| Background and Objective:Hepatocellular carcinoma (HCC) is one of the most common cancer and cause of cancer death worldwide, especially in China. Nowadays, surgical resection is still the best way to prolong patients'survival, but the high postoperative recurrence remains the major obstacle to improve prognosis. Thus, markers which can predict tumor recurrence ideally are signality to clinical treatment of liver cancer.Several researches in recent years supported the viewpoint that local inflammatory and immune response, mediated by tumor microenvironment, was correlated to the carcinogenesis and progression of liver cancer. Although the ability of some serum inflammatory and viral markers in prognosis of hepatocellular carcinoma has been reported, their value still remains inconclusive.In this study, we selected potential inflammatory and viral markers (ALT, GGT, GGT/ALT, HBeAg) to be evaluated and then screened the valuable ones in order to validated their relationship to survival and recurrence of HBV-associated hepatocellular carcinoma.Methods:A retrospective analysis was performed on 2011 patients with HCC in Liver Cancer Institute, Zhongshan Hospital, Fudan University between 2002 and 2007. The cumulative survival and recurrence was calculated by the Kaplan-Meier method and compared by Log-rank test between different groups. COX regression model was applied to determine the independent prognostic factors. Use 2 years as the cutoff value to distinguish the early recurrent cases from the late for the sake of analyzing the possible cause of recurrence. A further stratified analysis according to BCLC staging system was carried out to verify the correlation between the parameters and prognosis of HCC in different BCLC stages. Receiver operating curve (ROC) analysis was used to compare the prognostic value of the variables. Two-sided P<0.05 was judged to be statistically significant. Results:During the follow-up,1208(60.1%) of the 2011 patients died. The 1-,3-and 5-year survival rates were 80.9%,53.1% and 29.0% respectively. Recurrence was found in 963(47.9%) patients. The 1-,3-and 5-year recurrence rates were 29.6%,49.4% and 59.7% respectively.Univariate analysis of the whole cohort showed that patients with different level of ALT, GGT, GGT/ALT or HBeAg had a significant differences in survival and recurrence(all P<0.001); Multivariate analysis indicated that GGT, GGT/ALT and HBeAg were the independent risk factors of both survival and recurrence (all P<0.001), however, ALT was the independent risk factor of recurrence only (P=0.038).A further univariate analysis of early recurrence(TTR<2 years) revealed the remarkable differences in early recurrence rates between different ALT, GGT, GGT/ALT and HBeAg level groups (P<0.001,<0.001,<0.001,=0.002 respectively). COX regression analysis also identified the 4 variables as the factors contributing to early recurrence(P=0.049,0.004,0.002,0.001 respectively).Univariate analysis of late recurrence (TTR>2 years) showed remarkable differences in late recurrence rates between different GGT, GGT/ALT and HBeAg level groups (P=0.003,0.001,0.014 respectively), but not between different ALT level groups (P=0.100). COX regression analysis identified GGT, GGT/ALT and HBeAg as the factors contributing to early recurrence (P=0.07,0.002,0.017 respectively).In the study of BCLC stage 0-A patients, the survival and the recurrence rates were significant lower and higher in high level ALT, GGT/ALT and HBeAg groups(all P<0.05) and only lower survival rate was found in high GGT level groups (P=0.009). Multivariate analysis indicated that GGT, GGT/ALT and HBeAg were the independent risk factor of survival(P=0.024,0.002 and<0.001 respectively), and ALT, GGT/ALT and HBeAg was the independent risk factor of recurrence(P=0.005,0.018 and 0.001 respectively).In the study of BCLC stage B-C cases, significant lower survival rates and higher recurrence rates were seen in high level ALT, GGT, GGT/ALT and HBeAg level groups(all P<0.05). Multivariate analysis showed that all these variables were the independent risk factor of survival and recurrence(all P<0.05) except ALT.The combination of GGT/ALT and HBeAg contained a better ability to predict survival and recurrence of both early and advanced BCLC stage patients. When both high group(GGT/ALT high and HBeAg positive) was compared with both low group(GGT/ALT low and HBeAg negative), the corresponding hazard ratios(HRs) in COX regression test for survival and recurrence was much higher than the HRs of other single markers.ROC analysis revealed that the AUC of the combination in survival and recurrence was higher than that of other single markers. Meanwhile, the AUC of GGT/ALT was the highest among single markers.Conclusion:1. Preoperative serum ALT>40U/L was the independent risk factor of recurrence in early BCLC stage patients with HBV-associated HCC, but has no impact on survival.2. Preoperative serum GGT>90U/L was the independent risk factor of survival and recurrence in patients with HBV-associated HCC, but not significant in early BCLC stage patients.3. Preoperative serum GGT/ALT>1.5 and HBeAg positive were the independent risk factor of survival and recurrence in patients with HBV-associated HCC no matter in which BCLC stage, and the mechanism of the variables on tumor invasiveness might be both intrahepatic metastasis and multicentric tumor recurrence. The combination of the 2 variables was a better predictor for prognosis.
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