盐酸埃克替尼治疗晚期非小细胞肺癌的临床研究

目的：观察盐酸埃克替尼治疗晚期非小细胞肺癌（NSCLC）患者的疗效和安全性。方法126例Ⅲb~Ⅳ期NSCLC患者接受盐酸埃克替尼治疗,直至PD或出现不能耐受的重度毒副反应而终止治疗,并以93例接受吉非替尼治疗的Ⅲb~Ⅳ期NSCLC患者作为对照,评价2种药物的疗效和毒副反应。结果盐酸埃克替尼组饮食及睡眠质量改善率为53.2％,高于吉非替尼组的37.6％（P＜0.05）。盐酸埃克替尼组有效率为46.0％,吉非替尼组为45.2％（P＞0.05）;盐酸埃克替尼组疾病控制率为86.5％,高于吉非替尼组的74.2％（P＜0.05）。2组主要毒副反应均为皮疹、腹泻,发生率相近（P＞0.05）。结论盐酸埃克替尼在晚期NSCLC的治疗中与吉非替尼近期疗效和安全性相近,但均稍有优势。     

吉非替尼致问质性肺炎并文献回顾

目的：探讨吉非替尼治疗晚期非小细胞肺癌所致问质性肺炎的临床特点和治疗策略。方法：报告1例吉非替尼治疗晚期非小细胞肺癌所致间质性肺炎的临床资料,并进行系统文献回顾,对吉非替尼所致间质性肺炎的临床特点,机理和治疗进行分析。结果：综合本病例患者特点和国内外文献分析,老年男性、长期吸烟史、吸烟指数高、腺癌、特别是细支气管肺泡癌患者在服用吉非替尼期间更容易发生间质性肺炎,发生时间多在服药后1—2月,临床表现以胸闷、气短、进行性呼吸困难为特点,伴有严重低氧血症,甚至呼吸衰竭。影像学检查以双肺弥漫性浸润性阴影及蜂窝状间质改变为代表,及时判断病因并停药,给予糖皮质激素、吸氧、抗感染等对症处理可缓解。结论：一旦发现吉非替尼所致的间质性肺炎应及时停药,大多数患者病情可缓解,早期可控制的间质性肺炎,不是永久停用吉非替尼的绝对指标,应根据患者的获益和药物治疗相关风险综合考虑。     

吉非替尼对A549细胞增殖及细胞周期、凋亡的作用

目的：观察吉非替尼对人非小细胞肺癌A549的生长增殖、细胞周期及细胞凋亡的影响。方法：用5—40μmol／L浓度范围内的吉非替尼和A549细胞共培养24、48、72h,采用四甲基偶氮唑蓝（MTr）法检测吉非替尼对细胞增殖的影响;用流式细胞仪检测其对细胞凋亡及细胞周期分布的影响;利用抗Capspase-3的ELISA（酶联免疫吸附）法检测是否发生细胞凋亡。结果：在5—40μmol／L浓度范围内,吉非替尼对A549细胞的增殖有明显的抑制作用,并呈时间和剂量依赖性,以40μmol／L作用72h时的抑制率最高。流式细胞仪检测显示10μmol／L-401μmol／L的吉非替尼作用可使细胞发生G0／G,期阻滞,但即使作用48h也未发现凋亡细胞。ELISA法显示48h内,吉非替尼组与正常细胞组的Capspase-3浓度无统计学差异,但作用72h时出现凋亡。结论：吉非替尼在5—40μmol／L浓度下作用时间小于48h时,其对A549细胞的增殖抑制可能是通过阻滞A549细胞于G0／G1期而非引起细胞凋亡实现的,但作用时间达到72h时,其可以诱导A549发生细胞凋亡。     

阻断表皮生长因子受体和环氧合酶-2信号途径对肺腺癌细胞的抗增殖作用

目的:探讨表皮生长因子受体抑制剂吉非替尼(gefitinib)联合新型环氧合酶2（cyclooxygenase2, COX2）抑制剂塞来昔布(celecoxib)对肺腺癌A549细胞株的抑制作用及其可能机制。方法:肺腺癌A549细胞培养于RPMI 1640 培养液中,实验分为正常对照组、吉非替尼5 μmol/L组、塞来昔布25 μmol/L组、吉非替尼5 μmol/L加塞来昔布25 μmol/L组。药物干预细胞48 h后,倒置相差显微镜观察细胞形态学变化,锥虫蓝拒染法检测药物对细胞生长的影响,Annexin V/PI法和Hoechst33258染色法检测细胞凋亡,流式细胞术检测药物作用周期,免疫荧光和Realtime PCR法检测EGFR、COX2蛋白的表达及EGFR mRNA的表达情况。结果:吉非替尼联合塞来昔布组相比单药组,A549 细胞明显出现大量颗粒和空泡,细胞变圆并开始脱落。吉非替尼与塞来昔布单药对A549细胞抑制作用具有时间和剂量依赖性,加药48 h时吉非替尼（5 μmol/L）联合塞来昔布（25 μmol/L）组抑制率为(58.2±4.6)%,明显高于单药组（P<0.01）。联合用药组A549细胞凋亡率明显高于单独用药组（33.9% vs 6.0%,8.8%）,其S期细胞明显减少、G0/G1期明显增加（P<0.01）;EGFR、COX2蛋白的表达明显减弱（P<005）,EGFR mRNA相对表达量（028±0.05）明显高于单独用药组（P<0.05）。结论:吉非替尼和塞来昔布联合对肺腺癌A549 细胞增殖的抑制具有明显协同作用,其可能机制是诱导凋亡、增强G0/G1期阻滞和进步下调活化的EGFR与COX2的表达。     

抗瘤增效方联合吉非替尼治疗老年非小细胞肺癌患者及对炎症因子,T细胞亚群水平及血清肿瘤标志物的影响

目的:探讨抗瘤增效方联合吉非替尼治疗老年非小细胞肺癌及对患者炎症因子,T细胞亚群水平及血清肿瘤标志物影响。方法:选取郑州大学附属肿瘤医院肿瘤内科非小细胞肺癌Ⅳ期老年患者84例,患者或家属签字同意,积极配合此次研究,按随机数字表法分组,对照组患者(42例)予以单纯吉非替尼治疗,研究组患者(42例)予以吉非替尼联合抗瘤增效方治疗,观察并记录所有患者治疗前后生存质量、炎症因子及T细胞亚群水平,同时对比临床疗效及不良反应状况。结果:对照组有效率低于研究组(P0.05);与治疗前比较,两组患者治疗后生存质量、炎症因子及T细胞亚群水平均发生变化,研究组治疗后躯体功能,角色功能,社会功能,情绪功能评分高于对照组,研究组治疗后白细胞介素-2(interleukin-2,IL-2),白细胞介素-12(interleukin-12,IL-12)和γ-干扰素(interferon-γ,IFN-γ)水平高于对照组,研究组治疗后CD8+水平低于对照组,CD4+及CD4+/CD8+水平高于对照组(P0.05);治疗后,对照组血管内皮生长因子(vascular endothelial growth factor,VEGF)升高,治疗组VEGF下降(P0.05);与治疗前比较,两组患者癌胚抗原(carcinoembryonic antigen,CEA),糖抗原(carbohydrate antigen-125,CA125)及细胞角蛋白19片段21-1(cytokeratin 19 fragments,CYFRA21-1)差异无统计学意义,组间比较差异无统计学意义;两组患者不良反应较轻,无药物不良反应。结论:抗瘤增效方联合吉非替尼治疗老年非小细胞肺癌疗效确切,能提高生活质量及免疫功能。     

吉非替尼对肺鳞癌患者免疫功能的影响及其近期临床疗效

目的：研究吉非替尼对肺鳞癌患者免疫功能的影响及其近期临床疗效。方法选取诊断为肺鳞癌的患者84例,随机分为观察组和对照组,每组均为42例,两组患者均给予常规治疗,观察组在常规治疗的基础上给予口服吉非替尼,观察两组患者治疗后体液免疫和细胞免疫功能情况及其近期临床疗效。结果治疗后两组患者血清 CD3、CD4、IgG、IgM、IgA 浓度与 CD4／CD8较治疗前有所降低（P ＜0．05）,CD8较治疗前有所升高（P ＜0．05）;观察组患者血清 CD3、CD4、CD4／CD8、IgG、IgM、IgA 浓度明显高于对照组（P ＜0．05）,观察组 CD8较对照组低（P ＜0．05）;观察组临床疗效优于对照组,治疗后两组均出现恶心、恶心伴呕吐、骨髓抑制,差异无统计学意义（P ＞0．05）。结论在常规治疗的基础上给予口服吉非替尼能改善患者的免疫功能,提高临床疗效,且无严重不良反应。     

Targeting c-kit inhibits gefitinib resistant NSCLC cell growth and invasion through attenuations of stemness,EMT and acquired resistance

EGFR tyrosine kinase inhibitors (TKIs) are the first-line drugs for NSCLC. But, the acquired resistance limited their efficacy, so that the patients deteriorate eventually. Therefore, it is necessary to clarify the mechanism of the acquired resistance and overcome it for effective NSCLC therapy. In this experimental study, a stable gefitinib resistant lung adenocarcinoma cell line (PC9/GR) infected with shRNA-c-kit-homo-1386 were established; c-kit siRNA and c-kit inhibitors were used to block c-kit signaling; the acquired resistance of PC9/GR cells and the effects of c-kit siRNA and c-kit inhibitors on the growth and invasion of PC9/GR cells were investigated with CCK-8 assay, colony formation and cell invasion assays in vitro; the tumor growth inhibition effects of c-kit inhibitors on PC9/GR cell generated tumors were tested in vivo; the mechanisms involved in the acquired resistance reverse, growth and invasion inhibition effects of c-kit siRNA and c-kit inhibitors on PC9/GR cells were evaluated with qRT-PCR, Western blot and immunohistochemistry staining. The proliferation, colony formation, and invasion of PC9/GR cells were decreased by c-kit siRNA and inhibitors in vitro significantly; c-kit inhibitors suppressed the tumor growth of PC9/GR cell generated tumors in vivo. In the stable shRNA-c-kit transfected PC9/GR cells, the protein expressions of c-kit signaling and stemness phenotype related proteins, including ALDH1A1, Oct4, Sox2 and ABCG2 were decreased, and EMT phenotype related protein expressions including vimentin, N-cadherin, and Slug, were downregulated and with upregulation of E-cadherin; c-kit inhibitors reduced stemness phenotype related protein expressions, downregulated EMT phenotype related protein expressions including vimentin, N-cadherin, and Slug, with upregulation of E-cadherin, and the stemness related protein expressions of c-kit, ALDH1A1, ABCG2 and EMT-related proteins of vimentin and slug were decreased in the imatinib treated tumor tissues. The findings of this study indicated that c-kit signaling mediated the acquired gefitinib resistance, cell growth, invasion, stemness and EMT phenotype of PC9/GR cells. Targeting c-kit signaling with c-kit siRNA and small molecule c-kit inhibitors might overcome the acquired gefitinib resistance, and inhibit PC9/GR cell growth in vitro and in vivo.     

Gefitinib as neoadjuvant therapy for resectable stage II-IIIA non–small cell lung cancer: A phase II study

IntroductionCurrently, limited data on tyrosine kinase inhibitors as neoadjuvant therapy exist. This prospective study aimed to investigate the efficacy and safety of preoperative gefitinib in patients with stage II-IIIA operable non–small cell lung cancer (NSCLC).MethodsThis was a single-arm, phase II trial performed in the Shanghai Cancer Center. Between August 2013 and October 2015, patients with operable stage II-IIIA NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation were enrolled. Patients were treated with preoperative gefitinib (250 mg once daily for 42 days), followed by surgical resection. The primary endpoint was objective response rate (ORR); secondary endpoints were the rate of major pathologic response (MPR), disease-free survival (DFS), overall survival, and adverse events (AEs). ORR was defined as the proportion of patients achieving complete response or partial response radiologically. MPR was defined as no more than 10% viable tumor.ResultsOf the 35 eligible patients, 33 were considered as intention-to-treat population. ORR, the primary endpoint, was 54.5% (95% confidence interval [CI], 37.7-70.7), and the rate of MPR was 24.2% (95% CI, 11.9-40.4). Median DFS was 33.5 months (95% CI, 19.7-47.3); median overall survival was not reached. Skin toxicity (24/35,68.6%) and gastrointestinal symptoms (17/35,48.6%) were the most common AEs; no patients reported grade 3 or 4 AEs. After surgery, 4 patients experienced chylothorax (4/33,12.1%). Patients with MPR had a prolonged survival compared with those without (DFS, P = .019).ConclusionsNeoadjuvant therapy with gefitinib in patients with stage II-IIIA NSCLC is safe and may be a viable treatment for patients whose tumors have EGFR mutations. Patients with MPR were associated with improved survival.     

吉非替尼进展后再治疗在EGFR罕见突变非小细胞肺癌中的临床研究

目的 探讨表皮生长因子受体(EGFR)罕见突变非小细胞肺癌患者在吉非替尼治疗进展后,接受吉非替尼再治疗的疗效和安全性.方法 选择2011年1月至2015年12月的EGFR罕见突变基因的非小细胞肺癌患者,接受吉非替尼治疗和进展后再治疗.初次疗效评价采用RECIST 1.1版,分析指标为客观缓解率(RR)和第1次无进展生存时间(PFS-1);再治疗评价根据临床医师经验,分析指标为第2次无进展生存时间(PFS-2)和总生存时间(OS).毒性评价采用NCI-CTCAE 4.0版.采用Kaplan-Meier法对PFS-1、PFS-2和OS进行生存分析.结果 6例患者的初次疗效评价为部分缓解4例,稳定2例,RR达66.7％;中位PFS-1为10个月(95％CI:6.6～13.4);再治疗后的中位PFS-2为9个月(95％CI:6.9～11.1);中位OS为28个月(95％CI:10.4～45.6).最常见的治疗相关不良反应为1～2级的皮疹、腹泻、乏力、恶心呕吐和转氨酶增高.结论 本研究EGFR罕见突变肺癌患者在吉非替尼进展后再治疗中显示了较好的疗效和安全性.