We retrospectively evaluated variable clinical data on admission to reliably predict bleeding from esophageal varices after the first course of endoscopic treatment in liver cirrhosis patients with and without hepatocellular carcinoma.We analyzed 27 clinical factors from the medical records of 118 patients who received their first course of endoscopic treatment for esophageal varices. Factors significantly related to bleeding were extracted using Cox's regression model, and the bleeding index was prepared by combining these factors.The cumulative nonbleeding rates after treatment for esophageal varices were 82.1% at 1 year, 64.6% at 3 years and 53.7% at 5 years. By the multivariate analysis, age, the presence of hepatocellular carcinoma, hemoglobin, lactate dehydrogenase and alpha-fetoprotein were selected as significant factors that contributed independently to the post-therapeutic bleeding from esophageal varices (P<0.05). The bleeding index was calculated using the following formula: bleeding index = - 0.045 x Age + 0.934 x hepatocellular carcinoma - 0.151 x hemoglobin + 0.108 x lactate dehydrogenase + 0.842 x alpha-fetoprotein.The bleeding index, based on 5 factors, will in future be an appropriate index to predict the post-therapeutic bleeding from esophageal varices.
Interleukin (IL)-4 exhibits strong antitumor effects and IL-4 gene therapy has been used clinically in the treatment of some types of cancer. In the present study, we evaluated the efficacy of IL-4-transduced tumor cell vaccines in combination with blockade of programmed cell death 1 (PD-1) and investigated the mechanisms underlying the antitumor effects of this therapy. A poorly immunogenic murine colorectal cancer cell line (i.e. MC38) was transduced to overexpress IL-4. In a therapeutic model, MC38-IL4 cells and anti-PD-1 antagonistic antibodies (Ab) were inoculated into parental tumor-bearing mice. Immunohistochemical analyses and tumor-specific lysis were also performed. Additive antitumor effects were observed when mice were treated with IL-4 in combination with an anti-PD-1 Ab. Immunohistochemical analysis of the therapeutic model showed marked infiltration of CD4+ and CD8+ cells into established MC38 tumors of mice treated with anti-PD-1 Ab. Significant tumor-specific cytolysis was detected when the splenocytes of mice treated with both IL-4 and anti-PD-1 Ab were used as effector cells. These results suggest that blockade of the interaction between PD-1 and programmed death ligand 1 (PD-L1) enhances the antitumor immune responses induced by IL-4. Thus, IL-4 gene-transduced tumor cell vaccines in combination with PD-1 blockade may be considered as possible candidates for clinical trials of new cancer vaccines.
Aim ME3738 , a derivative of soyasapogenol B , enhances the anti‐hepatitis C virus ( HCV ) effect of interferon in an in vitro replication system and an in vivo mouse model of HCV infection. ME3738 plus pegylated interferon ( PEG IFN )‐α‐2a treatment for 12 weeks decreased HCV RNA levels in enrolled late virus responder ( LVR ) patients with relapsed HCV . Half of the patients reached undetectable HCV RNA level. The present clinical study of ME3738 was conducted in naïve chronic hepatitis C patients to investigate the sustained virological response ( SVR ) and safety of 48‐week treatment with ME3738 plus PEG IFN ‐α‐2a. Methods Subjects ( n = 135) with genotype 1b chronic hepatitis C with high viral loads were divided into three groups ( ME3738 50 mg b.i.d., 200 mg b.i.d. or 800 mg b.i.d.). ME3738 was administrated p.o. and PEG IFN ‐α‐2a (180 μg/week) s.c. for 48 weeks, and SVR was assessed at 24 weeks of treatment‐free follow up. Results The viral disappearance rates at 12 and 48 weeks were 23.0% and 48.9%, respectively. SVR was seen in 5.9% of subjects. ME3738 did not worsen the adverse reactions generally seen with PEG IFN ‐α‐2a treatment, and any adverse reactions specific to ME3738 were not observed. Conclusion ME3738 plus PEG IFN ‐α‐2a treatment to naïve chronic hepatitis C patients showed an antiviral effect and a good safety profile up to 48 weeks. However, HCV RNA was again detected in many subjects after treatment termination. Even though ME3738 is not enough to suppress HCV reproduction in this treatment. ME3738 was concurrently used with PEG IFN ‐α‐2a treatment; however, a clear additional effect on SVR was not confirmed.
Summary To analyse the immune response to the hepatitis C virus (HCV) core protein, we immunized mice with the protein. BALB/c (H‐2 d ) and C3H/He (H‐2 k ) mice were high responders, while C57BL/6 (H‐2 b ) mice were low responders in terms of Th cell proliferative responses. All the strains showed comparable levels of antibody responses to the HCV core protein. The Th cell lines recognized residues 61–90 of the HCV core protein in the context of I‐A d (BALB/c) and residues 11–30 in the context of I‐E k (C3H/He), respectively. The Th cell lines were restricted by I‐A b in C57BL/6 mice but recognized no synthetic peptide that spanned the region, although derivative clones from the line recognized residues 1–20 and 91–110 of the HCV core protein, respectively. The Th cell lines were Thl subset in all three strains based on the profile of lymphokine secretion. The major B cell epitope of the protein was found to be within residues 21–40 of the HCV core protein in all three strains. These observations should be useful for better understanding of the immune response to the HCV core protein in vivo.
Infection with hepatitis C virus(HCV)is associated with lymphoproliferative disorders(LPD) .Several abnormalities of LPD markers and clonal expansion of B cells are observed not only in HCV infected patients with LPD but also in asymptomatic patients, suggesting that reliable markers for B cell proliferation are required.Recently, serum B cell activating factor(BAFF) has been reported as a marker of B cell proliferation.Serum BAFF levels in European patients with HCV infection were reported higher than those in healthy subjects.In this study, we assessed serum BAFF levels in 75 Japanese patients with chronic hepatitis C(CH-C)and analyzed the associated factors with high levels of BAFF.Results showed that serum BAFF levels in patients with CH-C were higher than those in control subjects (1,560.5 153.1 vs. 891.455.6 pg / ml, P＜0.001) .Interferon-based therapy rapidly increased levels of BAFF during the therapy.BAFF levels were neither correlated with levels of other LPD markers(cryoglobulinemia, rheumatoid factor, complement 4 and CH 50 )nor the B-cell clonality.Decreased number of platelets and cirrhosis were correlated with high levels of serum BAFF, suggesting that the progression of liver diseases might induce the release of BAFF.Serum BAFF levels in patients with other liver diseases, autoimmune hepatitis and primary biliary cirrhosis, were also higher than those in controls(AIH, 1,084.877.6, P ＜0.05 ; PBC, 1,970.3202.6 pg / ml, P＜0.001) .In conclusion, HCV infection and / or the progression of hepatic in ammation stimulate the release of BAFF.This release is further enhanced by interferon which is associated with the development of LPD and autoimmune diseases.
