本文選題：巴塞羅那分期 + 香港分期��； 參考：《南京大學》2017年博士論文

【摘要】：肝細胞癌(hepatocellular carcinoma,HCC)是全球第五大惡性腫瘤,目前其發(fā)病率和死亡率仍高居不下。長期以來,形態(tài)各異的肝細胞癌與其生物學行為和預后的關(guān)系一直是學者們關(guān)注的熱點。目前認為,HCC的大體形態(tài)與其分子病理學特征有著密切的聯(lián)系。2011年,美國Johns Hopkins大學醫(yī)學院的研究團隊首先提出了呈浸潤性生長的HCC亞型(稱為浸潤型肝細胞癌,infiltrative hepatocellular carcinoma,iHCC),其臨床特征主要包括:①多數(shù)合并乙型肝炎病毒(hepatitis B virus,HBV)感染;②具有與傳統(tǒng)HCC不同的影像學特點,病灶邊界模糊不清,動脈期強化不明顯,極易發(fā)生脈管侵犯等;③大多數(shù)有血清甲胎蛋白(alpha-fetoprotein,AFP)顯著升高。iHCC的概念一經(jīng)提出,立刻引起國際上臨床學者的重視。目前普遍認為,iHCC呈浸潤性生長方式,腫瘤生長迅速、浸潤范圍廣,很快發(fā)生脈管癌栓、肝內(nèi)播散及全身轉(zhuǎn)移,是HCC中惡性程度最高的臨床亞型。但是,由于iHCC的高侵襲轉(zhuǎn)移特征,絕大多數(shù)病例被發(fā)現(xiàn)和確診時已到了晚期,失去了根治性治療的機會。因此,完整系統(tǒng)的臨床-影像-病理資料收集非常困難,限制了相關(guān)研究的深入。本研究團隊自2013年開始高度關(guān)注iHCC的相關(guān)臨床和基礎研究,經(jīng)過不斷積累獲得以下研究結(jié)果:①由于HBV感染是HCC主要發(fā)病因素,我國iHCC的發(fā)病率高于其他亞洲和歐美國家,我們統(tǒng)計的結(jié)果占HCC的30%,顯著高于歐美和日本的5～10%;②在不同大體分型的HCC中,iHCC的預后最差;③經(jīng)過大量臨床病例的觀察,我們在國內(nèi)外首先報道了在早-中期HCC中亦存在iHCC亞型。因此,本課題著重于iHCC的臨床和基礎研究。主要包括以下三個方面:①選擇適合浸潤型肝細胞癌診療決策和預后分析的臨床分期;②通過分析手術(shù)切除iHCC病人的臨床特征及預后等信息,探索合適的治療策略;③通過全外顯子測序技術(shù),探索iHCC的關(guān)鍵特異性基因,探討其分子病理學特征。第一部分選擇適合浸潤型肝細胞癌診療決策和預后分析的臨床分期目的:比較香港分期(Hong Kong Liver Cancer,HKLC)和巴塞羅那分期(Barcelona Clinic Liver Cancer,BCLC)在HBV相關(guān)性HCC病人中的預測預后能力。方法:668例HCC病人納入研究,應用赤池信息量準則(Akaike information criterion,AIC)、一致性指數(shù)(concordance-index,c-index)和 ROC 曲線下面積(area under the receiver operating characteristic curve,AUC)比較兩種分期的預后預測能力。通過單因素及多因素分析確定與生存相關(guān)的獨立危險因素。結(jié)果:與生存相關(guān)的獨立危險因素包括Child-Pugh評分、乳酸脫氫酶(lactate dehydrogenase,LDH)、白蛋白(albumin,ALB)、腫瘤部位、腫瘤數(shù)目、腫瘤大小和血管侵犯。HKLC分期的1、3、5年AUC分別為0.740,0.695和0.615,BCLC分期的1、3、5年AUC分別為0.622,0.569和0.548,提示HKLC分期的區(qū)分能力優(yōu)于BCLC分期。HKLC分期對生存的預測效能上亦優(yōu)于BCLC分期(HKLC 分期:AIC = 4709.480,c-index=0.805;BCLC 分期:AIC = 4852.708,c-index=0.717)。結(jié)論:HBV相關(guān)性HCC病人中,HKLC分期相比于BCLC分期來說預測預后能力更強,可能更適合以HBV感染為主要病因的中國HCC人群的預后分析以及治療決策。第二部分手術(shù)切除浸潤型肝細胞癌的臨床特征分析目的:探討接受手術(shù)切除的浸潤型肝細胞癌(infiltrative hepatocellular carcinoma,iHCC)病人的臨床特征及預后情況。方法:回顧性分析2003年1月至2012年12月在南京大學醫(yī)學院附屬鼓樓醫(yī)院肝膽胰外科行肝切除術(shù)的47名iHCC病人。通過單因素及多因素分析確定與生存及復發(fā)相關(guān)的獨立危險因素。運用卡方檢驗、t檢驗或Mann-Whitney 檢驗分析微血管侵犯(microvascular invasion,MVI)與相關(guān)臨床指標之間的關(guān)系。應用Kaplan-Meier曲線進行生存分析。結(jié)果:該組病人的中位生存時間為27.37個月,1年無復發(fā)生存率為61.7%。AFP并不是iHCC病人的特征性指標。解剖性肝切除與較高的無復發(fā)生存期顯著相關(guān)(P=0.007),存在MVI的病人無復發(fā)生存期較低(P0.001)。血清LDH水平較高的病人總生存期(P=0.003)及無復發(fā)生存期(P=0.020)均較低。病人的MVI與血清谷草轉(zhuǎn)氨酶(aspartate aminotransferase,AST)、谷氨酰轉(zhuǎn)肽酶(gamma glutamyl transpeptidase,GGT)以及LDH水平有關(guān)。亞組分析提示在高水平LDH的病人中,低級別MVI的病人有較高的無復發(fā)生存期(P=0.019)。結(jié)論:iHCC病人具有較高的MVI發(fā)生率,對于早中期的病人來說,解剖性肝切除仍能使病人獲益。MVI分級可以用來區(qū)分出預后更差的一部分病人,尤其是具有較高血清LDH水平的病人。第三部分浸潤型肝細胞癌分子病理學特點的探索目的:通過與單發(fā)結(jié)節(jié)型(single nodular,SN)HCC進行比較,探索浸潤型肝細胞癌(infiltrative hepatocellular carcinoma,iHCC)的特異性基因表達譜。方法:對6例腫瘤/相對正常的HCC組織樣本(3例iHCC、3例SN HCC)進行全外顯子測序。隨后在30例HCC組織樣本(15例iHCC、15例SN HCC)中采用Sanger測序及RT-PCR技術(shù)進行結(jié)果驗證。結(jié)果:在對相應組織樣本進行全外顯子測序、Sanger測序及生物信息學分析后,結(jié)果提示iHCC與SN HCC展現(xiàn)出顯著不同的基因譜。尤其在iHCC中發(fā)現(xiàn)了一個較為典型的生長因子受體酪氨酸激酶突變基因FGFR3,全外顯子測序發(fā)現(xiàn)了FGFR3的一個非同義突變位點c.G285T(p.Q95H),后續(xù)Sanger測序發(fā)現(xiàn)了另外五個突變位點(c.G938A:p.G313D,c.G1291A:p.A431T,c.C1355G:p.T452R,c.C1377T:p.L459L and c.A1445T:p.E482V)。免疫組化實驗證實了 FGFR3 在 iHCC中存在較高的蛋白表達。結(jié)論:FGFR3可能是具有早期復發(fā)特點的iHCC的潛在候選癌基因及治療分子靶標。
[Abstract]:Hepatocellular carcinoma (HCC) is the fifth largest malignant tumor in the world, and its morbidity and mortality still remain high. For a long time, the relationship between the different forms of hepatocellular carcinoma and its biological behavior and prognosis has been the focus of attention of scholars. At present, it is believed that the general morphology of HCC is closely related to its molecular pathological characteristics. In.2011, the research team of the medical school of Johns Hopkins University in the United States first proposed an infiltrative HCC subtype (called invasive hepatocellular carcinoma, infiltrative hepatocellular carcinoma, iHCC). Its clinical features mainly include: (1) most of the combination of hepatitis B virus (hepatitis B virus, HBV) infection; and (2) with traditional Chinese Medicine C has different imaging features, the boundary of the focus is unclear, the arterial phase is not obvious, and the vascular invasion is very easy to occur. (3) the concept of alpha-fetoprotein (AFP), which has a significant increase of.IHCC, is put forward immediately. Rapid, extensive infiltration, rapid vascular tumor thrombus, intrahepatic dissemination and whole body metastasis are the most malignant clinical subtypes in HCC. However, due to the high invasion and metastasis of iHCC, most cases have been found and confirmed at the late stage and lost the opportunity for radical treatment. The research team has been paying high attention to the related clinical and basic research of iHCC since 2013. The research team has accumulated the following results after continuous accumulation: (1) because HBV infection is the main factor of HCC, the incidence of iHCC in China is higher than that of other Asian and European countries, and our statistical results account for HC. The 30% of C was significantly higher than 5 to 10% in Europe and the United States and Japan; (2) the prognosis of iHCC was the worst in the HCC of different general classification. After a large number of clinical cases, we first reported the existence of iHCC subtype in the early and mid-term HCC. Therefore, this topic focuses on the clinical and basic research of iHCC, including the following aspects: (1) To select the clinical stages for the diagnosis and treatment of invasive hepatocellular carcinoma (HHC), and to explore the clinical features and prognosis of iHCC patients, explore the appropriate therapeutic strategies, and explore the key specific genes of iHCC through exon sequencing technology and explore its molecular pathological features. Clinical stages for the diagnosis and treatment of invasive hepatocellular carcinoma (Hong Kong Liver Cancer, HKLC) and Barcelona staging (Barcelona Clinic Liver Cancer, BCLC) in HBV associated HCC patients. Methods: 668 patients were included in the study. Ation criterion, AIC), the conformance index (concordance-index, c-index) and the area under the ROC curve (area under the receiver operating characteristic) compared the predictive ability of the two stages. Independent risk factors associated with survival were determined by single factor and multifactor analysis. Results: independent risk associated with survival Factors including Child-Pugh score, lactate dehydrogenase (LDH), albumin (albumin, ALB), tumor site, tumor number, tumor size, and vascular invasion.HKLC stages were 0.740,0.695 and 0.615, respectively, and 1,3,5 years of BCLC staging were different and 0.548. .HKLC staging was also superior to BCLC staging for survival (HKLC staging: AIC = 4709.480, c-index=0.805; BCLC staging: AIC = 4852.708, c-index=0.717). Conclusion: in HBV associated HCC patients, HKLC staging is more likely to predict prognosis than BCLC stages, and may be more suitable for the Chinese population with the main cause of infection. Prognostic analysis and treatment decisions. Clinical features of second parts of surgical excision of infiltrating hepatocellular carcinoma (infiltrative hepatocellular carcinoma, iHCC): the clinical features and prognosis of patients undergoing surgical excision (carcinoma, iHCC). Methods: retrospective analysis from January 2003 to December 2012 at the Nanjing University medicine 47 iHCC patients who underwent hepatectomy of hepatobiliary and pancreatic surgery affiliated to the College Affiliated Drum hospital. Independent risk factors associated with survival and recurrence were determined by single factor and multifactor analysis. The relationship between microvascular invasion (microvascular invasion, MVI) and related clinical indicators was analyzed by chi square test, t test or Mann-Whitney test. The application of K Survival analysis of the aplan-Meier curve. Results: the median survival time of the patients was 27.37 months, and the 1 year non recurrent survival rate was 61.7%.AFP, not the characteristic index of the iHCC patients. The anatomical hepatectomy was significantly correlated with the higher recurrence free survival (P=0.007), and the non recurrent survival time in the patients with MVI was lower (P0.001). The serum LDH level was low (P0.001). Higher patient total survival (P=0.003) and non recurrent survival (P=0.020) were lower. The patient's MVI was associated with serum aspartate aminotransferase (AST), glutamyl transpeptidase (gamma glutamyl transpeptidase, GGT), and LDH levels. Subgroup analysis suggested that patients with low level LDH were higher in the high level LDH patients. No recurrence of survival (P=0.019). Conclusion: iHCC patients have a high incidence of MVI. For patients with early and middle stages, anatomical hepatectomy can still benefit the patients with.MVI classification, which can be used to distinguish some patients with worse prognosis, especially in patients with higher serum LDH levels. Third part of the molecular pathology of infiltrating hepatocellular carcinoma. Objective: To explore the specific gene expression profiles of invasive hepatocellular carcinoma (infiltrative hepatocellular carcinoma, iHCC) by comparing with single nodular (SN) HCC. Methods: 6 cases of tumor / relatively normal HCC tissue samples (3 iHCC, 3 SN HCC) were sequenced in 30 cases. The fabric samples (15 iHCC, 15 SN HCC) were verified by Sanger sequencing and RT-PCR technology. Results: after the whole exon sequencing, Sanger sequencing and bioinformatics analysis of the corresponding tissue samples, the results showed that the iHCC and SN HCC showed significant different gene spectrum. In particular, a more typical growth factor was found in iHCC. Subreceptor tyrosine kinase mutation gene FGFR3, exon sequencing found a non synonymous mutation site of FGFR3 c.G285T (p.Q95H), followed by Sanger sequencing found five other mutation sites (c.G938A:p.G313D, c.G1291A:p.A431T, c.C1355G:p.T452R, c.C1377T:p.L459L and c.A1445T:p.E482V). Immunohistochemistry test confirmed FGFR3 in Conclusion: FGFR3 may be a potential candidate gene and therapeutic molecular target for iHCC with early recurrence characteristics. Conclusion: iHCC is a potential candidate gene for early relapse.

【學位授予單位】：南京大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R735.7

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