Liver transplant for large hepatocellular carcinoma in Malatya: Therole of gamma glutamyl transferase and alpha-fetoprotein, aretrospective cohort study

BACKGROUND There is increasing interest in transplanting patients with hepatocellularcarcinoma (HCC) with tumors greater than 5 cm (Milan criteria).AIM To investigate possible prognostically-useful factors for liver transplantation inHCC patients with large tumors.METHODS In this clinical study, 50 patients with HCC who were transplanted at our LiverTransplant Center between April 2006 and August 2019 and had tumors greaterthan 6 cm maximum diameter were retrospectively analyzed. Their survival andfull clinical characteristics were examined, with respect to serum alphafetoprotein(AFP) and gamma glutamyl transpeptidase (GGT) levels. Kaplan-Meier survival estimates were used to determine overall survival and disease-freesurvival in these patients. The inclusion criterion was evidence of HCC. Exclusioncriteria were the presence of macroscopic portal vein thrombosis or metastasisand a follow-up period of less than 90 d.RESULTS Using receiver operating characteristic curve (ROC) analysis, cutoff values of AFP200 ng/mL and GGT 104 IU/L were identified and used in this study.Significantly longer overall survival (OS) and disease-free-survival (DFS) were found in patients who had lower values of either parameter, compared withhigher values. Even greater differences in survival were found when the 2parameters were combined. Two tumor size bands were identified, in searchingfor the limits of this approach with larger tumors, namely 6-10 cm and > 10 cm.Combination parameters in the 6-10 cm band reflected 5-year OS of 76.2% inpatients with low AFP plus low GGT vs 0% for all other groups. Patients withtumors greater than 10 cm, did not have low AFP plus low GGT. The mostconsistent clinical correlates for longer survival were degree of tumordifferentiation and absence of microscopic portal venous invasion.CONCLUSION Serum levels of AFP and GGT, both alone and combined, represent a simpleprognostic identifier in patients with large HCCs undergoing liver transplantation.

Analysis of aggressiveness factors in hepatocellular carcinoma patients undergoing transarterial chemoembolization

AIM To investigate novel predictors of survival in hepatocellular carcinoma(HCC) patients following transarterial chemoembolization(TACE).METHODS One hundred sixty seven patients with un-resectable HCC were retrospectively analyzed to identify factors that might contribute to their HCC biology and aggressiveness. We correlated routine laboratory results(total bilirubin, AST, ALKP, GGTP, albumin etc.) to maximum tumor diameter, number of tumor nodules, portal vein thrombosis and blood alpha-fetoprotein levels. These 4 parameters were previously combined to form an aggressiveness index(AgI). We used The Wilcoxon ranksum(Mann-Whitney), to test the correlation between the AgI categories and liver function parameters. The Cox proportional hazards model was applied to evaluate the categories of AgI associated with overall survival. RESULTS The AgI was strongly correlated with survival in this novel patient population. Three year survival probability for AgI > or < 4 was 42.4% vs 61.8%; P < 0.0863 respectively. Several factors independently correlated with AgI using univariate multiple logistic regression of AgI with 8 laboratory parameters. Lower albumin levels had an OR of 2.56(95%CI: 1.120-5.863 P < 0.026), elevated Alkaline phosphatase and gamma glutamyl transpeptidase(GGTP) had ORs of 1.01(95%CI: 1.003-1.026, P < 0.017) and 0.99(95%CI: 0.99-1.00, P < 0.053) respectively. In a Cox proportional hazard model combining mortality for AgI score and liver function parameters, only GGTP levels and the AgI were independently associated with survival. An AgI > 4 had HR for mortality of 2.18(95%CI: 1.108-4.310, P < 0.024). GGTP's single unit change had a HR for mortality of 1.003(95%CI: 1.001-1.006, P < 0.016). These were considered in the final multivariate model with the total cohort. An AgI > 4 had a HR for mortality of 2.26(95%CI: 1.184-4.327, P < 0.016). GGTP had a HR of 1.003(95%CI: 1.001-1.004, P < 0.001).CONCLUSION Our study validates the AgI in a new population with un-resectable HCC patients undergoing TACE. The analysis establishes a correlation between GGTP and the AgI.

多途径丝裂原激活的蛋白激酶介导一氧化氮引起的肝癌细胞凋亡

目的 研究非离子型的diazeniumdiolate类一氧化氮供体引起肝癌细胞凋亡的分子机制。方法 利用免疫印迹、免疫沉淀、凝胶阻滞实验研究一氧化氮供体处理Hep3B肝癌细胞后,丝裂原激活的蛋白激酶、AP-1的激活以及和Hep3B肝癌细胞凋亡的关系。结果 一氧化氮可引起细胞外信号调节蛋白激酶、c-jun N末端激酶和p38激酶的激活,特别是细胞外信号调节的蛋白激酶的持续激活,其中细胞外信号调节的蛋白激酶和c-jun N末端激酶的特异的阻断剂U0126和JNK抑制剂Ⅱ可阻断AP-1的激活和Hep3B细胞的凋亡,而p38激酶的阻断剂SB203580不能阻断AP-1的激活和Hep3B肝癌细胞的凋亡。结论 一氧化氮通过激活细胞外信号调节蛋白激酶、c-jun N末端激酶,进而激活AP-1而引起Hep3B肝癌细胞的凋亡。