Kazufumi Dohmen

Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: A prospective, multicenter study ☆

BACKGROUND & AIMS The effects of pegylated interferon (PegIFN) α and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNα2b and RBV. METHODS This large-scale, prospective, multicenter study consisted of 1013 Japanese chronic hepatitis C patients with no history of HCC (non-cirrhosis, n=863 and cirrhosis, n=150). All patients were treated with PegIFNα2b and RBV and the follow-up period started at the end of the antiviral treatment (median observation period of 3.6 years). The cumulative incidence rate of HCC was estimated using the Kaplan-Meier method, according to treatment outcome. RESULTS Forty-seven patients (4.6%) developed HCC during the observation period. In the non-cirrhosis group, the 5-year cumulative incidence rates of HCC for the sustained virological response (SVR) (1.7%) and transient virological response (3.2%) (TVR: defined as relapse or breakthrough) groups were significantly lower than those of the non-virological response (NVR) group (7.6%) (p=0.003 and p=0.03, respectively). A significantly low rate of incidence of HCC by TVR patients in comparison with NVR patients was found for patients aged 60 years and over, but not for those under 60 years of age. In the cirrhosis group, the 5-year cumulative incidence rates of HCC for the SVR (18.9%) and TVR groups (20.8%) were also significantly lower than those of the NVR group (39.4%) (p=0.03 and p=0.04, respectively). CONCLUSIONS SVR and complete viral suppression during treatment with relapse (TVR) were associated with a lower risk of HCC development when compared with NVR.

Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C

BACKGROUND & AIMS This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. METHODS This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. RESULTS The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006). CONCLUSIONS TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C.

Clinical milestones for the prediction of severe anemia by chronic hepatitis C patients receiving telaprevir-based triple therapy

BACKGROUND & AIMS Anemia is a common adverse effect of telaprevir (TVR) in combination with pegylated interferon (PegIFN)α and ribavirin (RBV) therapy. It occurs at a higher incidence with the TVR relative to PegIFNα and RBV alone. We herein evaluate the baseline and on-treatment predictors of the development of severe anemia by chronic hepatitis C virus (HCV) patients receiving TVR-based triple therapy. METHODS This prospective, multicenter study consisted of 292 patients (median age: 62 years) infected with HCV genotype 1. All received 12 weeks of TVR in combination with 24 weeks of PegIFNα2b and RBV. The definition of severe anemia during antiviral treatment is hemoglobin (Hb)<85 g/L. RESULTS 101 (34.6%) patients developed severe anemia during the treatment period. Multivariable logistic regression analysis of possible pretreatment predictors of the development of severe anemia extracted baseline Hb < 135 g/L (Hazard ratio [HR], 2.53; p = 0.0013), estimated glomerular filtration rate <80 ml/min/1.73 m(2) (HR, 1.83; p = 0.0265), and inosine triphosphatase (ITPA) CC genotype (rs1127354) (HR, 2.91; p = 0.0024). For patients with ITPA CC (n = 227), multivariable logistic regression analysis of possible pretreatment and on-treatment predictors of the development of severe anemia extracted Hb level at week 2 (HR, 0.96; p = 0.0085) and the initial four weeks of weight-adjusted TVR (HR, 1.05; p = 0.0281). CONCLUSIONS Anemia remains a risk for all patients treated with TVR-based triple therapy. However, ITPA polymorphism (rs1127354) is useful for predicting the development of severe anemia and will be helpful in the management of treatment.

Optimal treatment strategy for elderly patients with hepatocellular carcinoma

Background and Aims:  The age distribution of patients with hepatocellular carcinoma (HCC) now peaks at nearly 70 years in Japan and this is continually increasing. Whether such elderly patients with HCC aged 80 years or older should be treated, and if so, how they should be selected for treatment remains uncertain. The present study was undertaken to determine any differences in the clinical characteristics and prognostic features between patients with HCC aged 80 years or older and those younger than 80 years of age. We also aimed to identify any significant variables in the prognosis of elderly patients with HCC aged 80 years or older.

Evaluation of the adverse effect of premature discontinuation of pegylated interferon α-2b and ribavirin treatment for chronic hepatitis C virus infection: Results from Kyushu University Liver Disease Study

Background and Aims:  Pegylated interferon (PEG‐IFN) α‐2b and ribavirin (RBV) treatment of chronic hepatitis C virus (HCV) infection is associated with a substantially elevated risk of discontinuation. The aim of this study is to evaluate the reason for premature discontinuation during PEG‐IFN α‐2b and RBV treatment due to adverse effects in patients with chronic HCV infection.

Telaprevir‐based triple therapy for chronic hepatitis C patients with advanced fibrosis: a prospective clinical study

Antiviral treatment is recommended for chronic hepatitis C patients with advanced fibrosis to reduce and prevent cirrhosis‐related complications.

Rotenone, a mitochondrial NADH dehydrogenase inhibitor, induces cell surface expression of CD 13 and CD38 and apoptosis in HL-60 cells

We previously demonstrated that the mitochondrial NADH dehydrogenase subunit 2 (ND2) gene was overexpressed in human acute myelogenous leukemia (AML) cells. Since this finding suggested that ND2 gene expression was related to myeloid differentiation, we here investigated the effects of rotenone, a specific NADH dehydrogenase inhibitor, on HL-60 cell growth, differentiation and death. Fifty nM rotenone inhibited the growth of HL-60 cells and caused an increase in the cell population in the G(2) +M phase. In the quantitative comparison of myeloid antigen, the expression of CD13 and CD38 were relatively increased in the rotenone-treated cells. These findings suggest that the inhibition of NADH dehydrogenase changes the cell cycle and induces some specific surface antigens of HL-60 cells. On the other hand, the expression of ND2 gene remained unchanged after the rotenone treatment, suggesting the rotenone-mediated mitochondrial inhibition did not affect the mitochondrial gene expression. Five mu M rotenone strongly inhibited the cellular proliferation. Electron microscopy and an electrophoretic analysis of DNA showed that the majority of the HL-60 cells were induced into typical apoptosis within 24-48 hours. On the basis of this and other studies, we believe that mitochondrial function is directly involved in both cellular differentiation and apoptotic cell death.

Many staging systems for hepatocellular carcinoma: Evolution from Child‐Pugh, Okuda to SLiDe

Clinical staging systems for cancer patients are designed to give a more accurate prognostic assessment and to guide decisions in planning optimal treatment strategies. Current advances in medical examinations and medical care for patients with hepatocellular carcinoma (HCC) have resulted in a dramatically increased patient survival rate. However, despite such progress, making a reliable estimate of the prognosis of patients with HCC still remains difficult. It is evident that the prognostic staging system is an important clinical issue in deciding whether to treat a patient aggressively, avoid over-treatment or choose the palliative care option for patients with HCC. Therefore, recently several models designed to more precisely predict the outcome of patients with HCC have been proposed. However, the problems regarding the appropriate weights given to the variables measuring the residual liver function according to their relative importance, and how tumor-related characteristics are statistically derived and then applied to a prognostic model for HCC, to more easily and more accurately predict the outcome, still remain.

Retroperitoneal fibrosis associated with scirrhous gastric cancer

SummaryA case of retroperitoneal fibrosis associated with scirrhous gastric cancer is reported. A sixty two-year-old Japanese female was admitted because of acute renal failure. The patient’s serum creatinine level showed 3.2 mg/dl while the blood urea nitrogen level was 23 mg/dl. An ultrasound study of the upper abdomen revealed bilateral hydronephrosis. Drip infusion pyelography revealed a dilated right renal pelvis without ureteral obstruction. The left kidney was not opacified, suggesting a functional disorder. Gastrography and gastrofiberscopy revealed scirrhous gastric cancer. Signet ring cell carcinoma was later demonstrated histologically by biopsy specimens. CT demonstrated a prominent thickening of the gastric wall and hydronephrosis, although no prevertebral soft tissue masses were observed. A total gastrectomy was performed with failure to surgically decompress the ureters because fibrous plaque had firmly enveloped the retroperitoneal structures. Biopsy specimens of the retroperitoneum revealed an invasion of the tumor cells and prominent fibrosis. As an etiology of renal failure, ureteral stenosis resulting from secondary retroperitoneal fibrosis was also considered.

Short‐term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct‐acting anti‐viral treatment

With the development of direct‐acting anti‐virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR).