Management of entecavir-resistant chronic hepatitis B with adefovir-based combination therapies

AIM: To evaluate the long-term efficacy adefovir(ADV)-based combination therapies in entecavir(ETV)-resistant chronic hepatitis B(CHB) patients. METHODS: F i fty CHB pat ient s wi t h genotypic resistance to ETV at 13 medical centers in South Korea were included for the analysis. All the patients received rescue therapy with the combination of ADV plus ETV(ADV/ETV,n = 23) or ADV plus lamivudine(LMV)(ADV/LMV,n = 27) for more than 12 mo. Patients were monitored at least every 3-4 mo during ADV-based combination therapy by clinical examination as well as biochemical and virological assessments. Hepatitis B virus(HBV) DNA levels were measured by realtime PCR and logarithmically transformed for analysis. Cumulative rates of virologic response(VR; HBV DNA < 20 IU/m L) were calculated using the Kaplan-Meier method,and the difference was determined by a logrank test. Multivariate logistic regression and Cox proportional hazards models were used to identify independent risk factors significantly associated with short-term and long-term VR,respectively.RESULTS: Baseline median HBV DNA levels were 5.53(2.81-7.63) log10 IU/m L. The most commonly observed ETV genotypic mutation sites were rt184 and rt202. Patients were treated for a median of 27(12-45) mo. Overall,cumulative VR rates at 6,12,24,and 36 mo were 26%,36%,45%,and 68%,respectively. Patients treated with the ADV/ETV combination showed higher cumulative VR rates(35%,43%,65%,and 76%,respectively) than those with the ADV/LAM combination(18%,30%,30%,and 62%,respectively; P = 0.048). In the multivariate analysis,low baseline HBV DNA levels(< 5.2 log10 IU/m L) and initial virologic response at 3 mo(IVR-3; HBV DNA < 3.3 log10 IU/m L after 3 mo) were independent predictive factors for VR. Patients with favorable predictors achieved cumulative VR rates up to 90% at 36 mo. During the same period,the cumulative incidence of virologic breakthrough was as low as 6% in patients with the both favorable predictors.CONCLUSION: If tenofovir is not available,ADV/ETV combination could be considered in ETV-resistant patients with low HBV DNA titers,and may becontinued if IVR-3 is achieved.

Recurrence after endoscopic piecemeal mucosal resection for large sessile colorectal polyps

AIM: To evaluate the safety and outcomes of endoscopic piecemeal mucosal resection (EPMR) for large sessile colorectal polyps. METHODS: The patients enrolled in this study were 47 patients with 50 large sessile polyps (diameter, 2 cm or greater) who underwent EPMR using a submucosal saline injection technique between December 2002 and October 2005. All medical records, including characteristics of the patients and polyps, complications, and recurrences, were retrospectively reviewed. The first follow-up endoscopic examination was performed at 3-6 mo after initial endoscopic resection, and the second at 12 mo postEPMR. Subsequent surveillance colonoscopic examinations were individualized, taking risk factors into account. RESULTS: The patients were 23 men and 24 women,with a mean age of 60 years. Mean polyp size was 30.1 mm. Of 50 polyps identified, 34 (68%) were benign and 16 (32%) were malignant. There were 6 (12%) cases with EPMR-related bleeding: 5 intra-procedural and 1 early post-procedural bleeding. All bleeding episodes were managed by endoscopic clipping or argon beam coagulation. There were no perforations. Recurrence was identified in 5 cases (12.2%): 4 local recurrences detected at 3 mo post-EPMR and 1 local recurrence detected at 14 mo post-EPMR. The recurrence rate after EPMR was 3.1% for benign polyps and 33.3% for malignant polyps (P < 0.05). Median follow-up time was 37 mo. CONCLUSION: EPMR is safe, but should be applied carefully in malignant polyps. Close follow-up endoscopic examinations are necessary for early detection of recurrence.

Differentiation of acute and chronic hepatitis B in IgM antiHBc positive patients

AIM: To identify the factors that differentiate acute hepatitis B(AHB) from chronic hepatitis B with acute exacerbation(CHB-AE).METHODS: From 2004 to 2013, a total of 82 patients(male n = 52, 63.4%; female n = 30, 36.6%) with clinical features of acute hepatitis with immunoglobulin M antibodies to the hepatitis B core antigen(Ig M antiHBc) were retrospectively enrolled and divided into two groups; AHB(n = 53) and CHB-AE(n = 29). The AHB group was defined as patients without a history of hepatitis B virus(HBV) infection before the episode and with loss of hepatitis B surface antigen within 6 mo after onset of acute hepatitis. Biochemical and virological profiles and the sample/cutoff(S/CO) ratio of Ig M anti-HBc were compared to determine the differential diagnostic factors.RESULTS: The multivariate analysis demonstrated that, the S/CO ratio of Ig M anti-HBc and HBV DNA levels were meaningful factors. The S/CO ratio of Ig M anti-HBc was significantly higher in the AHB group, while the HBV DNA level was significantly higher in the CHB-AE group. The optimal cutoff values of Ig M anti-HBc and HBV DNA levels for differentiating the two conditions were 8 S/CO ratio and 5.5 log10 IU/m L, respectively. The sensitivity and specificity were 96.2% and 89.7% for the S/CO ratio of Ig M anti-HBc and 81.1% and 72.4% for HBV DNA levels, respectively. The area under receiver operating characteristic curves of both the S/CO ratio of Ig M anti-HBc and HBV DNA levels were not significantly different(0.933 vs 0.844, P = 0.105). When combining Ig M anti-HBc and HBV DNA, the diagnostic power significantly improved compared to HBV DNA alone(P = 0.0056). The combination of these factors yielded a sensitivity and specificity of 98.1% and 86.2%, respectively.CONCLUSION: The combination of the S/CO ratio of Ig M anti-HBc and HBV DNA levels was a useful tool for differentiating AHB from CHB-AE in patients with positive Ig M anti-HBc.

Signet-ring cell carcinoma arising from a fundic gland polyp in the stomach

Fundic gland polyps(FGPs)are currently the most common type of gastric polyps and are usually benign.However,although rare,gastric adenocarcinoma of FGP has been recently proposed as a new variant of gastric adenocarcinoma.Here we report the first case of a49-year-old woman with focal signet ring cell carcinoma that arose from an FGP of the stomach.The tumor was completely excised by endoscopic snare polypectomy.FGPs should therefore be evaluated for malignant changes although they occur rarely,if the FGP has an erosive or irregular surface.

Pemetrexed in Previously Treated Non-small Cell Lung Cancer Patients with Poor Performance Status

Background and objective Pemetrexed have been approved for the treatment of patients affected by advanced non-small cell lung cancner(NSCLC) in progression after first-line chemotherapy.We evaluated the activity and feasibility of pemetrexed in previously treated NSCLC.Methods Patients with histologically or cytologically confirmed NSCLC were evaluated from April 2007 to March 2009.The patients had relapsed or progressed after prior chemotherapy treatment.Pemetrexed(500 mg/m2) was administered intravenously once every 3 weeks after progression to prior chemotherapy.The tumor response was evaluated according to RECIST criteria by chest CT at every 2 cycles of chemotherapy.Results A total 61 patients were eligible for analysis.Performance status of them(100%) was over 2.The response rate and disease control rate were 14.7% and 37.7% respectively.Non-squamous cell carcinoma histology was significantly associated with a superior response rate(P=0.045) and disease control rate(P=0.008).The median survival time and the median progression free survival(PFS) time were 6.11 months and 2.17 months,respectively.Comparing the efficacy of pemetrexed in these two settings [second-line versus(12/61) more than third(49/61)],there was no significant difference in regard to median survival(11.18 months vs 11.46 months,P=0.922,5),but PFS was more longer in third-or further-line groups than second-line group(1.39 months vs 2.25 months,P=0.015,3).Conclusion Pemetrexed is a feasible regimen in previously treated NSCLC with poor performance status.

Evidence from a familial case suggests maternal inheritance of primary biliary cholangitis

Primary biliary cholangitis(PBC) is an idiopathic autoimmune liver disease characterized by chronic cholestasis and destruction of the intrahepatic bile ducts. Similar to other autoimmune diseases, the pathogenesis of PBC is considered to be a complex etiologic phenomenon involving the interaction of genetic and environmental factors. Although a number of common variants associated with PBC have been reported from genome-wide association studies, a precise genetic mechanism underlying PBC has yet to be identified. Here, we describe a family with four sisters who were diagnosed with PBC. After the diagnosis of the index patient who was in an advanced stage of PBC, one sister presented with acute hepatitis, and two sisters were subsequently diagnosed with PBC. Notably, one half-sister with a different mother exhibited no evidence of PBC following clinical investigation. Our report suggests the possibility of a maternal inheritance of PBC susceptibility. Moreover, judging from the highpenetrance of the disease observed in this family, we inferred that a pathogenic genetic variant might be the cause of PBC development. We describe a family that exhibited diverse clinical presentations of PBC that included asymptomatic stages with mildly increased liver enzyme levels and symptomatic stages with acute hepatitis or advanced liver fibrosis. Additional studies are needed to investigate the role of genetic factors in the pathogenesis of this rare autoimmune disease.

Curvature range measurements of the arcuate fasciculus using diffusion tensor tractography

Because Broca＇s area and Wernicke＇s area in the brain are connected by the arcuate fasciculus, understanding the anatomical location and morphometry of the arcuate fasciculus can help in the treatment of patients with aphasia. We measured the horizontal and vertical curvature ranges of the arcuate fasciculus in both hemispheres in 12 healthy subjects using diffusion tensor tractography. In the right hemisphere, the direct curvature range and indirect curvature range values of the arcuate fasciculus horizontal part were 121.13 ± 5.89 and 25.99 ± 3.01 degrees, respectively, and in the left hemisphere, the values were 121.83 ± 5.33 and 27.40 ± 2.96 degrees, respectively. In the right hemisphere, the direct curvature range and indirect curvature range values of the arcuate fasciculus vertical part were 43.97 ± 7.98 and 30.15 ± 3.82 degrees, respectively, and in the left hemisphere, the values were 39.39 ± 4.42 and 24.08 ± 4.34 degrees, respectively. We believe that the measured curvature ranges are important data for localization and quantitative assessment of specific neuronal pathways in patients presenting with arcuate fasciculus abnormalities.

Changes in brain activation patterns according to cross-training effect in serial reaction time task An functional MRI study

Cross-training is a phenomenon related to motor learning, where motor performance of the untrained limb shows improvement in strength and skill execution following unilateral training of the homologous contralateral limb. We used functional MRI to investigate whether motor performance of the untrained limb could be improved using a serial reaction time task according to motor sequential learning of the trained limb, and whether these skill acquisitions led to changes in brain activation patterns. We recruited 20 right-handed healthy subjects, who were randomly allocated into training and control groups. The training group was trained in performance of a serial reaction time task using their non-dominant left hand, 40 minutes per day, for 10 days, over a period of 2 weeks. The control group did not receive training. Measurements of response time and percentile of response accuracy were performed twice during pre- and post-training, while brain functional MRI was scanned during performance of the serial reaction time task using the untrained right hand. In the training group, prominent changes in response time and percentile of response accuracy were observed in both the untrained right hand and the trained left hand between pre- and post-training. The control group showed no significant changes in the untrained hand between pre- and post-training. In the training group, the activated volume of the cortical areas related to motor function （i.e., primary motor cortex, premotor area, posterior parietal cortex） showed a gradual decrease, and enhanced cerebellar activation of the vermis and the newly activated ipsilateral dentate nucleus were observed during performance of the serial reaction time task using the untrained right hand, accompanied by the cross-motor learning effect. However, no significant changes were observed in the control group. Our findings indicate that motor skills learned over the 2-week training using the trained limb were transferred to the opposite homologous limb, and motor skill acquisition of the untrained limb led to changes in brain activation patterns in the cerebral cortex and cerebellum.

Efficacy of Pegylated Interferon Monotherapy versus Sequential Therapy of Entecavir and Pegylated Interferon in Hepatitis B e Antigen-Positive Hepatitis B Patients： A Randomized, Multicenter, Phase IIIb Open-Label Study （POTENT Study）

Background： Until now, various types of combined therapy with nucleotide analogs and pegylated interferon （Peg-INF） in patients with hepatitis B patients have been tried. Howe6ver, studies regarding the benefits of de novo combination, late-add on, and sequential treatmentare very limited. The objective of the current study was to identify the efficacy of sequential treatment of Peg-INF after short-term antiviral treatment. Methods： Between June 2010 and June 2015, hepatitis 13 e antigen （HBeAg）-positive patients （n = 162） received Peg-IFN for 48 weeks （mono-treatment group, n = 81） and entecavir （ETV） for 12 weeks with a 48-week course of Peg-IFN starting at week 5 of ETV therapy （sequential treatment group, n = 81）. The primary endpoint was HBeAg seroconversion at the end of follow-up period after the 24-week treatment. The primary endpoint was analyzed using Chi-square test, Fisher＇s exact test, and regression analysis.Results： HBeAg seroconversion rate （18.2% vs. 18.2%, t = 0.03, P = 1.000） and seroclearance rate （19.7% vs. 19.7%, t = 0.03, P = 1.000） were same in both mono-treatment and sequential treatment groups. The rate of alanine aminotransferase （ALT） normalization （45.5% vs. 54.5%, t = 1.12, P = 0.296） and serum hepatitis B virus （HBV）-DNA 〈2000 U/L （28.8% vs. 28.8%, t = 0.10, P = 1.000） was not different in sequential and mono-treatment groups at 24 weeks of Peg-INF. Viral response rate （HBeAg seroconversion and serum HBV-DNA 〈2000 U/L） was not different in the two groups （12.1% vs. 16.7%, t = 1.83, P = 0.457）. Baseline HBV-DNA level （7 log10 U/ml vs. 7.5 log10 U/ml, t = 1.70, P = 0.019） and hepatitis B surface antigen titer （3.6 log10 U/ml vs. 4.0 log10 U/ml, t = 2.19, P = 0.020） were lower and predictors of responder in mono-treatment and sequential treatment groups, respectively. Conclusions： The current study shows no differences in HBeAg seroconversion rate, ALT normalization, and HBV-DNA levels between mono-therapy and sequential therapy regimens.