联合应用临床指标和分子标记物指导非小细胞肺癌术后放疗
发布时间：2017-12-31 00:40
本文关键词：联合应用临床指标和分子标记物指导非小细胞肺癌术后放疗 出处：《天津医科大学》2015年硕士论文 论文类型：学位论文
【摘要】：目的本研究旨在分析淋巴结阳性率(lymph node ratio,LNR)、淋巴链阳性率(nodal chain ratio,NCR)、最新的淋巴结分区方法以及远处转移相关分子标记物对pIIIa-N2期非小细胞肺癌术后放射治疗的指导作用。方法回顾性分析2008年1月至2009年12月在天津医科大学肿瘤医院行手术治疗的肺癌患者。接受完全切除和系统淋巴结清扫的患者被纳入本研究。为排除远处转移,所有的患者在手术前均接受PET-CT或胸部CT、腹部CT或腹部B超、颅脑MRI和全身骨扫描。患者术前均接受了纤维支气管镜检查以明确术前诊断,部分患者接受术前纵隔镜检查以明确纵隔淋巴结转移情况。纳入标准包括无术前化疗或放射治疗,一般状况评分(ECOG评分)为0或1,术前签署知情同意书,进行肺内肿物完全切除及系统淋巴结清扫且术后病理证实为完全切除,术后病理证实为非小细胞肺癌,病理分期为pⅢa-N2。排除标准包括术前进行化疗或放射治疗,术后病理证实为小细胞肺癌,术后病理证实肺内肿物未达到完全切除标准,淋巴结清扫信息不明确,术后病理分期为p N0期、p N1期或p N3期,除肺癌外还患有其他恶性肿瘤,术后发生重度感染,手术时患有严重的心脏、肝脏、肾脏及精神疾病,术中使用抗肿瘤药物治疗。在对所随访的病人按照淋巴结阳性率、淋巴结阳性率或淋巴结区情况进行分组后,利用Kaplan-Meier法进行生存分析并用Log-rank法比较组间总生存率(overall survival,OS)和无病生存率(disease-free survival,DFS)的差异,采用逐步向前的Cox比例风险回归模型对生存进行多因素分析。同时,根据远处转移时间(1年或3年)将病人分为两组。利用倾向评分法对病人进行配对分析,收集配对后病人的冰冻新鲜肿瘤组织进行全基因表达谱芯片检测。最后进行聚类分析、基因本体论(Gene Ontology,GO)分析和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)通路分析。结果到随访结束共有218例p IIIa-N2期非小细胞肺癌患者被纳入本研究中。1.符合纳入标准的患者共208例。5年总生存率为29.3%,而中位总生存期为30.7个月;患者的5年无病生存率为22.0%,而中位无病生存期为14.2个月。LNR和NCR的中位值分别为0.31和0.45。根据LNR和NCR中位值将病人分为A组(NCR≤0.45且LNR≤0.31,共91例)、B组(NCR≤0.45且LNR0.31,或NCR0.45或LNR≤0.31,共51例)和C组(NCR0.45且LNR0.31,共66例)。A组、B组和C组的5年OS分别为43.7%、25.2%和12.3%(p0.0001),5年DFS分别为30.4%、23.3%和8.6%(p0.0001)。多因素分析结果表明这种分组方法是影响患者预后的独立因素。对于C组患者而言,未接受术后治疗、仅接受术后化疗和接受术后序贯化放疗的患者的5年OS分别为0.0%、11.6%和37.5%(p=0.003),5年DFS分别为0.0%、7.5%和25.0%(p=0.009)。2.根据病人是否发生肺门区淋巴结转移求出病人的倾向评分,并根据倾向评分的大小对患者进行配对分析。根据是否有肺门区淋巴结发生转移以及发生淋巴结转移的p N2区的多少,可将NSCLC分为p H0N2a(无肺门区淋巴结转移但有单个p N2区发生淋巴结转移)、p H1N2a(同时有肺门区淋巴结转移和单个p N2区淋巴结转移)、p H0N2b(无肺门区淋巴结转移但有多个p N2区发生淋巴结转移)和p H1N2b(同时有肺门区淋巴结转移和多个p N2区淋巴结转移)。患者匹配前后的5年OS分别为28.9%和30.5%,而匹配前后的中位总生存期分别为30.7个月和32.6个月;患者匹配前后的5年DFS分别为21.5%和16.8%,而匹配前后的中位无病生存期为14.3个月和14.0个月。匹配前,p H0N2a期、p H1N2a期、p H0N2b期和p H1N2b期NSCLC的5年OS分别为38.4%、32.8%、35.6%和10.3%,5年DFS分别为28.8%、22.0%、30.4%和6.5%。匹配后,p H0N2a期、p H1N2a期、p H0N2b期和p H1N2b期NSCLC的5年OS分别为37.8%、31.0%、37.5%和7.1%,5年DFS分别为27.1%、20.2%、31.8%和4.6%。多因素分析结果发现联合应用肺门区淋巴结转移和p N2区淋巴结转移分组是影响p IIIa-N2患者预后的独立因素。配对分析后,对于p H1N2b期NSCLC患者而言,未接受辅助治疗、仅接受化疗和接受辅助化放疗的5年OS分别为0.0%、0.0%和33.3%(p0.0001),而5年DFS分别为0.0%、0.0%和16.7%(p0.0001)。3.根据远处转移时间(1年或3年)的长短,到随访结束,共有95例患者被纳入本研究中。其中,有51(53.7%)例在1年内发生远处转移,有44(46.3%)例3年内未发生远处转移。倾向评分法后两组病人分别为32(50.0%)例和32(50.0%)例。本研究使用了共15419个基因探针对样本进行检测。结果共检测出1937个基因表达上调。在表达上调的基因中,表达差异倍数变化(foldchange,FC)大小在2-3、3-10、10-20、20-100或100范围内的基因的数目分别为1306、841、48、10和2。如果按FDR大小分类,那么FDR0.01、0.01-0.05或≥0.05的基因数目分别为178、457和1302。同样地,为检测表达下调的基因,本研究共使用15277个基因探针。结果共检测出2722个基因出现表达的下调。如果按FC大小分类,FC在2-3、3-10、10-20、20-100或100范围内的基因的数目分别为1536、1017、94、90和35。如果按错误发生率(false discovery rate,FDR)大小分类,那么FDR0.01、0.01-0.05或≥0.05的基因数目分别为581、870和1271。经过分析,p53相关信号转导通路和细胞周期相关通路所对应区域的基因表达差异性最大。表达上调的基因中,RFWD2、STEAP3和GADD45G的FC值分别为4.7714417、4.0083716和3.3749906,FDR分别为0.001114899、0.012841317和0.002412821。表达下调的基因中,CCNB3、CDK1、ORC6、TTK和BUB1B的FC值分别为3.1506035、4.3426501、4.7398555、5.0118984和5.6042476,FDR分别为0.007884298、0.000350073、0.002653766、0.009627135和0.009627135。结论1.联合应用NCR和LNR的分类方法是影响p IIIa-N2期NSCLC患者5年OS和5年DFS的独立预后因素。术后放疗能够明显提高LNR0.31且NCR0.45患者的预后。2.肺门区淋巴结转移状态明显影响p N2b期NSCLC患者的预后。倾向评分法配对分析发现术后化放疗能够明显提高p H1N2b期NSCLC患者的预后。3.RFWD2、STEAP3和GADD45G基因的上调以及CCNB3、CDK1、ORC6、TTK和BUB1B基因的下调可能与非小细胞肺癌组间不同的术后远处转移时间相关。
[Abstract]:The purpose of this study was to analyze the lymph node positive rate (lymph node, ratio, LNR), the positive rate of lymph node chain (nodal chain ratio, NCR), the latest lymph node classification methods and distant metastasis molecular markers for stage pIIIa-N2 non direct effects of radiation therapy of small cell lung cancer after surgery. Methods from January 2008 to December 2009 in the Cancer Hospital of Medical University Of Tianjin underwent surgical treatment in patients with lung cancer underwent complete resection. Review and systematic lymph node dissection patients were enrolled in this study. In order to exclude the transfer distance, all the patients were treated with PET-CT or CT in chest surgery, abdominal CT or abdominal ultrasound, brain MRI and bone scan. The patients were accepted fiberoptic bronchoscopy examination to confirm the diagnosis before surgery, patients received preoperative mediastinoscopy to clear mediastinal lymph node metastasis. The inclusion criteria include no preoperative chemotherapy or radiation therapy, The general condition score (ECOG score) was 0 or 1, signed informed consent before the operation of the lung tumor complete resection and systematic lymph node dissection and postoperative pathology were completely resected, pathologically confirmed non-small cell lung cancer, pathological stage P III a-N2. exclusion criteria included preoperative chemotherapy or radiotherapy, postoperative pathology confirmed non-small cell lung cancer, postoperative pathology confirmed pulmonary mass did not reach the standard of complete resection, lymph node dissection information is not clear, the postoperative pathological stage was p N0, P N1 or P N3, except for lung cancer with other malignant tumors, the occurrence of severe infection after operation, with surgery serious heart, liver, kidney and mental illness, the use of antitumor drug therapy. In the follow-up of patients with lymph node positive rate, the positive rate of lymph node or lymph nodes were grouped, survival analysis was performed using Kaplan-Meier method The total survival rate between groups were compared by Log-rank (overall survival OS) and disease-free survival (disease-free, survival, DFS) the difference, using forward stepwise Cox proportional hazards regression model for multivariate survival analysis. At the same time, according to the time of distant metastasis (1 years or 3 years) were divided into two group. Using the propensity score method of paired analysis of patients collected paired patients after fresh frozen tumor tissue microarray detection of gene expression. Finally, cluster analysis, Gene Ontology (Gene Ontology, GO) and the Kyoto Encyclopedia of genes and genomes analysis (Kyoto Encyclopedia of genes and genomes, KEGG). The results of path analysis to the end of follow-up there were small cell lung cancer patients were enrolled in the study in.1. met the inclusion criteria of patients with a total of 208 cases of.5 years total survival rate was 29.3% in 218 patients with P stage IIIa-N2, and median overall survival was 30.7 months; 鎮ｈ，
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