【作者】 李岩；

【导师】 王长利； 宫立群； 战忠利；

【作者基本信息】 天津医科大学 ， 肿瘤学， 2008， 硕士

【摘要】 目的:研究探讨Ⅲa期非小细胞肺癌(NSCLC)患者原始肿瘤转移性淋巴结组织内ERCC1、HMGB1、Bcl-2/Bax和Caspase-3蛋白的表达与以铂类药物为基础的三代化疗药物联合化疗的标准化疗方案的化疗敏感性的关系及预后影响因素分析。方法:收集2004年1月1日至2007年12月31日在天津医科大学附属肿瘤医院肺部肿瘤科住院行纵隔镜手术确诊,临床资料及随访资料完整的Ⅲa期NSCLC患者,入组标准为:①行纵隔镜手术前排除全身远处转移、②经讨论可手术切除者、③行纵隔镜手术前从未经过任何放化疗者共计85例,其中存档石蜡标本中符合实验条件的共有80例。入组患者确诊后行以铂类为基础的第三代化疗药物联合化疗的标准化疗方案化疗2～3周期,末次化疗2～3周后复查CT,影像学缓解者RR(CR:16例+PR:19例):35例(43.75%),SD:17例(21.25%),PD:28例(35.00%),影响学缓解者(RR)35例和估计可完全切除的SD中的14例共计49例患者均于末次化疗后3～4周行手术根治治疗:肺叶切除术+淋巴结清扫术:36例(73.47%);全肺切除术+淋巴结清扫术:8例(16.33%);姑息性局部切除术:5例(10.20%);其中支气管残端阳性者9例(18.37%)。所有术后病理类型报告与纵隔镜手术病理相同(其中鳞癌:38例,腺癌:42例)。术后再次进行TNM分期:Ⅲa期:39例,Ⅱb期:10例,按照术后组织病理缓解标准原纵隔镜所取区域淋巴结(N病理缓解):CR:10例,PR:23例,SD:16例。我们按组织病理缓解标准将CR+PR归入有效组(RR):33例,SD+PD(其中包括未手术的影响学SD和PD)归入无效组:47例。并进行临床资料进行分析,采用免疫组织化学ElivisionTM两步法检测80例由纵隔镜所取转移淋巴结有完整蜡块标本中ERCC1、HMGB1、Bcl-2/Bax和Caspase-3蛋白的表达状况,进一步行这5种蛋白表达水平与Ⅲa期NSCLC以铂类为基础的三代化疗药物联合化疗标准化疗方案化疗敏感性的关系及预后影响因素分析研究。结果:1、临床资料分析结果80例Ⅲa期NSCLC总体1年、2年、3年生存率分别为74.10%、62.20%和45.50%。Log-Rank单因素分析显示影响患者预后的因素为支气管断端是否阳性、原始T分期、影像类型、术后N分期、N病理缓解和是否手术切除等因素对患者预后的影响有统计学意义(P＜0.05);而病理类型、年龄大于或小于60岁、性别、吸烟史、影像类型、术后辅助化疗、生物治疗等因素对患者预后的影响无统计学意义(P＞0.05)。Cox回归多因素分析显示:是否手术切除、N病理缓解、残端阳性是Ⅲa期NSCLC患者独立的预后因素。2、ERCC1、HMGB1、Bcl-2/Bax和Caspase-3的蛋白表达水平与化疗有效率的关系本组患者中,ERCC1染色阳性42例(52.50%)、HMGB1染色阳性48例(60.00%)、Bcl-2染色阳性18例(22.50%)、Bax染色阳性44例(55.00%)、Caspase-3染色阳性35例(43.75%)。全组化疗总体病理缓解率RR为41.25%;单一蛋白表达显示:ERCC1、Bcl-2阴性表达者化疗有效率明显高于阳性者(P＜0.05),HMGB1、Caspase-3阳性表达者化疗有效率明显高于阴性者(P＜0.05);而Bax蛋白表达与化疗有效率未见相关性(P＞0.05)。蛋白联合表达显示:ERCC1和Bcl-2两种蛋白表达均阴性者化疗有效率显著高于均阳性者(P＜0.05)。HMGB1、Caspase-3两种蛋白表达均阳性者化疗有效率显著高于均阴性者(P＜0.05)。ERCC1(-)/HMGB1(+)者化疗有效率显著高于ERCC1(+)/HMGB1(-)者(P＜0.05)。3、ERCC1、HMGB1、Bcl-2/Bax和Caspase-3的蛋白表达水平与Ⅲa期NSCLC预后的关系Log-rank单因素分析显示ERCC1、HMGB1、Bcl-2、Caspase-3蛋白表达水平与Ⅲa期NSCLC预后相关,并具有统计学意义(P＜0.05)。而Bax蛋白表达水平与Ⅲa期NSCLC预后未见相关性(P＞0.05)。COX多因素回归分析示ERCC1、HMGB1与Caspase-3蛋白表达是影响Ⅲa期NSCLC患者预后的独立因素。结论:1、是否能手术切除、N病理缓解、残端阳性是Ⅲa期NSCLC患者临床上独立的预后因素。2、ERCC1、HMGB1、Bcl-2、Caspase-3蛋白的表达水平是影响标准化疗方案中铂类药物敏感性差别的重要因素,本研究可为临床Ⅲa期NSCLC患者提供个体化疗方案。ERCC1、HMGB1和Caspase-3蛋白的表达水平是Ⅲa期NSCLC患者独立的预后因素。更多还原

【Abstract】 Objective:To research the expression of ERCC1,HNGB1,Bcl-2/Bax, Caspase-3 in patients withⅢa stage non-small cell lung carcinoma(NSCLC)as well as their correlation with platinum-based chemotherapy sensitivity and clinical prognostic significance.Method:Clinic data of 85 inpatient cases in The Cancer Hospital of Tianjin Medical University,whose final diagnosis were conformed by Mediastinoscopy,from 2004-2008,were retrospectively reviewed.Expression of ERCC1、HMGB1、Bcl-2/Bax、caspase-3 of 80 cases that were surgically resected by Mediastinoscopy NSCLC specimens(including 38 Squamous carcinomas and 42 Adenocarcinomas) were studied by immunohistochemistry.The value of the five factors’ statistics analysis of the platinum-based chemotherapy sensitivity and clinical prognosis ofⅢa stage NSCLC were studied.Result:1.Results of clinical datasThe overall 1,2 and 3-year survival rates were 74.10%,62.20%and 45.50% respectively.Univariate analysis showed the main prognostic factors were primary tumor diameter,bronchial stump,post-surgery N stage,N patho-relieve,surgery and imaging category(P＜0.05).Cox regression analysis suggested that surgery,N patho-relieve and bronchial stump were the most important significant independent prognostic factor.2.The expression of ERCC1,HMGB1,Bcl-2/Bax and Caspase-3 and the correlation with platinum-based chemotherapy sensitivity inⅢa stage NSCLC.The positive rate of ERCC1,HMGB1,Bcl-2/Bax and Caspase-3 were 52.50%, 60.00%,22.50%,55.00%and 43.75%respectively in the 80 cases.The totol patho-relieve (RR)was 41.25%.The study on the expression of ERCC1,HNGB1, Bcl-2/Bax,Caspase-3 and chemotherapeutic response showed:the negative expression of ERCC1 and Bcl-2 have a significantly better patho-relieve than positive expression and the positive expression of HMGB1,Caspase-3 have a significantly better patho-relieve than negative expression.However,between the expression of Bax and patho-relieve have no significantly different.The study on the relationship between combined detection of every two proteins and chemotherapeutic response showed:the cases of ERCC1(-)/Bcl-2(-)have a significantly better patho-relieve than ERCC1(+)/Bcl-2(+),the cases of HMGB1(+)/Caspase-3(+)have a significantly better patho-relieve than the cases of HMGB1(-)/Caspase-3(-)and the cases HMGB1(+)/ERCC1(-)have a significantly better patho-relieve than the cases of HMGB1(-)/ERCC1(+).3.The expression of ERCC1,HMGB1,Bcl-2/Bax and Caspase-3 and the correlation with the prognosis inⅢa stage NSCLC.Log-rank mon-factor analysis showed that the expression of ERCC1,HMGB1, Bcl-2 and Caspase-3 have significantly correlation with the prognosis inⅢa stage NSCLC.COX multivariate regression analysis showed that the expression of ERCC1, HMGB1 and Caspase-3 were independent prognostic factors forⅢa stage NSCLC.Conclusion:1.surgery,N patho-relieve and bronchial stump were the most important significantly independent clinical prognostic factor inⅢa stage NSCLC.2. The expression of ERCC1,HNGB1,Bcl-2 and Caspase-3 were significantly independent factors with platinum-based chemotherapy sensitivity inⅢa stage NSCLC.The expression of ERCC1,HNGB1 and Caspase-3 were the most important significantly independent prognostic factors inⅢa stage NSCLC更多还原