肝细胞癌的早期临床结局和远期预后相关分子生物学因素研究

发布时间：2018-06-06 05:11

本文选题：肠内营养 + 肠外营养　；参考：《北京协和医学院》2015年博士论文

【摘要】：[目的]探讨微小RNA (microRNA, miRNA)相关单核苷酸多态性(Single Nucleotide Polymorphism, SNP)与肝细胞癌(hepatocellular carcinoma, HCC)病人预后之间的关系。[方法]首先利用生物信息学,筛选出26个与HCC发生发展关联的miRNA相关SNP位点。之后收集614例HCC病人外周静脉血标本,经提取DNA后,采用Sequenom SNP位点分型检测法检测26个SNP基因型,在结合外周静脉血甲胎蛋白(alpha-fetoprotein, AFP)水平、TNM分期(AJCC,2010版)、Karnofsky评分(KPS评分)、是否合并肝硬化及是否采取外科手术治疗等因素情况下,利用Stastic Analysis System 8.2版软件(Version 8.2, Cary, NC:SAS Institute Inc, USA)分析这些SNP与HCC病人总体生存时间(Overall Survival, OS)之间的关联性。[结果]发现AFP水平、TNM分期、KPS评分、肝硬化及手术治疗与否等指标与OS具有显著相关性。MiRNA 195的3个SNP位点：rs11078662 GA (HR=0.782,95% CI 0.643-0.950,P=0.0132), rs 12450517 GA (HR=0.785,95% CI 0.646-0.955, P=0.0154)和rs78312845 AG (HR=0.777,95% CI 0.639-0.946, P=0.0121)与OS有显著相关性。其余23个SNP位点与OS均无显著相关性。[结论]在结合外周静脉血甲胎蛋白(AFP)水平、TNM分期(AJCC,2010版)、Karnofsky评分(KPS评分)、是否合并肝硬化及是否采取外科手术治疗等因素情况下,miRNA 195的3个SNP位点：rs11078662, rs12450517和rs78312845,是与HCC的OS相关的预后因素。[目的] 临床部分对比评价了肝细胞癌肝部分切除术后早期肠内营养支持(Early Enteral Nutrition, EEN)联合肠外营养支持(Total Parenteral Nutrition, TPN) (EEN+PN)对早期临床结局的影响及两者的成本-效果分析(Cost-Effectiveness Analysis, CEA),进而对临床选择合理的营养支持方案提供指导。基础部分探讨了微小RNA (microRNA, miRNA)相关单核苷酸多态性(Single Nucleotide Polymorphism, SNP)与肝细胞癌(hepatocellular carcinoma, HCC)病人预后之间的关系。[方法] 临床部分选择了379例术后需营养支持的HCC病人,采用回顾性前瞻性收集数据的队列研究方法,将病人分为两个队列：研究组(142例)和对照组(237例),分别于术后连续4天使用EEN+PN和TPN。观察两组下列指标：年龄、性别、居住地、体重指数(BMI)、肿瘤最大径、术中失血量(m1)、手术时间、感染等并发症发生率,以及术前、术后第1天、术后第7天血常规、肝功能指标等,同时对比两组的总住院天数、术后住院天数、总住院费用、术后住院费用等。之后经构建决策模型,对两种营养支持方法进行成本-效果分析(CEA)。并将379例病人进一步分为两个亚组：cl-HCC亚组与ncl-HCC亚组。分别对比其亚组内部两种营养支持方法的结局异同。最后对决策模型结果的不确定性和稳定性进行了敏感性分析。基础部分的研究,首先是利用生物信息学,筛选出26个与HCC发生发展关联的miRNA相关SNP位点。之后收集614例HCC病人外周静脉血标本,经提取DNA后,采用Sequenom SNP位点分型检测法检测26个SNP基因型,在结合外周静脉血甲胎蛋白(alpha-fetoprotein, AFP)水平、TNM分期(AJCC,2010版)、Karnofsky评分(KPS评分)、是否合并肝硬化及是否采取外科手术治疗等因素情况下,利用Stastic Analysis System 8.2版软件(Version 8.2, Cary, NC:SAS Institute Inc, USA)分析这些SNP与HCC病人总体生存时间(Overall Survival, OS)之间的关联性。[结果] 临床部分的结果：两组及两种亚组内部对比结果提示,病人的年龄、性别、BMI、肿瘤大小(肿瘤最大径)、术中出血量、术后感染率等指标均无显著差异。同对照组相比,研究组的总住院天数计术后住院天数显著缩短,术后住院费用明显减少,但总住院费用无明显差异。应用EEN+PN营养支持方案时,每获得一个QALY,需支出的平均成本为3000.35 RMB；应用TPN营养支持方案时,每获得一个QALY,需支出的成本为3311.91 RMB。进一步的增量成本-效果分析(incremental cost-effectiveness ratio, ICER; incremental cost/incremental effectiveness, △C/△E),提示添加肠内营养的EEN+PN支持方法,为病人每提高一个QALY,需多支出583.38 RMB的成本,低于我国2010年的人均GDP(29992RMB),并低于意愿支付阂值(Willing-to-Pay,WTP)即人均GDP的3倍(89976RMB)。最后的敏感性分析验证了结果的可靠性和稳定性。基础部分的结果：发现AFP水平、TNM分期、KPS评分、肝硬化及手术治疗与否等指标与OS具有显著相关性。MiRNA 195的3个SNP位点：rs11078662 GA (HR=0.782,95% CI 0.643-0.950, P=0.0132), rs12450517 GA (HR=0.785,95% CI 0.646-0.955, P=0.0154)和rs78312845 AG(HR=0.777,95% CI 0.639-0.946, P=0.0121)与OS有显著相关性。其余23个SNP位点与OS均无显著相关性。[结论] 对于术后需营养支持的HCC病人,EEN+PN能够部分地改善肝功能,并明显缩短住院时间。从卫生经济学角度判断,EEN+PN是在这一类病人中值得推广的具有显著成本-效果优势的营养方法。在结合外周静脉血甲胎蛋白(AFP)水平、TNM分期(AJCC,2010版)、Karnofsky评分(KPS评分)、是否合并肝硬化及是否采取外科手术治疗等因素情况下,miRNA195的3个SNP位点：rs11078662, rs12450517和rs78312845,是与HCC的OS相关的预后因素。[目的]对比评价肝细胞癌肝部分切除术后早期肠内营养支持(Early Enteral Nutrition, EEN)联合肠外营养支持(Total Parenteral Nutrition, TPN) (EEN+PN)对早期临床结局的影响及两者的成本-效果分析(Cost-Effectiveness Analysis, CEA),指导临床选择合理的营养支持方案。[方法]选择379例术后需营养支持的HCC病人,采用回顾性前瞻性收集数据的队列研究方法,将病人分为两个队列：研究组(142例)和对照组(237例),分别于术后连续4天使用EEN+PN和TPN。观察两组下列指标：年龄、性别、居住地、体重指数(BMI)、肿瘤最大径、术中失血量(m1)、手术时间、感染等并发症发生率,以及术前、术后第1天、术后第7天血常规、肝功能指标等,同时对比两组的总住院天数、术后住院天数、总住院费用、术后住院费用等。之后经构建决策模型,对两种营养支持方法进行成本-效果分析(CEA)。并将379例病人进一步分为两个亚组：cl-HCC亚组与ncl-HCC亚组。分别对比其亚组内部两种营养支持方法的结局异同。最后对决策模型结果的不确定性和稳定性进行了敏感性分析。[结果]两组及两种亚组内部对比结果提示,病人的年龄、性别、BMI、肿瘤大小(肿瘤最大径)、术中出血量、术后感染率等指标均无显著差异。同对照组相比,研究组的总住院天数计术后住院天数显著缩短,术后住院费用明显减少,但总住院费用无明显差异。应用EEN+PN营养支持方案时,每获得一个QALY,需支出的平均成本为3000.35 RMB;应用TPN营养支持方案时,每获得一个QALY,需支出的成本为3311.91 RMB。进一步的增量成本-效果分析(incremental cost-effectiveness ratio, ICER; incremental cost/incremental effectiveness, △C/△E),提示添加肠内营养的EEN+PN支持方法,为病人每提高一个QALY,需多支出583.38 RMB的成本,低于我国2010年的人均GDP(29992 RMB),并低于意愿支付阈值(Willing-to-Pay,WTP)即人均GDP的3倍(89976 RMB)。最后的敏感性分析验证了结果的可靠性和稳定性。[结论]对于术后需营养支持的HCC病人,EEN+PN能够部分地改善肝功能,
[Abstract]:[Objective] to investigate the relationship between small RNA (microRNA, miRNA) related single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP) and the prognosis of patients with hepatocellular carcinoma (hepatocellular carcinoma, HCC). [Methods] 26 miRNA related sites associated with HCC development were first screened by bioinformatics. After that, 614 cases were collected. After extraction of DNA, 26 SNP genotypes were detected by Sequenom SNP site typing detection, combined with peripheral venous serum alpha fetoprotein (alpha-fetoprotein, AFP), TNM staging (AJCC, 2010), Karnofsky score (KPS score), whether cirrhosis and surgical treatment were combined, and so on. Stastic Analysis System 8.2 software (Version 8.2, Cary, NC:SAS Institute Inc, USA) was used to analyze the relationship between these SNP and HCC patients' survival time (Overall). There is a significant correlation between the rs11078662 GA (HR=0.782,95% CI 0.643-0.950, P=0.0132), RS 12450517 GA (HR=0.785,95% CI 0.646-0.955) and the others. [Conclusion] combined with peripheral venous blood alpha fetoprotein (conclusion) Levels, TNM staging (AJCC, 2010 Edition), Karnofsky score (KPS score), whether or not cirrhosis and surgical treatment are combined, 3 SNP loci of miRNA 195, rs11078662, rs12450517 and rs78312845, are the prognostic factors associated with HCC OS. [Objective] the clinical part compared the partial hepatectomy for hepatocellular carcinoma. The effect of Early Enteral Nutrition (EEN) combined with Total Parenteral Nutrition (TPN) (EEN+PN) on the early clinical outcome and the cost-effectiveness analysis (Cost-Effectiveness Analysis, CEA), and then provide guidance for the rational nutritional support scheme in the bed selection. The relationship between the small RNA (microRNA, miRNA) related single nucleotide polymorphisms (Single Nucleotide Polymorphism, SNP) and the prognosis of patients with hepatocellular carcinoma (hepatocellular carcinoma, HCC). [Methods] the clinical part selected 379 cases of postoperative nutritional support in HCC patients. A retrospective prospective data collection of data was used in a cohort study. The patients were divided into two groups: the study group (142 cases) and the control group (237 cases). The following indexes were observed in two groups by EEN+PN and TPN. after the operation: age, sex, residence, body mass index (BMI), tumor maximum diameter, intraoperative blood loss (M1), intraoperative time, infection and other complications, as well as preoperative, first days after operation, and blood seventh days after operation. The total hospitalization days of the two groups, the number of hospitalization days after the operation, the total hospitalization expenses and the hospitalization expenses after the operation were compared, and then the cost effectiveness analysis (CEA) was carried out on the two nutritional support methods by the construction decision model, and the 379 patients were further divided into two subgroups: the cl-HCC subgroup and the ncl-HCC subgroup. The outcome of the two nutritional support methods in the subgroup was different. Finally, the sensitivity and stability of the decision model results were analyzed. The first part of the study was to use bioinformatics to screen out 26 miRNA related SNP loci associated with the development of HCC. After that, 614 cases of HCC patients were collected from the peripheral venous blood samples. After the extraction of DNA, 26 SNP genotypes were detected by Sequenom SNP site typing detection, combined with the level of peripheral venous blood alpha fetoprotein (alpha-fetoprotein, AFP), TNM staging (AJCC, 2010 Edition), Karnofsky score (KPS score), whether or not liver cirrhosis and surgical treatment were taken, and Stastic Analysis 8. was used. The 2 version of the software (Version 8.2, Cary, NC:SAS Institute Inc, USA) analyzed the association between the SNP and the overall survival time of HCC patients (Overall Survival, OS). [results] the clinical part: the results of the two and two subgroups suggest that the patient's age, sex, BMI, tumor size (the maximum diameter of the tumor), the amount of intraoperative hemorrhage, and the operation There was no significant difference in the rate of post infection. Compared with the control group, the number of hospitalization days after the total hospitalization of the study group was significantly shortened, and the cost of hospitalization was significantly reduced, but there was no significant difference in total hospitalization expenses. When the EEN+PN nutrition support scheme was used, the average cost of a QALY was 3000.35 RMB, and the use of TPN nutrition branch was used. At the time of holding a program, the cost of each QALY is 3311.91 RMB. for further incremental cost effect analysis (incremental cost-effectiveness ratio, ICER; incremental cost/incremental effectiveness, Delta C/ Delta E), suggesting a EEN+PN support method for adding enteral nutrition, which requires 583.38 more expenditures for each increase of the patient. The cost of B was lower than the per capita GDP (29992RMB) of our country in 2010 and lower than the willingness to pay (Willing-to-Pay, WTP) 3 times as much as GDP per person (89976RMB). The final sensitivity analysis verified the reliability and stability of the results. The results of the basic part: the index and OS of AFP level, TNM staging, KPS score, cirrhosis and surgical treatment. There are 3 SNP loci with significant correlation.MiRNA 195: rs11078662 GA (HR=0.782,95% CI 0.643-0.950, P=0.0132) and rs12450517 GA (HR=0.785,95% CI) with significant correlation. There is no significant correlation between the other 23 sites. [Conclusion] HCC patients who need nutritional support after surgery, EEN+PN can partially improve liver function and significantly shorten the time of hospitalization. From a health economics point of view, EEN+PN is a nutritious method with significant cost effectiveness in this type of patients. In combination with peripheral venous blood alpha fetoprotein (AFP) level, TNM staging (2010 Edition), Karno Fsky score (KPS score), the combination of cirrhosis and surgical treatment, the 3 SNP loci of miRNA195, rs11078662, rs12450517 and rs78312845, are the prognostic factors associated with HCC's OS. [Objective] to compare and evaluate early enteral nutrition support (Early Enteral Nutrition) after partial hepatectomy for hepatocellular carcinoma (Early Enteral Nutrition) N) the effect of Total Parenteral Nutrition (TPN) (EEN+PN) on early clinical outcomes and the cost-effectiveness analysis (Cost-Effectiveness Analysis, CEA), guiding clinical selection of rational nutritional support programs. [Methods] 379 patients with postoperative nutritional support were selected for retrospective prospective collection. According to the cohort study, the patients were divided into two groups: the study group (142 cases) and the control group (237 cases). The following indexes were observed in two groups by EEN+PN and TPN. after the operation: age, sex, residence, body mass index (BMI), the maximum diameter of the tumor, the intraoperative blood loss (M1), the operation time, the incidence of infection and other complications, and preoperative and surgical procedures. After first days, seventh days after the operation, the blood routine, liver function index, and the total hospitalization days of the two groups, the number of hospitalization days after operation, the total hospitalization expenses, and the cost of hospitalization after the operation. After constructing the decision model, the cost effectiveness analysis (CEA) was carried out on the two nutritional support methods. And 379 patients were further divided into two subgroups: the cl-HCC subgroup and the NCL -HCC subgroup compared the outcome of two nutritional support methods in the subgroup. Finally, sensitivity analysis of the uncertainty and stability of the decision model results. [results] the comparison between the two groups and two subgroups suggested that the patient's age, sex, BMI, the tumor size, the amount of intraoperative bleeding, and the postoperative infection rate. Compared with the control group, compared with the control group, the number of hospitalization days after the total hospitalization of the study group was significantly shortened, the hospitalization cost after the operation was significantly reduced, but the total hospitalization cost had no significant difference. When the EEN+PN nutrition support scheme was applied, the average cost for each QALY was 3000.35 RMB; when the TPN nutrition support scheme was applied, For each QALY, the cost of expenditure is 3311.91 RMB. further incremental costs - effect analysis (incremental cost-effectiveness ratio, ICER; incremental cost/incremental effectiveness, Delta C/ Delta E), suggesting a EEN+PN support method for adding enteral nutrition, and the cost of 583.38 more expenses for each patient to be raised for each improvement. Lower than our country's per capita GDP (29992 RMB) in 2010, and lower than the willing payment threshold (Willing-to-Pay, WTP) 3 times (89976 RMB) of per capita GDP. The final sensitivity analysis verified the reliability and stability of the results. [Conclusion] EEN+ PN can partly improve the liver function for postoperative patients with nutritional support for HCC.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R735.7

【参考文献】