晚期非小细胞肺癌厄洛替尼耐药研究进展

酪氨酸激酶抑制剂(TKI)厄洛替尼作为晚期非小细胞肺癌(NSCLC)靶向治疗药物,延长了患者的生存时间,但其耐药性的发生成为其进一步应用的瓶颈.现已证实T790M突变、KRAS突变、c-met癌基因扩增在耐药机制中起重要作用.针对不同耐药机制,第2代TKI的应用、再次应用化疗或厄洛替尼以及针对失败模式进行后续治疗等多项临床试验不断开展.     

非小细胞肺癌患者血清CEA和CYFRA21-1检测预测疗效及预后价值的探讨

目的:评价晚期非小细胞肺癌(NSCLC)化疗后血清癌胚抗原(CEA)、细胞角蛋白19片段(CYFRA21-1)水平的下降在预测疗效及预后中的价值.方法:82例接受一线化疗的晚期NSCLC患者,于化疗前及第2个周期后分别以电化学发光免疫测定法检测血清CEA、CYFRA21-1的水平,同时行影像学检查评价客观疗效以及进行生存随访.通过建立ROC曲线,评估CEA、CYFRA21-1下降率在评价化疗疗效上的价值.结果:第2个周期后影像学方法评价的客观有效率为35%(29/82).以CEA、CYFRA21-1下降率评价的有效率分别为57%(47/82)、48%(39/82).影像学方法评价的客观有效率与CEA、CYFRA21-1评价的有效率差异有统计学意义,P=0.03.中位生存时间11个月.单因素分析显示体能评分(PS评分)、基线乳酸脱氢酶(LDH)水平及CYFRA21-1下降率与生存有显著相关性.经多因素分析显示,基线LDH(P=0.009)、CYFRA21-1下降率(P=0.02)是影响晚期NSCLC生存的独立预后因素.结论:晚期NSCLC化疗后血清CEA及CYFRA 21-1下降率是反映化疗疗效的可靠指标.血清CYFRA 21-1在化疗期间下降明显者提示预后较好.     

厄罗替尼治疗晚期非小细胞肺癌患者的临床疗效

背景与目的:厄罗替尼是一种表皮生长因子受体酪氨酸激酶的选择性抑制剂,临床常用于治疗晚期非小细胞肺癌。本研究旨在评价厄罗替尼治疗ⅢB/Ⅳ期非小细胞肺癌患者的疗效和不良反应。方法:本研究为开放的,记名供药计划。44例患者均为经病理证实的、至少接受过一个方案全身化疗的晚期非小细胞肺癌患者。厄罗替尼每次150mg每天口服一次直至病情进展或出现不能耐受的不良反应。采用RECIST实体瘤疗效评价标准评价疗效,NCI毒性评价标准评价不良反应。结果:44例患者客观有效率为27.3%(12/44),疾病控制率为65.9%(27/44),中位无疾病进展时间4.5个月(0.9～8.1个月),中位生存时间13.7个月(9.2～18.2个月)。不良反应主要是皮疹(81.8%)及腹泻(56.8%),多为Ⅰ～Ⅱ度。Ⅲ度转氨酶升高有1例(2.3%)。未出现Ⅳ度药物相关不良反应。结论:厄罗替尼对既往化疗失败的局部晚期或转移性非小细胞肺癌患者有较好的疗效和安全性。     

β catenin和E cadherin表达预测早期胃癌切除术后复发的临床意义#br# #br#

目的探讨β 连环蛋白（β catenin）和上皮型钙黏蛋白（E cadherin）对早期胃癌（T1～2N0期）患者行根治术后复发的预测价值。 方法选择2012年7月至2014年6月期间在遂宁市中心医院行手术切除的早期胃癌组织样本366例,随访患者复发情况。采用免疫组化染色法检测胃癌组织β catenin和E cadherin表达,及其表达与胃癌临床病理特征的关系。多因素Logistic回归模型分析影响复发的独立危险因素。 结果随访期内共有42例患者复发,复发和未复发患者在病理类型、浸润深度、分化程度、受教育程度以及居住地之间差异存在统计学意义（P＜005）。366例患者中221例β catenin高表达,150例E cadherin高表达,且β catenin和E cadherin表达与浸润深度、分化程度以及复发情况密切相关（P＜005）。多因素Logistic回归分析结果显示,浸润深度、β catenin和E cadherin异常表达是胃癌术后复发的独立因素（P＜005）。复发胃癌患者中β catenin和E cadherin表达无相关性（r=-0033,P=0836）。 结论β catenin和E cadherin表达异常可作为早期胃癌患者术后复发的预测指标,有助于筛选术后复发的高危患者。     

Efficacy and safety of first-line erlotinib in elderly patients with advanced non-small cell lung cancer

TaRceva LUng cancer Survival Treatment (TRUST) was an open-label, phase IV study of advanced non-small cell lung cancer (NSCLC). Patients failing or unsuitable for chemotherapy or radiotherapy received erlotinib 150 mg/day until progression. We examined a subpopulation of elderly patients (≥70 years) receiving first-line erlotinib (n=485) in TRUST. In this subpopulation, disease control rate (n=356 with best response data available) was 79% (vs. 69% for the overall TRUST population; p<0.0001); median progression-free survival (PFS) was 4.57 months [95% confidence interval (CI), 3.68-5.22]; median overall survival (OS) was 7.29 months (95% CI, 6.27-8.67); and one-year survival, was 36.6%. PFS and OS were significantly longer in patients developing rash, compared to those without, and in those with good performance status (PS; 0/1), compared to poor PS (≥2). Eighty-seven subpopulation patients (18%) had an erlotinib-related AE; other than the protocol-defined frequent adverse events (AEs); 4% had a grade ≥3 erlotinib-related AE, 7% had an erlotinib-related serious AE. In the subpopulation, dose reductions were required in 27%, most (97%) were reductions to 100 mg/day; treatment was discontinued in 10%, and one death was associated with treatment-related toxicity (<1%). Erlotinib was effective and well-tolerated and may be considered for elderly patients with advanced NSCLC who are unsuitable for standard first-line chemotherapy or radiotherapy.     

A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy

PURPOSE: To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non-small cell lung cancer patients refractory to platinum-based chemotherapy. EXPERIMENTAL DESIGN: Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks' treatment. RESULTS: Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease >/=12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR (P = 0.002), p-MAPK (P = 0.001), and Ki-67 (P = 0.025) levels were significantly reduced after 6 weeks' treatment. Apoptosis was significantly increased in patients with clinical benefit (P = 0.029), and may be a marker of clinical benefit. CONCLUSION: In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.     

Predictive and prognostic value of LPS-stimulated cytokine secretion in metastatic non-small cell lung cancer

Objective

Cancer patients usually develop malnutrition which may alter their innate immune system integrity. The aim of this study was to investigate the clinical relevance of chemokine response after lipopolysaccharide (LPS)-stimulation in metastatic non-small cell lung cancer (NSCLC).

Methods

Blood samples from metastatic NSCLC patients were incubated with LPS before the onset of systemic therapy. Interleukin (IL)-6 and IL-8 levels at baseline and after LPS-stimulation were measured and the fold change compared to baseline levels was evaluated as the stimulation index for each cytokine per patient. Results were correlated with sex, age, smoking status, histologic subtype, performance status (PS), albumin, Mini Nutritional Assessment (MNA) status and clinical outcomes.

Results

Totally 103 patients were evaluated. Mean (±SD) stimulation index was 37.6 (±57.8) for IL-6 and 76.7 (±133.4) for IL-8. The disease control rate after first-line chemotherapy was 44/80 (55 %) and the mean (±SD) progression-free survival (PFS) and overall survival (OS) were 4.2 (±3.9) and 9.2 (±1.1) months, respectively. MNA, PS, albumin, IL-6 and IL-8 stimulation indices were univariately associated with PFS and OS. IL-8 stimulation index emerged as an independent predictor of both PFS and OS, along with PS, and albumin levels.

Conclusion

The extent of IL-6 and IL-8 stimulation after ex vivo induction with LPS is an important predictor of clinical outcome in metastatic NSCLC patients.     

18FDG-PET评价局部晚期和晚期非小细胞肺癌化疗的客观疗效

 目的 前瞻性地探索18-氟脱氧葡萄糖-正电子发射计算机断层扫描（18FDG-PET）的SUV值标准与实体瘤疗效评价标准（RECIST）标准评价非小细胞肺癌（NSCLC）化疗的客观疗效是否具有一致性。方法 初治不可切除的局部晚期和晚期NSCLC患者前瞻性入组，行两周期含铂双药方案全身化疗。按RECIST标准和SUV值标准（2个周期化疗后SUV值下降大于30 %）互为盲法分别评价肿瘤客观疗效。用配对计数资料的χ2检验和κ系数检验比较18FDG-PET代谢缓解与RECIST标准的客观疗效是否具有一致性（SPSS13.0）。结果 不可切除的局部晚期8例，晚期35例。18FDG-PET代谢缓解与按RECIST标准评价的疗效具有明显的一致性（P＜0.001）。18FDG-PET评价NSCLC化疗客观疗效的敏感性、特异性、准确性、阳性预测值和阴性预测值分别是94 %、70 %、80 %、67 %和95 %。结论 18FDG-PET可以评价局部晚期和晚期NSCLC化疗的客观疗效。     

Clinical prognostic model for older patients with advanced non-small cell lung cancer

BackgroundOlder patients with non-small cell lung cancer (NSCLC) are often not prescribed standard therapy. It is important to know which older patients would be candidates for aggressive therapy based on their prognosis, and to develop a model that can help determine prognosis.MethodsData on older patients (≥70 years) enrolled on 38 NCI cooperative group trials of advanced NSCLC from 1991 to 2011 were analyzed. Multivariable Cox PH model was built with a stepwise selection. We derived a prognostic score using the estimated Cox PH regression coefficient. We then calculated the area under receiver operating characteristic (ROC) curve of survival in the testing set.ResultsThe final analysis included 1467 patients, who were randomly divided into a training (n = 963) and a testing set (n = 504). The prognostic risk score was calculated as: 3 (if male) + 3 (if PS = 1) + 8 (if PS = 2) + 11 (if initial stage = IV) + 4 (if weight loss). Patients were classified into two prognostic groups: good (0–8) and poor (≥9). The median survival in the two groups in the testing set were 13.15 (95% CI, 10.82–15.91) and 8.52 months (95% CI, 7.5–9.63), respectively. The model had area under the 1-year and 2-year ROCs (0.6 and 0.65, respectively) that were higher than existing models.ConclusionsMale gender, poor performance status, distant metastases and recent weight loss predict for poor overall survival (OS) in older patients with advanced NSCLC. This study proposes a simple prognostic model for older adults with advanced NSCLC.     

幼稚和记忆T 细胞在NSCLC 放疗患者中的表达及其预后价值

  目的  探讨幼稚和记忆T细胞在非小细胞肺癌（non-small cell lung cancer,NSCLC）放疗患者外周血中的表达及其与预后的关系。  方法  采用流式细胞仪检测2014年9月至2016年5月解放军307医院40例接受放疗的NSCLC首诊患者,治疗前外周血中幼稚CD4+T细胞、记忆CD4+T细胞、幼稚CD8+T细胞、记忆CD8+T细胞,与14例健康人进行对比,并分析其与临床病理特征及预后的关系。  结果  与健康组相比,NSCLC患者幼稚CD4+T细胞下降（P=0.031）,记忆CD4+T细胞和记忆CD8+T细胞升高（P=0.014、0.005）。与不吸烟患者相比,吸烟患者幼稚CD4+T细胞较低（P=0.043）,记忆CD4+T细胞较高（P=0.024）。与ECOG评分1～2分者相比,0分者幼稚CD8+T细胞较低（P=0.017）,记忆CD8+T细胞较高（P=0.020）。单因素分析显示幼稚CD4+T细胞较高组放疗后中位无进展生存期（median progression free survival,mPFS）更长（17个月vs. 9个月,P=0.044）、记忆CD4+T细胞较高组放疗后mPFS可能更短（9个月 vs. 15个月,P=0.069）。Cox多因素分析显示幼稚CD4+T细胞与患者放疗后无进展生存期（progression free survival,PFS）独立相关（P=0.009）。  结论  NSCLC患者外周血中幼稚T细胞储备下降,记忆T细胞上升。幼稚CD4+T细胞较高可能预示放疗后PFS更长。      

厄洛替尼治疗复治晚期非小细胞肺癌的临床分析

背景与目的:近年来,作为新的分子靶向药物-特罗凯(OSI774,Tarceva,厄洛替尼)在肺癌中得到越来越多的运用,并取得了可喜的成果。观察晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者接受厄洛替尼(erlotnib;商品名:特罗凯,OSI774,tarceva,)治疗后的近期疗效与毒副作用。方法:分析2005年12月-2006年9月上海市胸科医院肺部肿瘤临床医学中心40例接受特罗凯EAP(Expanded Access Program)项目慈善供药口服治疗复治的晚期NSCLC患者的疗效与毒副反应。结果:39例可评价的患者中位生存期(MST)为10.17个月(95%CI,6.98～13.35);无疾病进展时间(PFS)为7.83个月(95%CI,5.36～10.30)。不同程度皮疹的患者在PFS之间差异具有显著性(P=0.026)。所有患者中PR8人(20.51%),SD22人(56.41%),PD9人(23.08%)。(CR PR)缓解率为:20.51%;疾病控制率(CR PR SD):76.92%。Fisher'精确检验提示在疾病控制率方面,女性优于男性(94.44%vs.61.90%,P=0.023);不吸烟患者优于吸烟患者(91.67%vs.53.33%,P=0.015);出现皮疹患者优于无皮疹患者(P=0.006)。影响缓解率与疾病控制率的多因素分析提示年龄(P=0.035)是影响疾病控制率的独立因素。最常见的毒性反应为皮疹与腹泻,大部分为0～Ⅰ度,不需要特别处理。结论:特罗凯有效治疗复治、晚期NSCLC患者。     

Predictive and prognostic value of FDG-PET in nonsmall-cell lung cancer: a systematic review

For several years, molecular imaging with (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) has become part of the standard of care in presurgical staging of patients with nonsmall-cell lung cancer (NSCLC), focusing on the detection of malignant lesions at early stages, early detection of recurrence, and metastatic spread. Currently, there is an increasing interest in the role of FDG-PET beyond staging, such as the evaluation of biological characteristics of the tumor and prediction of prognosis in the context of treatment stratification and the early assessment of tumor response to therapy. In this systematic review, the literature on the value of the evolving applications of FDG-PET as a marker for prediction (ie, therapy response monitoring) and prognosis in NSCLC is addressed, divided in sections on the predictive value of FDG-PET in locally advanced and advanced disease, the prognostic value of FDG-PET at diagnosis, after induction treatment, and in recurrent disease. Furthermore, the background and recommendations for the application of FDG-PET for these indications will be discussed.     

CPEB4在非小细胞肺癌中表达及其对预后的预测价值

  目的  胞质多聚腺苷酸化元件结合蛋白4（cytoplasmic polyadenylation element binding protein 4,CPEB4）是胞质多聚腺苷酸化元件结合蛋白家族之一,与多种肿瘤发生发展密切相关,但在非小细胞肺癌（non-small cell lung cancer,NSCLC）中的研究相对较少。  方法  收集2007年6月至2012年12月郑州大学附属洛阳中心医院实施肺癌根治术102例患者临床病理资料。实时定量PCR（qRT-PCR）检测组织及细胞株中CPEB4 mRNA的表达,Western blot检测CPEB4在组织及细胞株中蛋白的表达,免疫组织化学法检测NSCLC患者石蜡标本中蛋白的表达。进一步分析CPEB4与NSCLC患者临床病理因素及预后的关系。  结果  CPEB4 mRNA和蛋白（P < 0.05）在NSCLC细胞株H322,H1975和A549表达明显高于WI-38正常肺细胞株,同时CPEB4 mRNA（P < 0.05）和蛋白（P < 0.05）在肺癌组织中高于邻近正常肺组织。免疫组织化学法检测CPEB4阳性表达率为38.2%。相关分析显示N分期为CPEB4表达的独立相关因素。预后生存分析结果显示T、N分期和CPEB4表达与本组NSCLC患者预后密切相关。  结论  CPEB4在NSCLC患者中高表达,并且与预后密切相关,可作为潜在靶点。