肝细胞癌根治性切除术后TACE治疗的临床价值及其相关因素分析
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摘要
第一部分肝细胞癌组织中P53蛋白、P21蛋白、nm23蛋白和VEGF蛋白表达及mtDNAD-Loop区变异情况的研究
目的通过对肝细胞癌（简称肝癌）组织中的P53、P21、nm23、血管内皮生长因子（Vascular endothelial growth factor，VEGF），以及线粒体DNA（mitochondrial DNA，mtDNA）D-Loop区进行研究，以期发现它们在肝癌中的表达情况以及它们与临床病理参数间的关系。
方法收集140例肝癌患者的临床病理资料，其中男123例，女17例，中位年龄47.0岁（25岁~79岁），这些患者需同时满足以下条件：（一）入选标准：（1）2003年1月至2012年8月在广西医科大学第一附属医院肝胆外科住院诊断为肝癌，并接受根治性手术切除；（2）手术切除后有明确的病理证实为肝细胞癌；（3）具有完整的临床病理资料，随访状态良好，有完整的住院和门诊信息。（二）排除标准：（1）非根治性手术切除患者；（2）围手术期死亡患者；（3）随访术后2个月内复发者；（4）临床病理资料、随访资料不完整者；（5）有其它严重基础疾病患者。（三）肝癌根治性手术切除标准：（1）完整切除肉眼所见肿瘤，切缘无残癌；（2）肿瘤数目≤2个；（3）无门脉主干及一级分支、总肝管及一级分支、肝静脉主干及下腔静脉癌栓；（4）无肝门淋巴结转移；（5）无肝外转移；（6）术前血清AFP增高者，术后2个月内AFP应降至正常和影像学检查未见肿瘤残留。用免疫组化方法检测肝癌组织中的P53、P21、nm23、VEGF的蛋白表达，同时应用PCR结合直接测序的方法检测各样本组织中mtDNA D-Loop区的序列。对所得资料进行统计分析。
结果（1）P53蛋白在140例肝癌患者组织中阳性表达率为58.6%（82/140），P53蛋白的表达与肝吸虫感染，肿瘤大小，HBV DNA，肿瘤坏死以及微癌栓等临床病理因素相关（P<0.05）；有肝吸虫感染者，肿瘤直径大于3cm（或8cm）者，HBV DNA阳性者，肿瘤组织有坏死者以及有微癌栓者，P53蛋白表达率较高，分别为75.0%，62.8%（或73.0%），72.2%，74.2%和80.0%。（2）P21蛋白在140例肝癌患者组织中阳性表达率为44.3%（62/140），P21蛋白的表达与癌组织病理分级和肝硬化等临床病理因素相关（P<0.05）；癌组织病理分化越低，P21蛋白表达率越高，病理分级高、中、低分化癌组织的P21蛋白表达率分别为25.9%，44.9%和62.5%；有肝硬化者P21蛋白表达率较高，为48.6%。（3）nm23蛋白在140例肝癌患者组织中阳性表达率为77.9%（109/140），nm23蛋白的表达与HBeAg，肿瘤坏死以及微癌栓等临床病理因素相关（P<0.05）；HBeAg阴性者，肿瘤组织无坏死者以及无微癌栓者，nm23蛋白表达率较高，分别为84.6%，81.9%和83.8%。（4）VEGF蛋白在140例肝癌患者组织中阳性表达率为75.7%（106/140），VEGF蛋白的表达与患者年龄，肝吸虫感染以及HBeAb等临床病理因素相关（P<0.05）；年龄≤47岁者，有肝吸虫感染者以及HBeAb阳性者，VEGF蛋白表达率较高，分别为82.9%，93.8%和82.5%。（5）140例肝癌组织标本的mtDNA D-Loop区序列测序结果分析表明，共150个位点发生碱基变异，其中13个位点为点突变，8个位点发生插入，20个位点发生缺失，共出现116个多态性变化，位点总变异率为13.4%（150/1122）。其中，绝大部分的变异位点位于mtDNA D-Loop区的两个高变异区（hypervariable segments I and II，HVS I和HVS II），分别为HVS I（NT57-372）：46个位点（46/150，30.7%）和HVS II（NT16024-16383）：63个位点（63/150，42.0%）。多态性的碱基变异类型分别为：T>A（18例），
A>T（29例），C>G（21例），G>C（34例），Del（缺失）（16例）。突变的
碱基变异类型分别为：G>A（5例），T>A（3例），A>T（3例），A>C（1例），C>G（1例），C>A（1例），突变率为10.0%（14/140）。共有137例
D310区发生单核苷酸重复序列的变异，其类型分别为：C5TC63例（2.1%），C8TC664例（45.7%），C8TC764例（45.7%），C9TC63例（2.1%），C8CC6（C15）3例（2.1%），余下3例为标准序列的C8TC6（2.1%）。
结论（1）P53蛋白在肝癌组织中表达率较高，肝吸虫感染造成的长期慢性炎症，尤其是合并乙肝感染的情况下，可能是P53蛋白高表达的原因之一；HBV相关性肝癌中，P53蛋白表达增高；P53蛋白高表达于进展期的肝癌。（2）P21蛋白在肝癌组织中的表达率变化大；P21蛋白表达与癌组织病理分化呈负相关；伴有肝硬化者P21蛋白表达率较高。（3）nm23蛋白在肝癌组织中表达率较高，HBeAg阴性者，肿瘤组织无坏死者以及无微癌栓者，nm23蛋白表达率较高；nm23蛋白有抑制肿瘤转移的作用。（4）VEGF蛋白在肝癌组织中表达率较高，肝吸虫感染造成的长期慢性炎症可能上调VEGF蛋白的表达。（5）mtDNAD-Loop区序列高度可变，主要集中在两个高变异区HVS I（NT57-372）和HVS II（NT16024-16383）；D310区是个高度可变区域。
第二部分肝癌根治性切除术后预后影响因素的分析以及TACE治疗的临床价值
目的探讨肝癌根治性切除术后的预后影响因素；同时分析肝癌术后TACE治疗的临床价值。
方法收集140例肝癌患者的临床病理资料及术后治疗措施，随访登记他们复发、死亡时间，采用单因素和多因素的统计方法对预后影响因素进行统计，并对他们进行生存分析。TACE术采用Seldinger法，化疗药物包括吡柔比星、顺铂、氟尿嘧啶（5-FU），栓塞剂为碘油。
结果（1）平均随访时间40.9个月（8~126个月），复发前共有100例肝癌患者术后行TACE术共119次，余40例肝癌患者行门诊常规随访治疗。随访至2013年12月31日，共有129例复发，107例死亡，中位无瘤生存期为12.0个月（3~77个月），中位生存期为37.0个月（8~126个月）。129例肝癌术后复发患者中有42例行复发后手术再切除治疗（共49次，其中7例行复发后2次手术治疗），共行TACE354次，RFA31次，PEI52次。（2）以肝癌根治性切除术后1年内复发者定义为早期复发，1年后复发者定义为晚期复发，统计分析发现年龄、肿瘤大小、肿瘤包膜、手术切缘、术中输血情况、HBeAg、HBV DNA、GGT、ALT、AST、癌组织病理分级、肝硬化、微癌栓、TNM分期、TACE以及mtDNA中的16129位点（G/A）、16192位点（C/T）、16297位点（T/C）、150位点（C/T）、199位点（T/C）和204位点（T/C）在早期复发组与晚期复发组间比较有统计学意义（P<0.05）。多因素logistic回归分析发现：年龄、HBV DNA、肝硬化、TNM分期、TACE（≤2次或＞2次组）和mtDNA150位点是影响早期复发的独立影响因素；其中TACE（≤2次或＞2次组）和mtDNA150位点是保护因素，其余均为危险因素。未发现P53、P21、nm23和VEGF蛋白表达与肝癌早期复发有关。分层分析发现TNM分期为Ⅱ期、癌组织病理分级为中分化、有肝硬化、HBsAg阳性、HBeAg阳性、mtDNA16162位点碱基为A、mtDNA16172位点碱基为T、mtDNA16304位点碱基为T、mtDNA150位点碱基为T者，接受TACE治疗可明显降低肝癌的早期复发几率，并且发现接受TACE＞2次组所受益的患者最多。（3）140例肝癌患者的中位无瘤生存时间为12.0个月，1、2、3、4、5年的复发率分别为50%、70%、79%、89%、92%，多因素Cox比例风险回归模型分析发现肝吸虫感染、HBVDNA、肝功能、TNM分期、TACE（≤2次或＞2次组）以及mtDNA310位点是肝癌术后无瘤生存时间的影响因素。从回归系数看，肝功能和TACE（≤2次或＞2次组）是保护因素，其余均为危险因素。即肝功能为A级，接受TACE＞2次的患者复发的风险性较低，可延长无瘤生存时间。未发现P53、P21、nm23和VEGF蛋白表达与肝癌的无瘤生存期有关。分层分析发现肿瘤直径≤3.0cm的患者接受2次以上TACE治疗后中位无瘤生存时间反而缩短（38.0个月vs19.0个月，P=0.024）。（4）140例肝癌患者的中位生存期为37.0个月，1、2、3、4、5年的生存率分别为94%、72%、56%、40%、27%，多因素Cox比例风险回归模型分析发现复发时间类型、GGT（100U/L组）、肝功能以及复发后辅助治疗措施（无或单项、多项辅助治疗措施）是肝癌术后生存时间的独立影响因素。从回归系数看，肝功能和复发后辅助治疗措施（无或单项、多项辅助治疗措施）是保护因素，而复发时间类型和GGT（100U/L组）是危险因素。即肝功能为A级，复发后接受多项辅助治疗措施的患者死亡的风险性较低，可延长生存时间。未发现P53、P21、nm23和VEGF蛋白表达与肝癌生存期有关。
结论（1）临床病理参数有助于预测肝癌术后早期复发，年龄≤47岁，肿瘤越大，无肿瘤包膜或不完整，手术切缘<2.0cm，术中有输血史，HBeAg（+），HBV DNA（+），GGT≥50U/L，ALT≥90U/L，AST≥80U/L，癌组织病理分级为中、低分化，有肝硬化，有微癌栓，TNM分期Ⅲ期，肝癌术后复发前行TACE术≤2次，以及mtDNA中的16129位点碱基为G，16192位点碱基为C，16297位点碱基为T，150位点碱基为C，199位点碱基为T和204位点碱基为T者，肝癌根治性切除术后早期复发的可能性大。其中年龄、HBV DNA、肝硬化、TNM分期、TACE（≤2次或＞2次组）和mtDNA150位点是独立影响因素。（2）TNM分期为Ⅱ期、癌组织病理分级为中分化、有肝硬化、HBsAg阳性、HBeAg阳性、mtDNA16162位点碱基为A、mtDNA16172位点碱基为T、mtDNA16304位点碱基为T、mtDNA150位点碱基为T者，接受TACE治疗可明显降低肝癌的早期复发几率，其中接受TACE＞2次者可能所受益更大。（3）肝癌术后复发率高，肝吸虫感染、
HBV DNA、肝功能、TNM分期、TACE（≤2次或＞2次组）以及mtDNA310
位点是术后复发的独立影响因素。治疗乙肝，改善肝功能，接受TACE＞2次有可能降低复发的风险性，延长无瘤生存时间。（4）术后TACE能延缓
肿瘤复发，不能避免复发；并非所有患者对TACE预防肝癌术后复发均受益，部分患者因此而缩短无瘤生存时间。（5）预防肝癌复发，改善肝功能，复发后采取多种辅助治疗措施有助于长期生存。（6）P53、P21、nm23和VEGF蛋白预测肝癌预后作用有限。（7）检测mtDNA D-Loop区的碱基变
异有助于预测肝癌预后。
第三部分TACE预防肝癌根治性切除术后肿瘤复发的成本效果分析
目的建立肝癌根治性切除术后预防性TACE治疗的卫生经济学评价模型。
方法根据肝癌根治性切除术后有无接受预防性TACE治疗，分为TACE组和非TACE组（即门诊随访组）。收集两组治疗方案直接医疗成本，统计两组的治疗效果（复发率及无瘤生存时间），对两组进行成本效果分析及增量成本效果分析，同时进行敏感性分析。
结果（1）非TACE组的患者共40例，门诊总平均费用为7121.44元/人；TACE组的患者共100例，门诊总平均费用为5234.81元/人，住院行TACE治疗平均总费用为23015.64元/人，复发前总费用为28250.45元/人。（2）非TACE组的1、2、3、4、5年复发率分别为：60.0%、76.0%、81.3%、89.3%、100.0%；TACE组的1、2、3、4、5年复发率分别为：46.0%、67.1%、78.6%、88.2%、92.9%，组间比较无统计学意义（P＞0.05）；两组无瘤生存时间比较无统计学意义（18.3±3.0月vs22.1±2.0月或中位无瘤生存时间10.0月vs15.0月，P=0.322）。（3）非TACE组的成本效果比为389.15元/月，TACE组为1278.30元/月。以非TACE组为基础，增量成本效果比为5560.27元/月。（4）相关成本波动10%进行敏感性分析，非TACE组的成本效果比为350.84元/月，TACE组为1215.81元/月。以非TACE组为基础，增量成本效果比为5381.35元/月。
结论从卫生经济学角度，预防肝癌术后复发，预防性TACE并不是最优方案，至少不是每个患者都应该或都适合做，在相同的效果下（复发率、无瘤生存时间）门诊随访治疗可能更经济。
Part I The Protein Expression of P53, P21, nm23and VEGF and theVariations of the MtDNA D-Loop Region in Hepatocellular Carcinoma
Objective To study the expression of P53, P21, nm23and vascularendothelial growth factor (VEGF) and analyze the sequences of themitochondrial DNA (mtDNA) D-Loop region in hepatocellular carcinoma(HCC). And the relationship between the protein expression or the sequencesvariations and the clinicopathologic characteristics were also explored.
Methods140cases with HCCs were employed, of them123cases weremale and17were female, and the median age was47.0years (ranged from25to79years). These cases should meet the criteria as follows:(1) Including criteria:first, the case diagnosed liver tumor should receive the radical resection in thedepartment of hepatobiliary surgery of the first affiliated hospital to Guangximedical university from January2003to August2012; second, the case wasdiagnosed as hepatocellular carcinoma in pathology; third, the records of theinpatient department and the outpatient department for the case should be integrated.(2) Excluding criteria: first, the case who didn’t receive radicalresection; second, the case who died during the perioperative period; third, thecase who recurred in two months after the operation; forth, the case whoserecords of the inpatient department and the outpatient department wereunintegrated; fifth, the case with other serious medical diseases.(3) Radicalresection criteria for HCC: first, the whole tumor was removed completely andthere was no residual tumor along the radical margins; second, tumor numberwas no more than2; third, without tumor embolus in trunk or branch portal vein,nor in common hepatic duct or the primary branches, nor in hepatic vein trunkor in postcava; forth, without porta hepatis lymph node metastases; fifth, withoutextrahepatic metastases; sixth, the serum AFP dropped to normal if preoperativeserum AFP was high and there was no residual tumor screened by images in twomonths after resection. The expression of P53, P21, nm23and VEGF weredetected by immunohistochemical method and the mtDNA D-Loop sequenceswere analyzed by polymerase chain reaction (PCR) and direct sequencing. Andthen the data were analyzed by medical statistics.
Results (1) Of the140cases, the positive expression for P53protein was58.6%(82/140), and it was significantly related with the infection of liver fluke,tumor size, HBV DNA, tumor necrosis and microscope embolus (P<0.05). Theexpression rates for P53protein in cases with liver fluke infected, tumor sizelarger than3cm (or8cm), HBV DNA positive, tumor necrosis and microscopeembolus were remarkably higher, and they were75.0%,62.8%(or73.0%),72.2%,74.2%and80.0%, respectively.(2) Of the140cases, the positiveexpression for P21protein was44.3%(62/140), and it was significantly relatedwith differentiation degrees (Edmondson grades) and cirrhosis (P<0.05). Theexpression rates for P21protein in cases with well, moderate or poor differentiation were25.9%,44.9%and62.5%; and48.6%for cases withcirrhosis.(3) Of the140cases, the positive expression for nm23protein was77.9%(109/140), and it was significantly related with HBeAg, tumor necrosisand microscope embolus (P<0.05). The expression rates for nm23protein incases with positive HBeAg, and without tumor necrosis nor microscope emboluswere remarkably higher, and they were84.6%,81.9%and83.8%, respectively.(4) Of the140cases, the positive expression for VEGF protein was75.7%(106/140), and it was significantly related with age, infection of liver fluke andHBeAb (P<0.05). The expression rates for VEGF protein in cases with youngerthan47years old, liver fluke infected and positive HBeAb were remarkablyhigher, and they were82.9%,93.8%and82.5%.(5) Of the140cases, there were150points variations (13.4%,150/1122) for the mtDNA D-Loop sequences,and of them13were point mutations,8were insertions and20were deletions.There were116polymorphisms altogether. Most of the variations were locatedin hypervariable segments I (NT57-372) and II (NT16024-16383), and theywere46points (30.7%,46/150) and63(42.0%,63/150), respectively. The typesof the bases variations were T>A (18), A>T (29), C>G (21), G>C (34) anddeletions (16). The types of the bases mutations were G>A (5), T>A (3), A>T (3),A>C (1), C>G (1), C>A (1), and the mutation rate was10.0%(14/140). Therewas a special region named D310with poly C, and the types for it were C5TC63(2.1%), C8TC664(45.7%), C8TC764(45.7%), C9TC63(2.1%), C8CC6(C15)3(2.1%), and the rest3cases were standard type C8TC6(2.1%).
Conclusion (1) There is a high rate for P53protein expression in HCCs,and it maybe related with the infection of liver fluke, especially coinfected withHBV. For the advanced HCCs, the expression of P53protein is remarkablyhigher.(2) The rates for P21protein expression in HCCs are variable. And there
maybe a negative correlation with the differentiation degrees (Edmondson
grades) and a positive correlation with cirrhosis.(3) The expression rates for
nm23protein in cases with positive HBeAg, and without tumor necrosis normicroscope embolus are remarkably higher. And it seems that the protein of
nm23could suppress tumor metastasis.(4) There is a high rate for VEGFprotein expression in HCCs, and it maybe related with the infection of liverfluke.(5) The sequences of the mtDNA D-Loop region are variable, and most ofthem are located in hypervariable segments I and II. The D310region is alsovariable.
Part II The Prognoses for Hepatocellular Carcinoma after RadicalResection and the Clinical Value of Postoperative Adjuvant TACE
Objective To explore the prognoses for hepatocellular carcinoma afterradical resection and analyze the clinical value of postoperative adjuvant TACE.
Methods The clinicopathologic characteristics and the postoperativetreatments were collected for140cases with hepatocellular carcinomas (HCCs).And the recurrent time as well as the dead time were recorded carefully.Univariate analysis and multivariate analysis were performed according to theclinicopathologic characteristics and the postoperative treatments. The survivalanalysis was also performed for the tumor free survival and the overall survival.TACE was performed by the Seldinger technique, and the chemotherapeutic agents included pirarubicin, cisplatin and fluorouracil (5-FU), and the embolicagent was lipiodol.
Results (1) The median follow-up was40.9months (ranged from8to126months), and there were100cases with HCCs received postoperative adjuvantTACE before recurrence and the rest40without, but just received follow-upvisits through outpatient department. Until31December,2013, there were129cases with recurrences (median time was12.0months, ranged from3to77) and107cases dead (median time was37.0months, ranged from8to126). For129cases with recurrences, operations were performed again for42cases (49timesaltogether, twice for7cases); the treatments of TACE were354times,radiofrequency ablation (RFA) were31, and percutaneous ethanol injection (PEI)were152.(2) If the recurrent time was no longer than1year after the radicalresection, it was characterized as early recurrence; if not, it was late recurrence.In the univariate analysis, the clinicopathologic characteristics including age,tumor size, tumor capsule, surgical margin, blood transfusion during operation,HBeAg, HBV DNA, gamma-glutamyl transpeptidase (GGT), alanineaminotransferase (ALT), aspartate amino transferase (AST), differentiationdegree (Edmondson grade), cirrhosis, microscope embolus, TNM stage,adjuvant TACE, the locus16129(G/A) of mtDNA, the locus16192(C/T) ofmtDNA, the locus16297(T/C) of mtDNA, the locus150(C/T) of mtDNA, thelocus199(T/C) of mtDNA, and the locus204(T/C) of mtDNA weresignificantly different between the early recurrent group and the late (P<0.05).But only age, HBV DNA, TNM stage, adjuvant TACE (≤2or>2) and the locus150(C/T) of mtDNA were independent factors in the logistic regression. And ofthem, adjuvant TACE (≤2or>2) and the locus150(C/T) of mtDNA were protective factors, while the rest were risk. It seemed that there was norelationship between the protein expression of P53, P21, nm23, VEGF and theearly recurrences. Stratification analysis was also performed, and the cases withTNM stage Ⅱ, moderate differentiation, cirrhosis, positive HBsAg, positiveHBeAg, the locus16162of mtDNA with A, the locus16172of mtDNA with T,the locus16304of mtDNA with T, or the locus150of mtDNA with T whoreceived adjuvant TACE might decrease the recurrent rate. And the best benefittimes for them were more than2.(3) For140cases, the median tumor freesurvival was12.0months, and the recurrent rate for1,2,3,4,5years were50%,70%,79%,89%and92%, respectively. The clinicopathologic characteristicsincluding infection of liver fluke, HBV DNA, Child pugh class, TNM stage,adjuvant TACE (≤2or>2) and the locus310of mtDNA were independentfactors for tumor free survival according to the Cox proportional hazardregression model. And of them, Child pugh class and adjuvant TACE (≤2or>2)were protective factors, while the rest were risk. The cases with Child pugh classA or received more than2times adjuvant TACE might decrease the recurrentrate and prolong the tumor free survival. It seemed that there was no relationshipbetween the protein expression of P53, P21, nm23, VEGF and the tumor freesurvival. Surprisingly, the cases with tumor size no larger than3cm whoreceived more than2times adjuvant TACE had a shorter median tumor freesurvival (38.0vs19.0months, P=0.024) according to the stratification analysis.(4) For140cases, the median overall survival was37.0months, and the survivalrate for1,2,3,4,5years were94%,72%,56%,40%and27%, respectively. Theclinicopathologic characteristics including recurrent types (early/late), GGT(≥100U/L/<100U/L), Child pugh class (A/B) and the adjuvant treatment aftertumor recurrence (none or one/more than one treatment) were independent factors for overall survival according to the Cox proportional hazard regressionmodel. And of them, Child pugh class (A/B) and the adjuvant treatment aftertumor recurrence (none or one/more than one treatment) were protective factors,while the rest were risk. The cases with Child pugh class A or received morethan one adjuvant treatment after tumor recurrence might decrease the mortalityrate and prolong the overall survival. It seemed that there was no relationshipbetween the protein expression of P53, P21, nm23, VEGF and the overallsurvival.
Conclusions To analyze the clinicopathologic characteristics might have aprediction for early recurrence after HCCs resection. The cases with age≤47years, larger tumor size, without tumor capsule, surgical margin <2.0cm,consisted of blood transfusion during operation, positive HBeAg, positive HBVDNA, GGT≥50U/L, ALT≥90U/L, AST≥80U/L, moderate or poor differentiationdegree (Edmondson grade), cirrhosis, microscope embolus, TNM stage Ⅲ,adjuvant TACE≤2times, the locus16129of mtDNA with G, the locus16192ofmtDNA with C, the locus16297of mtDNA with T, the locus150of mtDNAwith C, the locus199of mtDNA with T, or the locus204of mtDNA with Tmight have a high rate of early recurrence. And of them, age, HBV DNA, TNMstage, adjuvant TACE (≤2or>2) and the locus150of mtDNA were independentfactors.(2) The cases with TNM stage Ⅱ, moderate differentiation, cirrhosis,positive HBsAg, positive HBeAg, the locus16162of mtDNA with A, the locus16172of mtDNA with T, the locus16304of mtDNA with T, or the locus150ofmtDNA with T who received adjuvant TACE might decrease the recurrent rate.And the best benefit times for them were more than2.(3) The recurrent rate ishigh after radical resection for HCC. And the infection of liver fluke, HBV DNA,
Child pugh class, TNM stage, adjuvant TACE (≤2or>2) and the locus310of
mtDNA are independent factors for tumor free survival. To treat hepatitis B, to
improve liver function, and to receive more than2times adjuvant TACE mightdecrease the recurrent rate, and prolong the tumor free survival.(4) Thepostoperative adjuvant TACE might postpone the tumor recurrence but not
avoid.The postoperative adjuvant TACE doesn’t benefit every case; in fact,some of them might have a shorter tumor free survival.(5) To prevent the tumorrecurrence after operation, to improve the liver function, and to treat withdifferent treatments after tumor recurrence might have a favorable benefit foroverall survival.(6) There are less utilities for the expression of P53, P21, nm23and VEGF protein to predict the prognoses of HCC.(7) To analyze thesequences variations of the mtDNA D-Loop region might have a favorablebenefit to predict the prognoses of HCC.
Part Ⅲ The Cost Effectiveness Analysis of the Postoperative AdjuvantTACE for the Prevention for Hepatocellular Carcinoma Recurrence
Objective To establish the health economics evaluation model forpreventative treatment of TACE after the radical resection for hepatocellularcarcinoma (HCC).
Methods140cases were divided into TACE group and non-TACE group according to the treatment after the radical resection for HCCs. For the TACEgroup, TACEs were performed; and for the non-TACE group, without TACE butjust received follow-up visits through outpatient department. The direct medicalcosts of the two groups were collected and the recurrent rate and the tumor freesurvival were picked up as effectiveness. Then the cost effectiveness and theincremental cost effectiveness were analyzed. At last the sensitivity analysis wasalso conducted.
Results (1) For40cases in the non-TACE group, the average fee for theoutpatient care was7121.44yuan per patient. Meanwhile, for100cases in theTACE group, the average fees were5234.81yuan per patient for the outpatientcare and23015.64yuan per patient for the hospitalization treated with TACE.And the total fee for the TACE group was28250.45yuan per patient beforetumor recurrences.(2) The tumor free survival rate for1,2,3,4,5years were60.0%,76.0%,81.3%,89.3%and100.0%, respectively for the non-TACE groupwhile46.0%,67.1%,78.6%,88.2%and92.9%, respectively for the TACEgroup, and there was no significant difference between the two groups (P＞0.05).And the tumor free survivals were similarly between the two groups (18.3±3.0months vs22.1±2.0months or10.0months vs15.0months in median, P=0.322).(3) The cost effectiveness ratio was389.15yuan/month for non-TACE groupwhile1278.30yuan/month for TACE group. Based on the non-TACE group, theincremental cost effectiveness ratio was5560.27yuan/month.(4) For thesensitivity analysis, the cost rose up or declined with10%. And then the costeffectiveness ratio was350.84yuan/month for non-TACE group while1215.81yuan/month for TACE group. Based on the non-TACE group, the incrementalcost effectiveness ratio was5381.35yuan/month.
Conclusions For the health economics aspect, the preventative treatment ofTACE after the radical resection for hepatocellular carcinoma (HCC) is not thebest choice, at least is not suitable for every case to receive. It seems that theoutpatient care is more economic under the similar effectiveness (recurrent rateand tumor free survival).
目的通过对肝细胞癌（简称肝癌）组织中的P53、P21、nm23、血管内皮生长因子（Vascular endothelial growth factor，VEGF），以及线粒体DNA（mitochondrial DNA，mtDNA）D-Loop区进行研究，以期发现它们在肝癌中的表达情况以及它们与临床病理参数间的关系。
方法收集140例肝癌患者的临床病理资料，其中男123例，女17例，中位年龄47.0岁（25岁~79岁），这些患者需同时满足以下条件：（一）入选标准：（1）2003年1月至2012年8月在广西医科大学第一附属医院肝胆外科住院诊断为肝癌，并接受根治性手术切除；（2）手术切除后有明确的病理证实为肝细胞癌；（3）具有完整的临床病理资料，随访状态良好，有完整的住院和门诊信息。（二）排除标准：（1）非根治性手术切除患者；（2）围手术期死亡患者；（3）随访术后2个月内复发者；（4）临床病理资料、随访资料不完整者；（5）有其它严重基础疾病患者。（三）肝癌根治性手术切除标准：（1）完整切除肉眼所见肿瘤，切缘无残癌；（2）肿瘤数目≤2个；（3）无门脉主干及一级分支、总肝管及一级分支、肝静脉主干及下腔静脉癌栓；（4）无肝门淋巴结转移；（5）无肝外转移；（6）术前血清AFP增高者，术后2个月内AFP应降至正常和影像学检查未见肿瘤残留。用免疫组化方法检测肝癌组织中的P53、P21、nm23、VEGF的蛋白表达，同时应用PCR结合直接测序的方法检测各样本组织中mtDNA D-Loop区的序列。对所得资料进行统计分析。
结果（1）P53蛋白在140例肝癌患者组织中阳性表达率为58.6%（82/140），P53蛋白的表达与肝吸虫感染，肿瘤大小，HBV DNA，肿瘤坏死以及微癌栓等临床病理因素相关（P<0.05）；有肝吸虫感染者，肿瘤直径大于3cm（或8cm）者，HBV DNA阳性者，肿瘤组织有坏死者以及有微癌栓者，P53蛋白表达率较高，分别为75.0%，62.8%（或73.0%），72.2%，74.2%和80.0%。（2）P21蛋白在140例肝癌患者组织中阳性表达率为44.3%（62/140），P21蛋白的表达与癌组织病理分级和肝硬化等临床病理因素相关（P<0.05）；癌组织病理分化越低，P21蛋白表达率越高，病理分级高、中、低分化癌组织的P21蛋白表达率分别为25.9%，44.9%和62.5%；有肝硬化者P21蛋白表达率较高，为48.6%。（3）nm23蛋白在140例肝癌患者组织中阳性表达率为77.9%（109/140），nm23蛋白的表达与HBeAg，肿瘤坏死以及微癌栓等临床病理因素相关（P<0.05）；HBeAg阴性者，肿瘤组织无坏死者以及无微癌栓者，nm23蛋白表达率较高，分别为84.6%，81.9%和83.8%。（4）VEGF蛋白在140例肝癌患者组织中阳性表达率为75.7%（106/140），VEGF蛋白的表达与患者年龄，肝吸虫感染以及HBeAb等临床病理因素相关（P<0.05）；年龄≤47岁者，有肝吸虫感染者以及HBeAb阳性者，VEGF蛋白表达率较高，分别为82.9%，93.8%和82.5%。（5）140例肝癌组织标本的mtDNA D-Loop区序列测序结果分析表明，共150个位点发生碱基变异，其中13个位点为点突变，8个位点发生插入，20个位点发生缺失，共出现116个多态性变化，位点总变异率为13.4%（150/1122）。其中，绝大部分的变异位点位于mtDNA D-Loop区的两个高变异区（hypervariable segments I and II，HVS I和HVS II），分别为HVS I（NT57-372）：46个位点（46/150，30.7%）和HVS II（NT16024-16383）：63个位点（63/150，42.0%）。多态性的碱基变异类型分别为：T>A（18例），
A>T（29例），C>G（21例），G>C（34例），Del（缺失）（16例）。突变的
碱基变异类型分别为：G>A（5例），T>A（3例），A>T（3例），A>C（1例），C>G（1例），C>A（1例），突变率为10.0%（14/140）。共有137例
D310区发生单核苷酸重复序列的变异，其类型分别为：C5TC63例（2.1%），C8TC664例（45.7%），C8TC764例（45.7%），C9TC63例（2.1%），C8CC6（C15）3例（2.1%），余下3例为标准序列的C8TC6（2.1%）。
结论（1）P53蛋白在肝癌组织中表达率较高，肝吸虫感染造成的长期慢性炎症，尤其是合并乙肝感染的情况下，可能是P53蛋白高表达的原因之一；HBV相关性肝癌中，P53蛋白表达增高；P53蛋白高表达于进展期的肝癌。（2）P21蛋白在肝癌组织中的表达率变化大；P21蛋白表达与癌组织病理分化呈负相关；伴有肝硬化者P21蛋白表达率较高。（3）nm23蛋白在肝癌组织中表达率较高，HBeAg阴性者，肿瘤组织无坏死者以及无微癌栓者，nm23蛋白表达率较高；nm23蛋白有抑制肿瘤转移的作用。（4）VEGF蛋白在肝癌组织中表达率较高，肝吸虫感染造成的长期慢性炎症可能上调VEGF蛋白的表达。（5）mtDNAD-Loop区序列高度可变，主要集中在两个高变异区HVS I（NT57-372）和HVS II（NT16024-16383）；D310区是个高度可变区域。
第二部分肝癌根治性切除术后预后影响因素的分析以及TACE治疗的临床价值
目的探讨肝癌根治性切除术后的预后影响因素；同时分析肝癌术后TACE治疗的临床价值。
方法收集140例肝癌患者的临床病理资料及术后治疗措施，随访登记他们复发、死亡时间，采用单因素和多因素的统计方法对预后影响因素进行统计，并对他们进行生存分析。TACE术采用Seldinger法，化疗药物包括吡柔比星、顺铂、氟尿嘧啶（5-FU），栓塞剂为碘油。
结果（1）平均随访时间40.9个月（8~126个月），复发前共有100例肝癌患者术后行TACE术共119次，余40例肝癌患者行门诊常规随访治疗。随访至2013年12月31日，共有129例复发，107例死亡，中位无瘤生存期为12.0个月（3~77个月），中位生存期为37.0个月（8~126个月）。129例肝癌术后复发患者中有42例行复发后手术再切除治疗（共49次，其中7例行复发后2次手术治疗），共行TACE354次，RFA31次，PEI52次。（2）以肝癌根治性切除术后1年内复发者定义为早期复发，1年后复发者定义为晚期复发，统计分析发现年龄、肿瘤大小、肿瘤包膜、手术切缘、术中输血情况、HBeAg、HBV DNA、GGT、ALT、AST、癌组织病理分级、肝硬化、微癌栓、TNM分期、TACE以及mtDNA中的16129位点（G/A）、16192位点（C/T）、16297位点（T/C）、150位点（C/T）、199位点（T/C）和204位点（T/C）在早期复发组与晚期复发组间比较有统计学意义（P<0.05）。多因素logistic回归分析发现：年龄、HBV DNA、肝硬化、TNM分期、TACE（≤2次或＞2次组）和mtDNA150位点是影响早期复发的独立影响因素；其中TACE（≤2次或＞2次组）和mtDNA150位点是保护因素，其余均为危险因素。未发现P53、P21、nm23和VEGF蛋白表达与肝癌早期复发有关。分层分析发现TNM分期为Ⅱ期、癌组织病理分级为中分化、有肝硬化、HBsAg阳性、HBeAg阳性、mtDNA16162位点碱基为A、mtDNA16172位点碱基为T、mtDNA16304位点碱基为T、mtDNA150位点碱基为T者，接受TACE治疗可明显降低肝癌的早期复发几率，并且发现接受TACE＞2次组所受益的患者最多。（3）140例肝癌患者的中位无瘤生存时间为12.0个月，1、2、3、4、5年的复发率分别为50%、70%、79%、89%、92%，多因素Cox比例风险回归模型分析发现肝吸虫感染、HBVDNA、肝功能、TNM分期、TACE（≤2次或＞2次组）以及mtDNA310位点是肝癌术后无瘤生存时间的影响因素。从回归系数看，肝功能和TACE（≤2次或＞2次组）是保护因素，其余均为危险因素。即肝功能为A级，接受TACE＞2次的患者复发的风险性较低，可延长无瘤生存时间。未发现P53、P21、nm23和VEGF蛋白表达与肝癌的无瘤生存期有关。分层分析发现肿瘤直径≤3.0cm的患者接受2次以上TACE治疗后中位无瘤生存时间反而缩短（38.0个月vs19.0个月，P=0.024）。（4）140例肝癌患者的中位生存期为37.0个月，1、2、3、4、5年的生存率分别为94%、72%、56%、40%、27%，多因素Cox比例风险回归模型分析发现复发时间类型、GGT（100U/L组）、肝功能以及复发后辅助治疗措施（无或单项、多项辅助治疗措施）是肝癌术后生存时间的独立影响因素。从回归系数看，肝功能和复发后辅助治疗措施（无或单项、多项辅助治疗措施）是保护因素，而复发时间类型和GGT（100U/L组）是危险因素。即肝功能为A级，复发后接受多项辅助治疗措施的患者死亡的风险性较低，可延长生存时间。未发现P53、P21、nm23和VEGF蛋白表达与肝癌生存期有关。
结论（1）临床病理参数有助于预测肝癌术后早期复发，年龄≤47岁，肿瘤越大，无肿瘤包膜或不完整，手术切缘<2.0cm，术中有输血史，HBeAg（+），HBV DNA（+），GGT≥50U/L，ALT≥90U/L，AST≥80U/L，癌组织病理分级为中、低分化，有肝硬化，有微癌栓，TNM分期Ⅲ期，肝癌术后复发前行TACE术≤2次，以及mtDNA中的16129位点碱基为G，16192位点碱基为C，16297位点碱基为T，150位点碱基为C，199位点碱基为T和204位点碱基为T者，肝癌根治性切除术后早期复发的可能性大。其中年龄、HBV DNA、肝硬化、TNM分期、TACE（≤2次或＞2次组）和mtDNA150位点是独立影响因素。（2）TNM分期为Ⅱ期、癌组织病理分级为中分化、有肝硬化、HBsAg阳性、HBeAg阳性、mtDNA16162位点碱基为A、mtDNA16172位点碱基为T、mtDNA16304位点碱基为T、mtDNA150位点碱基为T者，接受TACE治疗可明显降低肝癌的早期复发几率，其中接受TACE＞2次者可能所受益更大。（3）肝癌术后复发率高，肝吸虫感染、
HBV DNA、肝功能、TNM分期、TACE（≤2次或＞2次组）以及mtDNA310
位点是术后复发的独立影响因素。治疗乙肝，改善肝功能，接受TACE＞2次有可能降低复发的风险性，延长无瘤生存时间。（4）术后TACE能延缓
肿瘤复发，不能避免复发；并非所有患者对TACE预防肝癌术后复发均受益，部分患者因此而缩短无瘤生存时间。（5）预防肝癌复发，改善肝功能，复发后采取多种辅助治疗措施有助于长期生存。（6）P53、P21、nm23和VEGF蛋白预测肝癌预后作用有限。（7）检测mtDNA D-Loop区的碱基变
异有助于预测肝癌预后。
第三部分TACE预防肝癌根治性切除术后肿瘤复发的成本效果分析
目的建立肝癌根治性切除术后预防性TACE治疗的卫生经济学评价模型。
方法根据肝癌根治性切除术后有无接受预防性TACE治疗，分为TACE组和非TACE组（即门诊随访组）。收集两组治疗方案直接医疗成本，统计两组的治疗效果（复发率及无瘤生存时间），对两组进行成本效果分析及增量成本效果分析，同时进行敏感性分析。
结果（1）非TACE组的患者共40例，门诊总平均费用为7121.44元/人；TACE组的患者共100例，门诊总平均费用为5234.81元/人，住院行TACE治疗平均总费用为23015.64元/人，复发前总费用为28250.45元/人。（2）非TACE组的1、2、3、4、5年复发率分别为：60.0%、76.0%、81.3%、89.3%、100.0%；TACE组的1、2、3、4、5年复发率分别为：46.0%、67.1%、78.6%、88.2%、92.9%，组间比较无统计学意义（P＞0.05）；两组无瘤生存时间比较无统计学意义（18.3±3.0月vs22.1±2.0月或中位无瘤生存时间10.0月vs15.0月，P=0.322）。（3）非TACE组的成本效果比为389.15元/月，TACE组为1278.30元/月。以非TACE组为基础，增量成本效果比为5560.27元/月。（4）相关成本波动10%进行敏感性分析，非TACE组的成本效果比为350.84元/月，TACE组为1215.81元/月。以非TACE组为基础，增量成本效果比为5381.35元/月。
结论从卫生经济学角度，预防肝癌术后复发，预防性TACE并不是最优方案，至少不是每个患者都应该或都适合做，在相同的效果下（复发率、无瘤生存时间）门诊随访治疗可能更经济。
Part I The Protein Expression of P53, P21, nm23and VEGF and theVariations of the MtDNA D-Loop Region in Hepatocellular Carcinoma
Objective To study the expression of P53, P21, nm23and vascularendothelial growth factor (VEGF) and analyze the sequences of themitochondrial DNA (mtDNA) D-Loop region in hepatocellular carcinoma(HCC). And the relationship between the protein expression or the sequencesvariations and the clinicopathologic characteristics were also explored.
Methods140cases with HCCs were employed, of them123cases weremale and17were female, and the median age was47.0years (ranged from25to79years). These cases should meet the criteria as follows:(1) Including criteria:first, the case diagnosed liver tumor should receive the radical resection in thedepartment of hepatobiliary surgery of the first affiliated hospital to Guangximedical university from January2003to August2012; second, the case wasdiagnosed as hepatocellular carcinoma in pathology; third, the records of theinpatient department and the outpatient department for the case should be integrated.(2) Excluding criteria: first, the case who didn’t receive radicalresection; second, the case who died during the perioperative period; third, thecase who recurred in two months after the operation; forth, the case whoserecords of the inpatient department and the outpatient department wereunintegrated; fifth, the case with other serious medical diseases.(3) Radicalresection criteria for HCC: first, the whole tumor was removed completely andthere was no residual tumor along the radical margins; second, tumor numberwas no more than2; third, without tumor embolus in trunk or branch portal vein,nor in common hepatic duct or the primary branches, nor in hepatic vein trunkor in postcava; forth, without porta hepatis lymph node metastases; fifth, withoutextrahepatic metastases; sixth, the serum AFP dropped to normal if preoperativeserum AFP was high and there was no residual tumor screened by images in twomonths after resection. The expression of P53, P21, nm23and VEGF weredetected by immunohistochemical method and the mtDNA D-Loop sequenceswere analyzed by polymerase chain reaction (PCR) and direct sequencing. Andthen the data were analyzed by medical statistics.
Results (1) Of the140cases, the positive expression for P53protein was58.6%(82/140), and it was significantly related with the infection of liver fluke,tumor size, HBV DNA, tumor necrosis and microscope embolus (P<0.05). Theexpression rates for P53protein in cases with liver fluke infected, tumor sizelarger than3cm (or8cm), HBV DNA positive, tumor necrosis and microscopeembolus were remarkably higher, and they were75.0%,62.8%(or73.0%),72.2%,74.2%and80.0%, respectively.(2) Of the140cases, the positiveexpression for P21protein was44.3%(62/140), and it was significantly relatedwith differentiation degrees (Edmondson grades) and cirrhosis (P<0.05). Theexpression rates for P21protein in cases with well, moderate or poor differentiation were25.9%,44.9%and62.5%; and48.6%for cases withcirrhosis.(3) Of the140cases, the positive expression for nm23protein was77.9%(109/140), and it was significantly related with HBeAg, tumor necrosisand microscope embolus (P<0.05). The expression rates for nm23protein incases with positive HBeAg, and without tumor necrosis nor microscope emboluswere remarkably higher, and they were84.6%,81.9%and83.8%, respectively.(4) Of the140cases, the positive expression for VEGF protein was75.7%(106/140), and it was significantly related with age, infection of liver fluke andHBeAb (P<0.05). The expression rates for VEGF protein in cases with youngerthan47years old, liver fluke infected and positive HBeAb were remarkablyhigher, and they were82.9%,93.8%and82.5%.(5) Of the140cases, there were150points variations (13.4%,150/1122) for the mtDNA D-Loop sequences,and of them13were point mutations,8were insertions and20were deletions.There were116polymorphisms altogether. Most of the variations were locatedin hypervariable segments I (NT57-372) and II (NT16024-16383), and theywere46points (30.7%,46/150) and63(42.0%,63/150), respectively. The typesof the bases variations were T>A (18), A>T (29), C>G (21), G>C (34) anddeletions (16). The types of the bases mutations were G>A (5), T>A (3), A>T (3),A>C (1), C>G (1), C>A (1), and the mutation rate was10.0%(14/140). Therewas a special region named D310with poly C, and the types for it were C5TC63(2.1%), C8TC664(45.7%), C8TC764(45.7%), C9TC63(2.1%), C8CC6(C15)3(2.1%), and the rest3cases were standard type C8TC6(2.1%).
Conclusion (1) There is a high rate for P53protein expression in HCCs,and it maybe related with the infection of liver fluke, especially coinfected withHBV. For the advanced HCCs, the expression of P53protein is remarkablyhigher.(2) The rates for P21protein expression in HCCs are variable. And there
maybe a negative correlation with the differentiation degrees (Edmondson
grades) and a positive correlation with cirrhosis.(3) The expression rates for
nm23protein in cases with positive HBeAg, and without tumor necrosis normicroscope embolus are remarkably higher. And it seems that the protein of
nm23could suppress tumor metastasis.(4) There is a high rate for VEGFprotein expression in HCCs, and it maybe related with the infection of liverfluke.(5) The sequences of the mtDNA D-Loop region are variable, and most ofthem are located in hypervariable segments I and II. The D310region is alsovariable.
Part II The Prognoses for Hepatocellular Carcinoma after RadicalResection and the Clinical Value of Postoperative Adjuvant TACE
Objective To explore the prognoses for hepatocellular carcinoma afterradical resection and analyze the clinical value of postoperative adjuvant TACE.
Methods The clinicopathologic characteristics and the postoperativetreatments were collected for140cases with hepatocellular carcinomas (HCCs).And the recurrent time as well as the dead time were recorded carefully.Univariate analysis and multivariate analysis were performed according to theclinicopathologic characteristics and the postoperative treatments. The survivalanalysis was also performed for the tumor free survival and the overall survival.TACE was performed by the Seldinger technique, and the chemotherapeutic agents included pirarubicin, cisplatin and fluorouracil (5-FU), and the embolicagent was lipiodol.
Results (1) The median follow-up was40.9months (ranged from8to126months), and there were100cases with HCCs received postoperative adjuvantTACE before recurrence and the rest40without, but just received follow-upvisits through outpatient department. Until31December,2013, there were129cases with recurrences (median time was12.0months, ranged from3to77) and107cases dead (median time was37.0months, ranged from8to126). For129cases with recurrences, operations were performed again for42cases (49timesaltogether, twice for7cases); the treatments of TACE were354times,radiofrequency ablation (RFA) were31, and percutaneous ethanol injection (PEI)were152.(2) If the recurrent time was no longer than1year after the radicalresection, it was characterized as early recurrence; if not, it was late recurrence.In the univariate analysis, the clinicopathologic characteristics including age,tumor size, tumor capsule, surgical margin, blood transfusion during operation,HBeAg, HBV DNA, gamma-glutamyl transpeptidase (GGT), alanineaminotransferase (ALT), aspartate amino transferase (AST), differentiationdegree (Edmondson grade), cirrhosis, microscope embolus, TNM stage,adjuvant TACE, the locus16129(G/A) of mtDNA, the locus16192(C/T) ofmtDNA, the locus16297(T/C) of mtDNA, the locus150(C/T) of mtDNA, thelocus199(T/C) of mtDNA, and the locus204(T/C) of mtDNA weresignificantly different between the early recurrent group and the late (P<0.05).But only age, HBV DNA, TNM stage, adjuvant TACE (≤2or>2) and the locus150(C/T) of mtDNA were independent factors in the logistic regression. And ofthem, adjuvant TACE (≤2or>2) and the locus150(C/T) of mtDNA were protective factors, while the rest were risk. It seemed that there was norelationship between the protein expression of P53, P21, nm23, VEGF and theearly recurrences. Stratification analysis was also performed, and the cases withTNM stage Ⅱ, moderate differentiation, cirrhosis, positive HBsAg, positiveHBeAg, the locus16162of mtDNA with A, the locus16172of mtDNA with T,the locus16304of mtDNA with T, or the locus150of mtDNA with T whoreceived adjuvant TACE might decrease the recurrent rate. And the best benefittimes for them were more than2.(3) For140cases, the median tumor freesurvival was12.0months, and the recurrent rate for1,2,3,4,5years were50%,70%,79%,89%and92%, respectively. The clinicopathologic characteristicsincluding infection of liver fluke, HBV DNA, Child pugh class, TNM stage,adjuvant TACE (≤2or>2) and the locus310of mtDNA were independentfactors for tumor free survival according to the Cox proportional hazardregression model. And of them, Child pugh class and adjuvant TACE (≤2or>2)were protective factors, while the rest were risk. The cases with Child pugh classA or received more than2times adjuvant TACE might decrease the recurrentrate and prolong the tumor free survival. It seemed that there was no relationshipbetween the protein expression of P53, P21, nm23, VEGF and the tumor freesurvival. Surprisingly, the cases with tumor size no larger than3cm whoreceived more than2times adjuvant TACE had a shorter median tumor freesurvival (38.0vs19.0months, P=0.024) according to the stratification analysis.(4) For140cases, the median overall survival was37.0months, and the survivalrate for1,2,3,4,5years were94%,72%,56%,40%and27%, respectively. Theclinicopathologic characteristics including recurrent types (early/late), GGT(≥100U/L/<100U/L), Child pugh class (A/B) and the adjuvant treatment aftertumor recurrence (none or one/more than one treatment) were independent factors for overall survival according to the Cox proportional hazard regressionmodel. And of them, Child pugh class (A/B) and the adjuvant treatment aftertumor recurrence (none or one/more than one treatment) were protective factors,while the rest were risk. The cases with Child pugh class A or received morethan one adjuvant treatment after tumor recurrence might decrease the mortalityrate and prolong the overall survival. It seemed that there was no relationshipbetween the protein expression of P53, P21, nm23, VEGF and the overallsurvival.
Conclusions To analyze the clinicopathologic characteristics might have aprediction for early recurrence after HCCs resection. The cases with age≤47years, larger tumor size, without tumor capsule, surgical margin <2.0cm,consisted of blood transfusion during operation, positive HBeAg, positive HBVDNA, GGT≥50U/L, ALT≥90U/L, AST≥80U/L, moderate or poor differentiationdegree (Edmondson grade), cirrhosis, microscope embolus, TNM stage Ⅲ,adjuvant TACE≤2times, the locus16129of mtDNA with G, the locus16192ofmtDNA with C, the locus16297of mtDNA with T, the locus150of mtDNAwith C, the locus199of mtDNA with T, or the locus204of mtDNA with Tmight have a high rate of early recurrence. And of them, age, HBV DNA, TNMstage, adjuvant TACE (≤2or>2) and the locus150of mtDNA were independentfactors.(2) The cases with TNM stage Ⅱ, moderate differentiation, cirrhosis,positive HBsAg, positive HBeAg, the locus16162of mtDNA with A, the locus16172of mtDNA with T, the locus16304of mtDNA with T, or the locus150ofmtDNA with T who received adjuvant TACE might decrease the recurrent rate.And the best benefit times for them were more than2.(3) The recurrent rate ishigh after radical resection for HCC. And the infection of liver fluke, HBV DNA,
Child pugh class, TNM stage, adjuvant TACE (≤2or>2) and the locus310of
mtDNA are independent factors for tumor free survival. To treat hepatitis B, to
improve liver function, and to receive more than2times adjuvant TACE mightdecrease the recurrent rate, and prolong the tumor free survival.(4) Thepostoperative adjuvant TACE might postpone the tumor recurrence but not
avoid.The postoperative adjuvant TACE doesn’t benefit every case; in fact,some of them might have a shorter tumor free survival.(5) To prevent the tumorrecurrence after operation, to improve the liver function, and to treat withdifferent treatments after tumor recurrence might have a favorable benefit foroverall survival.(6) There are less utilities for the expression of P53, P21, nm23and VEGF protein to predict the prognoses of HCC.(7) To analyze thesequences variations of the mtDNA D-Loop region might have a favorablebenefit to predict the prognoses of HCC.
Part Ⅲ The Cost Effectiveness Analysis of the Postoperative AdjuvantTACE for the Prevention for Hepatocellular Carcinoma Recurrence
Objective To establish the health economics evaluation model forpreventative treatment of TACE after the radical resection for hepatocellularcarcinoma (HCC).
Methods140cases were divided into TACE group and non-TACE group according to the treatment after the radical resection for HCCs. For the TACEgroup, TACEs were performed; and for the non-TACE group, without TACE butjust received follow-up visits through outpatient department. The direct medicalcosts of the two groups were collected and the recurrent rate and the tumor freesurvival were picked up as effectiveness. Then the cost effectiveness and theincremental cost effectiveness were analyzed. At last the sensitivity analysis wasalso conducted.
Results (1) For40cases in the non-TACE group, the average fee for theoutpatient care was7121.44yuan per patient. Meanwhile, for100cases in theTACE group, the average fees were5234.81yuan per patient for the outpatientcare and23015.64yuan per patient for the hospitalization treated with TACE.And the total fee for the TACE group was28250.45yuan per patient beforetumor recurrences.(2) The tumor free survival rate for1,2,3,4,5years were60.0%,76.0%,81.3%,89.3%and100.0%, respectively for the non-TACE groupwhile46.0%,67.1%,78.6%,88.2%and92.9%, respectively for the TACEgroup, and there was no significant difference between the two groups (P＞0.05).And the tumor free survivals were similarly between the two groups (18.3±3.0months vs22.1±2.0months or10.0months vs15.0months in median, P=0.322).(3) The cost effectiveness ratio was389.15yuan/month for non-TACE groupwhile1278.30yuan/month for TACE group. Based on the non-TACE group, theincremental cost effectiveness ratio was5560.27yuan/month.(4) For thesensitivity analysis, the cost rose up or declined with10%. And then the costeffectiveness ratio was350.84yuan/month for non-TACE group while1215.81yuan/month for TACE group. Based on the non-TACE group, the incrementalcost effectiveness ratio was5381.35yuan/month.
Conclusions For the health economics aspect, the preventative treatment ofTACE after the radical resection for hepatocellular carcinoma (HCC) is not thebest choice, at least is not suitable for every case to receive. It seems that theoutpatient care is more economic under the similar effectiveness (recurrent rateand tumor free survival).
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