撰文 | 邓海静、谢琦 （西湖大学生命科学学院） 前言： 越来越多的临床证据显示细胞因子风暴造成的多器官衰竭是导致新型冠状肺炎重症病人死亡的重要因素。笔者此前从事 CAR-T细胞治疗脑肿瘤的相关工作，对其引起的细胞因子风暴的一直保持密切的关注。在此，我们总结了目前细胞因子风暴的临床特点和治疗方法，希望能够为新型冠状肺炎重症病人的治疗提供一些提示和参考。 细胞因子风暴 (Cytokine release syndrome， CRS ) ，是一种全身性炎症反应，可由感染和某些药物等多种因素引发 ,表现为大量促炎症的细胞因子水平急剧升高 【 1】 。 “细胞因子风暴”多见于免疫系统相关疾病或者免疫相关疗法，比如CAR-T细胞疗法、器官移植以及病毒感染等。本文将对于CRS的临床症状、机制与治疗等进行简述。 1.CRS的临床症状与分子检测 CRS的临床症状和严重程度差异很大。轻度症状包括发热、疲劳、头痛、皮疹、关节痛和肌肉痛；严重症状包括高热和低血压，可进展为系统性炎症反应，伴有循环休克，血管渗漏，弥漫性血管内凝血和多器官功能衰竭等。相关的异常指标包括淋巴细胞减少、肌酐和肝酶升高、凝血参数紊乱、铁蛋白和C反应蛋白升高等 【 1,2】 。 CRS是一种免疫系统的超敏性激活，由多种细胞参与并以释放大量细胞因子为标志 【 3】 。 CRS释放的细胞因子在不同疾病中有所差别，CAR-T治疗引发的CRS所涉及的细胞因子包括IFN-γ、IL-2、IL-2Ra、IL-6、sIL-6R、GM-CSF、IL-1、IL-10、IL-12、TNF-a、IFN-a、MCP-1、MIP-1A等 【 3,4】 。外周血中的 IL-6常被用在CART治疗以及脓毒症的细胞因子风暴检测与靶向中，由于IL-6可由TNF和IL-1β刺激产生，因此其浓度间接反映了这两种重要的早期因子的表达水平，同时也提供了综合性的下游治疗靶点 【 5】 。在流感病毒相关的 CRS中，不同的病毒引发的CRS涉及的主要因子并不完全相同。Farrar等的研究比较了18位感染H5N1病毒的患者于8位感染了季节性H1N1普通流感的患者，他们发现H5N1感染患者具有更高水平的MCP-1、CXCL10、CXCL9以及IL-8的分泌 【 6】 。在 HIN1相关的研究报道中，Kelvin DJ等发现较严重的感染者具有更高的Th1和Th17细胞因子的分泌。IL-15、IL-12p70、IL-6是危重症的标志 【 7】 。 SARS引起的细胞因子风暴 主要涉及 IL-1β、IL-6、IL-12、IFN-γ、IP10 以及MCP-1等，而 MERS冠状病毒引起的细胞因子风暴 主要与 IFN-γ、TNF-α、IL-15 和IL-17相关 【 8-10】 。 Cao等对2019年新型冠状病毒COVID-19的检测发现，相对于非重症监护患者，重症监护（ICU）患者的血浆中存在更高水平的IL-2、IL-7、IL-10、G-SCF、IP10、MCP-1、MIP-1A以及TNF-α 【 11】 （ Table 1） 。除了病毒各自的特异性外，宿主对病毒的易感性以及免疫系统的反应性等差异都可能改善或加重感染状况并影响临床结果。 Table1. 不同原因诱发的 CRS 中涉及的主要细胞因子 诱发原因 细胞因子 CAR-T IFN-γ ， IL-2 ， IL-2Ra ， IL-6 ， sIL-6R ， GM-CSF ， IL-1 ， IL-10 ， IL-12 ， TNF-a ， IFN-a ， MCP-1 ， MIP-1A H5N1 MCP-1 ， CXCL10 ， CXCL9 ， IL-8 HIN1 IL-8 ， IL-9 ， IL-17 ， IL-6 ， TNF-α ， IL-15 ， IL-12p70 ， IL-6 SARS IL-1β ， IL-6 ， IL-12 ， IFN-γ ， IP10 ， MCP-1 MERS IFN-γ ， TNF-α ， IL-15 ， IL-17 COVID-19 IL-2 ， IL-7 ， IL-10 ， G-SCF ， IP10 ， MCP-1 ， MIP-1A ， TNF-α 因此，不同治疗方式与疾病引发的 CRS由于病理生理机制的差异临床表现与实验室检查可能存在一定的差异。但是尽早的寻找相关标志物并进行干涉治疗将有效的降低疾病中的病死率，提高治疗效果。 2.CRS的病理生理学机制 虽然 CRS的病理生理机制尚不完全清楚，但既往研究表明，其发生过程涉及促炎与抗炎机制的平衡失调，由多种细胞间与细胞因子间的相互作用与调节紊乱导致。 病毒一旦进入宿主，可以激活细胞内的模式识别受体分子，这些模式识别受体分子可以感知病毒的遗传物质，并分别通过先天免疫细胞和适应性免疫细胞 (主要为NK细胞和CD8 T细胞) 激发细胞溶解性免疫反应。因此， CRS的发生与参与该过程的免疫细胞及其他细胞显著相关，可能涉及到淋巴细胞 （ B/T淋巴细胞和NK细胞） ，髓样细胞 （巨噬细胞、树突状细胞和单核细胞） 以及内皮细胞间的复杂网络调控，并以多种细胞因子分泌 （ IFN-γ，TNF-α，IL-6等） 为主要标志 【 12】 （ Table 2） 。 Table2.CRS 中主要细胞因子及来源细胞 细胞因子 主要作用 来源细胞 IFN- γ 激活巨噬细胞，增强抗原处理，诱导上皮细胞死亡 T 细胞 and ILCs TNF- α 激活成纤维细胞，刺激促炎细胞因子产生和血管生成，诱导上皮细胞死亡，介导 T 细胞抵抗凋亡，诱导恶病质 巨噬细胞，树突状细胞和 T 细胞 IL-6 激活 T 细胞，防止细胞凋亡，诱导巨噬细胞活化，招募免疫细胞，激活急性期蛋白，诱导上皮细胞增殖，促进肿瘤生长 巨噬细胞、成纤维细胞和 T 细胞 G-SCF 刺激中性粒细胞的发育和分化 成纤维细胞和单核细胞 IP10 招募中性粒细胞，促进多种细胞因子分泌 单核 / 巨噬细胞和 T 淋巴细胞 MCP-1 特异性趋化激活单核 / 巨噬细胞 单核细胞、巨噬细胞、成纤维细胞、血管内皮细胞等 IL-1 β 激活血管内皮细胞，激活淋巴细胞，局部组织破坏，增加效应细胞浸润 巨噬细胞 , 上皮细胞 IL-8 趋化因子可招募嗜中性粒细胞、嗜碱性粒细胞、 T 细胞等到感染部位 巨噬细胞 , 上皮细胞 在适应性反应成熟前的早期抗病毒宿主防御中，浆细胞样树突状细胞专门产生高水平的 I型干扰素，并与NK细胞一起发挥核心作用，但高水平的I型干扰素或与感染早期的CRS发生相关。在病毒感染的最初反应阶段，单核/巨噬细胞是进入肺泡的主要细胞，可以产生IFN-γ、TNFα、IL-6等细胞因子，也可与A型流感病毒RNA形成炎症小体，促进IL-1β和IL-18的分泌，进而招募中性粒细胞等引发炎症反应。但是，也研究表明消耗单核/巨噬细胞并不能阻止病毒感染的免疫病理现象出现，这表明它们在病毒清除中起重要作用。虽然多种免疫细胞都在病毒感染引起的炎症反应与细胞因子产生中发挥重要作用，有趣的是，Teijaro等的研究显示，内皮细胞才是细胞因子风暴的核心调控者，通过S1P1激动剂调控内皮细胞上的S1P1表达可以抑制细胞因子和先天免疫细胞募集，抑制CRS发生与发展 【 13】 。此外，抗体可与感染细胞表面结合，诱导抗体依赖性细胞介导的细胞毒性或补体激活，因此，有报道表明补体系统也在抗病毒感染与 CRS发生中发挥重要作用，或成为潜在的治疗选择 【 14,15】 。 CRS中多种细胞因子的分泌与其临床症状密切相关。既往研究表明，IFN-γ可引起发烧、发冷、头痛、头晕和疲劳。TNF-α可引起类似IFN-γ的流感样症状，伴有发热、全身不适和疲劳，但还可引起水样腹泻、血管渗漏、心肌病、肺损伤和急性期蛋白的合成 。在过继性细胞治疗引发的CRS中作为重要靶点的IL-6可导致血管渗漏，激活补体和凝血级联导致弥散性血管内凝血(DIC)等严重CRS的特征性症状 【 16,17】 。值得关注的是， IL-6很可能通过促进心肌功能障碍而导致心肌病，这种疾病在CRS患者中经常被观察到 【 18】 。此外，内皮细胞的激活也可能是严重 CRS的标志之一。内皮功能障碍可导致毛细血管渗漏，低血压，凝血障碍等症状出现 【 4】 。 总之， CRS的病理生理学机制仍有待进一步探究，该过程中的主要调节细胞与因子，以及参与调节的细胞在病毒清除与CRS发生中的多重身份需要更深入的研究明确。 3.CRS的综合治疗 目前，由于对 CRS病理生理机制的认识有限，CRS的临床管理仍然具有挑战性，主要依靠专家的经验性疗法。美国国家癌症研究所提出的CTCAE v4.0制定了与抗体治疗相关的CRS的分级系统，为了最大限度地提高免疫治疗的疗效，同时最小化CRS危及生命的并发症出现的风险，Daniel W等提出了一种新的CRS严重程度分级系统，定义了5个级别的CRS，并根据该系统来指导治疗用药 【 19】 （ Table 3） 。 Table3.CRS 分级系统与治疗指南 分级 症状 治疗 1 级 症状不危及生命，只需要对症治疗，如发烧、恶心、疲劳、头痛、肌痛、不适； 对症治疗 ; 维护静脉输液 2 级 症状需要适度的干预并产生反应。需氧量 40% 或低血压对液体或低剂量的抗利尿激素有反应或二级器官毒性； 密切监测（心脏功能）；低血压应及时用 0.9% 生理盐水静脉输液 ; 其他症状对症处理。此外，推荐使用托珠单抗或西妥昔单抗 3 级 症状需要积极的干预并有反应。需氧量≥ 40% 或低血压需要高剂量或多种血管升压药或 3 级器官毒性或 4 级转氨酶升高； 密切监测（心脏功能）；重症监护病房进行 1:1 护理；同时使用抗 IL -6 治疗和糖皮质激素 4 级 危及生命的症状。呼吸机支持或四级器官毒性（不包括转氨酶升高）； 机械通气；免疫抑制剂，同时使用抗 IL -6 治疗和糖皮质激素；按标准指南对症处理器官毒性 5 级 死亡 目前，大部分 CRS临床管理经验都来自于免疫治疗尤其是过继性细胞治疗所引发的CRS症状，在流感病毒感染当中，该类症状没有明确的治疗指南，但是也相应的借鉴免疫治疗的管理办法。刘强等概述了目前在大流感中应用的免疫调节剂，包括：糖皮质激素、过氧化物酶体增殖物激活受体激动剂、鞘氨醇-1-磷酸酯受体激动剂、环氧化酶抑制剂、抗氧化剂、抗肿瘤坏死因子治疗、静脉注射免疫球蛋白以及其他疗法 （包括血管紧张素转换酶抑制剂； CCR抑制剂；腺苷酸活化蛋白激酶激动剂；OX40单抗；细胞因子信号转导抑制因子；大环内酯类抗生素以及中草药等） 【 20】 。此外，当下有大量新兴注册临床试验针对流感感染中的 CRS治疗。针对IL6的 托珠单抗 已经登记了一项在新型冠状病毒肺炎 （ COVID-19） 中的有效性及安全性的多中心、随机对照临床研究 （注册号： ChiCTR2000029765 ） ，但是 Cao等对2019年新型冠状病毒肺炎病人的细胞因子检测的结果却显示重症病人和轻症病人相比，IL6水平变化并不显著 （ ICU vs Non-ICU，p=0.13） 【 11】 （图 1） 。因为前期检测的样本数较少 （ ICU:n=13, Non-ICU:n=28） ，此有必要继续检测的样本量，筛选合适的病人进行临床试验。由于 CD24Fc可以有效的降低重度急性移植物抗宿主病以及能够有效控制SIV病毒引发的炎症细胞因子释放和炎症细胞浸润，也拟申请进行新型冠状病毒肺炎的治疗 【 21,22】 。值得关注的是，目前 COVID-19治疗中采用的治愈者血浆治疗制备中和抗体的方法，在SARS、H5N1与H1N1等流感治疗中广泛使用 【 23,24】 。研究报道，恢复期血浆治疗也可以减少血清中细胞因子反应，降低病死率 【 25】 。但同时，由中和抗体激发的免疫反应也有可能诱导 CRS的发生。此外，李兰娟院士主导的“人工肝”技术对于COVID-19引起的细胞因子风暴的治疗也已经显示出一定的疗效。 图 1. 健康对照组、 ICU 患者和非 ICU 患者血浆细胞因子和趋化因子水平。红色：血浆 IL-6 水平；蓝色：血浆 TNF- α水平。【 11 】 虽然不断深入的探究提供了更多的药物选择，但是针对 CRS发展的不同阶段以及出现的不同症状选择合适的药物仍存在问题，而且药物限制CRS发生发展的效果并不稳定。Russell等的研究表明， 在 COVID-19感染过程中，糖皮质激素的使用并不能缓解肺损伤进展 【 26】 。而且值得注意的是，许多参与 CRS过程的细胞因子也可能有助于病毒清除，Katze等的研究发现，IL-1受体缺失的小鼠在H5N1感染后预后更差，这说明IL-1受体通路参与急性炎症反应并发挥积极的防御作用 【 27】 。因此，如何平衡抗病毒与抑制 CRS症状的治疗仍需要有更详尽的研究去细节化临床用药。此外，结合Cao等对本次新型冠状病毒COVID-19感染患者的临床检测可知，TNF-α分泌在重症监护患者与非重症监护患者间水平差异显著，或可成为有效的抑制感染患者病情进展的靶点，英夫利昔单抗或者乌司他丁的使用有望缓解COVID-19引起的CRS症状 【 28,29】 （图 1） 。但是，既往在 H5N1病毒感染中有研究报道，TNF受体缺失的小鼠或者使用TNF抗体治疗的小鼠，相较于对照组并没有展现出生存优势 【 30】 。虽然不同病毒感染诱导的 CRS可能存在区别，但是这也提示我们 不同诱发因素导致的 CRS治疗手段可能存在差异，并且不同患者针对同一治疗也可能存在较大的个体异质性。因此，除却新型药物的筛选与研发外，如何寻找到有效的疗效预测因子、建立风险评估模型等，在临床用药指导中至关重要。 4.结语与展望 无论是 SARS、MERS还是这次的新型冠状肺炎COVID-19，CRS的出现都是导致患者死亡的重要原因，因此，对其病理生理学机制、临床标志物以及治疗方式的探究对降低感染者死亡率尤其重要。除此之外，值得注意的是病毒的清除依赖于宿主免疫系统及细胞因子调节，而该过程过度激活则会引发CRS，因此，如何平衡病毒感染中的生理性免疫反应与病理性CRS发生是治疗过程中亟待解决的问题。是否使用免疫激活药物，如何监测与评估免疫激活药物的疗效？CRS发生过程中如何使用免疫调节药物，如何平衡感染者的CRS症状与病毒负荷？ 免疫调节是否会影响病毒的抗原漂移与抗原转变等，这些不仅是当下面对新型冠状病毒肺炎 COVID-19需要解决的问题，同时也是在多种可引发CRS的治疗中需要考虑的问题，未来仍需通过临床样本的密切跟踪与检测，结合更深入的基础实验探究来认识与治疗CRS，以提高患者的生存获益。 参考文献 1.Shimabukuro-Vornhagen, A., et al., Cytokine release syndrome.J Immunother Cancer, 2018. 6(1): p. 56. 2.Chousterman, B.G., F.K. 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Kishimoto, Immunotherapeutic implications of IL-6 blockade for cytokine storm.Immunotherapy, 2016. 8(8): p. 959-70. 17.Hunter, C.A. and S.A. Jones, IL-6 as a keystone cytokine in health and disease.Nat Immunol, 2015. 16(5): p. 448-57. 18.Pathan, N., et al., Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.Lancet, 2004. 363(9404): p. 203-9. 19.Lee, D.W., et al., Current concepts in the diagnosis and management of cytokine release syndrome.Blood, 2014. 124(2): p. 188-95. 20.Liu, Q., Y.H. Zhou, and Z.Q. Yang, The cytokine storm of severe influenza and development of immunomodulatory therapy.Cell Mol Immunol, 2016. 13(1): p. 3-10. 21.Wilhelm, K., et al., Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R.Nat Med, 2010. 16(12): p. 1434-8. 22.Tian, R.R., et al., CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS.Antiviral Res, 2018. 157: p. 9-17. 23.Zhou, B., N. Zhong, and Y. 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Refining Advanced Breast Cancer Management: Developing Treatment Strategies to Improve Outcomes 专家讲座视频 http://www.peervoice.com/refining-advanced-breast-cancer-management-developing-treatment-strategies-improve-outcomes?person_id=5075234specialty=Oncology#featured-presentations Now Playing Presentation 1 HR‐Positive/HER2‐Negative Advanced Breast Cancer: Optimising Treatment and Managing Adverse Events With Targeted Therapies Hope S. Rugo, MD University of California, San Francisco Helen Diller Family Comprehensive Cancer Center San Francisco, California, USA Now Playing Presentation 2 HER2-Positive Advanced Breast Cancer: Targeted Options Beyond Trastuzumab Therapy Sara Hurvitz, MD, FACP UCLA Jonsson Comprehensive Cancer Center Los Angeles, California, USA 【原来，今天是无胸罩日】7月9日，无胸罩日（No-bra Day），是为预防妇女乳房疾病高发，倡导所有的女性这天不戴胸罩，目的是号召女性朋友在这天让乳房自由放松，远离疾病。研究指出，每天戴胸罩超过十二小时者比短时间或不穿内衣者，患乳腺癌的几率高出20倍以上。 Emerging Treatment Options for Crizotinib-Resistant ALK -Positive NSCLC Alice Shaw, MD, PhD Massachusetts General Hospital Cancer Center Boston, Massachusetts, USA Go Online Now Online Extras Podcast MP3 Printable Transcript Slides Dr. Shaw: My name is Alice Shaw; I’m one of the thoracic oncologists at Massachusetts General Hospital in Boston. While crizotinib is very effective for patients with advanced ALK -positive lung cancer, unfortunately, by about a year, many patients will have signs of developing resistance. This is a huge barrier in terms of the benefit of crizotinib. Today I’ll be talking about resistance to the ALK inhibitor crizotinib and some of the exciting new developments in overcoming crizotinib resistance; this focuses primarily on a whole class of new drugs that are called next-generation ALK TKIs . back to top Dr. Shaw: There’s been a lot of research into this question of crizotinib resistance how it develops in patients. One of the well-established mechanisms of crizotinib resistance involves alterations in the ALK gene. And that can either be in the form of a new resistance mutation that occurs within the ALK tyrosine kinase domain, or it can be amplification of the ALK fusion gene—and because of either a mutation or amplification of the target gene, that confers resistance to crizotinib. This particular category of crizotinib resistance mechanisms has been very well worked out, and we see resistance mutations or ALK fusion gene amplification in about one-third of our patients who have become resistant to crizotinib. In the remaining two-thirds of patients, a subset of them have evidence of activation of alternative signalling pathways—we often call these bypass tracks because they allow the tumour cells to bypass inhibition of ALK and now to use other signalling pathways, for example, EGFR signalling or KIT signalling. And this is just beginning to be validated in patient samples. back to top Go online to view the complete activity Dr. Shaw: The first report of a patient with crizotinib resistance was a younger patient who was ALK -positive and had been on crizotinib and responded, but unfortunately relapsed after just only about five months. And at the time of relapse, they re-biopsied his resistant tumour, and they identified two resistance mutations. The one that was most notable was the gatekeeper mutation in ALK , which is called L1196M , because it’s analogous to the T790M mutation in EGFR . The gatekeeper mutation is believed to confer resistance through steric interference of crizotinib binding to ALK . These authors also found a second independent resistance mutation, C1156Y . Since then, there have been a number of crizotinib-resistant patients identified that tell us that there are actually quite a few different resistance mutations beyond the gatekeeper L1196M . This is really in contrast to what we see with EGFR -mutant lung cancer, where T790M is really the only resistance mutation that we identify in EGFR -resistant patients. back to top Dr. Shaw: So with that background, we’ll move onto these new ALK inhibitors. This slide shows three ALK inhibitors that are the most advanced in clinical trials. This includes LDK378, which just opened phase 2 trials globally. The phase 1 trial of LDK378 has enrolled over 200 patients to date, so by far we have the most data on LDK378 compared to any of the other ALK inhibitors in development. That one is the one to keep an eye on, particularly in terms of registration trials, as well as potentially accelerated approval because the activity looks so promising in the crizotinib-refractory population. There’s also a compound called CH542802 (we often just call it AF802) that’s currently in a phase 1/2 study, and then, there’s a compound, AP26113, that’s currently in a phase 1 study in the US. What’s notable about all three of these compounds is that they are very selective for ALK, and they’re more potent against ALK than crizotinib. The other notable thing is that they inhibit ALK just like crizotinib, but they don’t inhibit MET. Crizotinib actually was first developed as an anti-MET drug, and it was only subsequently then developed to target ALK. None of these three drugs has any significant activity against MET, but they do have activity against other kinase targets. back to top Narrator: These potent ALK inhibitors have demonstrated preclinical activity that formed the rationale for recent and ongoing clinical trials, with LDK378 being furthest along in development. As of March 2013, the US FDA has granted LDK378 breakthrough drug status. Dr. Shaw: What’s notable immediately is that the response rate to LDK is remarkably high in these patients—80% at doses of 400 mg or higher—the majority of who had become resistant to crizotinib, although we also do have some patients who are crizotinib-nave. I should note that the phase 1 study of LDK378 has already established the maximum tolerated dose to be 750 mg. And this is the dose that has gone forward into the expansion phase of the phase 1 study, as well as the current phase 2 studies. back to top Dr. Shaw: This slide shows a patient who had crizotinib-resistant ALK -positive lung cancer and started on LDK378 at 400 mg a day. He was relapsing on crizotinib and very, very symptomatic—to the point where he had to be hospitalised. His CT scan shows significant lung disease bilaterally. This patient started on LDK378 and within a few days had a really remarkable clinical improvement; he was discharged from the hospital. By six weeks, you can see significant improvement in the disease in his lungs. And this patient was confirmed partial response. back to top Dr. Shaw: This has held up in most of the patients who have enrolled on the LDK378 study. This is a waterfall plot summarising the best response of patients who were treated with LDK378 at doses of 400 mg and higher—the response rate is close to the 80% mark. So very remarkable efficacy of this drug, particularly in a TKI-resistant population. back to top Dr. Shaw: Also, LDK378 does appear to have fairly good activity in the CNS. This clinical protocol allowed us to enrol patients with untreated, asymptomatic brain metastases. And in almost all of the patients we have observed a radiologic response. So this suggests that LDK378, because it is such a potent ALK inhibitor, does have the ability to penetrate the CNS, although we don’t know to what extent. back to top Dr. Shaw: AF802 is another highly potent selective ALK inhibitor. It has very potent activity against ALK and some of the resistance mutations that occur with an ALK it really has very little activity against any other kinases, and this includes METs and ROS. They established the treating dose to be 300 mg twice a day, and what they found is that the objective response rate in this crizotinib-nave population was very high at 85%. back to top Dr. Shaw: Here’s the waterfall plot showing you all the different responses of the crizotinib-nave population. Almost every single patient did respond to the AF802 compound. back to top Dr. Shaw: Finally, we’ll touch on the third ALK inhibitor, AP26113. This compound is interesting because it seems to inhibit quite a few other kinases, one of which is EGFR with an activating mutation together with the resistance mutation, T790M. And so there has been a lot of interest in trying to develop this compound for patients with EGFR-mutant lung cancer who have become resistant to EGFR inhibitors like gefitinib. So the preliminary results were presented, and I think the data was remarkable for the high response rate that has been seen in crizotinib-resistant patients—similar to what’s been reported for LDK378. So far these responses appear to be quite durable, but this study is still ongoing. back to top Dr. Shaw: Shown here is an example of a crizotinib-resistant patient who responded to AP26113 at the 180-mg dose after just four weeks. back to top Dr. Shaw: Like LDK378, AP26113 appears to have activity in the CNS. After just eight weeks of AP26113, you can see that there was near-complete resolution of this brain metastasis, suggesting that AP26113 does penetrate into the brain at least to levels high enough to inhibit ALK. back to top Narrator: Preliminary safety data suggest that these next-generation ALK inhibitors are generally well tolerated. Dr. Shaw: The most common side effects of LDK378 are gastrointestinal—so nausea, vomiting, and diarrhoea, seen in over 50% of patients. So these should be managed with antinausea medicines, oftentimes prophylactically, and also with antidiarrhoeal medicines. Other important adverse events to note include fatigue and asthenia, and transaminase elevation was also reported in a significant fraction of patients. Also, the AP26113 compound appeared to be very well tolerated, with some expected side effects from an oral TKI, like nausea, vomiting, diarrhoea, and some transaminase elevation. But the numbers of patients who have enrolled are still on the low side, so we probably don’t have a full profile yet, in terms of adverse events. back to top Dr. Shaw: So in conclusion, crizotinib is now a globally approved drug for patients with advanced ALK -positive lung cancer. Unfortunately, even though crizotinib is highly active, most patients will relapse, and so the new paradigm that has emerged in this field is that next-generation (or more potent) ALK inhibitors can salvage almost all patients who have relapsed on crizotinib. So I think going forward what we’re going to see is that the treatment paradigm for ALK -positive lung cancer will be to start with crizotinib and then at the time of relapse, to move to a more potent ALK inhibitor like LDK378. It’s very possible that these more potent ALK inhibitors will be able to get approval for the crizotinib-refractory population, and we’ll see whether or not those compounds will move even earlier to the crizotinib-nave population. And so larger phase 2 trials, and also even phase 3 trials, will be opening, looking at whether or not these more potent ALK inhibitors should be used first instead of crizotinib. back to top Go online to view this audiovisual presentation References and abbreviations available online. Expert perspectives • Concise 7-9 minute interviews • Interactive scientific discourse
阅读疗法 是一种藉由阅读图书或接触其他信息材料，帮助读者纾解负面情绪困扰，进而达到身心平衡之状态。通常是由 图书馆员 、心理治疗师，或其他相关专业人员，针对个别需求，进行材料选择，并利用这些材料给予读者治疗。 阅读疗法的英文名称为bibliotherapy，为希腊文biblion（图书）跟therpeia（治疗）两字的结合。其又有：读书疗愈、书目疗法、图书医疗法、图书治疗法、文献治疗、信息疗法等多种名称。书目疗法是一种辅助性的心理治疗方法。它并不直接教导读者如何做才能解决他们目前所遭遇的情绪问题，而是让读者在接触适合的图书信息资源（例如：书本、影片、音乐等）后，对其内容产生「认同」、「净化」、「领悟」，并在经历这些过程后，能对他们目前所遭遇的困难有新的认知与体会，进而解决自身遭遇的问题。 阅读疗法是由图书馆员或专业人士（例如：心理治疗师）依据读者的个人需求，选择适合的素材帮助读者从负面情绪中释放，读者进而自我治疗，找到恢复的力量。总而言之，阅读疗法除了具有心理、情绪治疗的功用之外，也能帮助读者解决问题、满足他们的心理需求，进而使他们从目前遭遇的问题中成长、发展；同时，阅读疗法也是一种藉由与材料内容互动，达到促进心理健康的方法。 http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/edit_b.cgi?refresh=TID=20214 Start A-Literature C-Literature B-list Filter Literature A-query: bibliotherapy C-query: Psychology The B-list contains title words and phrases (terms) that appeared in both the A and the C literature. 163 articles appeared in both literatures and were not included in the process of computing the B-list but can be viewed here . The results of this search are saved under id # 20214 and can be accessed from the start page after you leave this session. There are 934 terms on the current B-list ( 138 are predicted to be relevant), which is shown ranked according to predicted relevance. The list can be further trimmed down using the filters listed in the left margin. To assess whether there appears to be a biologically significant relationship between the AB and BC literatures for specific B-terms, please select one or more B-terms and then click the button to view the corresponding AB and BC literatures. Use Ctrl to select multiple B-terms. http://arrowsmith.psych.uic.edu/cgi-bin/arrowsmith_uic/view_b_txt.cgi?ID=20214 job id # 20214 started Tue Mar 29 22:16:42 2011 Max_citations: 50000 Stoplist: /var/www/html/arrowsmith_uic/data/stopwords_pubmed Ngram_max: 3 20214 Search ARROWSMITH A A_query_raw: bibliotherapyTue Mar 29 22:17:20 2011 A query = bibliotherapy started Tue Mar 29 22:17:20 2011 A query resulted in 360 titles 20214 Search ARROWSMITH C C_query_raw: Psychology Tue Mar 29 22:18:04 2011 C: Psychology 830323 A: pubmed_query_A 360 AC: ( bibliotherapy ) AND ( Psychology ) 163 C query = Psychology started Tue Mar 29 22:18:04 2011 C query resulted in 50000 titles A AND C query resulted in 163 titles 934 B-terms ready on Tue Mar 29 22:19:28 2011 B-list on Tue Mar 29 22:27:42 2011 1 compulsive buying 2 panic disorder 3 subthreshold depression 4 deficit hyperactivity disorder 5 self management 6 self harm 7 expressive writing 8 panic attack 9 depression anxiety 10 social skill 11 group cognitive 12 stimulant medication 13 anxiety disorder 14 social phobia 15 behavioral therapy 16 attention deficit hyperactivity 17 cognitive behavioral 18 deliberate self 19 lesbian 20 psychoeducation 21 smoking cessation 22 children externalizing 23 reminiscence therapy 24 major depressive disorder 25 major depressive 26 anxiety depression 27 mood anxiety 28 assisted cognitive 29 lifestyle 30 therapy depression 31 obsessive compulsive disorder 32 attention deficit 33 aphasia 34 treatment depression 35 anxiety depressive disorder 36 treatment anxiety 37 relapse prevention 38 behavioral treatment 39 cognitive behavioral therapy 40 spiritual 41 treatment fear 42 anxiety depressive 43 externalizing problem 44 telephone helpline 45 health related 46 skill training 47 cognitive treatment 48 insomnia 49 meta analysis 50 depressive symptom a 51 borderline personality 52 cardiac rehabilitation 53 underserviced area 54 weight loss 55 depression primary care 56 orgasmic 57 risk adolescent 58 healthy lifestyle 59 smoking cessation program 60 psychological distress 61 psychiatric outpatient 62 depressive symptom 63 alcoholic anonymous 64 systematic review economic 65 hearing 66 treatment anxiety disorder 67 family intervention 68 panic 69 phobia 70 group cognitive behavioral 71 therapy obsessive compulsive 72 unipolar depression 73 cognitive behavior therapy 74 obsessive compulsive 75 cognitive behavior 76 compulsive buying disorder 77 treatment attention deficit 78 internet 79 antidepressant medication 80 sexual dysfunction 81 depressive disorder primary 82 childhood anxiety disorder 83 cardiac event 84 drinker 85 deliberate self harm 86 obsessive 87 psychotherapy 88 treating depression 89 poetry 90 behavioral treatment chronic 91 fear flying 92 life anxiety disorder 93 website 94 behavioral therapy obsessive 95 psychotherapy depression 96 intimacy 97 marital 98 compulsive 99 late life 100 treatment behavioral 101 depressive 102 cbt 103 depression children 104 behavior therapy 105 computerised cognitive 106 randomized controlled 107 depression late 108 depression a meta 109 self help 110 chronic illness 111 spiritual care 112 borderline personality disorder 113 satisfaction 114 disorder primary care 115 spiritual nursing 116 human sexuality 117 therapist 118 health nursing 119 randomised controlled trial 120 benjamin 121 nursing intervention 122 personality 123 outcome study 124 personality disorder 125 randomised controlled 126 adolescent psychiatry 127 campus 128 depression older adult 129 stepfamily 130 attention 131 life anxiety 132 narrative skill 133 mental health 134 self help intervention 135 treatment chronic insomnia 136 economic evaluation 137 unipolar 138 student
标签: 治疗方法
