fillers need to be modified with magnetic particles or a strong magnetic field is needed for good alignment in high filler content.This prevents further improvement of the through-plane thermal conductivity.Herein,mesophase pitch-based carbon fibers(MPCFs)with a content as high as 76 wt.%are aligned vertically in water-soluble polyvinyl alcohol(PVA)under a low magnetic field(~0.4 T),forming a vertically aligned MPCF(VAMPCF)/PVA composite with an extraordinary through-plane thermal conductivity of 86 W/(m·K),which is higher than that of many alloys.In addition,both theoretical and experimental results demonstrate that the critical intensity of the magnetic field needed for good alignment of the fillers depends on their size and magnetic susceptibility.Furthermore,the water solubility of PVA makes it easy to recycle MPCFs.This study offers an inspired venue to develop excellent and eco-friendly TIMs to meet ever increasing demand in heat dissipation for electronics.

High-performance γ-MnO_(2) Dual-Core,Pair-Hole Fiber for Ultrafast Photonics

Manganese dioxide(MnO2)is a widely used and well-studied 3-dimensional(3D)transition metal oxide,which has advantages in ultrafast optics due to large specific surface area,narrow bandgap,multiple pores,superior electron transfer capability,and a wide range of light absorption.However,few studies have considered its excellent performance in ultrafast photonics.y-MnO2 photonics devices were fabricated based on a special dual-core,pair-hole fiber(DCPHF)carrier and applied in ultrafast optics fields for the first time.The results show that the soliton molecule with tunable temporal separation(1.84 to 2.7 ps)and 600-MHz harmonic solitons are achieved in the experiment.The result proves that this kind of photonics device has goodapplications in ultrafast lasers,high-performance sensors,fiber optical communications,etc.,which can help expand the prospect of combining 3D materials with novel fiber for ultrafast optics device technology.

Single-cell transcriptional profile of ACE2 in healthy and failing human hearts

Dear Editor,The coronavirus disease 2019(COVID-19)pandemic,which is caused by SARS-Co V-2,has gained serious attention from medical practitioners around the world in the past few months.Approximately 20%of critically ill COVID-19 patients were reported to have suffered myocardial injury.The specific mechanism of this pathology requires further investigation(Yang et al.,2020).

Necroptosis-elicited host immunity:GOx-loaded MoS_(2) nanocatalysts for self-amplified chemodynamic immunotherapy

Nanoparticles induced potent antitumor immunotherapy plays a significant role for enhancing conventional therapeutic effectiveness.However,revealing the pathway of how nanoagents themselves trigger the host immunity or how to maximize the immunotherapy efficacy still needs further exploration.Herein,rose-like MoS2 nanoflowers modified with 2-deoxy-D-glucose(2-DG)and glucose oxidase(GOx)(MPGGFs)have been successfully fabricated via a one-pot hydrothermal reaction and following one-by-one surface modification as a multifunctional nanocatalyst for photothermal therapy enhanced self-amplified chemodynamic immunotherapy(PTT-co-CDT).By introducing GOx,the obtained MPGGFs exhibited self-amplified chemodynamic therapeutic efficacy under hypoxia tumor microenvironment(TME)because of the raised intracellular H2O2 level via enzyme-catalysis of oxygen.Furthermore,combined with the intrinsic excellent photothermal conversion efficiency of MoS2 nanoflowers,PTT-co-CDT performances by MPGGFs could effectively induce the necroptosis of tumor cells both in vitro and in vivo.Then the induced necroptosis via PTT-co-CDT by MPGGFs could directly trigger host immunity by activating the antigen-specific T-cells(CD4^(+) and CD8^(+)).Finally,the excellent in vivo safety of MPGGFs makes us believe that the successful construction of rose-like multifunctional nanocatalyst not only has great potentials for self-amplified chemodynamic immunotherapy,but also provides a paradigm for exploring necroptosis triggered host immunity for cancer treatment.

SARS-CoV-2 leads to myocardial injury in rhesus macaque

Dear Editor,Coronavirus disease 2019(COVID-19)is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,which induces multiple cardiovascular complications including acute myocardial injury resulting from acute coronary syndrome,myocarditis,stress-cardiomyopathy,arrhythmias,cardiogenic shock,and cardiac arrest.The incidence of myocardial injury in COVID-19 patients was up to 20%or higher in the subpopulation with existing cardiovascular diseases,accounting for 69.4%of mortality.1 Although the presence of angiotensin-converting enzyme 2(ACE2)in cardiomyocytes could result in viral myocarditis in COVID-19 patients,the cardiopathology involved in COVID-19 is still unclear.