EGFR突变与替莫唑胺联合IGRT大分割放射治疗非小细胞肺癌脑转移瘤疗效的相关性

摘要 目的：研究表皮生长因子受体（EGFR）突变对替莫唑胺联合图像引导大分割放射（IGRT）治疗非小细胞肺癌脑转移瘤临床疗效的影响。方法：选择2015年1月到2018年12月在我院接受治疗的非小细胞肺癌脑转移患者86例,根据是否出现EGFR突变分为对照组（EGFR未突变组）和研究组（EGFR突变组）,每组43人,两组患者均接受替莫唑胺联合IGRT大分割放射治疗。比较两组患者临床治疗疗效、不良反应发生情况、复发时间、生存时间和生活质量。结果：研究组患者临床治疗总有效率较对照组患者高（P<0.05）。研究组患者治疗后复发时间和生存时间均显著高于对照组患者（P<0.05）。两组患者治疗期间头痛、恶心、疲乏以及神经毒性等不良反应的发生情况比较无显著差异（P>0.05）。两组患者治疗前生活质量KarnofSky活动状态评分（KPS）和肺癌相关症状量表（LCSS评分）无显著差异（P>0.05）;治疗后,研究组患者KPS评分显著高于对照组（P<0.05）,而LCSS评分显著低于对照组患者（P<0.05）。结论：替莫唑胺联合IGRT大分割放射治疗EGFR突变的非小细胞肺癌脑转移瘤临床疗效更好,并且治疗后患者生活质量更优。     

吉非替尼联合PC化疗方案对表皮生长因子受体突变阳性晚期肺腺癌患者免疫功能、凋亡因子和肿瘤标志物的影响

摘要 目的：探讨吉非替尼联合铂类加环磷酰胺（PC）化疗方案对表皮生长因子受体（EGFR）突变阳性晚期肺腺癌患者免疫功能、凋亡因子和肿瘤标志物的影响。方法：选取南通大学附属肿瘤医院2018年3月~2020年3月期间收治的92例EGFR阳性晚期肺腺癌患者,根据随机数字表法分为对照组（PC化疗）和实验组（吉非替尼联合PC化疗）,各为46例。观察两组疗效、肿瘤标志物、免疫功能、凋亡因子变化情况、肿瘤无进展生存时间（PFS）、总生存时间（OS）和不良反应发生率。结果：实验组的客观缓解率、疾病控制率均高于对照组（P<0.05）。两组治疗后血清癌胚抗原（CEA）、细胞角蛋白-19片段（CYFRA21-1）、鳞状细胞癌抗原（SCC-Ag）水平较治疗前均下降,且实验组较对照组低（P<0.05）。治疗后两组CD8⁺升高,但实验组较对照组低;而治疗后CD3⁺、CD4⁺、CD4⁺/CD8⁺均下降,但实验组较对照组高（P<0.05）。两组治疗后血清Livin水平较治疗前下降,且实验组低于对照组（P<0.05）,两组治疗后血清PDCD5、P53、Bax水平较治疗前均升高,且实验组均高于对照组（P<0.05）。两组不良反应发生率组间对比无明显差异（P>0.05）。实验组的PFS、OS高于对照组（P<0.05）。结论：吉非替尼联合PC化疗方案治疗EGFR突变阳性晚期肺腺癌患者,可调节血清凋亡因子和肿瘤标志物水平,有效改善患者的免疫功能和预后。     

吉非替尼治疗EGFR突变型晚期肺腺癌的近期疗效、毒副反应及疗效的影响因素分析

摘要 目的：探讨吉非替尼治疗表皮生长因子受体（EGFR）突变型晚期肺腺癌的近期疗效、毒副反应及疗效的影响因素。方法：选取2018年4月~2019年6月期间我院收治的EGFR突变型晚期肺腺癌患者97例。所有患者均给予吉非替尼治疗,观察其近期疗效及毒副反应情况。采用单因素和多因素 Logistic回归分析疗效的影响因素。结果：97例患者全部如期完成治疗,近期疗效评价：完全缓解（CR）、部分缓解（PR）、病情稳定（SD）、病情进展（PD）率分别为9.28%（9/97）、24.74%（24/97）、31.96%（31/97）、34.02%（33/97）。根据近期疗效结果将患者分为有效组（CR+PR,n=33）和无效组（SD+PD,n=64）。本研究中患者的毒副反应多为 I、Ⅱ度非血液学毒性,最常见的是皮肤毒性,如皮疹等;其他毒副反应如胃部不适、腹泻等,经对症治疗后均能缓解。单因素分析结果显示,吉非替尼治疗EGFR突变型晚期肺腺癌的疗效与性别、肿瘤临床分期、骨转移、肿瘤直径有关（P<0.05）,而与年龄、肾上腺转移、脑转移、吸烟史无关（P>0.05）。多因素Logistic回归分析结果显示,性别为男性、肿瘤分期Ⅳ期是影响吉非替尼治疗EGFR突变型晚期肺腺癌疗效的危险因素（OR=1.473、2.042,P<0.05）。结论：吉非替尼治疗EGFR突变型晚期肺腺癌具有不错的近期疗效,不良反应较少,性别为男性、肿瘤分期Ⅳ期是影响吉非替尼治疗EGFR突变型晚期肺腺癌疗效的危险因素。     

基于在线数据库和真实世界样本探讨肺腺癌患者POLE/POLD1突变的临床意义

摘要 目的：POLE和POLD1突变导致DNA聚合酶校对功能丧失可能会影响基因组稳定性并导致突变增加和肿瘤形成。本文结合在线数据库和真实世界样本进一步分析肺腺癌（LUAD）患者POLE和/或 POLD1 突变的临床意义。方法：纳入2021年1月～2021年8月徐州医科大学附属医院肺癌术后组织标本115例,利用二代测序技术（NGS）检测基因突变;从癌症基因组图谱（TCGA）数据库收集肺腺癌数据集,通过Cbioportal在线数据库获得肿瘤突变分布图,通过Cibersort法计算获得样本的免疫相关细胞浸润情况。结果：真实世界样本中POLE/ POLD1突变的比例为7.83%（9/115）。TCGA数据显示POLE/POLD1突变的LUAD患者总生存期（OS）减少（P=0.0359）。然而,携带该突变的患者并发其他基因改变的频率明显增加,尤其是与TP53突变存在正相关;同时,POLE/POLD1突变与LUAD组织浸润性免疫杀伤细胞呈正相关,与免疫抑制细胞呈负相关,提示这部分患者对免疫检查点抑制剂（ICI）敏感。结论：LUAD患者POLE/POLD1突变预示较高的肿瘤突变负荷和免疫微环境改变,可作为ICI疗效预测的潜在生物标志物,值得临床关注。     

血清ProGRP、TSGF与EGFR突变阳性晚期非小细胞肺癌患者疗效和预后的关系

摘要 目的：探讨血清胃泌素前体释放肽（ProGRP）、肿瘤特异性生长因子（TSGF）与表皮生长因子受体（EGFR）突变阳性晚期非小细胞肺癌（NSCLC）患者疗效和预后的关系。方法：选取2017年1月～2020年1月在青岛市中医医院、青岛市红岛人民医院、青岛市交运老年病医院、青岛市胸科医院接受EGFR-酪氨酸激酶抑制剂治疗的EGFR突变阳性晚期NSCLC患者95例。所有患者根据疗效情况分为有效组和无效组,采用化学发光法和速率法检测有效组与无效组血清ProGRP、TSGF的差异。随访3年统计总生存率和中位生存时间,根据血清ProGRP（365.73±14.35）pg/mL、TSGF（147.88±27.59）U/mL均值将EGFR突变阳性晚期NSCLC患者分为高ProGRP组（≥365.73 pg/mL,41例）、高TSGF组（≥147.88 U/mL,46例）、低ProGRP组（＜365.73 pg/mL,54例）、低TSGF组（＜147.88 U/mL,49例）。Kaplan-Meier法绘制高/低血清ProGRP、TSGF水平EGFR突变阳性晚期NSCLC患者的生存曲线。并根据预后情况将EGFR突变阳性晚期NSCLC患者分为存活组（56例）、死亡组（39例）。单因素和多因素Cox回归分析影响EGFR突变阳性晚期NSCLC患者预后的因素,受试者工作特征（ROC）曲线分析血清ProGRP、TSGF水平对EGFR突变阳性晚期NSCLC患者预后的预测价值。结果：治疗6周后,无效组血清ProGRP、TSGF水平高于有效组（P＜0.05）。随访期间无失访病例,95例EGFR突变阳性晚期NSCLC患者的客观缓解率为70.53%（67/95）,3年总生存率为41.05%（39/95）,中位生存时间16.00个月。Kaplan-Meier曲线分析显示,高ProGRP组、高TSGF组总生存率和中位生存时间低于低ProGRP组、低TSGF组（P＜0.05）。单因素和多因素Cox回归分析显示,TNM分期Ⅳ期、低分化、ProGRP升高、TSGF升高为影响EGFR突变阳性晚期NSCLC患者预后的独立危险因素（P＜0.05）。ROC曲线分析显示,血清ProGRP、TSGF水平联合预测EGFR突变阳性晚期NSCLC患者死亡的曲线下面积为0.879,大于血清ProGRP、TSGF水平单独预测的0.765、0.773。结论：血清ProGRP、TSGF水平升高与EGFR突变阳性晚期NSCLC患者疗效和预后密切相关,血清ProGRP、TSGF水平联合检测对其有较高的预测价值。     

青海地区非小细胞肺癌患者PLR、NLR、SIRI、HSP90α预测EGFR基因突变的临床价值研究

摘要 目的：探讨青海地区非小细胞肺癌（NSCLC）患者血小板/淋巴细胞比值（PLR）、中性粒细胞/淋巴细胞比值（NLR）、系统性炎症反应指数（SIRI）、热休克蛋白90α（HSP90α）预测表皮生长因子受体（EGFR）基因突变的临床价值。方法：选择2020年3月至2023年3月青海大学附属医院收治的青海地区135例NSCLC且行EGFR基因检测的患者为研究对象,根据EGFR突变发生情况将患者分为EGFR突变型组（64例）与野生型组（71例）。检测PLR、NLR、SIRI、HSP90α。采用多因素Logistic回归分析EGFR基因突变的影响因素,受试者工作特征（ROC）曲线分析PLR、NLR、SIRI、HSP90α联合应用预测NSCLC患者发生EGFR基因突变的效能。结果：EGFR突变型组血浆HSP90α水平高于野生型组（P＜0.05）,PLR、NLR、SIRI低于野生型组（P＜0.05）。多因素Logistic回归分析显示,女性、腺癌、高HSP90α是NSCLC患者发生EGFR基因突变的危险因素（P＜0.05）,高PLR、NLR、SIRI是保护因素（P＜0.05）。PLR、NLR、SIRI、HSP90α预测NSCLC患者发生EGFR基因突变的曲线下面积为0.783、0.826、0.815、0.811,联合预测曲线下面积为0.932,高于单独预测。结论：青海地区EGFR基因突变的NSCLC患者PLR、NLR、SIRI降低,HSP90α增高。联合PLR、NLR、SIRI,HSP90α对EGFR基因突变的发生具有较高的预测价值。     

谷胱甘肽转移酶ω1基于酶活位点调控波形蛋白表达并促进肺腺癌恶性进展

摘要 目的：探究谷胱甘肽转移酶ω1（Glutathione S-Transferase Omega 1, GSTO1）关键酶活位点Cys32与肺腺癌恶性进展的关系与初步作用机制。方法：构建GSTO1野生型与酶活失活点突变C32A型过表达的肺腺癌细胞系,观察过表达细胞的形态变化及增殖能力的变化。以临床数据生物信息学分析探究GSTO1调控的促肿瘤蛋白,使用免疫印迹法验证该蛋白在GSTO1野生型与酶活失活点突变C32A型过表达的肺腺癌细胞系中的表达差异,并结合临床公共数据库分析该蛋白与患者预后的关联。结果：发现过表达野生型GSTO1能够引起肺腺癌细胞PC9的形态变化并促进PC9细胞增殖,而过表达C32A突变型GSTO1的PC9细胞与空载体组细胞形态及增殖能力相似;临床数据提示GSTO1与波形蛋白（Vimentin, VIM）表达呈现正相关,免疫印迹法显示野生型GSTO1过表达能够引起Vimentin蛋白表达上调,而C32A酶活失活点突变型GSTO1过表达无法引起Vimentin蛋白表达上调;通过临床样本数据观察GSTO1与Vimentin共同高表达的肺腺癌患者肿瘤恶性程度更高、发生转移的比例更大,同时无病生存期与总生存期更短。结论：GSTO1基于其酶活位点调控Vimentin表达,改变肺腺癌细胞形态并促进肺腺癌细胞增殖,研究结果为靶向GSTO1的肺腺癌治疗提供了新思路。     

EGFR在晚期肺腺癌患者中的表达及临床意义

目的探讨表皮生长因子受体(EGFR)在晚期肺腺癌患者中的表达及其意义。方法收集60例晚期肺腺癌患者的胸腔积液及活检肺癌组织,采用免疫组化检测EGFR的表达,并探讨其表达与临床病理特征的关系。结果 EGFR在胸腔积液及肺癌组织中的阳性表达率分别为75.0%(45/60)、63.3%(38/60),两者差异无统计学意义(P0.05)。结论 EGFR均高表达于肺腺癌胸腔积液及腺癌组织,且与年龄、性别、吸烟史、分化程度及肿瘤的大小无明显相关,可指导肺腺癌患者的靶向治疗。     

Smac调控Caspase-3对耐药肺腺癌细胞株生物活性及相关信号的研究

摘要 目的：探讨Smac基因调控Caspase-3表达对紫杉醇耐药肺腺癌细胞株生物活性及经典凋亡信号通路的作用机制。方法：取构建好的耐药A549细胞,将其分为A549细胞（LC）组、A549细胞+Smac-NC（SN）组、A549细胞+Smac抑制剂（SI）组、A549细胞+Smac激动剂（SM）组、A549细胞+Caspase-3-NC（CN）组、A549细胞+Caspase-3抑制剂（CI）组、A549细胞+Caspase-3激动剂（CM）组、A549细胞+Smac激动剂+Caspase-3激动剂（MM）组;Real-time PCR法检测正常肺上皮细胞及4种肺腺癌细胞系中Smac、Caspase-3表达水平,将阴性对照、Smac、Caspase-3类似物转染至紫杉醇耐药肺腺癌细胞株,MTT法检测细胞增殖,流式细胞仪检测细胞凋亡,免疫印迹法检测经典凋亡信号通路表达,并分析Smac与Caspase-3的相关性。结果：肺腺癌细胞系中的Smac、Caspase-3 mRNA表达量显著低于正常肺上皮细胞系BEAS-2B（P＜0.05）,其中A549的Smac、Caspase-3 mRNA值最小（P＜0.05）,因此选取其作为此次实验细胞;LC组与SN组相比,细胞增殖率、凋亡率及Caspase-3、Bcl-2、Bax、Cyto-C蛋白表达基本无差异（P＞0.05）,与SN组相比,SI组细胞凋亡率及Caspase-3、Bax、Cyto-C蛋白表达明显降低（P＜0.05）,增殖率、Bcl-2表达明显升高（P＜0.05）,与SI组相比,SM组细胞凋亡率及Caspase-3、Bax、Cyto-C蛋白表达明显升高（P＜0.05）,增殖率、Bcl-2表达明显降低（P＜0.05）;LC组与CN组相比,细胞增殖率、凋亡率及Caspase-3、Bcl-2、Bax、Cyto-C蛋白表达基本无差异（P＞0.05）,与CN组相比,CI组细胞凋亡率及Caspase-3、Bax、Cyto-C蛋白表达明显降低（P＜0.05）,增殖率、Bcl-2表达明显升高（P＜0.05）,与CI组相比,CM组细胞凋亡率及Caspase-3、Bax、Cyto-C蛋白表达明显升高（P＜0.05）,增殖率、Bcl-2表达明显降低（P＜0.05）;SM组与CM组相比,细胞增殖率、凋亡率及Caspase-3、Bcl-2、Bax、Cyto-C蛋白表达基本无差异（P＞0.05）,与CM组相比,MM组细胞凋亡率及Caspase-3、Bax、Cyto-C蛋白表达明显升高（P＜0.05）,增殖率、Bcl-2表达明显降低（P＜0.05）;Smac与Caspase-3呈现正相关（r=0.470,P=0.002）,组间具有显著差异。结论：Smac基因可显著改善紫杉醇耐药肺腺癌细胞株细胞生物活性,并激活经典凋亡信号通路,其作用机制可能与调控Caspase-3表达有关。     

肺鳞状细胞癌和腺癌PD-L1蛋白及相关miRNA表达差异的研究

摘要 目的：探讨肺鳞状细胞癌（鳞癌）和腺癌PD-L1蛋白及相关miRNA表达的差异。方法：2019年5月至2020年11月来我院就诊的非小细胞肺癌初治患者纳入本项研究；按照病理类型，将患者分为腺癌组和鳞癌组；H&E染色检测免疫细胞数量；免疫组化检测PD-L1、ki-67、PD-1、CTLA-4和LAG-3的表达；miRNA测序筛选鳞癌和腺癌间差异表达的miRNA。结果：H&E染色结果显示鳞癌组微环境中免疫细胞的数量为86.86±8.96个/高倍视野（HPF），腺癌组的数量为26.29±3.99个/HPF（t=6.173，P＜0.001）；肺鳞癌组微环境免疫细胞PD-1、CTLA-4和LAG-3阳性表达的比例分别为53.71±6.88%、35.29±3.25%和34.43±3.29%，腺癌组阳性表达的比例分别为22.29±3.80%、13.43±2.32%和24.00±1.98%（t=3.997，P=0.002；t=5.476，P＜0.001；t=2.719，P=0.019）；肺鳞癌组患者PD-L1蛋白阳性表达的比例为76.67%，腺癌组的比例为36.67%（P=0.001）；肺鳞癌PD-L1（miR-135、miR-24和miR-30b等）和PD-1（miR-802、miR-155和miR-3127-5p等）相关miRNA的表达均显著高于腺癌。结论：肺鳞癌PD-L1蛋白及相关miRNA的表达、微环境免疫细胞PD-1、CTLA-4和LAG-3阳性比例均显著高于腺癌。     

EGFR基因21外显子L858R突变肺腺癌患者化疗和靶向治疗疗效的对比研究

目的:研究化疗和靶向治疗对EGFR基因21外显子L858R突变肺腺癌患者的临床疗效和患者生存率的影响。方法:选择2012年1月~2016年1月在重庆市肿瘤医院治疗的95例EGFR基因21外显子L858R突变的肺腺癌患者,按患者治疗方式不同分为化疗组(n=54)和靶向组(n=41)。化疗组患者采用一线化疗药物进行治疗,靶向组患者采用EGFR基因靶向制剂进行治疗。在完成一个周期治疗后,比较两组患者的近期疗效及治疗过程中不良反应的发生情况。对患者进行为期1年的随访,比较其生存情况。结果:(1)化疗组患者治疗后临床总有效率为92.59%(50/54),靶向组总有效率为73.17%(30/41),化疗组显著高于靶向治疗组(P=0.010)。(2)化疗组不良反应发生率为25.93%(14/54),靶向治疗组则为19.51%(8/41),组间比较差异无统计学意义(P=0.463)。(3)在随访过程中,化疗组患者有18例死亡,36例存活,患者生存率为例66.67%;靶向组患者有24例死亡,17例存活,患者生存率为41.46%,化疗组生存率显著高于靶向治疗组(P=0.014)。结论:对于EGFR基因21外显子L858R突变肺腺癌患者而言,采用化疗治疗的疗效明显优于靶向治疗,且二者安全性相当,化疗治疗的患者预后较靶向治疗者更好。     

陕西省南部地区非小细胞肺癌EGFR基因突变分析

目的:探讨陕西南部非小细胞肺癌表皮生长因子受体基因的突变状况。方法:采用测序方法检测陕西省南部地区233例非小细胞肺癌(non-small cell lung cancer,NSCLCs)患者表皮生长因子受体(epithelial growth factor receptor,EGFR)基因第18、19、20和21号外显子突变情况,并分析其基因突变与肺癌人口学分布及组织类型的关系。结果:233例非小细胞肺癌患者中,共检出82例含有EGFR基因突变,其中第18、19、21号外显子突变率分别为1.3%、16.3%和18.0%,第20号外显子无突变;男性EGFR基因突变率(31.2%,39/125)低于女性(39.8%,43/108);腺癌EGFR基因突变率(39.1%,75/192)高于鳞癌(22%,9/41)。结论:陕西南部NSCLC的EGFR基因突变率较高,以第19、21号外显子突变为主。EGFR基因变率与NSCLC患者性别和病理类型均无关。     

The Relationship between TTF-1 Expression and EGFR Mutations in Lung Adenocarcinomas

Objective

To explore the relationship between TTF-1 and EGFR mutations in lung adenocarcinoma tissues to guide clinical treatment timely and effectively.

Materials and Methods

we collected 664 tissue samples from patients with histologically confirmed lung adenocarcinoma from May 2010 to April 2013. All tumor tissues were collected prior to administering therapy. TTF-1 was detected byimmunohistochemistry and EGFR mutations by DNA direct sequencing. Finally, the correlation between TTF-1 expression and the presence of EGFR mutations was analyzed using χ² test or Fisher’s exact test with SPSS software version 18.0.

Results

Of the 664 lung adenocarcinoma tissue samples, 18 were partially positive for TTF-1 (+−), and 636 were positive for TTF-1 (+) resulting in a total positive rate of 98.49% (+,+−)(including partial positive). In only 10 cases was the TTF-1 negative (−); the negative rate was 1.51%. There were 402 cases without an EGFR mutation and 262 cases with EGFR mutations; the rate of mutations was 39.46%. The location of the EGFR mutation was exon 19 for 121 cases resulting in a mutation rate in exon 19 of 18.22%. The location of the EGFR mutation was exon 21 for 141 cases resulting in a mutation rate in exon 21 of 21.23%. Exon 18 and 20 detected by DNA direct sequencing no mutations.A Fisher’s exact test was used to determine the correlation between EGFR mutations and TTF-1 expression.for the whole, TTF-1 positive expression(including partial positive) has correlation with EGFR mutations (p<0.001),especially for Exon 21 expression,the correlation is significant (p = 0.008).

Conclusion

In lung adenocarcinomas, positive and partial positive TTF-1 expression has a significant positive correlation with EGFR mutations(exon 19 and 21). In clinical practice, TTF-1 expression combine with EGFR mutations, especially exon 21 mutation can guide clinical treatment timely for lung adenocarcinomas.     

Detecting ALK,ROS1 and RET Fusion Genes in Cell Block Samples

Whether Cell block (CB) samples are applicable to detect anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and ret proto-oncogene (RET) fusion genes in lung adenocarcinoma is still unknown. In this study, 108 cytological samples that contained lung adenocarcinoma cells were collected, and made into CB. The CB samples all contained at least 30% lung adenocarcinoma cells. In these patients, 48 harbored EGFR mutation. Among the 50 EGFR wild type patients who detected fusion genes, 14 carried EML4-ALK fusion (28%), 2 had TPM3-ROS1 fusion (4%), and 3 harbored KIF5B-RET fusion (6%). No double fusions were found in one sample. Patients with fusion genes were younger than those without fusion genes (p = 0.032), but no significant difference was found in sex and smoking status (p > 0.05). In the thirty-five patients who received first-line chemotherapy, patients with fusion gene positive had disease control rate (DCR) (72.7% VS 50%, p > 0.05) and objective response rate (ORR) (9.1% VS 4.2%, p > 0.05) compared with those having fusion gene negative. The median progression free survival (mPFS) were 4.0 and 2.7 months in patients harbored fusion mutations and wild type, respectively (p > 0.05). We conclude that CB samples could be used to detect ALK, ROS1 and RET fusions in NSCLC. The frequency distribution of three fusion genes is higher in lung adenocarcinoma with wild-type EGFR, compared with unselected NSCLC patient population. Patients with fusion genes positive are younger than those with fusion gene negative, but they had no significantly different PFS in first-line chemotherapy.     

Molecular Epidemiology of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology – Mainland China Subset Analysis of the PIONEER study

Epidermal growth factor receptor (EGFR) mutations are the strongest response predictors to EGFR tyrosine kinase inhibitors (TKI) therapy, but knowledge of the EGFR mutation frequency on lung adenocarcinoma is still limited to retrospective studies. The PIONEER study (NCT01185314) is a prospective molecular epidemiology study in Asian patients with newly diagnosed advanced lung adenocarcinoma, aiming to prospectively analyze EGFR mutation status in IIIB/IV treatment-naïve lung adenocarcinomas in Asia. We report the mainland China subset results. Eligible patients (≥20 yrs old, IIIB/IV adenocarcinoma and treatment-naïve) were registered in 17 hospitals in mainland China. EGFR was tested for mutations by amplification refractory mutation system using biopsy samples. Demographic and clinical characteristics were collected for subgroup analyses. A total of 747 patients were registered. Successful EGFR mutation analysis was performed in 741, with an overall mutation rate of 50.2%. The EGFR active mutation rate is 48.0% (with 1.3% of combined active and resistance mutations). Tobacco use (>30 pack-year vs. 0–10 pack-year, OR 0.27, 95%CI: 0.17–0.42) and regional lymph nodes involvement (N3 vs. N0, OR 0.47, 95%CI: 0.29–0.76) were independent predictors of EGFR mutation in multivariate analysis. However, even in regular smokers, the EGFR mutation frequency was 35.3%. The EGFR mutation frequency was similar between diverse biopsy sites and techniques. The overall EGFR mutation frequency of the mainland China subset was 50.2%, independently associated with the intensity of tobacco use and regional lymph nodes involvement. The relatively high frequency of EGFR mutations in the mainland China subset suggest that any effort to obtain tissue sample for EGFR mutation testing should be encouraged.     

TP53 mutations in circulating tumor DNA in advanced epidermal growth factor receptor-mutant lung adenocarcinoma patients treated with gefitinib

Tumor protein p53 (TP53) is a tumor suppressor gene and TP53 mutations are associated with poor prognosis in non-small cell lung cancer. However, the in-depth classification of TP53 and its relationship with treatment response and prognosis in epidermal growth factor receptor (EGFR)-mutant tumors treated with EGFR tyrosine kinase inhibitors are unclear. Circulating tumor DNA was prospectively collected at baseline in advanced treatment-naïve EGFR-mutant lung adenocarcinoma patients treated with gefitinib in an open-label, single-arm, prospective, multicenter, phase 2 clinical trial (BENEFIT trial) and analyzed using next-generation sequencing. Survival was estimated using the Kaplan–Meier method. Of the 180 enrolled patients, 115 (63.9%) harbored TP53 mutations. The median progression-free survival (PFS) and overall survival (OS) of patients with TP53-wild type tumors were significantly longer than those of patients with TP53-mutant tumors. Mutations in exons 5–8 accounted for 80.9% of TP53 mutations. Mutations in TP53 exons 6 and 7 were significantly associated with inferior PFS and OS compared to wild-type TP53. TP53 mutation also influenced the prognosis of patients with different EGFR mutations. Patients with TP53 and EGFR exon 19 mutations had significantly longer PFS and OS than patients with TP53 and EGFR L858R mutations, and both groups had worse survival than patients with only EGFR mutations. Patients with TP53 mutations, especially in exons 6 and 7, had a lower response rate and shorter PFS and OS when treated with gefitinib. Moreover, TP53 exon 5 mutation divided TP53 mutations in disruptive and non-disruptive types.     

Epidermal Growth Factor Receptor Exon 20 Mutation Increased inPost-Chemotherapy Patients with Non-Small Cell Lung Cancer Detected with Patients' Blood Samples

PURPOSE: Patients with non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR)-mutations have excellent response to EGFR tyrosine kinase inhibitors (TKIs), and exon 20 mutation accounts for most of TKI drug resistance. Nested polymerase chain reaction (PCR) was used to detect EGFR exon 20 mutations of patients with NSCLC after chemotherapy. The same is being analyzed with patients' characteristics. METHODS: Peripheral blood samples were collected from 273 patients with NSCLC, including 143 with adenocarcinoma (ADC) and 130 with squamous cell carcinoma (SCC), after chemotherapy. DNA was extracted from whole blood for nested PCR amplification and purification. Sequencing was carried out in an automated 3730 sequencer, followed by analysis of EGFR exon 20 mutations from nested PCR products. RESULTS: The mutations of EGFR exon 20 were mainly point mutations in rs1050171 (c.2361A>G) and rs56183713 (c.2457G>A). The point mutation was 28.21%, 28.46%, and 27.97% in patients with NSCLC, ADC and SCC, respectively. Men had an equivalent mutation (27.18%) to women (30.77%). The mutation in smokers and nonsmokers was 27.68% and 29.17%, respectively. In unselected patients, there was no correlation between EGFR exon 20 mutations and patients' characteristics of age, gender, smoking history, histologic type, or tumor-node-metastasis (TNM) staging system. In subgroup analyses, the EGFR mutation of patients with SCC was correlated with TNM stage [P = .013; odds ratio = 1.758; 95% confidence interval (CI) = 1.125-2.747]. CONCLUSIONS: The data indicate that the chemotherapy may induce EGFR-TKI-resistant mutation in NSCLC cells and EGFR-TKI should be used in the early stage of NSCLC but not after chemotherapy.     

AD-MPE与TPE患者血常规参数变化及其诊断价值

目的:比较结核性胸腔积液(tuberculous pleural effusion, TPE)和肺腺癌性胸腔积液(malignant pleural effusion associated with lung adenocarcinoma, AD-MPE)血常规参数及相关炎症指标的比值,探讨单项指标或联合分析的鉴别诊断价值。方法:对临床确诊的100例AD-MPE患者和84例TPE患者的血常规参数进行分析,比较各指标在两组疾病中的差异,并用ROC曲线分析以确定单项指标以及联合分析的鉴别诊断性能。结果:AD-MPE组的白细胞数(WBC)、中性粒细胞绝对值(NEUT)、淋巴细胞数(LYMPH)、淋巴细胞/单核细胞比值(LMR)、平均血小板体积(MPV)、大血小板比率(P-LCR)和血小板分布宽度(PDW)水平高于TPE组(P<0.05),TPE组的单核细胞百分比(MONO%)、血小板/淋巴细胞比值(PLR)、血小板数(PLT)和血小板比积(PCT)水平均高于AD-MPE组(P<0.05);ROC曲线分析显示WBC、MONO%和PLR相比较其它单项指标,具有较好的鉴别诊断价值(AUC>0.7)并且三者联合有最高的鉴别诊断价值(Youden Index>0.5,AUC>0.7)。结论:AD-MPE和TPE在炎症反应和凝血功能方面有不同程度的变化,血常规参数分析对TPE和AD-MPE中具有一定的鉴别诊断价值,尤其是WBC、MONO%和PLR的联合分析。