埃克替尼联合放疗治疗晚期非小细胞肺癌的研究进展

研究证实埃克替尼治疗表皮生长因子受体突变的非小细胞肺癌(NSCLC)患者疗效明确,并具有放疗增敏效果。国内有大量的研究表明埃克替尼联合放疗能显著提高NSCLC患者生存时间,特别是对老年患者或脑转移患者,且不良反应较小。因此,埃克替尼联合放疗有可能成为治疗晚期NSCLC患者的有效治疗手段。现对其相关研究进展作一综述。     

Survivin蛋白在非小细胞肺癌中表达的研究

目的探讨Survivin、突变型P53、Bcl-2蛋白在非小细胞肺癌组织中的表达及其三者之间的关系。方法用链霉菌生物素蛋白-过氧化物酶免疫组织化学法(SP法)检测71例手术切除的非小细胞肺癌(NSCLC)组织和30例正常肺组织中Survivin、突变型P53、Bcl-2蛋白的表达;用原位末端标记(TUNEL)法检测凋亡指数(AI)。结果在NSCLC组织中Survivin、突变型P53、Bcl-2蛋白的表达率分别为61.97%、52.52%、22.54%;30例正常肺组织中无Survivin、突变型P53蛋白表达(P<0.001),Bcl-2蛋白表达率为3.33%(P<0.005);肺癌Survivin阳性、阴性表达组织、正常肺组织的平均凋亡指数分别为11.86±4.67‰、18.67±7.93‰、23.32±6.98‰,肺癌Survivin阳性表达组织与正常肺组织的平均AI相比(P<0.001),肺癌Survivin阴性表达组织与正常肺组织的平均AI相比(P<0.05),差异有显著的统计学意义。结论Survivin蛋白在肺癌组织中的表达,提示该凋亡抑制蛋白在肺癌的发生发展中起抑制癌细胞凋亡的重要作用,AI显示出了Survivin蛋白的抗凋亡作用,Survivin基因有望成为基因治疗的新靶点。     

中性-淋巴比和预后营养指数与非小细胞肺癌患者预后的相关性研究

目的探讨中性粒细胞-淋巴细胞比率和预后营养指数与进展期非小细胞肺癌预后的相关性。方法回顾性分析安徽医科大学第一附属医院呼吸内科2010年1月至2013年1月确诊的Ⅲb期及Ⅳ期非小细胞肺癌患者109例,根据首次化疗前中性粒细胞-淋巴细胞比率及预后营养指数,分为低中性粒细胞-淋巴细胞比率组(2.97)和高中性粒细胞-淋巴细胞比率组(≥2.97),低预后营养指数组(45.95)和高预后营养指数组(≥45.95)。分析潜在的预后因素如中性粒细胞-淋巴细胞比率、预后营养指数、性别、年龄、组织类型、转移部位数、化疗次数、化疗方案等。结果多因素分析结果示:中性粒细胞-淋巴细胞比率(无进展生存期:P=0.015,总生存期:P=0.018),预后营养指数(无进展生存期:P=0.012,总生存期:P=0.006)、年龄(无进展生存期:P0.001,总生存期:P0.001)及化疗次数(无进展生存期:P0.001,总生存期:P0.001)是影响进展期非小细胞肺癌患者的独立预后因素,中性粒细胞-淋巴细胞比率≥2.97及预后营养指数45.95预示非小细胞肺癌患者无进展生存期或总生存期较短。结论中性粒细胞-淋巴细胞比率和预后营养指数均是预测进展期非小细胞肺癌患者预后的独立因素,高的中性粒细胞-淋巴细胞比率及低的预后营养指数与患者预后差相关。     

非小细胞肺癌的联合靶向治疗

虽然化疗对于晚期非小细胞肺癌患者的预后有一定疗效,但已进入一个平台期.特别对于化疗无效的患者,亟需新的、更有效的治疗方法.随着研究人员对肿瘤细胞生长、运动、转移以及肿瘤血管生成机制的深入了解,靶向治疗成为研究的热点.本文综述了现在主要使用的分子靶向药物及重要的临床试验,并对联合靶向治疗进行了阐述.     

Role of vindesine in induction chemotherapy in locally-advanced non-small-cell lung cancer

Locally advanced non-small-cell lung cancer (NSCLC) in most cases is not curable at the present time. Owing to the local extent of the tumor, the rate of complete resections is low and, therefore, survival in these patients is poor. For this reason, induction chemotherapy is being investigated in patients expected to have a poor prognosis after standard surgery and radiotherapy. The rationale for induction chemotherapy is to increase the rate of complete resections and achieve early elimination of micrometastases. Clinical investigations have reported an improvement of survival in stage III NSCLC after induction chemotherapy by using different combinations of cytotoxic drugs. Vindesine ranks among the most active single agents in this disease and has been part of a number of combination regimens in induction chemotherapy. The combination of mitomycin, vindesine or vinblastine and cisplatin has produced encouraging results in several studies, indicating a possible improvement of survival in stage III NSCLC, although its superiority to other combinations yet has to be demonstrated. Received: 11 July 1997 / Accepted: 30 September 1997     

非小细胞肺癌146例诊断来源分析

目的进一步规范非小细胞肺癌的诊断,为其治疗和判断预后提供依据。方法统计2002年2月至2005年8月沈阳军区总医院接受治疗的146例非小细胞肺癌的诊断结果。结果总体有完整病理诊断的123例,占84·2%。其中经手术获得病理诊断的42例,占28·8%;未手术的104例中,经痰细胞学检查、淋巴结针吸活检、胸腔积液细胞学和支气管镜获得诊断的分别为31例(21·2%)、18例(12·3%)、15例(10·3%)和11例(7·5%)。经临床诊断(无明确病理诊断,依据临床体征和影像学检查)的23例,占15·7%。结论在治疗前对非小细胞肺癌作出明确的病理诊断,会使治疗更准确无误,对判定肿瘤的发展和预后更有帮助。     

吉西他滨联合铂类治疗晚期非小细胞肺癌的临床分析

目的评价吉西他滨联合不同铂类化疗药物治疗ⅢB～Ⅳ期非小细胞肺癌（NSCL）的临床疗效和毒副反应。方法45例经细胞学或病理学证实ⅢB～Ⅳ期NSCLC患者（初治35例,复治10例）,患者的预计生存时间均超过2个月。按三种方案联合化疗：（1）吉西他滨＋顺铂（GEM／DDP）,每3周重复1次;（2）吉西他滨＋卡铂（GEM／CBP）,每3周重复1次;（3）吉西他滨＋顺铂（GEM／DDP）,每4周重复1次。按美国癌症研究所（NCI）实体瘤疗效评价标准（Recist标准）对目标病灶评价,毒性反应按2007中国肺癌临床指南（NCI—CTCV2．0）标准进行评价。随访患者中位生存时间并计算1年生存率。结果共完成158个周期全身化疗,平均每个病人接受3．5个周期化疗。吉西他滨联合顺铂3周及4周方案、吉西他滨联合卡铂三种方案的有效率分别为45．8％（11／24）、45．5％（5／11）和50％（5／10）,总有效率为46．7％（21／45）,35例初治患者中有效18例,有效率51．4％,10例复治患者中有效3例,有效率30％。毒副反应主要为白细胞减少、血小板减少、消化道反应、皮疹和搔痒。中位生存时间（MST）为8．9个月,1年生存率为38．7％。结论吉西他滨联合铂类化疗药物治疗晚期NSCL疗效较好,且毒性反应少,耐受性好。     

鸦胆子油乳联合化疗治疗中晚期非小细胞肺癌临床观察

目的评价鸦胆子油乳联合化疗方案治疗中晚期非小细胞肺癌的临床疗效和副反应。方法将83例中晚期非小细胞肺癌患者随机分为两组,试验组的45例研究对象采用鸦胆子油乳联合TP方案化疗治疗,对照组的患者仅接受TP方案化疗。结果试验组和对照组的治疗有效率分别为57.8%和47.4%,差异无统计学意义(P=0.344)。试验组的贫血,白细胞减低,恶心呕吐的发生率显著低于对照组(P<0.05)。结论鸦胆子油乳的应用可显著减轻中晚期非小细胞肺癌患者化疗所引起的毒副反应,提高了患者的耐受性。     

老年人晚期非小细胞型肺癌适形放疗的临床研究

目的 探讨老年人晚期非小细胞型肺癌适形放射治疗的价值。方法 对24例老年晚期非小细胞型肺癌患者实施适形放疗，进行低姑息性达根治剂量的治疗。结果 全组1、2、3年的生存率分别是：91．67％、54．16％、43．33％；放疗期间无急性放射性肺炎发生；统计分析显示：治疗前是否合并上腔静脉综合征、肿瘤体积大小、治疗前后生活质量(KPS)评分、适形放疗剂量为有意义的预后因素。结论 适形放疗对老年人晚期非小细胞型肺癌有治疗意义。     

多西他赛联合奈达铂治疗一线化疗失败的非小细胞肺癌的临床研究

目的观察多西他赛联合奈达铂二线治疗晚期非小细胞肺癌（NSCLC）的临床疗效及毒副反应,并进行安全评估。方法 65例一线治疗失败的晚期NSCLC患者采用多西他赛＋奈达铂化疗4周期后,用世界卫生组织（WHO）的疗效及抗肿瘤药物急性及亚急性毒性反应分度评价疗效和毒性。结果 65例患者均完成4周期以上化疗,完全缓解（CR）5例,部分缓解（PR）16例,总有效率32.0%,临床症状明显改善,常见的毒性反应有骨髓抑制、胃肠道症状和脱发。结论多西他赛联合奈达铂治疗一线化疗失败的NSCLC疗效确切,可以提高生活质量,毒副反应较轻,耐受性好,值得临床进一步推广研究。     

p53 tumour-suppressor gene in non-small-cell lung cancer with neoadjuvant therapy

In a phase II study for optimizing therapeutic management of locally advanced non-small-cell lung cancer the prognostic and therapeutic relevance of the p53 status was investigated. Biopsy or mediastinoscopy samples, collected prior to neoadjuvant chemoradiotherapy and corresponding resection specimens, were analysed immunohistochemically (CM1 antiserum) for p53 accumulation and molecular biologically (polymerase chain reaction/single-strand conformation polymorphism) for p53 mutations. The results were correlated to the response to therapy (regression grade) and to the survival times. p53 accumulation was found in 41.7% (prior to neoadjuvant therapy) and in 40.0% (after surgery) of the tumours. p53 mutation was demonstrated in 45.4% (prior to neoadjuvant therapy) and in 46.4% (after surgery) of the investigated tumours. Neither before nor after therapy was any correlation to the survival times or to the response to therapy seen in the collective analysed. Thus, such investigations are not suitable for identifying patients with locally advanced non-small-cell lung cancer who might benefit, to different extents, from neoadjuvant therapy. Received: 14 September 1999 / Accepted: 8 November 1999     

Novel immunological and nutritional-based prognostic index for gastric cancer

AIM: To assess the prognostic significance of immunological and nutritional-based indices, including the prognostic nutritional index(PNI), neutrophillymphocyte ratio(NLR), and platelet-lymphocyte ratio in gastric cancer.METHODS: We retrospectively reviewed 632 gastric cancer patients who underwent gastrectomy between1998 and 2008. Areas under the receiver operating characteristic curve were calculated to compare the predictive ability of the indices, together with estimating the sensitivity, specificity and agreement rate.Univariate and multivariate analyses were performed to identify risk factors for overall survival(OS). Propensity score analysis was performed to adjust variables to control for selection bias.RESULTS: Each index could predict OS in gastric cancer patients in univariate analysis, but only PNI had independent prognostic significance in multivariate analysis before and after adjustment with propensity scoring(hazard ratio, 1.668; 95% confidence interval:1.368-2.035). In subgroup analysis, a low PNI predicted a significantly shorter OS in patients with stage Ⅱ-Ⅲ disease(P = 0.019, P 0.001), T3-T4 tumors(P 0.001), or lymph node metastasis(P 0.001). Canton score, a combination of PNI, NLR, and platelet, was a better indicator for OS than PNI, with the largest area under the curve for 12-, 36-, 60-mo OS and overall OS(P = 0.022, P = 0.030, P 0.001, and P = 0.024,respectively). The maximum sensitivity, specificity, and agreement rate of Canton score for predicting prognosis were 84.6%, 34.9%, and 70.1%, respectively.CONCLUSION: PNI is an independent prognostic factor for OS in gastric cancer. Canton score can be a novel preoperative prognostic index in gastric cancer.     

Tumour regression in non-small-cell lung cancer following neoadjuvant therapy. Histological assessment

In the scope of a prospective multi-centre study after neoadjuvant combined chemotherapy (carboplatin, ifosfamide, etoposide, vindesine) and radiotherapy (45 Gy) 40 resection specimens of locally advanced non-small-cell lung cancer were analysed in order to establish reproducible pathological/anatomical results of tumour regression. Resection specimens of 28 squamous cell carcinomas and 12 adenocarcinomas were investigated using serial sections of the primary lesion. The mean age of the patients was 57 years. The results were compared to spontaneous regressive changes in a control group of 50 untreated non-small-cell lung cancers. Marked scarry fibrosis in the region of the former primary tumour, concentric foci of fresh tumour necroses and surrounding foam cell clusters with transition into vascular granulation tissue could be established as characteristic features of therapy-induced tumour regression, whereas untreated carcinomas revealed necroses with adjoining vital tumour tissue. Using a threestep regression system, 3 tumours could be classified as grade I (no or only slight tumour regression), 10 tumours as grade IIA (marked but incomplete tumour regression, more than 10% vital tumour tissue), 20 tumours as grade IIB (less than 10% vital tumour tissue) and 7 tumours as grade III (complete tumour regression without vital tumour tissue). After a median follow-up period of 32.3 months in patients with grade IIB or III tumour regression (responders) the median survival time of 27.9 months was found to be significantly longer than in patients with grade I or IIA tumour regression (non-responders) with a median survival period of 13.7 months (log-rank test,P=0.020). The resection specimens analysed, which were obtained 7 weeks (on average) after the end of radiochemotherapy, did not show specific changes due to preoperative therapy, but quite characteristic histological alterations in the former tumour area were registered, which had been induced by combined neoadjuvant radiation and chemotherapy. The grade of therapy-induced tumour regression could be shown to be a significant prognostic factor in non-small-cell lung cancer.     

Immunohistochemical detection of neuroendocrine differentiation in non-small-cell lung cancer and its clinical implications

Purpose  The purpose of this study was to prospectively assess the clinical implications of neuroendocrine (NE) differentiation in non-small-cell lung cancer (NSCLC) tumors. Methods  This study accrued subjects suspected to have lung cancer who underwent diagnostic bronchoscopy. Bronchoscopically-biopsied specimens were subjected to routine pathologic examination, and immunohistochemical studies were then performed if lung cancer was diagnosed. Chromogranin-A, synaptophysin, neural cell adhesion molecule, and Leu7 were used to demonstrate NE differentiation. Results  A total of 280 subjects were accrued to this study over a period of 2 years. Among them, 149 subjects were assessable for this study, and 130 were diagnosed as having NSCLC tumors (55 adenocarcinomas, 50 squamous cell carcinomas, 24 NSCLCs not otherwise specified, and 1 typical carcinoid). Large cell NE carcinoma was not observed in this study. Immunohistochemically, NE differentiation was detected in 16% of NSCLC tumors excluding typical carcinoid. By status of NE differentiation of NSCLC tumors, progression-free survivals were similar in 73 patients undergoing non-surgical treatment (positive, n = 10; negative, n = 63) and 43 patients undergoing surgical resection (positive, n = 8; negative, n = 35), respectively. Overall survival of patients with NE-positive tumors appeared to be favorable both for those undergoing non-surgical treatment and those undergoing surgical resection, though the differences in survival were not significant (P = 0.11 and 0.35, respectively). Conclusions  NE differentiation was detected in 16% of NSCLC tumors in our study. However, the prognostic implications of the presence of this feature could not be clearly determined in this study.     

The association between RAD18 Arg302Gln polymorphism and the risk of human non-small-cell lung cancer

Purpose The repair enzyme RAD18 plays a key role in the post-replication repair process in various organisms from yeast to human, and the molecular function of the RAD18 protein has been elucidated. Single nucleotide polymorphism (SNP) of arginine (Arg, CGA) or glutamine (Gln, CAA) at codon 302 is known on RAD18; however, the association between the SNP and the risk of any human cancers including non-small-cell lung cancer (NSCLC) has not been reported. We therefore investigated the relationship between the polymorphism and the development and progression of human NSCLC. Methods The study population included 159 patients with NSCLC and 200 healthy controls. The SNP was genotyped by polymerase chain reaction with the confronting two-pair primer (PCR-CTPP) assay. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological parameters was also studied. Results The Gln/Gln genotype was significantly more frequent in NSCLC patients (20.7%) than in healthy controls (11.5%)(P = 0.003). The increased risk was detected in NSCLC patients with the Gln/Gln genotype [Odds ratio (OR) = 2.63, 95% confidence interval (CI)=1.38–4.98]. As to the relationship of the SNP with clinicopathological parameters of NSCLC, significantly higher risks were detected in lung squamous cell carcinoma (LSC) (OR = 4.40, 95% CI = 1.60–12.1). Conclusions Our results suggested that Gln/Gln genotype of the RAD18 SNP has the increased risk of NSCLC, especially of LSC. This is the first report to provide evidence for an association between the RAD18 Arg302Gln polymorphism and human NSCLC risk.     

Pharmacokinetics and clinical outcomes of nivolumab administered every 4 weeks in patients with advanced non-small-cell lung cancer: A four-case pilot study

This pilot study evaluated the pharmacokinetics and clinical outcome of nivolumab, administered every 4 weeks to patients with advanced non-small-cell lung cancer. The interval of nivolumab administration was changed from 2 to 4 weeks in four patients in whom tumor growth had been controlled for more than 6 months. Pharmacokinetics and clinical outcomes of nivolumab were prospectively investigated. The estimated steady-state nivolumab mean plasma concentration (±standard deviation) of each interval in the four patients was 53.1 (±15.0) at 4 weeks and 105.2 (±29.5) μg/mL at 2 weeks. No disease progression was observed in three patients for at least 1 year after the interval change; however, one patient developed interstitial lung disease within 5.6 months after the change. In conclusion, the pharmacological effects of nivolumab continued with doses administered less frequently than the standard schedule. Nevertheless, further research on nivolumab administration intervals is necessary.