本文選題：腸內(nèi)營(yíng)養(yǎng) + 腸外營(yíng)養(yǎng)��； 參考：《北京協(xié)和醫(yī)學(xué)院》2015年博士論文

【摘要】：[目的]探討微小RNA (microRNA, miRNA)相關(guān)單核苷酸多態(tài)性(Single Nucleotide Polymorphism, SNP)與肝細(xì)胞癌(hepatocellular carcinoma, HCC)病人預(yù)后之間的關(guān)系。[方法]首先利用生物信息學(xué),篩選出26個(gè)與HCC發(fā)生發(fā)展關(guān)聯(lián)的miRNA相關(guān)SNP位點(diǎn)。之后收集614例HCC病人外周靜脈血標(biāo)本,經(jīng)提取DNA后,采用Sequenom SNP位點(diǎn)分型檢測(cè)法檢測(cè)26個(gè)SNP基因型,在結(jié)合外周靜脈血甲胎蛋白(alpha-fetoprotein, AFP)水平、TNM分期(AJCC,2010版)、Karnofsky評(píng)分(KPS評(píng)分)、是否合并肝硬化及是否采取外科手術(shù)治療等因素情況下,利用Stastic Analysis System 8.2版軟件(Version 8.2, Cary, NC:SAS Institute Inc, USA)分析這些SNP與HCC病人總體生存時(shí)間(Overall Survival, OS)之間的關(guān)聯(lián)性。[結(jié)果]發(fā)現(xiàn)AFP水平、TNM分期、KPS評(píng)分、肝硬化及手術(shù)治療與否等指標(biāo)與OS具有顯著相關(guān)性。MiRNA 195的3個(gè)SNP位點(diǎn)：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)與OS有顯著相關(guān)性。其余23個(gè)SNP位點(diǎn)與OS均無顯著相關(guān)性。[結(jié)論]在結(jié)合外周靜脈血甲胎蛋白(AFP)水平、TNM分期(AJCC,2010版)、Karnofsky評(píng)分(KPS評(píng)分)、是否合并肝硬化及是否采取外科手術(shù)治療等因素情況下,miRNA 195的3個(gè)SNP位點(diǎn)：rs11078662, rs12450517和rs78312845,是與HCC的OS相關(guān)的預(yù)后因素。[目的] 臨床部分對(duì)比評(píng)價(jià)了肝細(xì)胞癌肝部分切除術(shù)后早期腸內(nèi)營(yíng)養(yǎng)支持(Early Enteral Nutrition, EEN)聯(lián)合腸外營(yíng)養(yǎng)支持(Total Parenteral Nutrition, TPN) (EEN+PN)對(duì)早期臨床結(jié)局的影響及兩者的成本-效果分析(Cost-Effectiveness Analysis, CEA),進(jìn)而對(duì)臨床選擇合理的營(yíng)養(yǎng)支持方案提供指導(dǎo)。基礎(chǔ)部分探討了微小RNA (microRNA, miRNA)相關(guān)單核苷酸多態(tài)性(Single Nucleotide Polymorphism, SNP)與肝細(xì)胞癌(hepatocellular carcinoma, HCC)病人預(yù)后之間的關(guān)系。[方法] 臨床部分選擇了379例術(shù)后需營(yíng)養(yǎng)支持的HCC病人,采用回顧性前瞻性收集數(shù)據(jù)的隊(duì)列研究方法,將病人分為兩個(gè)隊(duì)列：研究組(142例)和對(duì)照組(237例),分別于術(shù)后連續(xù)4天使用EEN+PN和TPN。觀察兩組下列指標(biāo)：年齡、性別、居住地、體重指數(shù)(BMI)、腫瘤最大徑、術(shù)中失血量(m1)、手術(shù)時(shí)間、感染等并發(fā)癥發(fā)生率,以及術(shù)前、術(shù)后第1天、術(shù)后第7天血常規(guī)、肝功能指標(biāo)等,同時(shí)對(duì)比兩組的總住院天數(shù)、術(shù)后住院天數(shù)、總住院費(fèi)用、術(shù)后住院費(fèi)用等。之后經(jīng)構(gòu)建決策模型,對(duì)兩種營(yíng)養(yǎng)支持方法進(jìn)行成本-效果分析(CEA)。并將379例病人進(jìn)一步分為兩個(gè)亞組：cl-HCC亞組與ncl-HCC亞組。分別對(duì)比其亞組內(nèi)部?jī)煞N營(yíng)養(yǎng)支持方法的結(jié)局異同。最后對(duì)決策模型結(jié)果的不確定性和穩(wěn)定性進(jìn)行了敏感性分析�；A(chǔ)部分的研究,首先是利用生物信息學(xué),篩選出26個(gè)與HCC發(fā)生發(fā)展關(guān)聯(lián)的miRNA相關(guān)SNP位點(diǎn)。之后收集614例HCC病人外周靜脈血標(biāo)本,經(jīng)提取DNA后,采用Sequenom SNP位點(diǎn)分型檢測(cè)法檢測(cè)26個(gè)SNP基因型,在結(jié)合外周靜脈血甲胎蛋白(alpha-fetoprotein, AFP)水平、TNM分期(AJCC,2010版)、Karnofsky評(píng)分(KPS評(píng)分)、是否合并肝硬化及是否采取外科手術(shù)治療等因素情況下,利用Stastic Analysis System 8.2版軟件(Version 8.2, Cary, NC:SAS Institute Inc, USA)分析這些SNP與HCC病人總體生存時(shí)間(Overall Survival, OS)之間的關(guān)聯(lián)性。[結(jié)果] 臨床部分的結(jié)果：兩組及兩種亞組內(nèi)部對(duì)比結(jié)果提示,病人的年齡、性別、BMI、腫瘤大小(腫瘤最大徑)、術(shù)中出血量、術(shù)后感染率等指標(biāo)均無顯著差異。同對(duì)照組相比,研究組的總住院天數(shù)計(jì)術(shù)后住院天數(shù)顯著縮短,術(shù)后住院費(fèi)用明顯減少,但總住院費(fèi)用無明顯差異。應(yīng)用EEN+PN營(yíng)養(yǎng)支持方案時(shí),每獲得一個(gè)QALY,需支出的平均成本為3000.35 RMB；應(yīng)用TPN營(yíng)養(yǎng)支持方案時(shí),每獲得一個(gè)QALY,需支出的成本為3311.91 RMB。進(jìn)一步的增量成本-效果分析(incremental cost-effectiveness ratio, ICER; incremental cost/incremental effectiveness, △C/△E),提示添加腸內(nèi)營(yíng)養(yǎng)的EEN+PN支持方法,為病人每提高一個(gè)QALY,需多支出583.38 RMB的成本,低于我國(guó)2010年的人均GDP(29992RMB),并低于意愿支付閡值(Willing-to-Pay,WTP)即人均GDP的3倍(89976RMB)。最后的敏感性分析驗(yàn)證了結(jié)果的可靠性和穩(wěn)定性�；A(chǔ)部分的結(jié)果：發(fā)現(xiàn)AFP水平、TNM分期、KPS評(píng)分、肝硬化及手術(shù)治療與否等指標(biāo)與OS具有顯著相關(guān)性。MiRNA 195的3個(gè)SNP位點(diǎn)：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)與OS有顯著相關(guān)性。其余23個(gè)SNP位點(diǎn)與OS均無顯著相關(guān)性。[結(jié)論] 對(duì)于術(shù)后需營(yíng)養(yǎng)支持的HCC病人,EEN+PN能夠部分地改善肝功能,并明顯縮短住院時(shí)間。從衛(wèi)生經(jīng)濟(jì)學(xué)角度判斷,EEN+PN是在這一類病人中值得推廣的具有顯著成本-效果優(yōu)勢(shì)的營(yíng)養(yǎng)方法。在結(jié)合外周靜脈血甲胎蛋白(AFP)水平、TNM分期(AJCC,2010版)、Karnofsky評(píng)分(KPS評(píng)分)、是否合并肝硬化及是否采取外科手術(shù)治療等因素情況下,miRNA195的3個(gè)SNP位點(diǎn)：rs11078662, rs12450517和rs78312845,是與HCC的OS相關(guān)的預(yù)后因素。[目的]對(duì)比評(píng)價(jià)肝細(xì)胞癌肝部分切除術(shù)后早期腸內(nèi)營(yíng)養(yǎng)支持(Early Enteral Nutrition, EEN)聯(lián)合腸外營(yíng)養(yǎng)支持(Total Parenteral Nutrition, TPN) (EEN+PN)對(duì)早期臨床結(jié)局的影響及兩者的成本-效果分析(Cost-Effectiveness Analysis, CEA),指導(dǎo)臨床選擇合理的營(yíng)養(yǎng)支持方案。[方法]選擇379例術(shù)后需營(yíng)養(yǎng)支持的HCC病人,采用回顧性前瞻性收集數(shù)據(jù)的隊(duì)列研究方法,將病人分為兩個(gè)隊(duì)列：研究組(142例)和對(duì)照組(237例),分別于術(shù)后連續(xù)4天使用EEN+PN和TPN。觀察兩組下列指標(biāo)：年齡、性別、居住地、體重指數(shù)(BMI)、腫瘤最大徑、術(shù)中失血量(m1)、手術(shù)時(shí)間、感染等并發(fā)癥發(fā)生率,以及術(shù)前、術(shù)后第1天、術(shù)后第7天血常規(guī)、肝功能指標(biāo)等,同時(shí)對(duì)比兩組的總住院天數(shù)、術(shù)后住院天數(shù)、總住院費(fèi)用、術(shù)后住院費(fèi)用等。之后經(jīng)構(gòu)建決策模型,對(duì)兩種營(yíng)養(yǎng)支持方法進(jìn)行成本-效果分析(CEA)。并將379例病人進(jìn)一步分為兩個(gè)亞組：cl-HCC亞組與ncl-HCC亞組。分別對(duì)比其亞組內(nèi)部?jī)煞N營(yíng)養(yǎng)支持方法的結(jié)局異同。最后對(duì)決策模型結(jié)果的不確定性和穩(wěn)定性進(jìn)行了敏感性分析。[結(jié)果]兩組及兩種亞組內(nèi)部對(duì)比結(jié)果提示,病人的年齡、性別、BMI、腫瘤大小(腫瘤最大徑)、術(shù)中出血量、術(shù)后感染率等指標(biāo)均無顯著差異。同對(duì)照組相比,研究組的總住院天數(shù)計(jì)術(shù)后住院天數(shù)顯著縮短,術(shù)后住院費(fèi)用明顯減少,但總住院費(fèi)用無明顯差異。應(yīng)用EEN+PN營(yíng)養(yǎng)支持方案時(shí),每獲得一個(gè)QALY,需支出的平均成本為3000.35 RMB;應(yīng)用TPN營(yíng)養(yǎng)支持方案時(shí),每獲得一個(gè)QALY,需支出的成本為3311.91 RMB。進(jìn)一步的增量成本-效果分析(incremental cost-effectiveness ratio, ICER; incremental cost/incremental effectiveness, △C/△E),提示添加腸內(nèi)營(yíng)養(yǎng)的EEN+PN支持方法,為病人每提高一個(gè)QALY,需多支出583.38 RMB的成本,低于我國(guó)2010年的人均GDP(29992 RMB),并低于意愿支付閾值(Willing-to-Pay,WTP)即人均GDP的3倍(89976 RMB)。最后的敏感性分析驗(yàn)證了結(jié)果的可靠性和穩(wěn)定性。[結(jié)論]對(duì)于術(shù)后需營(yíng)養(yǎng)支持的HCC病人,EEN+PN能夠部分地改善肝功能,
[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.
【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】：2015
【分類號(hào)】：R735.7

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