Effect of interferon therapy on first and second recurrence after resection of hepatitis C virus-related hepatocellular carcinoma
ABSTRACT Aim: Several investigators have shown that interferon (IFN) therapy can suppress the recurrence of hepatocellular carcinoma (HCC) after curative treatment. We investigated the effect of IFN therapy on the first and second HCC recurrence following hepatic resection of hepatitis C virus (HCV)-related HCC. Methods: Subjects included 166 patients who had undergone curative resection for a single HCV-related HCC. We analyzed the outcome after initial hepatic resection and risk factors of a second HCC recurrence following treatment for the first HCC recurrence. Results: Using multivariate analysis, a non-sustained virological response (non-SVR) was significantly associated with a high incidence of first HCC recurrence. The rate of second HCC recurrence tended to be higher in the non-SVR group than in the SVR group. In the patients with recurrence of multiple tumors or who received non-curative treatment for recurrent HCC, the second HCC recurrence rates were significantly higher. Multivariate analysis demonstrated that non-curative treatment for first HCC recurrence was an independent risk factor for a second HCC recurrence. Among the patients who received curative treatment for their first HCC recurrence, the rates of second recurrence were significantly higher in the non-SVR group than in the SVR group. Multivariate analysis also revealed that SVR was independently associated with prevention of a second HCC recurrence. Conclusions: These results suggest that on first HCC recurrence, a curative treatment should be considered in order to prevent a second recurrence if possible. In addition, IFN therapy contributes to improved prognosis after curative treatment, even in patients with recurrent HCC.
SourceAvailable from: María Paula Ceballos[Show abstract] [Hide abstract]
ABSTRACT: Interferon-α2b (IFN-α2b) reduces proliferation and increases apoptosis in hepatocellular carcinoma cells by decreasing β-catenin/TCF4/Smads interaction. Forkhead box O-class 3a (FoxO3a) participates in proliferation and apoptosis and interacts with β-catenin and Smads. FoxO3a is inhibited by Akt, IκB kinase β (IKKβ), and extracellular-signal-regulated kinase (Erk), which promote FoxO3a sequestration in the cytosol, and accumulates in the nucleus upon phosphorylation by c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (p38 MAPK). We analyzed FoxO3a subcellular localization, the participating kinases, FoxO3a/β-catenin/Smads association, and FoxO3a target gene expression in IFN-α2b-stimulated HepG2/C3A and Huh7 cells. Total FoxO3a and Akt-phosphorylated FoxO3a levels decreased in the cytosol, whereas total FoxO3a levels increased in the nucleus upon IFN-α2b stimulus. IFN-α2b reduced Akt, IKKβ, and Erk activation, and increased JNK and p38 MAPK activation. p38 MAPK inhibition blocked IFN-α2b-induced FoxO3a nuclear localization. IFN-α2b enhanced FoxO3a association with β-catenin and Smad2/3/7. Two-step coimmunoprecipitation experiments suggest that these proteins coexist in the same complex. The expression of several FoxO3a target genes increased with IFN-α2b. FoxO3a knockdown prevented the induction of these genes, suggesting that FoxO3a acts as mediator of IFN-α2b action. Results suggest a β-catenin/Smads switch from TCF4 to FoxO3a. Such events would contribute to the IFN-α2b-mediated effects on cellular proliferation and apoptosis. These results demonstrate new mechanisms for IFN-α action, showing the importance of its application in antitumorigenic therapies.Journal of Interferon & Cytokine Research 06/2014; 34(11). DOI:10.1089/jir.2013.0124 · 3.90 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Previous reports have shown that interferon (IFN)-based therapy decreases the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection. However, it remains to be fully elucidated whether elimination of HCV by IFN-based therapy inhibits HCC recurrence after curative treatment, such as surgical resection and local ablation therapies. In this study, we aimed to clarify the influence of a sustained virological response (SVR) after IFN-based therapy on recurrence and survival after curative treatment of HCC. Fifty-one patients who underwent curative treatment of HCV-related HCC after receiving IFN-based therapy were analyzed retrospectively. They were classified into SVR (N = 14) and non-SVR groups (N = 37). In the SVR group, serum levels of aspartate aminotransferase and alanine aminotransferase, the indocyanine green retention rate at 15 min, and the percentages of patients with liver cirrhosis and HCV serotype 1 were significantly lower, whereas serum albumin level and platelet count were significantly higher upon HCC occurrence. Recurrence-free survival (RFS) for the first recurrence was significantly higher in the SVR group (P < 0.01). Multivariate analysis showed that SVR at initial HCC treatment (P < 0.01) and multiple tumors (P < 0.01) are prognostic factors for RFS. Moreover, RFS for the second recurrence showed a similar trend to that for the first recurrence. In conclusion, patients who underwent IFN-based therapy before initial curative treatment of HCC had a favorable clinical outcome compared with non-SVR patients.International journal of medical sciences 01/2014; 11(7):707-12. DOI:10.7150/ijms.8764 · 1.55 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: The impact of antibodies to hepatitis B core antigen (anti-HBc) on survival after curative surgical resection (SR) for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) remains unclear. The aim of the present study was to examine the relationship between anti-HBc positivity and survival of HCV-related HCC patients who underwent curative SR. A total of 222 patients with HCV-related, hepatitis B surface antigen (HBsAg)-negative HCC who underwent curative SR were analyzed. They included 119 anti-HBc-positive patients (53.6%) and 103 anti-HBc-negative patients (46.4%). Overall survival (OS) and recurrence-free survival (RFS) rates were compared between the two groups. The median follow-up periods in the anti-HBc-positive and anti-HBc-negative groups were 3.4 years (range, 0.3-10.9 years) and 3.2 years (range, 0.5-10.9 years), respectively. The 1-, 3- and 5-year cumulative OS rates were 88.8, 70.2 and 50.0%, respectively, in the anti-HBc-positive group and 95.8, 77.1 and 61.7% in the anti-HBc-negative group (P=0.300). The corresponding RFS rates were 68.7, 33.0 and 20.0%, respectively, in the anti-HBc-positive group and 74.4, 38.5 and 16.5% in the anti-HBc-negative group (P=0.482). Multivariate analyses identified serum albumin ≥3.8 g/dl (P=0.005) and the presence of microvascular invasion (P<0.001) as independent factors linked to OS, and interferon therapy after surgery (P=0.011), α-fetoprotein ≥40 ng/ml (P=0.030) and the presence of microvascular invasion (P<0.001) were significant predictors linked to RFS. In subgroup analyses according to maximum tumor size and background liver disease in terms of OS and RFS, no significant difference between the anti-HBc-positive and anti-HBc-negative groups was observed except in patients with non-cirrhotic liver in terms of RFS. In conclusion, anti-HBc-positivity is not a useful predictor for survival of patients with HCV-related HCC after curative SR.Oncology Reports 04/2013; 30(1). DOI:10.3892/or.2013.2422 · 2.19 Impact Factor