克唑替尼治疗ALK阳性非小细胞肺癌脑转移的疗效观察

背景与目的：克唑替尼对间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)阳性非小细胞肺癌(non-small cell lung cancer,NSCLC)具有显著疗效,但在治疗中往往出现脑转移,本研究旨在探讨克唑替尼在ALK阳性NSCLC脑转移患者中的治疗疗效和治疗模式。方法：对2011年1月—2014年8月在解放军八一医院接受克唑替尼治疗的6例ALK阳性NSCLC脑转移患者的临床资料进行回顾性分析。结果：3例克唑替尼治疗前基线有脑转移患者,颅内疗效部分缓解(partial response,PR)1例、疾病稳定(stable disease,SD)2例;第1次服用克唑替尼治疗至第1次出现疾病进展(progressive disease,PD)的中位时间为5.7个月,且第1次疾病进展的部位均为脑。6例患者脑病灶进展接受放疗后继续服用克唑替尼治疗,中位无进展生存期(progression free survival,PFS)为4.0个月,其中1例患者继续接受克唑替尼治疗的PFS达23.3个月,颅内病灶疗效完全缓解(complete response,CR)。结论：克唑替尼治疗ALK阳性NSCLC脑转移患者有效,且对于单纯颅内病灶进展放疗后,继续接受克唑替尼治疗仍然有效,是临床上可以选择的治疗方式。     

Role of pemetrexed in non-small cell lung cancer

Pemetrexed was approved for the treatment of relapsed or chemotherapy refractory non-small cell lung cancer patients, as it produced similar response and survival outcomes and less toxicity as compared to taxotere. Pemetrexed in combination with platinum analogs or with gemcitabine or vinorelbine, produce equivalent responses and overall survival results compared to combinations of platinum analogs with other drugs. The role of bevacizumab and the inhibitors of epithelial growth factor receptor also should be evaluated in selected patients with NSCLC treated with pemetrexed combinations. Further increases in drug dose may be possible using transfer of drug resistance genes in hematopoietic stem cells.     

EML4-ALK阳性表达非小细胞肺癌患者的临床特征及治疗现状

棘皮动物微管相关类蛋白4（EML4）与间变性淋巴瘤激酶（ALK）融合基因首次被发现存在于部分非小细胞肺癌中。该融合基因是由2号染色体上2区1带和2区3带易位形成,可以诱导肿瘤生成,而ALK 抑制剂能够拮抗其促肿瘤生成活性。本文旨在介绍EML4-ALK基因阳性表达肺癌患者的临床特征及该基因在肺癌诊断、治疗中的意义。     

Current treatment landscape for oligometastatic non-small cell lung cancer

The management of patients with advanced non-small cell lung carcinoma (NSCLC) has undergone major changes in recent years. On the one hand, improved sensitivity of diagnostic tests, both radiological and endoscopic, has altered the way patients are staged. On the other hand, the arrival of new drugs with antitumoral activity, such as targeted therapies or immunotherapy, has changed the prognosis of patients, improving disease control and prolonging survival. Finally, the development of radiotherapy and surgical and interventional radiology techniques means that radical ablative treatments can be performed on metastases in any location in the body. All of these advances have impacted the treatment of patients with advanced lung cancer, especially in a subgroup of these patients in which all of these treatment modalities converge. This poses a challenge for physicians who must decide upon the best treatment strategy for each patient, without solid evidence for one optimal mode of treatment in this patient population. The aim of this article is to review, from a practical and multidisciplinary perspective, published evidence on the management of oligometastatic NSCLC patients. We evaluate the different alternatives for radical ablative treatments, the role of primary tumor resection or radiation, the impact of systemic treatments, and the therapeutic sequence. In short, the present document aims to provide clinicians with a practical guide for the treatment of oligometastatic patients in routine clinical practice.     

蛞蝓对人肺鳞癌、肺腺癌细胞抑癌作用初探

 在对肺鳞癌、乳腺癌、原发性肝癌、直肠癌手术切除标本和肺腺癌胸膜侵犯胸水中的癌细胞进行双层琼脂克隆培养和药敏试验的同时, 进行3H－胸腺嘧啶掺入试验(3H-TdR), 结果显示蛞蝓对肺鳞癌、肺腺癌细胞有明显的抑制作用:对肺鳞癌细胞的3H－TdR摄入抑制率93.08%, 与顺铂(93.33%相当；对肺腺癌克隆集落抑制率65.24%, 3H-TdR摄入抑制率46.21%, 比顺铂的34.77%和15.23%显著增高, 这一结果, 为今后进一步研究蛞蝓的抗癌作用提供了体外抑瘤的实验依据。     

Targeted therapies in non-small cell lung cancer: a focus on ALK/ROS1 tyrosine kinase inhibitors

Introduction: Anaplastic lymphoma kinase (ALK) and ROS1 rearrangements define important molecular subgroups of advanced non-small cell lung cancer (NSCLC). The identification of these genetic driver alterations created new potential for highly active therapeutic interventions. After discovery of ALK rearrangements in NSCLC, it was recognized that these confer sensitivity to ALK inhibition.

Areas covered: Crizotinib, the first-in-class ALK/ROS1/MET inhibitor, was initially approved as second-line treatment of ALK-positive advanced NSCLC but after this, it was firmly established as the standard first-line therapy for advanced ALK-positive NSCLC. After initial response to crizotinib, tumors inevitably relapse. Next-generation ALK inhibitors, more potent and brain-penetrable than crizotinib, may be effective in re-inducing remissions when cancers are still addicted to ALK. Ceritinib and alectinib are approved for metastatic ALK positive NSCLC patients, while brigatinib received granted accelerated approval by the United States Food and Drug Administration. Regarding ROS1 rearrangement, to date crizotinib is the only ALK-tyrosine kinase inhibitor receiving indication as treatment of ROS1 positive advanced NSCLC.

Expert commentary: Although novel ALK-inhibitors are under clinical investigation compared to crizotinib as front-line treatment for ALK-positive NSCLC, nowadays the current standard first-line therapy for these patients is crizotinib. Further research will clarify the best management of ALK-positive NSCLC, above all who progress on first-line crizotinib.     

非小细胞肺癌的免疫治疗策略及研究进展

非小细胞肺癌（NSCLC）是一种高发病率和死亡率的恶性肿瘤。近年来以手术、放疗、化疗和靶向治疗为主的综合治疗均取得了一定进展,但晚期NSCLC患者的远期生存率仍然较低。免疫治疗主要通过特异性地增强机体的抗肿瘤免疫应答来杀伤肿瘤细胞。以免疫检查点抑制剂、抗原特异性肿瘤疫苗等为代表的多种新型免疫治疗药物在近期临床试验中显示出较好的疗效,从而使得NSCLC的治疗取得突破性进展。免疫治疗将成为NSCLC重要的治疗新模式。     

MTSS1在非小细胞肺癌中的表达及临床意义

目的 探讨转移抑制因子1（MTSS1）在非小细胞肺癌（NSCLC）发生发展中的作用及临床价值。方法 收集本院2006年3月至2008年3月存档的98例NSCLC石蜡标本,构建组织芯片并采用免疫组织化学法检测98例NSCLC组织及对应癌旁组织中MTSS1的表达,分析其与临床病理参数（年龄、性别、淋巴结转移、病理类型、分化程度和TNM分期）的关系;随访不同MTSS1表达者的生存情况;构建pcDNA3.1-MTSS1表达载体（pcDNA3.1-MTSS1组）和pcDNA3.1空载体（pcDNA3.1组）并分别转染肺癌A549细胞,采用Western blotting法检测两组MTSS1的蛋白水平,采用四甲基偶氮唑盐MTT法和划痕试验检测两组细胞的增殖与迁移情况。结果 癌组织中MTSS1阳性表达率低于癌旁组织（56.1％ vs. 100.0％;P＜0.05）,MTSS1的表达与性别、年龄、分化程度和病理类型均无关,而与淋巴结转移和TNM分期有关（P＜0.05）;MTSS1阳性表达者的中位总生存期为40.9个月,高于阴性表达者的21.5个月,差异有统计学意义（P＜0.05）。Cox多因素分析显示MTSS1表达是影响NSCLC患者预后的独立因素。pcDNA3.1-MTSS1组的MTSS1蛋白水平高于pcDNA3.1组,且增殖比例和迁移率均低于pcDNA3.1组,差异均有统计学意义（P＜0.05）。结论 MTSS1缺失表达在NSCLC的发生发展过程中发挥了重要作用,逆转MTSS1的表达有助于肺癌的防治。     

非小细胞肺癌放化综合治疗的前瞻性随机研究

目的 对比观察非小细胞肺癌单纯放疗和放化综合治疗的疗效。方法 从１９９５年１月 到１９９７年１２月,将符合入组条件的８２例非小细胞肺癌患者随机分为放疗组和化放疗综合治疗组。其中完成治疗计划的有７４例,３５例属单纯放疗组,３９例属化放疗综合治疗组。综合治疗组中２１例为增敏化疗（氟脲嘧啶、顺铂）,在放疗的第１、４周给药;１８例为联合方案化疗,在放疗前、中、后进行,最少两周期,药物为卡铂、顺铂、足叶乙甙     

培美曲塞治疗晚期非小细胞肺癌近期疗效分析

目的　观察培美曲塞治疗５０例晚期非小细胞肺癌（ＮＳＣＬＣ）患者的疗效和毒副反应。方法　收集２００６年６月至２０１０年４月接受培美曲塞化疗的５０例ＮＳＣＬＣ患者,分为单药组１３例和联合组３７例。单药组：培美曲塞５００ｍｇ／ｍ２ｄ１,ｑ３ｗ。联合组：培美曲塞５００ｍｇ／ｍ２ｄ１,卡铂（ＡＵＣ＝５）ｄ１,或顺铂２５ｍｇ／ｍ２ｄ１～ｄ３,或奈达铂８０ｍｇ／ｍ２ｄ１,ｑ３ｗ。所有患者接受至少２个周期化疗。近期疗效评价采用ＲＥＣＩＳＴ１.０标准,毒副反应评价按照ＷＨＯ毒性评定标准。生活质量评价参照孙燕提出的生活质量（ＱＯＬ）评分表。结果　５０例患者均可评价疗效,完全缓解（ＣＲ）２例,部分缓解（ＰＲ）７例,稳定（ＳＤ）２２例,进展（ＰＤ）１９例,有效率（ＲＲ）１８.０％,疾病控制率（ＤＣＲ）６２.０％。生活质量改善率达５８.０％。主要毒性反应为１～２级骨髓抑制和胃肠道反应,经对症处理后不影响化疗进行。结论　以培美曲塞为主的化疗方案治疗晚期ＮＳＣＬＣ疗效较好,可明显改善患者生活质量,且毒性反应轻,易于耐受。     

改善肿瘤细胞乏氧状态对非小细胞肺癌放疗效果的影响

 目的 为了观察改善肿瘤细胞的乏氧状态对非小细胞肺癌（NSCLC）放疗效果的影响。方法 随机选择Ⅱ~Ⅳ期的NSCLC患者42例，资料完整者38例，在放射治疗前30 min内，采用舒氧康静脉内给氧的方法，提高血液中的氧分压，改善肿瘤细胞的乏氧状态；给氧前、后分别作血气分析，然后及时给予放射治疗，每次2 Gy，每日1次，每周5 d，总剂量60 ~ 70 Gy，随机选取同期的常规普放NSCLC患者37例作对照，按WHO疗效评价标准评价疗效，并作统计学处理。结果 试验组内给氧前后的动脉氧分压（PO2）分别为（85.6±7.5）mmHg，（103±9.7）mmHg；内给氧前后的血氧饱和度（SaO2）分别为（89.5±6.1）%和（94.4±5.2）%；放疗有效率为63.16 %（24／38）。对照组的有效率为43.24 %（16／37），试验组的疗效优于对照组（0.05＜P＜0.1），而两组之间毒副反应的发生率差异无统计学意义（P）。结论 放疗前静脉内给氧可改善肿瘤细胞的乏氧状态，提高放射治疗效果。     

肺癌神经内分泌分化与术后生存关系探讨

目的 探讨非小细胞肺癌神经内分泌(NSCLC—NE)分化与患者手术后生存关系。方法 收集1997年4月至1999年4月98例肺癌手术切除病理标本，采用免疫组化标记特异性烯醇化酶(NSE)及突触素(SY)，并按强弱区分为“ 、 、 ”。对同一手术病例标本采用电镜观察特异性NE颗粒。术后病例随访36月，最长60月。采用Cox多因素风险模型分析NSCLC-NE分化与患者术后生存的关系。结果 91例为非小细胞肺癌。非小细胞肺癌NF阳性表达率为63．7％(58/91)，其中NSE阳性表达54例(59．3％)，SY阳性表达22例(24．1％)，电镜观察NE持异性颗粒30例(33．0%)。结合免疫组化和电镜观察，NSCLC-NE分化44例(48．4％)。Cox模型多因素分析结果表明NSCLC-NE分化者术后生存时间明显缩短(P=0.048)。术后生存与肺癌细胞分化程度(P=0．006)、病理分期(P=0．001)、NE表达强弱(P=0．054)有密切关系。结论 NSCLC-NE分化与肿瘤细胞分化和患者术后生存有关。采用NE标志物标记肿瘤，并观察其强弱改变．对术后评估具有较重要的参考意义，可作为为临床判断患者预后指标之一。     

SPARC expression and prognostic value in non-small cell lung cancer

Secreted protein,acidic and rich in cysteine(SPARC) is expressed in numerous types of tumors and is suggested to have prognostic value.Moreover,because of its strong affinity for albumin,and hence albumin-bound drugs,SPARC has increasingly become a focus for research.In this study,we aimed to determine SPARC expression in patients with non-small cell lung cancer(NSCLC) and investigate the association of SPARC with disease prognosis.Tissue microarrays were constructed with specimens from 105 patients with NSCLC treated at Sun Yat-sen University Cancer Center,and immunohistochemical analysis was performed on these tissue microarrays to assess SPARC expression.Our results showed that SPARC expression status did not significantly relate with age,gender,and tumor stage.However,SPARC was expressed more frequently in squamous cell carcinoma than in adenocarcinoma(75% vs.43.5%,P = 0.004).Patients with smoking history had higher SPARC expression than non-smokers(68.2% vs.33.3%,P = 0.002).In both univariate and multivariate analyses,SPARC was a prognostic factor of overall survival(HR = 0.32;95% CI:0.16-0.65) but not disease-free survival.Our study indicates that SPARC expression is higher in squamous cell carcinoma than in adenocarcinoma in NSCLC.Most notably,SPARC can be used as a prognostic factor for NSCLC.     

非小细胞肺癌体外化疗药物敏感性与GRP78表达的相关性

背景和目的 糖调节蛋白78（GRP78）在乳腺癌细胞中表达增高并与其对化疗药物的耐药性有关，而非小细胞肺癌（NSCLC）中GRP78的表达与其对化疗药物的耐药性是否相关，研究较少。本研究拟探讨NSCLC对8种化疗药物的体外敏感性与GRP78表达的相关性。方法 采用四噻唑蓝（MTT）法对52例手术切除的新鲜NSCLC组织进行8种化疗药物体外敏感性检测；采用免疫组织化学方法检测其GRP78的表达水平。采用Spearman相关分析对NSCLC的耐药性与GRP78表达的相关性进行分析。结果 52例NSCLC对紫杉醇（PTX）、阿霉素（ADM）、卡铂（CBP）、拓扑替康（TPT）、长春瑞滨（NVB）、长春新碱（VCR）、顺铂（DDP）和鬼臼乙叉苷（VP-16）8种化疗药物的耐药率分别为42．31％、57．69％、63．46％、65．38％、67．31％、73．08％、78．85％、90．38％，其中14例表现为完全耐药。GRP78的表达水平随着肺癌恶性程度的提高而增加，且其高表达与肺癌细胞对VP-16、ADM、VCR和TPT的耐药具有相关性（P〈0．05）。结论 MTT法体外化疗药物敏感性实验对NSCLC的治疗具有一定的指导作用，GRP78对判定NSCLC的恶性程度及其耐药性具有一定的参考意义。     

State of the art in therapy for non-small cell lung cancer

The treatment of lung cancer has changed rapidly over the last few years and now more than ever a multi-disciplinary approach is vital to patient care. Surgical resection remains the mainstay of treatment for patients with operable disease. Recent studies have clearly demonstrated the survival benefits of adjuvant chemotherapy and this is now considered the standard of care. Despite efforts to improve early detection the majority of patients present with advanced lung cancer. The combination of radiation and chemotherapy should be considered for patients with locally advanced disease. Chemotherapy and the newer generation of molecularly targeted agents, provide quality of life benefits and modest gains in survival for patients with metastatic disease. Though there is room for improvement there is no justification for the therapeutic nihilism once surrounding the treatment of lung cancer.     

凋亡抑制因子（IAPs）在非小细胞肺癌患者中的表达及意义

 目的 探讨凋亡抑制基因（IAPs）家族在非小细胞肺癌（NSCLC）患者组织中的表达及其意义。方法 采用半定量反转录聚合酶链反应（RT-PCR）及Western blotting分别从mRNA和蛋白水平对36例NSCLC、36例肺部良性病变进行研究，检测生存蛋白（survivin）（human IAP-1）hIAP-1，（human IAP-2）hIAP-2及（X chromosome-linked IAP）XIAP表达情况。结果 36例NSCLC组织中有32例sur-vivin mRNA表达阳性，而对照组无一例阳性表达；26例癌组织中XIAP mRNA处于高表达，与对照组比较差异有统计学意义（P＜0.05）；hIAP-1 mRNA仅仅在腺癌组织中高表达（P＜0.05），具有组织学类型特异性。Western blotting显示在survivin mRNA阳性组织中均可检测到survivin蛋白的表达；XIAP和hIAP-1 mRNA高表达的组织同样可检测到相应蛋白。相关性分析表明只有hIAP-1的表达与NSCLC组织学类型相关。结论 survivin mRNA高表达可以作为NSCLC辅助诊断的重要指标，hIAP-1可用来协助鉴定NSCLC亚型，survivin和XIAP在肿瘤基因治疗中具有潜在的应用价值和前景。     

局部晚期非小细胞肺癌外科治疗中的气道重建

背景与目的部分局部晚期非小细胞肺癌患者需要采取不同的气道重建方式，以彻底切除病变并最大限度保存肺功能。本研究旨在探讨气道重建中的外科相关问题。方法回顾分析研究2003年1月～2005年6月2206例肺癌手术中100例气道重建患者的临床资料，其中鳞癌42例，腺鳞癌23例，腺癌11例，粘液表皮样癌5例，腺样囊性癌4例，类癌3例及其它混合散在分布类型12例。ⅠB期34例，ⅡB期23例，ⅢA期23例，ⅢB期20例。主要手术方式包括：右上叶袖状切除42例，右下叶袖状切除1例，左上叶袖状切除24例，左下叶袖状切除4例。两叶袖状切除8例，隆凸成形重建17例，肺叶袖状切除合并肺动脉成形4例。结果97例患者为完全性切除（R0），3例为不完全性切除（R1）。术后5例出现并发症，分别为肺部感染2例，胸腔感染1例，支气管胸膜瘘1例，肺泡胸膜瘘1例，并发症发生率为5％。术后住院日为4～27日（中位11日）。99例治愈出院，肺部感染导致死亡1例，手术死亡率为1％。结论对局部晚期非小细胞肺癌采取适当的气道重建方式，符合外科手术原则，可取得较满意的治疗效果。对血管、气管、支气管的处理技巧是手术获得成功的关键。