Long-term surveillance of liver histological changes in chronic hepatitis C patients completing pegylated interferon-α plus ribavirin therapy: an observational cohort study.

BACKGROUND: For chronic hepatitis C (CHC) patients completing pegylated interferon (PegIFN)-α/ribavirin therapy, long-term liver histological changes remain largely unexplored. METHODS: This observational cohort study included 85 CHC patients completing PegIFN-α/ribavirin therapy with liver biopsies performed at baseline and the end of surveillance (EOS). Median years between paired biopsies were 6.75 (interquartile range: 5.63-7.54). RESULTS: In patients with baseline METAVIR fibrosis stages (F) <4 (able to undergo fibrosis progression; n = 77), cases achieving sustained virological response (SVR) (n = 52) had a significantly lower rate of fibrosis progression than non-SVR cases (n = 25) (3.8% versus 24.0%, p = 0.012). Among the entire cohort (n = 85), the rate of activity response [METAVIR activity grades (A) decreasing or maintaining at A0] in SVR cases (n = 59) was significantly higher than that in non-SVR cases (n = 26) (94.9% versus 65.4%, p = 0.001). For SVR cases among the entire cohort, independent predictors of fibrosis clearance included baseline F <2 [odds ratio (OR) = 7.877, p = 0.042] and aspartate transaminase (AST) levels declining by >70% at EOS compared with baseline (OR = 9.013, p = 0.038). For non-SVR cases among the entire cohort, baseline AST levels >80 U/l and glucose levels ⩽ 105 mg/dl independently predicted significant fibrosis (F2/F3/F4) at EOS (OR = 12.558, p = 0.049) and activity response (OR = 17.741, p = 0.047), respectively. CONCLUSIONS: Among CHC patients completing PegIFN-α/ribavirin therapy, SVR lowers the risk of liver histological progression but does not guarantee fibrosis clearance. For SVR cases, those with baseline F ⩾ 2 or without significantly declined follow-up AST levels should be specifically monitored. As for non-SVR cases, those with a higher baseline AST or glucose level should preferentially receive retreatment.

Prognostic roles of diabetes mellitus and hypertension in advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND & AIMS: It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib. METHODS: From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups. RESULTS: DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026). CONCLUSIONS: Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.

Impact of tumor burden on prognostic prediction for patients with terminal stage hepatocellular carcinoma: A nomogram study.

BACKGROUND: The recently proposed nomogram of Barcelona Clinic Liver Cancer (BCLC) lacks predictive accuracy for patients with stage D hepatocellular carcinoma (HCC). Tumor burden is crucial in prognostic prediction but is not included in the criteria of stage D HCC. This study aims to develop a nomogram with tumor burden as the core element for BCLC stage D patients. METHODS: A total of 386 patients were randomly grouped into derivation and validation sets (1:1 ratio). The multivariate Cox proportional hazards model was used to select factors with significant prognostic effect and generate the nomogram. Concordance indices and calibration plots were used to evaluate the performance of nomogram. RESULTS: Overall survival of study patients was significantly associated with tumor burden as well as hepatitis B, serum α-fetoprotein level, cirrhosis and performance status in multivariate Cox regression (all p<0.05). Beta-coefficients of these variables in derivation set were used to generate the nomogram. Each patient was assigned with a total nomogram point that predicted individualized 6-month and 1-year survival. The derivation and validation sets had a c-index of 0.759 (95% confidence interval [CI]: 0.552-0.923) and 0.741 (95% CI: 0.529-0.913), respectively. The calibration plots were close to the 45-degree line for 6-month and 1-year survival prediction for all quarters of patients in both derivation and validation sets. CONCLUSION: Tumor burden is significantly associated with the outcome for patients with stage D HCC. The tumor burden-incorporated nomogram may serve as a feasible and easy-to-use tool in predicting survival on an individual level.

A Single Postnatal Dose of Dexamethasone Enhances Memory of Rat Pups Later in Life.

Postnatal dexamethasone (Dex) therapy is associated with adverse neurodevelopmental outcomes, which might be related to its timing of administration. We used time-dated pregnant Wistar albino rats, whose litters were divided into experimental (Dex) and control groups intraperitoneally administered one dose of Dex (0.5 mg/kg) or normal saline (NS), respectively, at either day 1 (P1) or 7 (P7). The magnitude of the contextual freezing response and performance on the Morris water maze were significantly higher in the Dex-P7 group than in those of the other groups at P56. Dendritic spine density, membranous expression of the N-methyl-d-aspartate receptor (NMDAR) subunit NR2A/2B, and postsynaptic density-95 (PSD-95) were significantly higher in the Dex-P7 group than in the other groups. Furthermore, cytosolic expression of nuclear factor kappa B (NF-κB) and phosphatidylinositol 3-kinase (PI3K) was significantly higher in the Dex group than in NS group. Moreover, Dex administration at P7 increased cell proliferation, neuronal differentiation, and the survival of newly born neurons in the dentate gyrus. These results suggest Dex at P7 enhances the acquisition of contextual fear and spatial memory later in life due to the modulation of the newly born neurons, increase in dendritic spine number, and NMDAR expression.

The role of glucocorticoid receptors in dexamethasone-induced apoptosis of neuroprogenitor cells in the hippocampus of rat pups.

BACKGROUND: Dexamethasone (Dex) has been used to reduce inflammation in preterm infants with assistive ventilation and to prevent chronic lung diseases. However, Dex treatment results in adverse effects on the brain. Since the hippocampus contains a high density of glucocorticoid receptors (GCRs), we hypothesized that Dex affects neurogenesis in the hippocampus through inflammatory mediators. METHODS: Albino Wistar rat pups first received a single dose of Dex (0.5 mg/kg) on postnatal day 1 (P1) and were sacrificed on P2, P3, P5, and P7. One group of Dex-treated pups (Dex-treated D1D2) was given mifepristone (RU486, a GCR antagonist) on P1 and sacrificed on P2. Hippocampi were isolated for western blot analysis, TUNEL, cleaved-caspase 3 staining for cell counts, and morphological assessment. Control pups received normal saline (NS). RESULTS: Dex reduced the developmental gain in body weight, but had no effect on brain weight. In the Dex-treated D1D2 group, apoptotic cells increased in number based on TUNEL and cleaved-caspase 3 staining. Most of the apoptotic cells expressed the neural progenitor cell marker nestin. Dex-induced apoptosis in P1 pups was markedly reduced (60%) by pretreatment with RU486, indicating the involvement of GCRs. CONCLUSION: Early administration of Dex results in apoptosis of neural progenitor cells in the hippocampus and this is mediated through GCRs.

Endoscopic treatment of anastomotic biliary strictures after living donor liver transplantation: outcomes after maximal stent therapy.

BACKGROUND: Living-donor liver transplantation (LDLT) has emerged as a viable strategy in an era of organ shortage. However, biliary strictures are a common complication of LDLT, and these strictures frequently require surgical revision after unsuccessful endoscopic therapy. The optimal endoscopic treatment for anastomotic biliary strictures (ABSs) after LDLT is undefined. OBJECTIVE: To determine the outcome of an aggressive endoscopic approach to ABSs after LDLT that uses endoscopic dilation followed by maximal stent placement. DESIGN: A retrospective study. SETTING: A tertiary-care academic medical center. PATIENTS: Forty-one patients with a diagnosis of ABS. INTERVENTIONS: Endoscopic retrograde cholangiography with balloon dilation and maximal stenting. MAIN OUTCOME MEASUREMENTS: Stricture resolution, stricture recurrence, and complication rates. RESULTS: Of 110 LDLTs completed, a biliary stricture developed after transplantation in 41 (37.3%), which included 38 patients with duct-to-duct anastomosis. The median (interquartile range [IQR]) follow-up time is 74.2 (2.5-120.8) months. Among them, 23 (60.5%) were male, and 20 (52.6%) had bile leakage associated with ABSs. The median time (IQR) to the development of an ABS after LDLT was 2.1 (1.2-4.1) months. Endoscopic retrograde cholangiography was attempted as initial therapy in all patients: 32 were managed entirely by endoscopic therapy, and 6 required initial percutaneous transhepatic cholangiography (PTC) to cross the biliary stricture, with endoscopic therapy performed thereafter. A median (IQR) of 4.0 (3.0-5.3) endoscopic interventions and 7.0 (4.0-10.3) stents were required to resolve the stricture. The time from the first intervention to stricture resolution was 5.3 (range 3.8-8.9) months. Biochemical markers including aspartate transaminase (76 vs 39 U/L, P = .001), alanine transaminase (127.5 vs 45.5 U/L, P < .001), alkaline phosphatase (590 vs 260 IU/L, P < .001), and total bilirubin (2.57 vs 1.73 mg/dL, P = .017) significantly improved after intervention. Recurrent stricture was observed after initial treatment in 8 (21%) patients. All recurrences were successfully re-treated endoscopically. All patients have been managed without surgical revision or retransplantation, resulting in 100% success by an intention-to-treat analysis. LIMITATIONS: Retrospective study, small sample size. CONCLUSIONS: In this series, aggressive endoscopy-based treatment with maximal stent placement strategy allows 100% resolution of all duct-to-duct ABSs after LDLT without the need for surgical intervention or retransplantation.

Hepatitis B virus genotype B has an earlier emergence of lamivudine resistance than genotype C.

BACKGROUND: Hepatitis B virus (HBV) genotype B and C seem not to affect the therapeutic response to lamivudine (3TC). Whether a given genotype has an earlier emergence of 3TC resistance remains unclear. We thus conducted this study to elucidate the association of HBV genotype with the emergence of 3TC-resistant strains in Taiwanese patients. METHODS: Forty chronic hepatitis B patients who developed resistance after 3TC therapy were retrospectively enrolled. HBV genotype, serum alanine aminotransferase (ALT) and HBV DNA levels were determined at baseline. The presence of 3TC-resistant mutations was confirmed by direct sequencing whenever biochemical breakthrough developed. RESULTS: The distribution of HBV genotype B and C in 40 patients receiving 3TC therapy were 60% and 40%, respectively. The mean interval to detect 3TC-resistant strain was 19.6 +/-1.7 months. By using multivariate analysis, HBV genotype B and higher pre-treatment HBV DNA level were independently associated with earlier detection of 3TC-resistant strains. In addition, genotype B was significantly associated with development of 3TC resistance within the first 12 months of 3TC therapy compared with genotype C (odds ratio 8.27; P=0.004). CONCLUSIONS: Compared with HBV genotype C, genotype B appears to have an earlier biochemical resistance to 3TC than genotype C. Therefore, more frequent monitoring of viral load or genotypical resistance might be needed for patients with HBV genotype B infection receiving 3TC therapy, especially during the first year.

Natural course and treatment of hepatitis D virus infection.

Hepatitis D virus (HDV) is a subviral satellite with hepatitis B virus (HBV) as its natural helper virus. After entry into hepatocytes, it utilizes host cellular enzymes to replicate by a double-rolling-circle mechanism. HDV is most often transmitted by contact with contaminated blood and body fluid, similar to HBV infection. Approximately 5% of the global HBV carriers are coinfected with HDV, leading to a total of 10-15 million HDV carriers worldwide. HDV infection can occur concurrently with HBV infection (coinfection) or in a patient with established HBV infection (superinfection). The pathogenesis of HDV remains controversial. A decline in the prevalence of both acute and chronic hepatitis D (CHD) has been observed worldwide. At present, therapy for chronic HDV infection is by the use of interferon-alpha. Compared to chronic hepatitis B or C, CHD treatment requires a higher dosage and a longer duration of treatment, and post-treatment relapses are common. In order to prevent the progression of CHD and its related morbidity and mortality, more effective treatments are needed.

Successful treatment with peginterferon and ribavirin in a patient with acute hepatitis C evolving into chronicity.

Acute hepatitis C has a high frequency of chronic evolution, which may progress to cirrhosis and hepatocellular carcinoma. However, only a small proportion of acute hepatitis C patients are incidentally identified and then treated. Controversial issues regarding treatment of acute hepatitis C include optimal time of treatment initiation, best treatment regimen and appropriate duration of treatment. We report a symptomatic acute hepatitis C patient in the late acute phase evolving into chronicity successfully treated by peginterferon and ribavirin combination therapy for 6 months at late acute phase, with sustained virologic response for up to 18 months. Our findings indicate that combination peginterferon and ribavirin therapy may be as effective in treating acute hepatitis C as it is in chronic hepatitis C.