Teh-Ia Huo

Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma ☆

BACKGROUND/AIMS Hepatitis B virus (HBV) levels correlate with the development of hepatocellular carcinoma (HCC), but the role of viral load in HCC recurrence after tumor resection remains unclear. Herein we aimed to investigate the role of viral load in HCC recurrence following tumor resection. METHODS From 1990 to 2002, 193 HBV-related HCC patients who underwent tumor resection in Taipei Veterans General Hospital were enrolled. Serum HBV DNA level and mutations were analyzed for association with early and late recurrence, together with other clinical variables. RESULTS During a follow-up of 58.2+/-44 months, 134 patients had HCC recurrence. Multivariate analysis showed that multinodularity (Hazard ratio [HR], 95% confidence interval [CI]; 2.232, 1.021-4.878), macroscopic venous invasion (4.693, 1.645-13.391), AFP >20 ng/ml (3.891, 1.795-8.475), and cut margin <or= 1cm (3.333, 1.487-7.470) were correlated with early recurrence (within two years of operation) of HCC. In addition, multivariate analysis determined that Ishak hepatic inflammatory activity >6 (4.658, 1.970-11.017), multinodularity (3.266, 1.417-7.526), ICG-15 >10% (2.487, 1.095-5.650) and HBV DNA level >10(6) copies/ml (2.548, 1.040-6.240) were significantly associated with late recurrence (>two years after resection). Patients with high viral loads tended to have higher Ishak inflammatory (7.00+/-3.07 vs. 5.33+/-2.96, p=0.001) and fibrosis scores (4.17+/-2.01 vs. 3.20+/-2.41, p=0.007) than those with lower loads. CONCLUSIONS Tumor factors were associated with early HCC recurrence while high viral loads and hepatic inflammatory activity were associated with late recurrence. Pre- and post-operative antiviral and anti-inflammatory therapies may be crucial in reducing late recurrence.

Molecular pathogenesis of human hepatocellular carcinoma.

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the viral-chemical etiology as well as molecular mechanisms of HCC pathogenesis remains largely unknown. Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC. Oxidative stress and chronic inflammation have been linked to an increased risk of liver cancer. For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumor suppressor gene. The Hepatitis B virus X gene (HBx), a viral transactivator with oncogenic potentials, has been shown to bind to and inactivate p53-mediated apoptosis. HBx mutants derived from HCC have a diminished ability to act as a transactivator. However, they still retain the ability to bind to and abrogate p53-mediated apoptosis. The comparison of gene expression profiles between HBx-expressing primary human hepatocytes and HBV-infected liver samples by cDNA microarrays indicate a unique alteration of a subset of oncogenes and tumor suppressor genes including p53. Our studies implicate both viral and endogenous chemical processes in the etiology of HCC, and p53 may be a common target for the inactivation during liver carcinogenesis.

A new prognostic model for hepatocellular carcinoma based on total tumor volume: The Taipei Integrated Scoring system

BACKGROUND & AIMS The currently used staging systems for hepatocellular carcinoma (HCC) are not satisfactory. The optimal prognostic model for HCC is still under intense debate. This study aimed to propose a new staging system for HCC based on total tumor volume (TTV) and to compare it with the currently used systems. METHODS A total of 2030 HCC patients undergoing different treatment strategies were retrospectively analyzed. TTV was defined as the sum of the volume of each tumor [(4/3)x3.14x(radius of tumor in cm)(3)]. The discriminatory ability of the TTV-based staging system and the four current systems, including the Barcelona Clinic Liver Cancer, Cancer of the Liver Italian Program (CLIP), Japan Integrated Staging system, and Tokyo system, was examined by comparing the Akaike information criterion (AIC) using the Cox proportional hazards model. RESULTS A higher TTV correlated well with the decreased survival in HCC patients (p<0.001). Among the 12 TTV-based staging systems, the TTV-Child-Turcotte-Pugh (CTP)-alpha-fetoprotein (AFP) combination provided the lowest AIC value. The TTV-CTP-AFP model consistently showed a better prognostic ability in comparison to the current four staging systems. In 936 HCC patients receiving curative treatment, the TTV-CTP-AFP model provided the second best predictive accuracy following the CLIP score. Alternatively, in 1094 patients undergoing non-curative treatment, the TTV-CTP-AFP model exhibited the smallest AIC value. CONCLUSIONS TTV may be a feasible tumoral prognostic predictor for HCC. In this single-hospital study that included patients with early to advanced cancer stages, the TTV-CTP-AFP model provides the best prognostic ability among 12 TTV-based and currently used staging systems.

Survival Rates Are Comparable After Radiofrequency Ablation or Surgery in Patients With Small Hepatocellular Carcinomas

BACKGROUND & AIMS Differences in efficacy of radiofrequency ablation (RFA) and surgical resection (SR) are not clear for patients with hepatocellular carcinoma (HCC). METHODS From 2002 to 2007, 419 patients with HCCs ≤5 cm were enrolled consecutively in the study. Among these patients, 190 and 229 patients received RFA and SR, respectively, as their first treatment. Factors were analyzed in terms of overall survival and recurrence by multivariate analysis and propensity score matching analysis. RESULTS The SR group had younger age, a higher male-to-female ratio, higher prevalence of hepatitis B virus, lower prevalence of hepatitis C virus, better liver function reserve, and larger tumor size than the RFA group. The cumulative 5-year overall survival rates were 79.3% in the SR group and 67.4% in the RFA group. During the follow-up period, tumors recurred in 244 patients in a median time of 14.5 ± 15.7 months. Before propensity-score matching, the RFA group had shorter overall survival time (P = .009) and higher tumor recurrence rate (P < .001) than the SR group. After matching, RFA was comparable to SR in overall survival time (P = .519), but the RFA group still had a greater incidence of tumor recurrence (P < .001). In patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC, RFA was as effective as SR for overall survival time and recurrence. CONCLUSIONS Patients with small HCCs have a higher rate of tumor recurrence following RFA than surgery, but overall survival rates are comparable between therapies. RFA is as effective as surgery in patients with BCLC stage 0 HCC.

Performance status in patients with hepatocellular carcinoma: Determinants, prognostic impact, and ability to improve the Barcelona Clinic Liver Cancer system

Performance status is included in the Barcelona Clinic Liver Cancer (BCLC) system for hepatocellular carcinoma (HCC). Few studies specifically evaluated the role of performance status in patients with HCC. This study investigated its distribution, determinants, and prognostic impact, aiming to improve the performance of the BCLC system. A total of 2,381 HCC patients were enrolled. Performance status was determined according to the Eastern Cooperative Oncology Group scale. The prognostic ability of the original and three modified BCLC systems in HCC patients was compared by the Akaike information criterion (AIC). There were 60, 17, 11, 8, and 4% of patients who were classified as performance status 0, 1, 2, 3, and 4, respectively. A worse performance status significantly correlated with age, alcoholism, hypoalbuminemia, hyperbilirubinemia, renal insufficiency, hyponatremia, and prothrombin time prolongation (all P < 0.001). Larger tumor burden, poorer residual liver function, more frequent vascular invasion, and diabetes mellitus were also observed in patients with worse performance status (all P < 0.001). Patients with poorer performance status more often received best supportive care (P < 0.001). In the Cox proportional hazards model, performance status was an independent prognostic predictor and the long‐term survival tended to be worse in patients with progressively poor performance status (all P < 0.05). Reassigning patients with performance status 0 or 1 to stage B provided the lowest AIC among the four BCLC‐based staging systems.

Selecting an optimal staging system for hepatocellular carcinoma: comparison of 5 currently used prognostic models.

Selecting an appropriate staging system is crucial to predict the outcome of patients with hepatocellular carcinoma (HCC). The optimal prognostic model for HCC is under intense debate. This study investigated the prognostic ability of the 5 currently used staging systems, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Japan Integrated Scoring (JIS) system, tumor‐node‐metastasis (TNM), and Tokyo score, for HCC.

Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis

Chronic hepatitis B virus (HBV) infection and the integration of its X gene (HBx) are closely associated with the development of hepatocellular carcinoma (HCC). The integrated HBx frequently is truncated or contains point mutations. Previous studies indicated that these HBx mutants have a diminished co-transactivational activity. We have compared the effects of wild-type (wt) HBx and its naturally occurring mutants derived from human HCCs on transcriptional co-transactivation, apoptosis and interactive effects with p53. We demonstrated that overexpression of mutant, but not wt HBx, is defective in transcriptional co-transactivation of the NF-κB-driven luciferase reporter. By using a microinjection technique, the HBx mutants were shown to have an attenuated pro-apoptotic activity. This deficiency may be attributed to multiple mutations in the co-transactivation domain of HBx, that leads to decreased stability of the translated product. However, wt or mutant HBx bind to p53 in vitro and retain their ability to block p53-mediated apoptosis in vivo, which has been implicated as its major tumor suppressor function. The abrogation of p53-mediated apoptosis by integrated HBx mutants may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis.

Model for end-stage liver disease score to serum sodium ratio index as a prognostic predictor and its correlation with portal pressure in patients with liver cirrhosis

Background: The models for end‐stage liver disease (MELD) and serum sodium (SNa) are important prognostic markers in cirrhosis. A novel index, MELD to SNa ratio (MESO), was developed to amplify the opposing effect of MELD and SNa on outcome prediction.

Comparison of percutaneous acetic acid injection and percutaneous ethanol injection for hepatocellular carcinoma in cirrhotic patients: a prospective study.

Background: Ultrasound-guided percutaneous ethanol injection (PEI) and percutaneous acetic acid injection (PAI) are effective in the treatment of hepatocellular carcinoma (HCC). We conducted a prospective study to compare the therapeutic efficacy of both these methods. Methods: Sixty-three patients were treated by PAI using 50% acetic acid and 62 by PEI using pure ethanol. There were no significant baseline differences in age, sex, Child-Pugh class, tumour size and number, or other clinico-biochemical parameters between the two groups. Results: During a follow-up period of 24 ± 9 (range 6-38) months, 19 (30%) of the PAI group and 21 (34%) of the PEI group died ( P r = r 0.704). The 1- and 3-year survival rates were 84% and 51% for the PAI group and 81% and 46% for the PEI group ( P r = r 0.651). The corresponding tumour recurrence rates were 51% and 74% for the PAI group, and 54% and 64% for the PEI group ( P r = r 0.787). The treatment sessions were 3.9 ± 1.6 and 6.2 ± 2.3 for the PAI and PEI groups, respectively, in each treatment cycle ( P r = r 0.008). A multivariate analysis using the Cox regression model revealed that ascites (relative risk (RR) 3.1, 95% confidence interval (CI) 1.5-6.3, P r = r 0.002), large (>3 r cm) or multinodular HCCs (RR 2.4, 95% CI 1.1-5.4, P r = r 0.04), and development of tumour recurrence (RR 7.0, 95% CI 3.1-16.0, P r < r 0.001) were independent, poor prognostic factors in both groups. Conclusions: PAI and PEI are equally effective in the treatment of HCC. PAI has the advantage of fewer treatment sessions in each treatment course. Careful pretreatment patient selection may improve survival.BACKGROUND Ultrasound-guided percutaneous ethanol injection (PEI) and percutaneous acetic acid injection (PAI) are effective in the treatment of hepatocellular carcinoma (HCC). We conducted a prospective study to compare the therapeutic efficacy of both these methods. METHODS Sixty-three patients were treated by PAI using 50% acetic acid and 62 by PEI using pure ethanol. There were no significant baseline differences in age, sex, Child-Pugh class, tumour size and number, or other clinico-biochemical parameters between the two groups. RESULTS During a follow-up period of 24 +/- 9 (range 6-38) months, 19 (30%) of the PAI group and 21 (34%) of the PEI group died (P = 0.704). The 1- and 3-year survival rates were 84% and 51% for the PAI group and 81% and 46% for the PEI group (P = 0.651). The corresponding tumour recurrence rates were 51% and 74% for the PAI group, and 54% and 64% for the PEI group (P = 0.787). The treatment sessions were 3.9 +/- 1.6 and 6.2 +/- 2.3 for the PAI and PEI groups, respectively, in each treatment cycle (P = 0.008). A multivariate analysis using the Cox regression model revealed that ascites (relative risk (RR) 3.1, 95% confidence interval (CI) 1.5-6.3, P = 0.002), large (>3 cm) or multinodular HCCs (RR 2.4, 95% CI 1.1-5.4, P = 0.04), and development of tumour recurrence (RR 7.0, 95% CI 3.1-16.0, P < 0.001) were independent, poor prognostic factors in both groups. CONCLUSIONS PAI and PEI are equally effective in the treatment of HCC. PAI has the advantage of fewer treatment sessions in each treatment course. Careful pretreatment patient selection may improve survival.

Selecting an optimal prognostic system for liver cirrhosis: the model for end-stage liver disease and beyond.

In comparison with the Child–Turcotte–Pugh (CTP) system, recent studies suggested that the model for end‐stage liver disease (MELD) may more accurately predict the survival for patients with cirrhosis. In the US, the liver allocation system was changed in 2002 from a status‐based algorithm utilizing CTP scores to one using continuous MELD severity scores as a reference system in prioritizing adult patients on the waiting list. Direct evidence that demonstrates the benefits of MELD is the fact that the mortality rates of transplant candidates on the waiting list have remarkably decreased after the implementation of the MELD. The MELD score is closely associated with the degree of portal hypertension as reflected by the hepatic venous pressure gradient. Hyponatraemia occurs as a result of advanced cirrhosis, and a serum sodium (Na) level <126 mEq/L at the time of listing for transplantation is a strong independent predictor of mortality. Several MELD‐derived prognostic models that incorporate serum Na into calculation have been proposed in the hopes of further improving the MELDs prognostic accuracy. Additionally, serum parameters such as creatinine and international normalized ratio are subject to interlaboratory variations and may need unifying standardizations. Patients with refractory complications of cirrhosis may need a priority MELD score to prioritize them on the waiting list. Appropriate modifications and the fine‐tuning of the MELD based on well‐designed prospective studies are necessary in solving the current controversial issues.