Surgical Treatment Strategy For Hepatocellular Carcinoma And Prevention And Treatment For Postoperative Tumor Recurrence

Part I. Surgical treatment strategy for small hepatocellular carcinoma: liver transplantation or liver resection?Aim:Both liver transplantation and resection are effective treatments for single hepatocellular carcinoma (HCC) fulfilling the Milan criteria, however, their indications are still controversial in those patients with Child-Pugh A liver disease. This study aims to compare the long-term survival of patients with single HCC fulfilling the Milan criteria treated by liver resection or transplantation, and elucidate the prognostic factors of Child-Pugh A patients with single HCC fulfilling the Milan criteria after liver resection.Methods:A consecutive series of276patients with single HCC fulfilling the Milan criteria undergoing either liver resection or liver transplantation in Tongji Hospital from April2001to October2009were retrospectively reviewed. The long-term survivals of the resection group (n=256) and the transplantation group (n=20) were analyzed. The Child-Pugh A patients in the resection group were stratified by the different grades of cirrhosis (no, mild, moderate and severe) according the Laennec scoring system, and the survivals of the subgroups with different grades of cirrhosis were then analyzed and compared with those of the transplantation group. The prognostic factors of Child-Pugh A patients with single HCC fulfilling the Milan criteria were analyzed.Results:The5-year recurrence-free and overall survival rates were49.3%and71.8%, respectively, in the resection group, and83.6%and89.2%, respectively, in the transplantation group. The patients in the transplantation group had significantly better recurrence-free survival than those in the resection group, whereas there was no significant difference between the two groups in overall survival. Among241patients with Child-Pugh A in the resection group,44patients diagnosed with no cirrhosis,101patients with mild cirrhosis, and96patients with moderate/severe cirrhosis. The5-year recurrence-free and overall survival rates were68.5%and92.5%, respectively, in the subgroup of no cirrhosis;63.4%and85.9%, respectively, in the subgroup of mild cirrhosis; and28.6%and50.4%, respectively, in the subgroup of moderate/severe cirrhosis. There was no significant difference between the resection subgroups of either no cirrhosis or mild cirrhosis and the transplantation group in recurrence-free survival or overall survival, whereas patients in the resection subgroup of moderate/severe cirrhosis had significantly worse recurrence-free and overall survival compared with those in the transplantation group. Moreover, the patients in the subgroups of either no cirrhosis or mild cirrhosis had significantly better recurrence-free and overall survival than those in subgroup of moderate/severe cirrhosis. The patients in the subgroup of mild cirrhosis had comparable recurrence-free and overall survivals with those in the subgroup of no cirrhosis. Moderate/severe cirrhosis, absence of tumor capsule, presence of microvascular invasion and moderate/poor tumor differentiation were independent adverse prognostic factors for recurrence-free survival of Child-Pugh A patients after resection. Moderate/severe cirrhosis, lower platelet count (<100×109/L) and moderate/poor tumor differentiation were independent adverse prognostic factors for overall survival of Child-Pugh A patients after resection.Conclusions:Liver resection achieves similar outcomes as liver transplantation in patients both with single HCC fulfilling the Milan criteria and without cirrhosis or with Child-Pugh A mild cirrhosis, and it should be the first-line treatment for these patients. Liver transplantation should be confined to those with Child-Pugh A moderate or severe cirrhosis, or with Child-Pugh B and C cirrhosis. Liver biopsy should be performed to evaluate severity of cirrhosis and to optimize the indications for liver transplantation. Part Ⅱ. The outcomes of repeat hepatic resection in patients with recurrent hepatocellular carcinoma and analysis of recurrent typesAim:Recurrent hepatocellular carcinoma (HCC) after curative resection usually originates from intrahepatic metastasis (IM) or multicentric occurrence (MO). The long-term outcomes of repeat hepatic resection in patients with different types of recurrence have not been evaluated in a large number of patients. The surgical indications for recurrent HCC remain controversial. The purpose of this study was to investigate long-term outcomes of repeat hepatic resection and clinicopathologic factors associated with different types of recurrent HCC, and to single out principle differentiating factors between IM and MO.Methods:Eighty-two patients undergoing repeat hepatic resection for recurrent HCC were retrospectively studied. The recurrent type was evaluated by histopathologic analysis of primary and recurrent HCC. The recurrence and survival rates as well as clinicopathologic factors associated with different types of recurrence were analyzed.Results:Forty-five patients (54.9%) had confirmed with IM, and37patients (45.1%) had with MO. The recurrence rates in the MO patients after initial or repeat resection were significantly lower than those in the IM patients. The overall survival rates in the MO patients after initial or repeat resection were significantly higher than those in the IM patients. Recurrence-free time was identified as the most significant differentiating factor between IM and MO. A recurrence-free time of18months after initial resection was a significant cutoff time point for differentiating between IM and MO. A recurrence-free time of less than or equal to18months and microvascular invasion at repeat resection were independent adverse prognostic factors for overall survival after repeat hepatic resection.Conclusions:Repeat hepatic resection resulted in much higher survival rates in the MO patients than in the IM patients. Repeat hepatic resection could be recommended for those patients in whom the recurrent HCC occurs in more than18months after initial resection. Part Ⅲ. Synergistic effect of PARP-1inhibitor PJ34and HDAC inhibitor SAHA on inhibiting the proliferation of liver cancer cellsAim:Molecular targeted therapy is an effective treatment method for advanced liver cancer. This study aimed to explore whether the combination of molecular targeted drugs, PARP-1inhibitor PJ34and HDAC inhibitor SAHA, have a synergistic effect on inhibiting the proliferation of liver cancer cells.Methods:The human liver cancer cell lines HepG2, Hep3B, HCC-LM3and the human normal liver cell line L02which express PARP-1positively were selected as the research subjects. Each group of cells were administered with different groups of drugs (PJ34, SAHA, PJ34+SAHA) respectively. Cell proliferation assay (CCK-8Kit) was employed to investigate cell proliferation of each group following drug administration. The cell apoptosis rates of each group following drug administration were analyzed by flow cytometry. HepG2cells were inoculated subcutaneously into nude mice and formed subcutaneous tumors. The nude mice bearing subcutaneous tumors were grouped randomly and administered with different groups of drugs (PBS, PJ34, SAHA, PJ34+SAHA) respectively. The inhibition rates of tumor growth were compared among each group.Results:Both PJ34and SAHA inhibited the proliferation of HepG2cells in a dose-dependent manner. There was no significant cell cytotoxicity on human normal liver cell line L02with the concentrations of8μmol/L PJ34and1μmol/L SAHA. However, the combination of PJ34(8μmol/L) and SAHA (1μmol/L) have a synergistic effect on inhibiting the proliferation of liver cancer cells, such as HepG2, Hep3B and HCC-LM3, and the coefficient of drug interaction were0.67,0.81and0.76, respectively (CDI<1means synergy). The apoptosis rates of the combined application of PJ34and SAHA on HepG2cells was significantly higher than those of the separate application of PJ34or SAHA. In vivo, the tumor inhibition rates of PJ34alone (10mg/kg), SAHA alone (25mg/kg) and PJ34combined with SAHA (10mg/kg PJ34+25mg/kg SAHA) were53.5%,61.4%and82.6%, respectively. The combined application of PJ34and SAHA had significantly more efficacy on inhibiting xenograft tumor grow than the application of PJ34or SAHA alone.Conclusions:The combination of PARP-1inhibitor PJ34and HDAC inhibitor SAHA have a synergistic effect on inhibiting the proliferation of liver cancer cells.