Efficacy and safety of sorafenib in very elderly patients aged 80 years and older with advanced hepatocellular carcinoma.

AIM: Sorafenib is the standard systemic therapy for patients with advanced hepatocellular carcinoma (HCC). We aimed to assess the efficacy and safety of sorafenib therapy in very elderly patients aged 80 years and older with advanced HCC. METHODS: In a retrospective multicenter study in Japan, we reviewed 185 patients (median age, 71 years; 82% male; 95% Child-Pugh class A) with advanced HCC who received sorafenib therapy. Data were compared between 24 (13%) patients aged 80 years and older and 161 (87%) patients aged less than 80 years. We used propensity score matching to adjust for differences between the two groups. RESULTS: Median overall survival was 10.6 months in all patients: 11.7 months in patients aged 80 years and older and 10.5 months in those aged less than 80 years. There were no significant differences in overall survival, tumor response, and frequency and severity of drug-related adverse events between patients aged 80 years and older and those aged less than 80 years in both the entire study cohort and the propensity-matched cohort. CONCLUSION: Sorafenib may be effective and well tolerated, even in patients with advanced HCC who are aged 80 years and older, as well as those aged less than 80 years.

Prediction of a favorable clinical course in hepatitis C virus carriers with persistently normal serum alanine aminotransferase levels: A long-term follow-up study.

AIM: This study examined serum alanine aminotransferase (ALT) levels at first visit and their relationship with long-term normal serum ALT levels in hepatitis C virus (HCV) carriers with persistently normal ALT (PNALT). METHODS: HCV carriers with PNALT were identified as those patients with positivity of serum HCV RNA, ALT levels of 30 IU/L or less over a 12-month period on at least three different occasions, platelet count of more than 15 × 10(4) µl/mL and body mass index of 30 kg/m(2) or less. Outcome was retrospectively studied in 49 HCV carriers with PNALT, who were followed up for more than 10 years. RESULTS: During the mean follow-up period of 14.7 ± 2.5 years, ALT levels of 30 IU/L or less were preserved in only eight patients (8/49; 16.3%). Among the 17 patients with initial ALT levels of 19 IU/L or less, nine patients remained with ALT levels of 30 IU/L or less after 10 years (9/17; 52.9%). The probability of ALT levels in PNALT being maintained at 30 IU/L or less was significantly higher (P = 0.001) in these patients than in those with initial ALT levels of 20 IU/L or more (n = 32). Abnormal ALT levels were more common in female PNALT patients aged 45-55 years, which is usually the time of menopause onset. CONCLUSION: Because antiviral therapy in the treatment of chronic hepatitis C is rapidly advancing, waiting for more effective and safer treatments may be an option. The results of this study provide an important insight into this issue.

Treatment extension may benefit female genotype 1 chronic hepatitis C patients with complete early virological response to peginterferon-alpha-2b and ribavirin combination therapy.

AIM: Little is known about the appropriate use of peginterferon-α-2b (PEG IFN-α-2b) or ribavirin (RBV) in genotype 1 chronic hepatitis C (CH-C) patients with complete early virological response (cEVR). Female patients, especially the older, are known to experience inferior treatment outcomes. METHOD: A total of 150 CH-C patients with cEVR treated for 48 weeks (n = 104) or 52-64 weeks (n = 46) with PEG IFN-α-2b and RBV combination therapy were retrospectively analyzed to evaluate the benefits of extended treatment. RESULTS: In the 48-week group, patients without a sustained virological response (SVR) were more often female (P = 0.004) and had received a significantly lower total RBV dose (P = 0.003) than those with SVR. The SVR rate in these female patients was similar to males with hepatitis C virus (HCV) RNA negativity at treatment week 8 (P = 0.413); however, it was lower than that in males with HCV RNA negativity at treatment week 12 (P = 0.005). In the 52-64-week group, although the total RBV dose (mg/kg) after treatment week 48 was less in females than in males (P = 0.027), the SVR rate in females was equivalent to that in males (P = 0.604). CONCLUSION: Genotype 1 CH-C patients treated with PEG IFN-α-2b and RBV combination therapy without SVR were more often female and had received a lower total RBV dose than males. The smaller SVR rate in female patients with cEVR compared to males may be overcome by extending treatment even if the RBV dose is lowered due to anemia.

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-fed db/db mice.

Our previous study revealed that blockade of interleukin-6 (IL-6)-STAT3 signaling ameliorated liver injury, although hepatic STAT3(-/-) or GP130(-/-) mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6-STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD diet-fed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although 'moderate' blockade of enhanced IL-6-STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.

Simple formula to predict response to peginterferon alpha2b and ribavirin combination therapy in genotype 1 chronic hepatitis C patients with high viral loads.

AIM: We advocate a simple formula which can conveniently predict the outcome of Peg-interferon (IFN) alpha2b and ribavirin (RBV) combination therapy for genotype 1 chronic hepatitis C (CH-C) with high viral load. METHODS: A total of 338 (group A: 230, Group B: 108) genotype 1 CH-C patients treated with Peg-IFN alfa-2b and RBV were enrolled. Clinical parameters differing significantly between sustained virological responders (SVRs) and non-SVRs in group A were categorized, then a simple formula to predict SVR was constructed and re-evaluated in group B. Another formula containing hepatitis C virus amino acid mutations/substitutions also was constructed. RESULTS: In group A, gender and HCV RNA load <1000 KIU were significant predictors of SVR by multivariate logistic regression analysis. A simple formula was constructed (formula A): male gender (point 2) + HCV RNA load <1000 KIU (3) + platelet counts ≥15 × 10(4) /mm(3) (1) + age <60 (1). In group A, score (0-1) predicted SVR rate 23.8% (2-4): 48.1% and (5-7): 70.2%. According to this formula, score (0-1) predicted SVR rate 7.1% (2-4): 38.6%, and (5-7): 70.3% in group B. Information on HCV amino acid mutations/substitutions seemed to add some accuracy. CONCLUSIONS: This simple formula can be used to roughly determine, at the patients' first/second visit, the probability of response to Peg-IFN alpha2b and RBV combination therapy for genotype 1 CH-C with high viral load.

Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice.

Inflammatory processes have an important role in the development of hepatic steatosis and progression to nonalcoholic steatohepatitis (NASH). Interleukin-6 (IL-6) is known to be a proinflammatory cytokine, but also promotes liver regeneration and protects the liver against various forms of damage. The role of IL-6/Glycoprotein 130 (GP130) in NASH remains unclear. In this study, we determined whether blocking IL-6/GP130 signaling prevents progression of steatohepatitis in a mouse NASH model. Six-week-old male C57/BL6 mice were fed either chow control or a methionine choline-deficient (MCD) diet for 8 weeks. Half of the MCD diet-fed mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor antibody (MR16-1), intraperitoneally twice weekly, the remainder and chow-fed mice were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, apoptosis, markers of lipid peroxidation/oxidant stress and IL-6-related gene expressions were evaluated. MR16-1 treatment decreased signal transducer and activator of transcription 3 activities and expression of suppressor of cytokine signaling 3 in MCD diet-treated mouse livers. Although this treatment enhanced intrahepatic lipid accumulation accompanied by increased sterol regulatory element-binding protein 1 and decreased peroxisome proliferator-activated receptor-alpha expression, elevated plasma alanine aminotransferase levels were improved with decreased plasma free fatty acid levels, lipid peroxidation/oxidant stress and hepatic apoptosis. Blocking IL-6/GP130 signaling by MR16-1 enhanced MCD diet-induced hepatic steatosis, but ameliorated liver injury. These findings suggest that hepatic IL-6 signaling has a protective role against the progression of hepatic steatosis but may enhance liver inflammation.