Rey-Heng Hu

Percutaneous Ethanol Injection Versus Surgical Resection for the Treatment of Small Hepatocellular Carcinoma: A Prospective Study

Objective:To compare disease recurrence and survival among patients with small hepatocellular carcinoma after surgical resection or percutaneous ethanol injection therapy, 2 treatments that have not been evaluated with a prospective study. Methods:A total of 76 patients were randomly assigned to 2 groups based on treatment; all had one or 2 tumors with diameter ≤3 cm, with hepatitis without cirrhosis or Child class A or B cirrhosis without evident ascites or bleeding tendency. Results:Follow-up ranged from 12 to 59 months. Among percutaneous injection patients, 18 had recurrence 1 to 37 months after treatment (true recurrence, 11; original safety margin inadequate, 3; limitation of imaging technology to detect tiny tumors, 4). Three injection therapy patients died of cancer 25, 37, and 57 months after treatment. For the surgical resection group, 15 had recurrence 2 to 54 months after treatment (true recurrence, 12; limitation of imaging, 2; neck metastasis, 1). Five resection patients died of cancer at 11, 20, 23, 26, and 52 months, respectively. By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for recurrence and survival between treatment groups. However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival. Conclusions:Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments can be considered first-line options for small hepatocellular carcinoma.

Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: A randomized phase II trial for safety and optimal dosage

BACKGROUND/AIMS Hepatocellular carcinoma recurrence after curative treatment adversely influences clinical outcome. It is important to explore adjuvant therapies. This phase II/stage 1 multi-center, randomized trial investigated the safety, optimal dosage and preliminary efficacy of PI-88, a novel heparanase inhibitor, in the setting of post-operative recurrence of HCC according to a Simons 2-stage design. METHODS Three groups were included: one untreated arm (Group A) and two PI-88 arms (Group B: 160 mg/day; Group C: 250 mg/day). Treatment groups received PI-88 over nine 4-week treatment cycles, followed by a 12-week treatment-free period. Safety and optimal dosage were assessed. RESULTS Overall, 172 patients were randomized and 168 were included in the intention-to-treat (ITT) population. Treatment-related adverse effects included cytopenia, injection site hemorrhage, PT prolongation, etc. Four serious adverse events were possibly related to PI-88 treatment. One (1.8%) group B patients and six (10.5%) group C had hepatotoxicity-related withdrawals. Among the ITT population, 29 patients (50%) in Group A, 35 (63%) in Group B, and 22 (41%) in Group C remained recurrence-free at completion. Calculated T(1) value suggested 160 mg/day treatment satisfied the criteria for the next stage of the trial. CONCLUSIONS PI-88 at 160 mg/day is optimal and safe, and shows preliminary efficacy as an adjunct therapy for post-operative HCC.

Clinical Management of Recurrent Hepatocellular Carcinoma

ObjectiveThe aim of this study was to evaluate the long-term benefits of the aggressive treatments with resection or transarterial chemoembolization (TACE) for recurrent hepatocellular carcinoma (HCC). Summary Background DataPrimary HCC is one of the most fatal malignancies in Taiwan. The result of resection for HCC remains unsatisfactory, primarily due to the high recurrence rate. To improve surgical results, recurrent HCC must be treated with aggressive resection or TACE. MethodsThe authors evaluated the results of repeated hepatic resection among 25 patients with recurrent HCC and of TACE among 12 patients with resectable recurrent HCC. The outcomes of an additional 64 patients with unresectable recurrent HCC were also evaluated. ResultsDuring the follow-up period from 2–112 months, 52% (13/25) of patients receiving repeat resection (group 1) were alive, whereas 42% (5/12) of patients receiving TACE (group 2) were alive. No perioperative deaths within 30 days after surgery occurred in the repeated resection group. The cumulative survival rates at 1,2,3, and 5 years after the first operation were 92%, 84%, 71.6%, and 65.1 % in group 1 and 83.3%, 75%, 75%, and 22.5% in group 2. The survival rates at 6 months and at 1,2, and 3 years after recurrence were 92%, 72%, 64%, and 44.8% in group 1 and 83.3%, 75%, 66.7%, and 48% in group 2.The survival of patients with unresectable recurrent HCC was much worse: 1 -, 2-, 3-, and 5-year survival after surgery was 57.8%, 29.8%, 15.5%, and 0%; and 6-month and 1-, 2-, and 3-year survival after recurrence was 46.5%, 29.2%, 12.5% and 7.8%. ConclusionsMore aggressive treatment with repeated hepatic resection can prolong survival time after recurrence of HCC in selected patients. However, TAGE can also achieve good results although it is not thought of as curative.

Surgical resection for recurrent hepatocellular carcinoma: Prognosis and analysis of risk factors

BACKGROUND Hepatocellular carcinoma (HCC) is common in Asian countries, and tumor recurrence is the most common cause of treatment failure after curative resection. Repeated hepatectomy is performed only for selected patients because most patients with HCC also have liver cirrhosis and poor liver function reserve. The purposes of this study were to clarify the outcome of the patients after second hepatectomy for recurrent HCC and to evaluate the prognostic factors after second hepatectomy. METHODS We used retrospective cohort study to examine the disease-free survival, cumulative survival, and possible prognostic factors for recurrence and death in 59 patients who underwent surgical resection for recurrent HCC at the National Taiwan University Hospital from August 1986 to December 1993. Another 64 patients with unresectable recurrent HCC were used as a historical control group. The survival curves between those patients with resectable HCC and those with unresectable HCC were compared. RESULTS After resection for recurrent HCC, gender and multiplicity (n > 3) of tumor affect recurrence rate (p = 0.046 and 0.021, respectively), whereas gender, age, and tumor invasiveness affect survival rate significantly (p = 0.024, 0.021, and 0.046, respectively). The survival rate of patients with resectable HCC was significantly better than that of those with unresectable HCC. CONCLUSIONS For recurrent HCC surgical resection is an effective mode of treatment in selected patients. Whether surgery is better than other modes of treatment in the treatment of resectable recurrent HCC demands further investigation.

Expanding the donor pool: use of renal transplants from non-heart-beating donors supported with extracorporeal membrane oxygenation

Abstract:  In response to organ shortage, we used the renal grafts from non‐heart‐beating donors (NHBDs). Extracorporeal membrane oxygenation (ECMO) was used to maintain NHBDs before organ procurement. We compared the results of renal transplantation from different donors, including heart‐beating donors (HBDs), living‐related donors (LDs), and NHBDs supported with ECMO. From February 1998 to June 2003, we recruited 219 patients receiving renal transplantation at National Taiwan University Hospital. Among them, 31 received kidneys from NHBDs supported with ECMO, 120 from HBDs, and 68 from LDs. Multiple organ transplant recipients were not included in this study. We compared the graft survival, serum creatinine levels, and estimated glomerular filtration rates of the three groups. The rate of delayed graft function was higher in NHBD recipients (41.9%) than in HBD recipients (27.0%) and LD recipients (10.9%) (p = 0.003). In the NHBD group, the recipients of grafts with delayed function had significantly longer ECMO runs (63.1 ± 3.0 min) than those without delayed function (53.7 ± 2.5 min) (p = 0.024). Estimated glomerular filtration rate (p = 0.472) and mean serum creatinine level (p = 0.286) were not significantly different between the three groups using a longitudinal approach. The 5‐yr graft survival rates for NHBD (88.4%, 95% CI: 0.680–0.962), HBD (83.2%, 95% CI: 0.728–0.899), and LD transplant recipients (89.3%, 95% CI: 0.619–0.974) were not significantly different (p = 0.239). The 5‐yr patient survival rates for NHBD, HBD, and LD transplant recipients were 100, 93.0 (95% CI: 0.859–0.966) and 100% respectively. The long‐term allograft survival and function of kidneys from NHBDs supported by ECMO, HBD, and LD did not differ significantly. Long ECMO running time tended to delay graft function.

Mucin glycosylating enzyme GALNT2 regulates the malignant character of hepatocellular carcinoma by modifying the EGF receptor.

Extracellular glycosylation is a critical determinant of malignant character. Here, we report that N-acetylgalactosaminyltransferase 2 (GALNT2), the enzyme that mediates the initial step of mucin type-O glycosylation, is a critical mediator of malignant character in hepatocellular carcinoma (HCC) that acts by modifying the activity of the epidermal growth factor receptor (EGFR). GALNT2 mRNA and protein were downregulated frequently in HCC tumors where these events were associated with vascular invasion and recurrence. Restoring GALNT2 expression in HCC cells suppressed EGF-induced cell growth, migration, and invasion in vitro and in vivo. Mechanistic investigations revealed that the status of the O-glycans attached to the EGFR was altered by GALNT2, changing EGFR responses after EGF binding. Inhibiting EGFR activity with erlotinib decreased the malignant characters caused by siRNA-mediated knockdown of GALNT2 in HCC cells, establishing the critical role of EGFR in mediating the effects of GALNT2 expression. Taken together, our results suggest that GALNT2 dysregulation contributes to the malignant behavior of HCC cells, and they provide novel insights into the significance of O-glycosylation in EGFR activity and HCC pathogenesis.

Feasibility of salvage liver transplantation for patients with recurrent hepatocellular carcinoma

Abstract:  Background:  Recurrence is the most frequent cause of treatment failure after hepatocellular carcinoma (HCC) resection. Salvage liver transplantation is an alternative treatment for recurrent HCC. The transplantability for patients with recurrent HCC has not been well studied.

Survival in patients with recurrent hepatocellular carcinoma after primary hepatectomy: Comparative effectiveness of treatment modalities

BACKGROUND Insufficient data are available on the survival of recurrent hepatocellular carcinoma after primary hepatectomy in patients receiving different treatments. We evaluated retrospectively the effects of treatment modalities on long-term survival. METHODS Between 2001 and 2007, 435 posthepatectomy hepatocellular carcinoma patients who developed recurrence were grouped by treatment modality into re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups. Treatment strategies for both primary hepatocellular carcinoma and its recurrence were selected using the same criteria. Postrecurrence survival was estimated using the Kaplan-Meier method and compared using the Cox proportional hazard model with adjusted independent prognostic factors. Survival rates after primary resection without recurrence were also compared. RESULTS In re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups, the 2-year postrecurrence survival rates were 90%, 96%, 75%, and 20%, respectively, and the 5-year survival rates were 72%, 83%, 56%, and 0%, respectively. The adjusted hazard of death was less for the re-resection and radiofrequency ablation groups than for the transarterial chemoembolization group, and the adjusted hazard ratios for the re-resection and radiofrequency ablation groups were 0.45 (95% confidence interval, 0.20-0.98) and 0.25 (0.08-0.81), respectively. The adjusted hazard ratio (95% confidence interval) of death for the radiofrequency ablation group compared to the re-resection group was 0.64 (0.19-2.19). Survival in the single resection group did not differ from that in the re-resection and radiofrequency ablation groups. CONCLUSION Postrecurrence survival in the re-resection and radiofrequency ablation groups was significantly better than that in the transarterial chemoembolization group and similar to that of patients in the primary resection without recurrence group.

High-Titer Antibody to Hepatitis B Surface Antigen Before Liver Transplantation Can Prevent De Novo Hepatitis B Infection

Objective: De novo hepatitis B virus (HBV) infection is defined as infection occurring in HBV surface antigen (HBsAg)–negative patients who become HbsAg positive after organ transplantation. We assessed the incidence and risk factors of de novo HBV infection in pediatric liver transplant recipients. Patients and Methods: From 1996 to 2006, 71 Taiwanese children with non-HBV-related liver diseases underwent orthotopic liver transplantation (OLT) at the National Taiwan University Hospital. All of the surviving recipients were tested regularly for liver function, serum levels of immunosuppressant, HBsAg, titers of antibodies to hepatitis B surface antigen (anti-HBs), antibodies to hepatitis B core antigen (anti-HBc), and antibodies to hepatitis C virus (anti-HCV). HBV vaccination histories and the anti-HBs titers before OLT were recorded. No regular prophylaxis was given. Results: Fifty-nine patients (33 girls and 26 boys) were followed up for a median of 4.4 years (range 1.0–10.0). Of those, 36 (61.0%) received allografts from anti-HBc-positive and HBsAg-negative donors. De novo HBV infection was found in 9 (15.3%) patients after OLT, 8 of whom received allografts from HBsAg-negative and anti-HBc-positive donors. Forty-eight (81.4%) patients received 3 or more doses of HBV vaccine before OLT. Pre-OLT anti-HBs titers were available for 49 recipients. Of the 9 de novo HBV-infected recipients, 8 had anti-HBs titers <200 mIU/mL. No graft loss or fulminant hepatitis was noted. Conclusions: In the absence of adequate prophylaxis, the incidence of de novo HBV infection in pediatric OLT recipients is 15.3%. An anti-HBs titer of >200 mIU/mL before OLT may be sufficient to prevent de novo HBV infection in HBsAg-negative recipients.

Role of p53 and β-catenin Mutations in Conjunction with CK19 Expression on Early Tumor Recurrence and Prognosis of Hepatocellular Carcinoma

BackgroundCytokeratin 19 (CK19), a molecular marker of hepatic progenitor cells and cholangiocytes, is expressed in hepatocellular carcinomas (HCC), but not in normal hepatocytes. However, role of CK19 in HCC progression, especially when interacted with p53 and β-catenin mutations, remained largely unknown.Materials and MethodsFrom January 1983 to December 1997, 210 surgically resected, unifocal, primary HCCs were studied retrospectively. CK19 protein expression was detected by immunohistochemistry while mutations of p53 and β-catenin genes were detected by direct DNA sequencing.ResultsCK19 protein expression was detected in 35.7% (75/210), p53 mutation in 47.2% (83/176) and β-catenin mutation in 14.5% (27/186). The tumor size (p = 0.0023), grade (p = 0.00093), tumor stage (p = 4 × 10−7), high α-fetoprotein (p = 0.0004), p53 mutation (p = 0.024), absence of β-catenin mutation (p = 0.0013), and CK19 expression (p = 3 × 10−5) were markers predictive of early tumor recurrence (ETR). CK19 expression, stage, and ETR were strong indicators of poor prognosis (all p < 0.0001). Importantly, combination analysis showed an additive unfavorable prognostic interaction of CK19 expression and p53 mutation. On the contrary, concurrent CK19 expression and β-catenin mutation was rare and CK19 expression abolished the suppression effect of β-catenin mutation on HCC progression.ConclusionsCK19 expression is associated with more aggressive HCC. CK19 cooperates with p53 mutation towards advanced disease. In contrast, CK19 expression and β-catenin mutation play dramatic opposite roles in vascular invasion, ETR and the prognosis of HCC.