本文關(guān)鍵詞： 肝癌 酒精 ALT 預(yù)后 肝細(xì)胞癌 多灶 腫瘤微環(huán)境　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

【摘要】：該博士學(xué)位論文由臨床研究及基礎(chǔ)研究工作兩部分組成。第一部分98例小肝癌的臨床病理及預(yù)后相關(guān)分析[目的]分析小肝癌患者的臨床病理特征及影響預(yù)后的相關(guān)因素。[方法]回顧性分析2009年1月至2013年12月行外科手術(shù)R0切除的98例小肝癌患者的臨床病理資料,并進(jìn)行完整隨訪。采用Kaplan-Meier法計(jì)算生存率,Logrank法進(jìn)行生存曲線比較,多因素分析采用Cox比例風(fēng)險(xiǎn)模型,檢驗(yàn)水準(zhǔn)α=0.05。[結(jié)果]98例患者全部獲得隨訪,98例患者術(shù)后1、3、5年生存率分別為99.0%、91.7%和76.3%,中位總生存時(shí)間(OS)為52個(gè)月。98例患者術(shù)后1、3、5年無(wú)進(jìn)展生存率分別為86.7%、66.2%和55.0%,中位無(wú)病生存時(shí)間(DFS)為43.5個(gè)月。單因素分析顯示,衛(wèi)星結(jié)節(jié)、肝被膜侵犯和術(shù)后復(fù)發(fā)時(shí)間與OS有關(guān)(均P0.05),長(zhǎng)期大量飲酒、衛(wèi)星結(jié)節(jié)和肝被膜侵犯與PFS有關(guān)(均P0.05)。多因素分析顯示,長(zhǎng)期大量飲酒是影響小肝癌無(wú)病生存時(shí)間的獨(dú)立因素(P=0.003),術(shù)后復(fù)發(fā)時(shí)間和肝被膜侵犯是影響小肝癌總生存時(shí)間的獨(dú)立因素(均P0.05)。分組分析影響長(zhǎng)期大量飲酒患者及非長(zhǎng)期大量飲酒患者的預(yù)后因素,對(duì)于無(wú)長(zhǎng)期大量飲酒患者,術(shù)前ALT是無(wú)病生存時(shí)間及總生存時(shí)間的顯著性不良因素。對(duì)于有長(zhǎng)期大量飲酒患者,單因素分析顯示衛(wèi)星灶對(duì)總生存時(shí)間及無(wú)病生存時(shí)間的影響有統(tǒng)計(jì)學(xué)差異(P0.05)。多因素分析結(jié)果顯示:術(shù)后復(fù)發(fā)時(shí)間是影響總生存時(shí)間的獨(dú)立危險(xiǎn)因素(P0.05)。[結(jié)論]對(duì)于小肝癌的手術(shù)治療,在保證腫瘤R0切除的前提下,盡量減少正常肝的切除范圍對(duì)患者有利。小肝癌術(shù)后復(fù)發(fā)時(shí)間≤2年提示預(yù)后不良,長(zhǎng)期大量飲酒能夠促進(jìn)小肝癌術(shù)后復(fù)發(fā)。對(duì)于無(wú)長(zhǎng)期大量飲酒的患者,術(shù)前ALT升高能夠影響小肝癌術(shù)后復(fù)發(fā)。第二部分多灶與單灶肝細(xì)胞肝癌外周血白細(xì)胞基因表達(dá)譜的差異研究[目的]多灶與單灶肝細(xì)胞癌是具有不同臨床表現(xiàn)和分子生物學(xué)特征的異質(zhì)性疾病。探索多灶與單灶病變的外周血單個(gè)核細(xì)胞發(fā)生的不同分子事件,分析多灶與單灶肝細(xì)胞癌腫瘤微環(huán)境的差異。[方法]本實(shí)驗(yàn)收集同一治療組治療的15例單灶肝癌與9例多灶肝癌患者外周血,采用Agilent 4*44k基因芯片平臺(tái),檢測(cè)外周血單個(gè)核細(xì)胞的mRNA表達(dá)譜,通過(guò)生物信息學(xué)分析,獲得差異表達(dá)基因。[結(jié)果]通過(guò)表達(dá)譜芯片分析,在多灶與單灶肝癌外周血單個(gè)核細(xì)胞中發(fā)現(xiàn)592個(gè)差異表達(dá)基因。主成分分析顯示,多灶性肝癌患者與單發(fā)性肝癌患者外周血白細(xì)胞基因表達(dá)譜有明顯差異。GO富集分析結(jié)果顯示,536個(gè)上調(diào)的差異表達(dá)基因涉及的生物學(xué)過(guò)程包括:細(xì)胞因子介導(dǎo)的免疫應(yīng)答、細(xì)胞間的信號(hào)傳導(dǎo)、損傷修復(fù)反應(yīng),p38MAPK信號(hào)通路的正性調(diào)控,免疫系統(tǒng)過(guò)程調(diào)節(jié)以及神經(jīng)系統(tǒng)和突觸的形成等。56個(gè)表達(dá)下調(diào)的差異基因涉及的生物學(xué)過(guò)程主要包括DNA的轉(zhuǎn)錄過(guò)程與調(diào)控、核糖體的生物合成以及膠原纖維的合成過(guò)程等。Pathway分析結(jié)果顯示,上調(diào)的差異表達(dá)基因主要與以下通路相關(guān):酪氨酸代謝過(guò)程,神經(jīng)活性配體-受體相互作用,細(xì)胞的緊密連接過(guò)程,血清素突觸以及礦物質(zhì)的吸收等信號(hào)通路相關(guān)。樣本GSVA分析顯示:多灶與單灶肝癌外周血白細(xì)胞對(duì)比,篩選出有顯著性差異的基因集(p0.05)共339個(gè),主要涉及:各種免疫細(xì)胞的功能調(diào)控(CD4T細(xì)胞,樹突狀細(xì)胞,CD8T細(xì)胞等),肝癌干細(xì)胞的功能,腫瘤微環(huán)境的細(xì)胞因子功能(TGF-β,IL-1,IL-6,IFN,HIF等),MAPK信號(hào)通路的調(diào)節(jié),脂類代謝穩(wěn)態(tài)與脂類合成的調(diào)節(jié)等。[結(jié)論]多灶與單灶肝癌患者外周血白細(xì)胞基因表達(dá)譜存在明顯差異,多灶肝癌患者白細(xì)胞TGF-β信號(hào)通路、脂類合成過(guò)程以及HIF等促進(jìn)腫瘤進(jìn)展及轉(zhuǎn)移的基因較單灶肝癌患者的表達(dá)明顯上調(diào),而p38/MAPK信號(hào)通路在多灶患者基因表達(dá)譜中下調(diào)。多灶肝癌較單灶肝癌在腫瘤微環(huán)境中存在更多促轉(zhuǎn)移及進(jìn)展的上調(diào)基因。
[Abstract]:This doctoral dissertation by clinical research and basic research work is composed of two parts. The first part of the 98 cases of small hepatocellular carcinoma clinical pathological and prognostic analysis to analyze prognostic factors. Methods: the clinical and pathological features and effects of small liver cancer patients were retrospectively analyzed from January 2009 to December 2013 underwent surgical resection of 98 cases of small hepatocellular carcinoma R0 the clinicopathological data of patients, and complete follow-up. The survival rate was calculated by Kaplan-Meier method, Logrank method to compare the survival curves, multivariate analysis using Cox proportional hazard model, a =0.05.[level test results]98 patients were followed up, 98 cases of patients with postoperative 1,3,5 year survival rates were 99%, 91.7% and 76.3%. The median survival time was 52 months (OS) of.98 patients after 1,3,5 years of progression free survival rates were 86.7%, 66.2% and 55%, the median disease-free survival time (DFS) for 43.5 months for single. Analysis showed that the satellite nodules, liver capsule invasion and recurrence time associated with OS (P0.05), a large number of long-term drinking, satellite nodules and liver capsule invasion associated with PFS (P0.05). Multivariate analysis showed that a large number of long-term drinking are independent factors affecting small liver disease free survival (P=0.003), postoperative recurrence time and liver membrane invasion were independent factors affecting the survival of small hepatocellular carcinoma (P0.05). Group analysis of long-term heavy drinking and non drinking a lot of patients with long-term prognostic factors for patients with long-term drinking, for patients, preoperative ALT is significant adverse factors of disease free survival time and total the survival time for patients with long-term drinking, the single factor analysis showed that the satellite focus on overall survival time and disease-free survival time was statistically different (P0.05). The results of multivariate analysis showed that postoperative recurrence time is the total effect Independent risk factors for the survival time (P0.05). Conclusion] for surgical treatment of small hepatocellular carcinoma, tumor resection under the premise of ensuring R0, try to reduce the resection range of normal liver is beneficial in patients with small hepatocellular carcinoma. Postoperative recurrence time is less than 2 years of poor prognosis, long-term drinking can promote the postoperative recurrence of small hepatocellular carcinoma. For a large number of long-term drinking in patients with elevated preoperative ALT can influence the recurrence of small hepatocellular carcinoma after operation. The second part multifocal hepatocellular carcinoma and single lesion of peripheral white blood cell differential gene expression study [Objective] multifocal spectrum and single lesion of hepatocellular carcinoma is a heterogeneous disease with different clinical manifestations and characteristics of molecular biology the different molecular events. Explore multifocal and single focal lesion of the peripheral blood mononuclear cells of the tumor and the difference analysis of multifocal single focal hepatocellular carcinoma microenvironment. Methods: We collected 15 cases with single lesion treatment in treatment group 9 cases of multifocal hepatocellular carcinoma and peripheral blood of patients with hepatocellular carcinoma, using Agilent 4*44k microarray platform, detection of peripheral blood mononuclear cells mRNA expression, bioinformatics analysis of differentially expressed genes. The results obtained by microarray expression analysis, in multifocal and single focal liver cancer in peripheral blood mononuclear cells found 592 differentially expressed genes. Principal component analysis showed that the multifocal hepatocellular carcinoma patients with solitary white blood cell gene expression profile of peripheral blood of patients with hepatocellular carcinoma were significantly different.GO enrichment analysis showed that the genes involved in the biological process including 536 up-regulated expression of immune response mediated by cytokines, cellular signal transduction the injury repair response, positive regulation of p38MAPK signaling pathway, immune system regulation and nervous system formation and synaptic.56 expression of genes down regulated biological process differences include The process of transcription and regulation of DNA, and ribosome biosynthesis of collagen synthesis process of.Pathway analysis showed that the upregulation of differentially expressed genes mainly with the following pathway: tyrosine metabolism, neuroactive ligand receptor interaction, is closely connected to the process of cell, serotonin synapses and mineral absorption and sample GSVA related signal pathway. Analysis showed that: compared to white cells in the peripheral blood of multifocal and single focal liver cancer, screening significant gene sets (P0.05) a total of 339, mainly involves: the functional regulation of various immune cells (CD4T cells, dendritic cells, CD8T cells), liver cancer stem cell function, cytokine function of tumor the environment (IL-1, IL-6, TGF- beta, IFN, HIF), MAPK pathway, lipid metabolism homeostasis and lipid synthesis regulation. Conclusion] multifocal hepatocellular carcinoma patients with single lesion of peripheral white blood cells There are obvious differences in gene expression spectrum, multifocal white blood cells in patients with hepatocellular carcinoma TGF- beta signaling pathway, lipid synthesis process and promote HIF expression was significantly increased in tumor progression and metastasis genes than a single lesion in patients with hepatocellular carcinoma, and p38/MAPK signaling pathway in patients with multifocal gene expression. Lower multifocal hepatocellular carcinoma than single focal hepatocellular carcinoma was up-regulated more progress and promoting gene transfer in the tumor microenvironment.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R735.7

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