c-kit在小细胞肺癌中的研究进展

小细胞肺癌约占全部肺癌的15％-20％,其因复杂的病理生理学特征和高度恶性引起了医学界的广泛关注。c-kit受体属于III型酪氨酸激酶受体家族,对某些正常细胞的分化、增殖、发育及功能维持起重要作用。近来研究发现小细胞肺癌组织有c-kit受体的异常表达,e-kit基因的突变,由此推测C-kit受体的异常表达及突变与小细胞肺癌的发生存在一定的关系。本文阐述了C-kit在小细胞肺癌中的研究进展。     

2011年非小细胞肺癌研究进展

回首2011年,在肺癌领域的我们收获颇丰,靶向治疗特别是新型靶向药物的研究、生物标志物分析以及与疾病相关的基因研究仍是目前的研究热点。基于分子分型的研究硕果累累,影响和改变着     

非小细胞肺癌EGFR基因突变异质性研究进展

 表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）在EGFR基因活化突变阳性晚期非小细胞肺癌（NSCLC）患者中疗效显著,然而,同样是EGFR活化突变阳性的NSCLC患者接受EGFR-TKIs治疗后,疗效仍有明显差异;同一个患者的不同瘤灶也会对EGFR-TKIs出现不同的反应,这些现象可能与EGFR基因突变异质性有关,同一瘤灶的不同部分、同一患者的不同瘤灶、以及同一瘤灶治疗前后EGFR突变状态都有可能不一致。本文将从这三个方面对EGFR突变异质性研究进展作一综述。     

树突状细胞在非小细胞肺癌治疗中的研究进展

非小细胞肺癌（non—small cell lung cancer,NSCLC）,包括腺癌、鳞状细胞癌、大细胞肺癌,占据了肺癌的大多数并且受到传统治疗方式的限制,标准治疗方法的缺乏促进了NSCLC新疗法的研究和发展。树突状细胞（dendritic cell,DC）作为专职的抗原提呈细胞（antigen—presenting cell,APC）,是机体免疫应答的主要启动者,在免疫应答的诱导中发挥关键作用,为其用于癌症治疗开辟了新的道路。本文就近几年来有关DC的研究进行回顾,重点阐述NSCLC中DC的研究进展。     

EGFR T790M突变在非小细胞肺癌中的研究进展

表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)可以改善EGFR阳性非小细胞肺癌(NSCLC)患者的预后,但在TKIs的应用中,基因检测发现EGFR T790M突变的患者越来越多,这一现象的发生对患者治疗及预后产生了严重的影响。本文综述了T790M突变与一、二、三代EGFR-TKIs的关系,评估了原发性T790M突变人群的特征及应用EGFR-TKIs治疗的疗效及预后,同时也关注了第三代EGFR-TKIs的新型继发性耐药问题,为NSCLC的精准治疗提供临床依据和思路。     

TERT基因在非小细胞肺癌易感性及预后中的研究进展

肺癌是世界上最常见的恶性肿瘤之一，具有很高的死亡率，85%的肺癌患者组织学类型为非小细胞肺癌(non-small cell lung cancer, NSCLC)。非小细胞肺癌的预后较差，与诊断晚、复发风险高、药物耐药等有关。端粒酶是细胞存活的关键酶，它能维持细胞端粒的长度，使细胞具有无限增殖和永生化的潜能。端粒酶逆转录酶(TERT基因编码)是端粒酶的催化亚基，能激活端粒酶，为细胞提供癌变的可能。TERT启动子突变被证明是激活端粒酶的一种新的遗传机制，并存在于多种人类肿瘤中。端粒酶激活和端粒损伤与人类肺癌的发生有关，且TERT基因多态性与非小细胞肺癌的易感性及预后有关。本文总结了TERT启动子突变及TERT多态性在非小细胞肺癌中的研究，以及它对非小细胞肺癌预后的影响及靶向治疗前景。     

药物基因组学在非小细胞肺癌化疗耐药中的研究进展

非小细胞肺癌（non-small cell lungca Bcer,NSCLC）是目前肿瘤导致死亡的主要病因之一。应用化疗药物可以延长NSCLC患者的生存期,但耐药、副作用等情况限制了其临床应用。药物基因组学（pharmacogenomics）认为药物代谢过程中的相关基因突变会影响药物在体内的作用活性。本文总结了NSCLC常用化疗药物在药物基因组学方面的研究进展。     

检查点抑制剂在非小细胞肺癌中的研究进展

近年来,非小细胞肺癌(non small cell lung cancer,NSCLC)在手术、放疗、化疗等方面均取得了很大进展,但NSCLC患者5年生存率仍只有15%,因此探索NSCLC新的治疗模式尤为重要。免疫治疗以其低毒、高效等特点成为当前肿瘤治疗的重要手段。检查点抑制剂作为新型抗肿瘤免疫治疗药物,通过阻断T细胞的负性信号传递使其大量活化增值,增强机体的抗肿瘤免疫功能,显现出了良好的抗瘤效果。目前,细胞毒性T淋巴细胞相关抗原-4(cytotoxic T lymphocyte associated antigen 4,CTLA-4)、程序性细胞死亡蛋白1(programmed death-1,PD-1)及其受体PD-L1、淋巴细胞活化基因-3分子(lymphocyte activation gene-3,LAG-3,CD223)和T细胞免疫球蛋白3(T-cell immunoglobulin and mucin-domain-containing molecule 3,TIM-3)等分子的抑制剂均在NSCLC中开展了广泛的研究。在治疗NSCLC的临床试验中,检查点抑制剂Ipilimumab、Nivoluma等取得了一定的成功,前景值得期待。     

cfDNA在非小细胞肺癌中的研究进展

肺癌发病率及死亡率居全球癌症之首,尽管近年来肺癌的分子靶向治疗和免疫治疗技术不断发展,但患者的总生存并未显著延长。尽早确定肺癌患者的临床分期和分子分型,提升早期临床诊断效率,以及监测患者耐药性和探究其耐药机制,对提高肺癌患者生存率具有重要意义。对于晚期患者而言,由于取材等问题,作为金标准的病理诊断并不一定可用,且在非小细胞肺癌的发展过程中,连续手术组织活检仍然是一大难题,而cfDNA（cell-free DNA,cfDNA）的液体活检技术,正迅速成为标准肿瘤活检的重要微创辅助手段。肿瘤细胞可以通过凋亡或坏死释放DNA片段进入血液循环,形成细胞游离DNA,非小细胞肺癌患者的血浆cfDNA水平较高,分析患者血浆中cfDNA对非小细胞肺癌患者的早期临床诊断、基因突变检测以及预后的预测、耐药性监测等方面均有着重要价值,并有望成为重要的液体生物标志物和指导非小细胞肺癌精准治疗模式中的新方法。本文就cfDNA在非小细胞肺癌研究中的最新进展情况作一综述。     

小细胞肺癌组织中c-kit蛋白的表达及其原癌基因的检测

目的：探讨c-kit蛋白在小细胞肺癌（Small cell lung cancer,SCLC）组织中的表达及c-kit原癌基因第9和11号外显子突变状态,及其与临床病理特点之间的关系。方法：采用免疫组化方法检测13例手术切除SCLC组织标本中c-kit蛋白的表达,并用PCR扩增和基因测序的方法检测其第9和11号外显子序列。结果：c-kit蛋白的阳性表达率为69.2%（9/13）。13例SCLC组织中,1例（7.7%）c-kit基因9号外显子突变,5例（38.5%）c-kit基因11号外显子突变。突变方式有点突变和插入突变。结论：c-kit蛋白表达与SCLC发生发展密切相关,c-kit原癌基因第9和11号外显子均检测到突变,为临床靶向治疗SCLC提供依据。     

小细胞肺癌组织c-kit蛋白表达的临床分析

目的　探讨c kit蛋白在小细胞肺癌中的表达及其临床病理意义。方法　采用兔抗人c kit蛋白抗体、SP免疫组化方法检测 5 2例福尔马林固定、石蜡包埋的原发小细胞肺癌组织、10例正常肺组织和 2 0例非小细胞肺癌组织的c kit蛋白表达状况。结果　小细胞肺癌组织中c kit蛋白阳性表达率为 61.5 %( 3 2 /5 2 ) ,c kit蛋白表达定位于胞浆 ;其中强阳性者占 65 .6%( 2 1/3 2 ) ,弱阳性者占 3 4.4%( 11/3 2 )。 10例正常肺组织及 2 0例非小细胞肺癌组织c kit蛋白呈阴性表达。c kit蛋白表达与小细胞肺癌肿瘤大小 (P =0 .0 10 )及预后 (P =0 .0 0 0 1)有密切关系 ,但与性别、年龄及临床分期均无明显关系 (P >0 .0 5 )。结论　c kit蛋白表达可能与小细胞肺癌的预后相关。c kit蛋白的原位检测较为直观 ,有利于小细胞肺癌的临床病理诊断、靶向药物治疗和预后评估     

Progress in immunotherapy for small cell lung cancer

Small-cell lung cancer (SCLC) is a special type of lung cancer that belongs to highly aggressive neuroendocrine tumors. At present, radiotherapy and chemotherapy remain the mainstay of treatment for SCLC. Progress in targeted therapies for SCLC with driver mutations has been slow, and these therapies are still under investigation in preclinical or early-phase clinical trials, and research on antiangiogenic tyrosine kinase inhibitors (e.g., anlotinib) has achieved some success. Immunotherapy is becoming an important treatment strategy for SCLC after radiotherapy and chemotherapy. In this article we review the recent advances in immunotherapy for SCLC.     

小细胞肺癌蛋白质组学研究进展

目的总结蛋白质组学在小细胞肺癌中的研究进展。方法应用PubMed、EMBASE及CNKI期刊数据库检索系统,以＂肺癌,小细胞肺癌、蛋白质组学和研究进展＂等为关键词,检索1995-01-2013-12的相关文献,共检索到英文文献556条,中文文献317条。纳入标准：1）小细胞肺癌;2）蛋白质组学研究;3）蛋白质组学技术。剔除标准：非小细胞肺癌。最后符合分析的文献24篇。结果目前蛋白质组学在小细胞肺癌中的研究主要集中于细胞、组织和血清三个方面,并且已发现多种不同的候选肿瘤标志。结论蛋白质组学研究已广泛深入到小细胞肺癌发病机制、临床早期诊断和治疗等各个方面,为发现小细胞肺癌诊断、治疗及预后判断的潜在生物标志提供了新的思路。     

Analysis of c-kit expression in small cell lung cancer: prevalence and prognostic implications

c-kit, a growth factor receptor with tyrosine kinase activity, plays an important role in the biology of cancer. Its expression has been documented in several malignancies. We performed a retrospective study in 85 patients diagnosed with small cell lung cancer (SCLC) to determine the prevalence and role of c-kit as a possible prognostic marker in this lung cancer malignancy. Demographic and clinical data were obtained from patient charts. c-kit, analyzed as immunohistochemical expression in paraffin-embedded tumour tissues, was observed in 60% of patients. All patients were former or present smokers. At diagnosis, 46% of the patients had limited disease (LD) and 54% extended disease (ED). c-kit expression was observed in 59% of LD and 61% of ED patients (p=0.4). Patients received a median of 4 cycles first-line combination chemotherapy (platinum and etoposide). In LD patients, time to progression (TTP) was 11.5 months in c-kit (+) versus 5.9 in c-kit (-) patients (p=0.14), and median survival 15.4 and 12.8 months, respectively (p=0.33). In the ED group, TTP was 5.5 months in c-kit (+) versus 3.8 in c-kit (-) patients (p=0.34), whereas median survival was 6.3 and 7.9 months, respectively (p=0.45). With the limited number of patients in mind, our findings tended towards an association between c-kit expression and survival in the LD group.     

Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications.

PURPOSE: The tyrosine-kinase receptor c-kit and its ligand stem cell factor are coexpressed in many small cell lung cancer (SCLC) cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop. To further evaluate the frequency and pathogenic relevance of c-kit expression, tumor tissue together with the corresponding clinical data of SCLC patients was analyzed. EXPERIMENTAL DESIGN: Tumor tissue of 102 consecutive SCLC cancer patients was analyzed immunohistochemically using an affinity-purified polyclonal c-kit antibody. Immunostaining data were correlated with survival and other relevant clinical parameters. RESULTS: A positive c-kit expression was observed in 37% of patients. c-kit expression was associated with decreased survival in the likelihood-ratio-forward selection model of the Cox regression including clinically relevant risk factors (c-kit expression, age, gender, stage, tumor stage, node stage, metastasis stage, weight loss, performance status, response to chemotherapy, lactate dehydrogenase, neuronspecific enolase, hemoglobin). Only c-kit expression [hazard ratio, 2.00; confidence interval (CI), 1.17-3.41; P = 0.012], response to chemotherapy (hazard ratio, 4.49; CI, 2.36-8.55; P < 0.001), and tumor stage (hazard ratio, 2.11; CI, 1.18-3.74; P = 0.008) were explanatory prognostic factors. These factors and all possible interactions between them were further analyzed in a second Cox regression model. As expected, response to chemotherapy had the highest impact on survival (hazard ratio, 3.06; CI, 1.69-5.54; P < 0.001). In patients with extensive disease, minor response to chemotherapy, and positive c-kit expression, the risk to die increased to 8.4 (hazard ratio, 2.74; CI, 1.52-4.91; P = 0.002). In a Kaplan-Meier analysis median survival of patients with minor response to chemotherapy and extensive stage was 288 days (CI, 255-321 days) when c-kit expression was negative compared with only 71 days (CI, 0-237 days) for c-kit-positive patients (log rank test: P = 0.003). CONCLUSIONS: c-kit represents a new prognostic factor in SCLC. c-kit expression is of particular clinical relevance in patients with advanced disease and poor response to chemotherapy. Given the very limited therapeutic options and unfavorable prognosis of these patients, clinical studies aimed at targeting c-kit (e.g., STI571) are clearly warranted.     

广泛期小细胞肺癌内科治疗进展

广泛期小细胞肺癌预后极差，中位生存期约8~10个月，其治疗几十年来进展甚微，含铂两药的治疗方案一直是一线治疗的不二选择。几乎所有的患者都会发生复发或耐药，可选的方案十分有限，现有的治疗方式已达瓶颈，随着对小细胞肺癌分子生物学认识的深入，研究重点转向了分子靶向和免疫治疗。伴随着大批试验性药物的涌现，促进了新药物的研发，一系列药物在早期临床试验中的表现似乎打破了“小细胞肺癌是药物开发坟墓”的诅咒。这些新药主要包括抗血管生成抑制剂、免疫检查点抑制剂、抗凋亡蛋白抑制剂、抗藕联药物等，我们期待能为广泛期小细胞肺癌患者的治疗带来一丝曙光。     

Progress and challenges in the treatment of small cell lung cancer

Small cell lung cancer (SCLC) is a very aggressive malignancy characterized by high cellular proliferation and early metastatic spread. In fact, although SCLC is a chemosensitive and radiosensitive disease, the initial responsiveness to chemotherapy is usually followed by development of resistance and the prognosis remains poor with a median survival of less than 12 months in patients with extensive disease (ED-SCLC). Furthermore, no significant progress has been made over the last years, with no newly approved drug. For all these reasons, SCLC represents for the oncologists a major challenge and an exciting field of clinical research. In this review, we analyze the most promising advances in development for SCLC with a special focus on antiangiogenic treatments, immunotherapy, novel chemotherapeutic and targeted agents.