本文關(guān)鍵詞：聯(lián)合應(yīng)用臨床指標(biāo)和分子標(biāo)記物指導(dǎo)非小細(xì)胞肺癌術(shù)后放療　出處：《天津醫(yī)科大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 淋巴結(jié) 非小細(xì)胞肺癌 放射治療 預(yù)后 基因

【摘要】：目的本研究旨在分析淋巴結(jié)陽性率(lymph node ratio,LNR)、淋巴鏈陽性率(nodal chain ratio,NCR)、最新的淋巴結(jié)分區(qū)方法以及遠(yuǎn)處轉(zhuǎn)移相關(guān)分子標(biāo)記物對pIIIa-N2期非小細(xì)胞肺癌術(shù)后放射治療的指導(dǎo)作用。方法回顧性分析2008年1月至2009年12月在天津醫(yī)科大學(xué)腫瘤醫(yī)院行手術(shù)治療的肺癌患者。接受完全切除和系統(tǒng)淋巴結(jié)清掃的患者被納入本研究。為排除遠(yuǎn)處轉(zhuǎn)移,所有的患者在手術(shù)前均接受PET-CT或胸部CT、腹部CT或腹部B超、顱腦MRI和全身骨掃描。患者術(shù)前均接受了纖維支氣管鏡檢查以明確術(shù)前診斷,部分患者接受術(shù)前縱隔鏡檢查以明確縱隔淋巴結(jié)轉(zhuǎn)移情況。納入標(biāo)準(zhǔn)包括無術(shù)前化療或放射治療,一般狀況評分(ECOG評分)為0或1,術(shù)前簽署知情同意書,進(jìn)行肺內(nèi)腫物完全切除及系統(tǒng)淋巴結(jié)清掃且術(shù)后病理證實(shí)為完全切除,術(shù)后病理證實(shí)為非小細(xì)胞肺癌,病理分期為pⅢa-N2。排除標(biāo)準(zhǔn)包括術(shù)前進(jìn)行化療或放射治療,術(shù)后病理證實(shí)為小細(xì)胞肺癌,術(shù)后病理證實(shí)肺內(nèi)腫物未達(dá)到完全切除標(biāo)準(zhǔn),淋巴結(jié)清掃信息不明確,術(shù)后病理分期為p N0期、p N1期或p N3期,除肺癌外還患有其他惡性腫瘤,術(shù)后發(fā)生重度感染,手術(shù)時(shí)患有嚴(yán)重的心臟、肝臟、腎臟及精神疾病,術(shù)中使用抗腫瘤藥物治療。在對所隨訪的病人按照淋巴結(jié)陽性率、淋巴結(jié)陽性率或淋巴結(jié)區(qū)情況進(jìn)行分組后,利用Kaplan-Meier法進(jìn)行生存分析并用Log-rank法比較組間總生存率(overall survival,OS)和無病生存率(disease-free survival,DFS)的差異,采用逐步向前的Cox比例風(fēng)險(xiǎn)回歸模型對生存進(jìn)行多因素分析。同時(shí),根據(jù)遠(yuǎn)處轉(zhuǎn)移時(shí)間(1年或3年)將病人分為兩組。利用傾向評分法對病人進(jìn)行配對分析,收集配對后病人的冰凍新鮮腫瘤組織進(jìn)行全基因表達(dá)譜芯片檢測。最后進(jìn)行聚類分析、基因本體論(Gene Ontology,GO)分析和京都基因與基因組百科全書(Kyoto encyclopedia of genes and genomes,KEGG)通路分析。結(jié)果到隨訪結(jié)束共有218例p IIIa-N2期非小細(xì)胞肺癌患者被納入本研究中。1.符合納入標(biāo)準(zhǔn)的患者共208例。5年總生存率為29.3%,而中位總生存期為30.7個(gè)月;患者的5年無病生存率為22.0%,而中位無病生存期為14.2個(gè)月。LNR和NCR的中位值分別為0.31和0.45。根據(jù)LNR和NCR中位值將病人分為A組(NCR≤0.45且LNR≤0.31,共91例)、B組(NCR≤0.45且LNR0.31,或NCR0.45或LNR≤0.31,共51例)和C組(NCR0.45且LNR0.31,共66例)。A組、B組和C組的5年OS分別為43.7%、25.2%和12.3%(p0.0001),5年DFS分別為30.4%、23.3%和8.6%(p0.0001)。多因素分析結(jié)果表明這種分組方法是影響患者預(yù)后的獨(dú)立因素。對于C組患者而言,未接受術(shù)后治療、僅接受術(shù)后化療和接受術(shù)后序貫化放療的患者的5年OS分別為0.0%、11.6%和37.5%(p=0.003),5年DFS分別為0.0%、7.5%和25.0%(p=0.009)。2.根據(jù)病人是否發(fā)生肺門區(qū)淋巴結(jié)轉(zhuǎn)移求出病人的傾向評分,并根據(jù)傾向評分的大小對患者進(jìn)行配對分析。根據(jù)是否有肺門區(qū)淋巴結(jié)發(fā)生轉(zhuǎn)移以及發(fā)生淋巴結(jié)轉(zhuǎn)移的p N2區(qū)的多少,可將NSCLC分為p H0N2a(無肺門區(qū)淋巴結(jié)轉(zhuǎn)移但有單個(gè)p N2區(qū)發(fā)生淋巴結(jié)轉(zhuǎn)移)、p H1N2a(同時(shí)有肺門區(qū)淋巴結(jié)轉(zhuǎn)移和單個(gè)p N2區(qū)淋巴結(jié)轉(zhuǎn)移)、p H0N2b(無肺門區(qū)淋巴結(jié)轉(zhuǎn)移但有多個(gè)p N2區(qū)發(fā)生淋巴結(jié)轉(zhuǎn)移)和p H1N2b(同時(shí)有肺門區(qū)淋巴結(jié)轉(zhuǎn)移和多個(gè)p N2區(qū)淋巴結(jié)轉(zhuǎn)移)。患者匹配前后的5年OS分別為28.9%和30.5%,而匹配前后的中位總生存期分別為30.7個(gè)月和32.6個(gè)月;患者匹配前后的5年DFS分別為21.5%和16.8%,而匹配前后的中位無病生存期為14.3個(gè)月和14.0個(gè)月。匹配前,p H0N2a期、p H1N2a期、p H0N2b期和p H1N2b期NSCLC的5年OS分別為38.4%、32.8%、35.6%和10.3%,5年DFS分別為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分別為37.8%、31.0%、37.5%和7.1%,5年DFS分別為27.1%、20.2%、31.8%和4.6%。多因素分析結(jié)果發(fā)現(xiàn)聯(lián)合應(yīng)用肺門區(qū)淋巴結(jié)轉(zhuǎn)移和p N2區(qū)淋巴結(jié)轉(zhuǎn)移分組是影響p IIIa-N2患者預(yù)后的獨(dú)立因素。配對分析后,對于p H1N2b期NSCLC患者而言,未接受輔助治療、僅接受化療和接受輔助化放療的5年OS分別為0.0%、0.0%和33.3%(p0.0001),而5年DFS分別為0.0%、0.0%和16.7%(p0.0001)。3.根據(jù)遠(yuǎn)處轉(zhuǎn)移時(shí)間(1年或3年)的長短,到隨訪結(jié)束,共有95例患者被納入本研究中。其中,有51(53.7%)例在1年內(nèi)發(fā)生遠(yuǎn)處轉(zhuǎn)移,有44(46.3%)例3年內(nèi)未發(fā)生遠(yuǎn)處轉(zhuǎn)移。傾向評分法后兩組病人分別為32(50.0%)例和32(50.0%)例。本研究使用了共15419個(gè)基因探針對樣本進(jìn)行檢測。結(jié)果共檢測出1937個(gè)基因表達(dá)上調(diào)。在表達(dá)上調(diào)的基因中,表達(dá)差異倍數(shù)變化(foldchange,FC)大小在2-3、3-10、10-20、20-100或100范圍內(nèi)的基因的數(shù)目分別為1306、841、48、10和2。如果按FDR大小分類,那么FDR0.01、0.01-0.05或≥0.05的基因數(shù)目分別為178、457和1302。同樣地,為檢測表達(dá)下調(diào)的基因,本研究共使用15277個(gè)基因探針。結(jié)果共檢測出2722個(gè)基因出現(xiàn)表達(dá)的下調(diào)。如果按FC大小分類,FC在2-3、3-10、10-20、20-100或100范圍內(nèi)的基因的數(shù)目分別為1536、1017、94、90和35。如果按錯(cuò)誤發(fā)生率(false discovery rate,FDR)大小分類,那么FDR0.01、0.01-0.05或≥0.05的基因數(shù)目分別為581、870和1271。經(jīng)過分析,p53相關(guān)信號轉(zhuǎn)導(dǎo)通路和細(xì)胞周期相關(guān)通路所對應(yīng)區(qū)域的基因表達(dá)差異性最大。表達(dá)上調(diào)的基因中,RFWD2、STEAP3和GADD45G的FC值分別為4.7714417、4.0083716和3.3749906,FDR分別為0.001114899、0.012841317和0.002412821。表達(dá)下調(diào)的基因中,CCNB3、CDK1、ORC6、TTK和BUB1B的FC值分別為3.1506035、4.3426501、4.7398555、5.0118984和5.6042476,FDR分別為0.007884298、0.000350073、0.002653766、0.009627135和0.009627135。結(jié)論1.聯(lián)合應(yīng)用NCR和LNR的分類方法是影響p IIIa-N2期NSCLC患者5年OS和5年DFS的獨(dú)立預(yù)后因素。術(shù)后放療能夠明顯提高LNR0.31且NCR0.45患者的預(yù)后。2.肺門區(qū)淋巴結(jié)轉(zhuǎn)移狀態(tài)明顯影響p N2b期NSCLC患者的預(yù)后。傾向評分法配對分析發(fā)現(xiàn)術(shù)后化放療能夠明顯提高p H1N2b期NSCLC患者的預(yù)后。3.RFWD2、STEAP3和GADD45G基因的上調(diào)以及CCNB3、CDK1、ORC6、TTK和BUB1B基因的下調(diào)可能與非小細(xì)胞肺癌組間不同的術(shù)后遠(yuǎn)處轉(zhuǎn)移時(shí)間相關(guān)。
[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(zhèn)ｈ，

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