We investigated the long-term risk of hepatocellular carcinoma (HCC) in dual-infected hepatitis B and C patients after eradication of hepatitis C virus (HCV). A total of 164 (62% male, median age, ...50.5 years) hepatitis B and C dual-infected patients who achieved HCV sustained virological response were recruited. Half the patients were HCV genotype 1 with a median viral load of 5.5 log10 IU/mL, and 22.6%had an HBV DNA level ≥ 2000 IU/mL before therapy. HCC developed in 14 patients (8.5%), with an annual incidence of 1.38% per person-year. The 3-year, 5-year, 10-year, and 15-year cumulative probabilities were 2.5%, 5.1%, 12.6%, and 22.7%, respectively. Six months after treatment, a Cox regression hazard analysis revealed platelet level (HR: 0.98, 95% CI: 0.957-0.999,
= 0.038) and AFP level (HR: 1.20, 95% CI: 1.031-1.400,
= 0.019) to be independent factors in HCC. A higher 10-year cumulative risk of HCC was detected in patients with 6-month post-treatment AFP levels > 5.0 ng/mL and platelet levels < 130 x1000/µL (54.9%), compared to patients with neither (8.6%). Although the risk of HCC is low, surveillance of HCC is encouraged in dual-infected patients after eradication of HCV. Post-treatment AFP and platelet levels predict HCC development.
Intestine-specific homeobox (ISX), a newly identified proto-oncogene, is involved in cell proliferation and progression of hepatocellular carcinoma (HCC). However, the underlying mechanisms linking ...gene expression and tumor formation remain unclear. In this study, we found that ISX transcriptionally activated E2F transcription factor 1 (E2F1) and associated oncogenic activity by directly binding to the E2 site of its promoter. Forced expression of ISX increased the expression of and phosphorylated the serine residue at position 332 of E2F1, which may be translocated into the nucleus to form the E2F1-DP-1 complex, suggesting that the promotion of oncogenic activities of the ISX-E2F1 axis plays a critical role in hepatoma cells. Coexpression of ISX and E2F1 significantly promoted p53 and RB-mediated cell proliferation and anti-apoptosis, and repressed apoptosis and autophagy. In contrast, short hairpin RNAi-mediated attenuation of ISX and E2F1 decreased cell proliferation and malignant transformation, respectively, in hepatoma cells in vitro and in vivo. The mRNA expression of E2F1 and ISX in 238 paired specimens from human HCC patients, and the adjacent, normal tissues exhibited a tumor-specific expression pattern which was highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. Therefore, our results indicate that E2F1 is an important downstream gene of ISX in hepatoma progression.
AIM: To study the manifestations of perihepatic lymph nodes during the episode of acute hepatitis flare by point-of-care ultrasonography.METHODS: One hundred and seventy-six patients with an episode ...of acute hepatitis flare(ALT value > 5 × upper normal limit) were enrolled retrospectively. Diagnosis of etiology of the acute hepatitis flare was based on chart records and serological and virological assays. The patients were categorized into two groups(viral origin and non-viral origin) and further defined into ten subgroups according to the etiologies. An ultrasonograpy was performed within 2 h to 72 h(median, 8 h). The maximum size of each noticeable lymph node was measured. Correlation between clinical parameters and nodal manifestations was analyzed RESULTS: Enlarged lymph nodes(width ≥ 5mm)were noticeable in 110(62.5%) patients, mostly in acute on chronic hepatitis B(54.5%). The viral group had a higher prevalence rate(89/110 = 80.9%) and larger nodal size(median, 7 mm) than those of the non-viral group(21/66 = 31.8%; median, 0 mm)(P < 0.001 for both). Meanwhile, there were significant differences in the nodal size between acute and chronic viral groups(P < 0.01), and between acute hepatitis A and non-hepatitis A viral groups(P < 0.001). In logistical regression analysis, the nodal width still showed strong significance in multivariate analysis(P < 0.0001) to stratify the two groups. The area under the curve of ROC was 0.805, with a sensitivity of 80.9%, a specificity of 68.2%, positive predictive value of 80.92%, negative predictive value of 68.18%, and an accuracy of 76.14%. CONCLUSION: Point-of-care ultrasonography to detect perihepatic nodal change is valuable for clarifying the etiologies in an episode of acute hepatitis flare.
Latent hepatitis B virus (HBV) reactivation related to rituximab use is associated with an increase in morbidity and mortality. We report a case of latent HBV reactivation with decompensated ...hepatitis that occurred 10 months after the completion of rituximab therapy. Initially, the patient's condition deteriorated, even during combination antiviral drug therapy (tenofovir plus entecavir). However, it dramatically improved after treatment with intravenous Stronger Neo Minophagen C (SNMC). Glycyrrhizin is the main component of SNMC, which plays a role inbridging therapy to allow the efficiency of antiviral drugs to develop. In addition, prolonged use of the antiviral drug after the completion of rituximab and chemotherapy should be considered to extend beyond 6 months, which is currently advised by the National Health Insurance in Taiwan.
Abstract Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are thought to be the result of breakdown of immune tolerance on the natural history of chronic hepatitis B virus (HBV) infection. ...Immune tolerance to HBV maintained in CH-B patients without hepatitis is under the control of the host's forkhead box p3-expressing regulatory T cells (Tregs). Its breakdown mimics the occurrence of autoimmune diseases. Severe AEs may lead to liver decompensation and mortalities. Consequently, AEs are currently the major therapeutic targets in patient treatment. In this study, we employed the SYFPEITHI scoring system to identify epitopes on HBV core antigen (HBcAg) for the construction of human leukocyte antigen class II tetramers to measure HBcAg-specific Treg frequencies (Tregf). Upregulation of Treg gene profiling accompanied by increased HBcAg-specific Tregf was detected in AE patients with sustained remission (SR) to anti-HBV therapy. Depletion of Tregs from peripheral blood mononuclear cells enhanced proliferation to HBcAg. HBcAg-specific Treg clones inhibited the killing capacity of cytotoxic T lymphocyte clones in an antigen-independent manner. A greater posttherapy increase in HBcAg-specific Tregf correlated with a higher SR rate to anti-HBV therapy. These results suggest that HBcAg-specific Tregs function as suppressor effectors and confer SR to anti-HBV therapy.
In chronic hepatitis C, the change of perihepatic lymph nodal size after antiviral therapy could be a marker of virologic response. Whether the on-treatment nodal manifestations predict virologic ...responses is unknown.
Patients (n=88) with biopsy-proven chronic hepatitis C received standard doses of bi-therapy for 24 weeks; sequential changes of the perihepatic lymph nodes were evaluated prospectively by ultrasound. Pretreatment and on-treatment factors were analyzed and correlated with sustained virologic response, focusing on early on-treatment nodal changes (12 weeks).
Perihepatic lymph nodes were prevalent in 75% of the patients; 72 patients (81.8%) achieved sustained viral response. Before treatment, no factor was significantly associated with the nodal prevalence or size. The pretreatment nodal width (mean 5.3 vs. 3.6 mm; P=0.023) and the on-treatment nodal manifestations including a reduction in nodal width at 12 weeks of antiviral treatment (median; 1.05 vs. 0 mm, P=0.029) and a reduction of nodal volume at the end of treatment (24 weeks; median 0.62 vs. -0.01 ml, P=0.015) were significantly correlated with the sustained virologic response. A reduction of nodal width greater than 2.5 mm at 12 weeks always predicts sustained virologic response (100 vs. 77%; P=0.019).
Results confirm the high prevalence of perihepatic lymphadenopathy in patients with chronic hepatitis C. The use of the nodal width measurement in routine ultrasound follow-up may be a simpler early predictor of sustained virologic response during standard bi-therapy.
To elucidate the genotype-specific virus-host–drug interaction and the on-treatment viral kinetics in predicting sustained virologic response (SVR), serial serum hepatitis C virus (HCV) ribonucleic ...acid (RNA) levels at baseline, treatment week 2 (W2), treatment week 4 (W4), and treatment week 12 (W12) were measured in 199 chronic HCV-infected Taiwanese patients receiving interferon-alpha (INF-α) 6 million units (MU) three times weekly plus 1000 to 1200 mg/day of ribavirin for 24 weeks. The SVR rate was 90.5% (95/105) for HCV genotype 2 (HCV-2) patients and 47.9% (45/94) for HCV-1 patients (
P < 0.0001). HCV-2 patients had a significantly higher rate of rapid virologic response (RVR) at W2 than HCV-1 patients. HCV RNA negativity at W4 had the highest accuracy of prediction (80%) of SVR with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81%, 79%, 78%, and 82%, respectively, for HCV-1 patients. HCV RNA negativity or 2 logs drop at W4 had the highest accuracy of prediction (92%) with sensitivity, specificity, PPV, and NPV of 100%, 20%, 92%, and 100%, respectively, for HCV-2 patients. In multivariate analysis, the significant factors associated with SVR in HCV-1 patients were HCV RNA negativity at W12 and W4. HCV RNA negativity or 2 logs drop was the only significant factor associated with SVR in HCV-2 patients. In conclusion, a RVR at W4 could predict an SVR with a high degree of accuracy to a 24-week course of high-dose IFN/ribavirin for both HCV-1 patients and HCV-2 patients. With respect to each HCV genotype, the on-treatment virologic responses are the most important factors associated with SVR.
Summary
Background
Hepatocellular carcinoma is a common cancer with an increasing incidence worldwide because of the dissemination of hepatitis B and hepatitis C virus infection. Surgical resection ...is the most important therapeutic option with a curative intent. Early tumor detection through screening and improvements in surgical techniques have significantly improved the outcome of patients with hepatocellular carcinoma. However, local recurrence after curative hepatic resection is common and is the most frequent cause of death in these patients.
Patients and Methods
In an attempt to identify the risk factors that predict tumor recurrence, we conducted this retrospective study in a single institution for a 6‐year period. Of the 100 consecutive patients who underwent curative tumor resection, we analyzed age, sex, viral etiology (hepatitis B virus vs. hepatitis C virus), preoperative levels of aspartate aminotransferase and alanine aminotransferase, the α‐fetoprotein level, underlying liver disease status (chronic hepatitis vs. cirrhosis), number and size of tumors, type of resection, and presence of microvascular invasion.
Results
In the median follow‐up period of 36 months (range, 12–85 months), the 1‐year, 3‐year, and 5‐year overall survival rates were 90%, 84%, and 73%, respectively; tumor recurrence occurred in 38 (38%) patients and was the leading cause of death among the patients who died (15 of 17 patients; 88%). On univariate analysis, the only factor significantly associated with a higher incidence of tumor recurrence was preoperative levels of aspartate aminotransferase greater than twice the upper normal value (p < 0.01) and this factor remained significant with multivariate analysis. Subgroup analysis of the risk factor of early tumor recurrence (≤2 years) and late tumor recurrence (>2 years) was conducted and a preoperative aspartate aminotransferase level greater than twice the upper normal value was still significant in both groups (p = 0.02 and p = 0.044, respectively).
Conclusion
Although this is a small‐scale study, our findings could be easily applied clinically and used as readily available indicators to help the follow‐up algorithm. We also suggest antiviral management as soon as possible for patients with hepatocellular carcinoma undergoing curative resection, especially those with a high preoperative aspartate aminotransferase level.
Acute exacerbation (AE) of chronic hepatitis B virus (HBV) infection in cancer chemotherapy patients and in organ transplant recipients receiving immunosuppressants may cause catastrophe and high ...mortality. Hence, immediate treatment with nucleoside analogues for such patients has become a consensus. Anti-HBV therapeutic trials in Asia have shown that AE of chronic hepatitis B (CH-B) may result in increased sustained remission (SR) rate with lamivudine monotherapy. Nonetheless, AE episodes in CH-B patients may evolve uneventfully and lead to spontaneous remission. Thus, the policy of immediate anti-HBV therapy for AE patients reaches an impasse. Once treatment is initiated, life long HBV suppression may be necessary.
To determine whether lamivudine monotherapy during an AE of CH-B results in an increase in SR compared with no therapy.
A cohort of 154 CH-B patients seropositive for hepatitis B e antigen with AE formed the study group. This included 102 cases receiving a nationwide therapeutic trial of 18-month lamivudine monotherapy that were compared with 52 cases with no therapy. All were observed for at least 30 months, which encompassed the 18-month on treatment period and a 12-month posttreatment follow-up.
No significant increase was observed in the SR rate in the lamivudine treatment group compared with the spontaneous remission rate in the untreated patients (P=0.782, Fisher's exact test).
AE does not increase the SR rate during 18-month lamivudine monotherapy. Immediate lamivudine therapy for AE patients is not justified as mandatory. The policy should be only applied to AE patients with impending liver failure.
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