See Ching Chan

Continuous Improvement of Survival Outcomes of Resection of Hepatocellular Carcinoma: A 20-Year Experience

Objective:To investigate the trend of the posthepatectomy survival outcomes of hepatocellular carcinoma (HCC) patients by analysis of a prospective cohort of 1198 patients over a 20-year period. Background:The hospital mortality rate of hepatectomy for HCC has improved but the long-term survival rate remains unsatisfactory. We reported an improvement of survival results 10 years ago. It was not known whether there has been further improvement of results in recent years. Methods:The patients were categorized into two 10-year periods: period 1, before 1999 (group 1, n = 390) and period 2, after 1999 (group 2, n = 808). Patients in group 2 were managed according to a modified protocol and technique established in previous years. Results:The patients in group 2 were older and had a higher incidence of comorbid illness and cirrhosis. They had a lower hospital mortality rate (3.1% vs 6.2%, P = 0.012) and longer 5-year overall survival (54.8% vs 42.1%, P < 0.001) and disease-free survival rates (34.8% vs 24%, P = 0.0024). An improvement in the overall survival rate was observed in patients with cirrhosis, those undergoing major hepatectomy, and those with tumors of tumor-node-metastasis stages II, IIIA, and IVA. A significant increase in the survival rates was also seen in patients whose tumors were considered transplantable by the Milan criteria (72.5% vs 62.7%, P = 0.0237). Multivariate analysis showed a significantly more favorable patient survival for hepatectomy in period 2. Conclusions:A continuous improvement of survival outcomes after hepatectomy for HCC was achieved in the past 20 years even in patients with advanced diseases. Hepatectomy remains the treatment of choice for resectable HCC in a predominantly hepatitis B virus-based Asian population.

A Randomized, Controlled Trial of Postoperative Adjuvant Interferon Therapy After Resection of Hepatocellular Carcinoma

Objective:We conducted a randomized controlled trial of adjuvant interferon therapy in patients with predominantly hepatitis B-related hepatocellular carcinoma (HCC) to investigate whether the prognosis after hepatic resection could be improved. Summary Background Data:Recurrence is common after hepatic resection for HCC. Interferon possesses antiviral, immunomodulatory, antiproliferative, and antiangiogenic effects and may be an effective form of adjuvant therapy. Patients and Methods:Since February 1999, patients with no residual disease after hepatic resection for HCC were randomly assigned with stratification by pTNM stage to receive no treatment (control group), interferon alpha-2b 10 MIU/m2 (IFN-I group) or 30 MIU/m2 (IFN-II group) thrice weekly for 16 weeks. Enrollment to the IFN-II group was terminated from January 2000 because adverse effects resulted in treatment discontinuation in the first 6 patients. By June 2002, 40 patients each had been enrolled into the control group and IFN-I group. The baseline clinical, laboratory, and tumor characteristics of both groups were comparable. Results:The 1- and 5-year survival rates were 85% and 61%, respectively, for the control group and 97% and 79%, respectively, for the IFN-I group (P = 0.137). After adjusting for the confounding prognostic factors in a Cox model, the relative risk of death for interferon treatment was 0.42 (95% CI, 0.17–1.05; P = 0.063). Exploratory subset analysis showed that adjuvant interferon had no survival benefit for pTNM stage I/II tumor (5-year survival 90% in both groups; P = 0.917) but prevented early recurrence and improved the 5-year survival of patients with stage III/IVA tumor from 24% to 68% (P = 0.038). Conclusion:In a group of patients with predominantly hepatitis B-related HCC, adjuvant interferon therapy showed a trend for survival benefit, primarily in those with pTNM stage III/IVA tumors. Further larger randomized trials stratified for stage are needed.

Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation.

BACKGROUND & AIMS We investigated the efficacy of entecavir, a cyclopentyl guanosine nucleoside analogue, as monoprophylaxis in patients with chronic hepatitis B who received a liver transplant. METHODS We studied data from 80 consecutive patients who received a liver transplant (47 from living donors and 33 from deceased donors) for hepatitis B-related disease and entecavir monotherapy as prophylaxis. None of the patients received hepatitis B immunoglobulin. Indications for transplant included decompensation from cirrhosis (27.5%), acute-on-chronic hepatitis B (47.5%), and hepatocellular carcinoma (25%). The median follow-up time was 26 months (range, 5-40 months). Before transplant, 33 patients were not on antiviral therapy and 47 were on oral therapy (18 had received less than 3 months of treatment). RESULTS At the time of transplant, the median log HBV DNA level was 3.5 copies/mL (range, 1.54-8.81); 21 patients (26%) had undetectable levels of HBV DNA. The cumulative rate of hepatitis B surface antigen (HBsAg) loss was 86% and 91% after 1 and 2 years, respectively. Ten patients had reappearance of HBsAg. Eighteen patients (22.5%) were HBsAg positive at the time of their last examination; 17 of these had undetectable levels of HBV DNA, and the remaining patient had a low level of HBV DNA (217 copies/mL). There was no evidence of mutations at sites that confer resistance to entecavir among patients who were HBsAg positive. CONCLUSIONS Although only 26% of patients had complete viral suppression at the time of transplant, 91% lost HBsAg, with 98.8% achieving undetectable levels of HBV DNA. A hepatitis B immunoglobulin-free regimen of entecavir monotherapy is effective after liver transplantation for chronic hepatitis B.

Long-term survival analysis of pure laparoscopic versus open hepatectomy for hepatocellular carcinoma in patients with cirrhosis: A single-center experience

Introduction: Laparoscopic liver resection has been reported as a safe and effective approach to the management of liver cancer. However, studies of long-term outcomes regarding tumor recurrence and patient survival in comparison with the conventional open approach are limited. The aim of this study was to analyze the survival outcome of laparoscopic liver resection versus open liver resection. Patients and Methods: Between October 2002 and September 2009, 32 patients underwent pure laparoscopic liver resection for hepatocellular carcinoma (HCC). Case-matched control patients (n = 64) who received open liver resection for HCC were included for comparison. Patients were matched in terms of cancer stage, tumor size, location of tumor, and magnitude of resection. Immediate operation outcomes, operation morbidity, disease-free survival, and overall survival were compared between groups. Results: With the laparoscopic group compared with the open resection group, operation time was 232.5 minutes versus 204.5 minutes (P = 0.938), blood loss was 150 mL versus 300 mL (P = 0.001), hospital stay was 4 days versus 7 days (P < 0.0001), postoperative complication was 2 (6.3%) versus 12 (18.8%) (P = 0.184), disease-free survival was 78.5 months versus 29 months (P = 0.086), and overall survival was 92 months versus 71 months (P = 0.142). The disease-free survival for stage II HCC was 22.1 months versus 12.4 months (P = 0.075). Conclusions: Laparoscopic liver resection for HCC is associated with less blood loss, shorter hospital stay, and fewer postoperative complications in selected patients with no compromise in survival.

Toward current standards of donor right hepatectomy for adult-to-adult live donor liver transplantation through the experience of 200 cases.

Objective:To define the current standards of donor right hepatectomy, including the middle hepatic vein for adult-to-adult live donor liver transplantation. Summary Background Data:Donor morbidity and mortality are inevitable given the ultra-major nature of the donor operation. Results from a matured center could define the true impact of this donor procedure most accurately. Patients and Methods:From May 9, 1996 to April 13, 2005, 200 consecutive donors underwent donor right hepatectomy at the University of Hong Kong Medical Center. All right liver grafts except one included the middle hepatic vein. Donor characteristics, operation time, blood loss, hospital stay, laboratory results, and complications graded by Claviens classification divided into four eras (each consecutive 50 cases) were compared. Results:Donor characteristics of the four eras were generally comparable. Operative outcomes improved progressively through the four eras. From era 1 to era 4, operation time decreased from 598 minutes (range, 378–932 minutes) to 391 minutes (range, 304–635 minutes). Blood loss also decreased from 500 mL (200–1600 mL) of era 1 to 251 mL (range, 95–595 mL) of era 4. Overall complication rate was 20.5% (41 of 200). Complications rates from eras 1 to 4 were 34%, 16%, 16%, and 16%, respectively. The most common complications were of grade I (24 of 41, 58.5%). A late donor death occurred in era 4 from the development of a duodenocaval fistula 10 weeks postoperation, giving a donor mortality of 0.5% (1 of 200). Conclusions:This study validated the estimated morbidity and mortality of donor right hepatectomy of 20% and 0.5%, respectively. The data provide reference for counseling potential donors and setting the standards of donor right hepatectomy in the current era.

Liver transplantation for chronic hepatitis B with lamivudine-resistant YMDD mutant using add-on adefovir dipivoxil plus lamivudine.

Lamivudine treatment in patients with chronic hepatitis B virus (HBV) infection may improve clinical state and suppress viral replication before liver transplantation. Emergence of lamivudine‐resistant YMDD mutant is common. We report the results of liver transplantation in 16 patients with pretransplantation YMDD mutants after receiving lamivudine treatment for a median of 738 days (range, 400‐1799 days). Adefovir dipivoxil (10 mg daily) was added on to lamivudine for a median of 20 days (range, 8‐271 days) before (n = 11) or at (n = 5) liver transplantation, and the combination was continued indefinitely thereafter. Eight patients received additional intravenous hepatitis B immune globulin (HBIG) for a median of 24 months. Fifteen patients with known pre‐adefovir HBV DNA levels had a median titer of 14,200 × 103 copies/mL (2 × 103 to 4,690,000 × 103 copies/mL), and 14 had HBV DNA >105 copies/mL. All but 1 patient remained positive for HBV DNA (by quantitative polymerase chain reaction [qPCR]) at the time of liver transplantation, and the titer was greater than105 copies/mL in 8 patients. The median follow‐up after liver transplantation was 21.1 (range, 4.4‐68.9) months. One patient (6%) died of an unrelated cause 12.2 months after transplantation, and 15 patients (94%) were alive with the original graft. All patients cleared HBV DNA and had no detectable HBV DNA by qPCR at the latest follow‐up. Fourteen patients had cleared hepatitis B surface antigen (HBsAg), but 2 patients who received only adefovir dipivoxil and lamivudine without HBIG remained HBsAg positive after 7.7 and 9.5 months. Serum HBV DNA, however, was negative, and there was no biochemical or histological evidence of recurrence. Adefovir dipivoxil was well tolerated with no significant renal toxicity. In conclusion, a combination of add‐on adefovir dipivoxil plus lamivudine therapy provides effective prophylaxis in patients with pretransplantation YMDD mutant that may be actively replicating. The cost effectiveness of additional passive immunoprophylaxis remains to be defined. (Liver Transpl 2005;11:807–813.)

Impact of Antiviral Therapy on the Survival of Patients After Major Hepatectomy for Hepatitis B Virus–Related Hepatocellular Carcinoma

OBJECTIVES To assess whether commencement of antiviral therapy after hepatectomy improves the prognosis of hepatocellular carcinoma (HCC) in preoperatively antiviral-naive patients with chronic hepatitis B virus (HBV) infection. DESIGN Retrospective analysis of a prospectively collected database. SETTING University teaching hospital. MAIN OUTCOME MEASURES Disease-free and overall survival rates. RESULTS One hundred thirty-six patients received major hepatectomy for HBV-related HCC from September 1, 2003, through December 31, 2007. Among them, 42 patients received antiviral therapy (treatment group) after hepatectomy, whereas 94 did not (control group). Patient demographics, preoperative liver function, tumor characteristics, and liver function at the time of tumor recurrence were comparable between the 2 groups. Disease-free and overall survival rates were significantly prolonged in the treatment group. The 1-, 3-, and 5-year overall survival rates in the treatment group were 88.1%, 79.1%, and 71.2%, respectively; in the control group, 76.5%, 47.5%, and 43.5%, respectively (P = .005). The 1-, 3-, and 5-year disease-free survival rates in the treatment group were 66.5%, 51.4%, and 51.4%, respectively; in the control group, 48.9%, 33.8%, and 33.8%, respectively (P = .05). Subgroup analysis stratified against tumor stage and major vascular invasion showed that posthepatectomy antiviral treatment conferred a significant survival benefit in stages I and II tumors or HCCs without major venous invasion. CONCLUSIONS Antiviral therapy improves the prognosis of HBV-related HCC. It should be considered after hepatectomy for HBV-related HCC, especially in early-stage tumors.

Operative Outcomes of Adult-to-Adult Right Lobe Live Donor Liver Transplantation: A Comparative Study With Cadaveric Whole-Graft Liver Transplantation in a Single Center

Objective:To evaluate and compare the operative and survival outcomes of patients who underwent right lobe live donor liver transplantation (RLDLT) and cadaveric whole-graft liver transplant (CWLT) recipients in a single institution. Summary Background Data:Current data suggest that RLDLT has an inferior graft survival outcome when compared with CWLT. Patients and Methods:A prospective study was performed on 180 consecutive adult patients who underwent primary liver transplantation from January 2000 to February 2004. The operative and survival outcomes of RLDLT (n = 124) were compared with those of CWLT (n = 56). Results:Fifty-five (44%) and 16 (29%) patients were on high-urgency list in the RLDLT group and the CWLT group, respectively (P = 0.045). The preoperative Model for End-Stage Liver Disease scores were comparable in both groups. The waiting time for liver transplantation was significantly shorter in the RLDLT group. The graft weight to estimated standard liver weight ratio was significantly lower in the RLDLT group. The postoperative hospital stay and hospital mortality were comparable in the RLDLT group (1.6%) and the CWLT group (5.4%). Thirty-one (25%) patients in the RLDLT group and 3 (5%) patients in the CWLT group developed biliary stricture on follow-up (P = 0.002). At a median follow-up of 27 months, the actuarial graft and patient survival rates were 88% and 90%, respectively, in the RLDLT group, and both were 84% in the CWLT group. Conclusion:RLDLT results in favorable operative outcomes comparable with those of CWLT. However, there is a significantly higher incidence of biliary stricture associated with RLDLT.

Interleukin-2 receptor antibody (basiliximab) for immunosuppressive induction therapy after liver transplantation: A protocol with early elimination of steroids and reduction of tacrolimus dosage

A prospective evaluation was performed to study the potential benefits of the use of interleukin‐2 receptor antibody (IL‐2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty‐one liver transplant recipients who underwent right‐lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL‐2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL‐2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new‐onset diabetes (0% vs 28%, P = .011), acute cellular rejection (6% vs 27%, P = .038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P = .011) in the IL‐2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL‐2Rab group (median, 4.0 vs 4.4 mmol/L, P = .007). On follow‐up, none of the patients in the IL‐2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL‐2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new‐onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long‐term follow‐up are required to document their potential benefits on hepatitis B and HCC recurrences. (Liver Transpl 2004;10:728–733.)

High-Intensity Focused Ultrasound for Hepatocellular Carcinoma A Single-Center Experience

Objective: This study aims to evaluate the outcome of patients with hepatocellular carcinoma (HCC) treated by high-intensity focused ultrasound (HIFU) in a single tertiary referral center. Background: HIFU is the latest developed local ablation technique for unresectable HCC. The initial experience on its efficacy is promising, but the survival benefit of patients undergoing HIFU for HCC is poorly defined. Methods: From October 2006 to December 2008, 49 patients received HIFU for unresectable HCC. Each patient underwent a single session of HIFU with a curative intent. Treatment efficacy and survival outcome were evaluated. Clinicopathologic factors affecting the primary technique effectiveness and overall survival rates were investigated by univariate analysis. Results: The median size of the treated tumors was 2.2 cm, ranging from 0.9 to 8 cm. The majority of patients had single tumors (n = 41, 83.6%). Thirty-one patients (63.2%) had artificial right pleural effusion during HIFU treatment to reduce damage to the lung and diaphragm. The hospital mortality rate was 2% (n = 1) and the complication rate was 8.1% (n = 4). The primary technique effectiveness rate was 79.5% (39 of 49 patients). It increased from 66.6% in the initial series to 89.2% in the last 28 patients. Tumor size (≥3.0 cm) was the significant risk factor affecting the complete ablation rate. The 1- and 3-year overall survival rates were 87.7% and 62.4%, respectively. Child-Pugh liver function grading was the significant prognostic factor influencing the overall survival rate. Conclusions: HIFU is an effective treatment modality for unresectable HCC with a high technique effectiveness rate and favorable survival outcome.