Chan Ran You

Serum interleukin-6 and C-reactive protein as a prognostic indicator in hepatocellular carcinoma

The development of hepatocellular carcinoma (HCC) is often associated with chronic inflammation, suggesting a strong relationship between inflammation and carcinogenesis. This study evaluated the prognostic values of inflammatory and T-helper (Th) cytokines in the clinical outcome and survival of HCC. The study included 110 patients with HCC undergoing loco-regional therapy and 24 healthy controls. Five Th1/Th2 cytokines and C-reactive protein (CRP) were quantified before and after loco-regional treatment, using enzyme-linked immunosorbent assays. Levels of CRP, interleukin (IL)-4, and IL-6 were higher in patients with HCC than those in healthy subjects. Tumor characteristics, Child-Pugh class, and CRP, IL-6, and IL-10 levels were associated with HCC survival (all P<0.05). With multivariate analysis, higher IL-6 levels were identified as the independent cytokine for shorter survival (P=0.010). Higher CRP and IL-6 levels correlated well with larger tumor size, poor Child-Pugh function, and shorter survival, with a significant inter-correlation (r=0.667). On serial measurements, the association of CRP with tumor response was stronger than that of α-fetoprotein or other cytokines. IL-6 and CRP are strong inflammatory indicators predictive of outcome in patients with HCC receiving loco-regional therapy. This study suggests that inflammatory activation of the IL-6/CRP network may be a potential therapeutic target and biomarker for HCC.

Benefit of downsizing hepatocellular carcinoma in a liver transplant population

Aliment Pharmacol Ther 31, 415–423

Simultaneous Multitarget Irradiation Using Helical Tomotherapy for Advanced Hepatocellular Carcinoma With Multiple Extrahepatic Metastases

PURPOSE The prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases is extremely poor. Helical tomotherapy, an image-guided, intensity-modulated radiotherapy system, can allow for simultaneous and precise targeting of multiple cancerous lesions, while sparing normal tissues. This study evaluated the feasibility and outcome of tomotherapy for advanced HCC with metastases. PATIENTS AND METHODS A total of 42 consecutive HCC patients with metastases were treated with tomotherapy using the Hi-Art system. A total of 152 intra- and extrahepatic lesions (3.5 lesions/patient) were treated simultaneously, with a dose of 51.03 Gy (range, 30-57.61) in 10 fractions. Transarterial chemolipiodolization using epirubicin (50 mg) and cisplatin (60 mg) was repeated in patients with intrahepatic HCC (mean size, 9.0 cm) after tomotherapy. RESULTS An objective response (complete response and partial response) was achieved in 45.2% of patients with intrahepatic tumors, 68.4% of patients with pulmonary lesions, 60.0% of patients with lymph node/adrenal lesions, and 66.7% of patients with soft-tissue metastases. The complete response rate for those with pulmonary and lymph node/adrenal metastases was 26.3% and 5.0%, respectively. The overall survival rate at 1 and 2 years was 50.1% and 14.9%, respectively, with a median survival of 12.3 months. The actuarial in-field tumor control rate for < or =1 year was 79.0%. No cases of Grade 4-5 acute toxicity occurred. CONCLUSION The results of this study have shown that helical tomotherapy is safe and feasible without major toxicities for the treatment of advanced HCC and results in excellent tumor control and a potential survival benefit. This approach is expected to be a useful palliative option for selected HCC patients with metastases.

Risk of HBV reactivation according to viral status and treatment intensity in patients with hepatocellular carcinoma.

BACKGROUND There are no convincing data supporting the routine use of pre-emptive therapy against HBV reactivation in various loco-regional therapies for hepatocellular carcinoma (HCC). This study investigated the incidence, severity and risk factors of HBV reactivation during loco-regional therapies. METHODS A total of 205 prospectively enrolled patients were classified in order of increasing intensity of loco-regional therapies: local ablation therapy (LAT; 43 patients), transarterial chemotherapy using adriamycin (TAC-ADR; 93 patients) or combined epirubicin-cisplatin (TAC-EC; 26 patients), and combined chemo-radiotherapy (TAC-EC+RT; 43 patients). RESULTS During the follow-up, 62 (30.2%) patients developed HBV reactivation. Multivariate analysis identified HBV DNA levels >10⁴ copies/ml (P=0.041) and treatment option (P=0.001) to be independent predictors of HBV reactivation. There was a significant trend for increasing risk of reactivation with increasing intensity of therapy, with hazard ratios of 1.0 for LAT, 2.45 for TAC-ADR, 4.19 for TAC-EC and 10.17 for TAC-EC+RT. The severity of reactivated disease was also increased with increasing treatment intensity (P-value for trend <0.05). Only one of the patients with low-level viraemia receiving LAT alone developed reactivation, whereas a substantial number of patients with high-level viraemia eventually developed reactivation. CONCLUSIONS High-level viraemia and high-level treatment intensity are the major risk factors for HBV reactivation during loco-regional therapy. Trends are evident for the increased risk and severity of reactivation with the aggressiveness of treatment. Pre-emptive antiviral therapy should be recommended for all patients with high-level viraemia irrespective of treatment option, or those undergoing any intensive therapy.

Safety and immunogenicity of therapeutic DNA vaccine with antiviral drug in chronic HBV patients and its immunogenicity in mice

Here, we evaluated the safety and immunogenicity of hepatitis B virus (HBV) DNA vaccine, HB‐110, in mice and Korean patients with chronic hepatitis B (CHB) undergoing adefovir dipivoxil (ADV) treatment.

Update on hepatitis B virus infection

Chronic infection with hepatitis B virus (HBV) leads to the development of hepatocellular carcinoma and/or chronic liver failure. Despite extensive research, the immunopathogenesis is not completely understood. Viral persistence and clinical outcomes following HBV infection depend on viral factors and host factors; including genetic factors that determine a hosts immune mechanisms. The primary goal of chronic hepatitis B (CHB) treatment is to eradicate HBV or to at least maintain suppression of HBV replication. Despite recent advances in anti-viral agents for chronic HBV infection, complete eradication of the virus has been difficult to achieve. Agents for the treatment of CHB are divided mainly into two groups: immunomodulating agents and antiviral nucleos(t)ide analogues (NAs). Although NAs are safe, effective and easily administered orally, their long-term use poses the risk of drug resistance. Currently, international evidence-based guidelines have been developed to support physicians in managing CHB patients. However, treatment of patients with drug resistance is still challenging, as only a few classes of anti-HBV drugs are available and cross-resistance between drugs can occur. In addition, as the currently available genotypic test for detection of drug resistance still has limitations in identifying the different substitutions present in the same viral genome, the development of a new virologic test to overcome this limitation is necessary. Among the predictive factors associated with response to pegylated interferon (PEG-IFN) therapy, hepatitis B surface antigen quantification is considered to be a surrogate marker for monitoring response to PEG-IFN. Current practice guidelines stress the importance of profound and durable HBV viral suppression in the treatment of CHB patients. To this end, it is essential to choose a potent antiviral drug with a low risk of resistance for initial treatment of CHB to achieve sustained virological response. This review highlights recent advances in the understanding of the immunopathogenesis of HBV and currently available and developing treatment strategies against HBV infection.

Role of intrahepatic tumor control in the prognosis of patients with hepatocellular carcinoma and extrahepatic metastases.

Background and Aim:  There has been little information about the long‐term outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. The purpose of this study was to investigate the clinical factors affecting survival after extrahepatic metastasis and to determine the survival benefit of controlling intrahepatic HCC.

Serum hepatitis B surface antigen levels in the natural history of chronic hepatitis B infection

Aliment Pharmacol Ther 2011; 34: 1337–1346

Oleuropein prevents the progression of steatohepatitis to hepatic fibrosis induced by a high-fat diet in mice

Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD-induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (α-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, α-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans.

Role of long-term lamivudine treatment of hepatitis B virus recurrence after liver transplantation.

In this study, the long‐term (>3 years) efficacy of combination therapy for hepatitis B virus (HBV) recurrence and the associated factors were investigated. One hundred and sixty‐five consecutive HBsAg‐positive patients (92 with liver cirrhosis, 73 with hepatocellular carcinoma; HCC) who underwent liver transplantation were assessed with a median follow‐up time of 40 months. One hundred and twenty‐one patients (121/165, 73.3%) were treated with lamivudine before transplantation for a mean of 8.4 months (range 0.1–72 months). The post‐transplantation treatment protocol consisted of a high dose intravenous hepatitis B immunoglobulin (HBIg) followed by a low dose intramuscular HBIg and lamivudine combination therapy. Seven (4.2%, 7/165) recipients experienced HBV recurrence at a median time of 19 months (range 5–36 months) following transplantation. Six of seven cases of HBV recurrence were treated with lamivudine before transplantation for a median period of 15 months (range 0.6–30 months). Eighteen (24.6%, 18/73) patients had HCC recurrences after transplantation. Of the four patients with both HCC and HBV recurrence, three experienced HBV recurrence after recurrence of HCC. The clinical factor associated with HBV recurrence in the total cohort (n = 165) was the duration of antiviral treatment (over 6 months) before transplantation (P = 0.004). In the HCC group, HCC recurrence after transplantation (P = 0.002), tumor burden before transplantation (P = 0.005), and postoperative adjuvant chemotherapy (P = 0.002), were additional factors for HBV recurrence. Combination therapy of HBIg and antiviral drugs was effective over 3 years regardless of the pretransplantation viral load. However, the possible recurrence of HBV needs to be monitored cautiously in patients treated with long‐term (over 6 months) lamivudine. J. Med. Virol. 80:1891–1899, 2008.