Lower Mutation Frequency of BCP/Precore Regions in e Antigen-Negative Chronic HBV-Infected Children instead of Adults Patients

To describe the Hepatitis B e antigen(HBeAg) seroconversion related mutation profiles of the basal core promoter(BCP)/precore regions in e antigen seroconverted child patients, a cohort of 245 child patients with CHB and a control patients group of 92 adult patients with CHB were recruited. The mutation frequencies of six nucleotides or nucleotide combinations including nucleotide (nt)1896, nt1762/1764, nt1752, nt1846, nt1899 and nt1753 showed significant differences between HBeAg positive and HBeAg-negative child patients groups. The frequencies of these HBeAg seroconversion-related mutations were significantly lower in HBeAg-negative children with CHB than in HBeAg-negative adults with CHB, especially for the mutation G1896A (41.1% vs 91.7%, P<0.001), and the average number of BCP/precore region mutations in samples from HBeAg-negative child patients was also obviously lower than in HBeAg-negative adult patients(3.62±3.03 vs 4.89±2.09, P<0.001), suggesting less impact of mutations in the BCP/precore region on HBeAg seroconversion in child patients than adult patients.     

Discordance between Liver Biopsy and FibroTest in Assessing Liver Fibrosis in Chronic Hepatitis B

Background and Aims

The FibroTest (FT) demonstrated excellent diagnostic performance in the prediction of liver fibrosis in patients with chronic hepatitis B (CHB). Here, we aimed to identify predictors of discordance between FT and liver biopsy (LB) in Asian patients with CHB.

Methods

Consecutive patients with CHB who underwent both LB and FT on the same day between 2007 and 2010 were recruited from three medical institutes. Laboratory evaluations including specific parameters for calculating FT score, such as α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl transpeptidase, and total bilirubin levels, were obtained. The Batts and Ludwig scoring system was used for histological analysis.

Results

A total of 330 patients (200 male and 130 female) were analyzed. Discordances of at least two fibrosis stages between FT and LB were observed in 30 (9.1%) patients; using FT, fibrosis was underestimated in 25 patients and overestimated in 5 patients with reference to LB. Patients with discordance had a higher proportion of F3–4 (P<0.001) and F4 (P = 0.012) compared with those with nondiscordance. The discordance rate was significantly higher in those with F3–4 than those with F1–2 (15.4% vs. 3.0%, P<0.001). Multivariate analysis demonstrated F3–4 at LB as the only independent factor for discordance (P<0.001; odds ratio 5.95). After adjusting fibrosis stages, neither necroinflammatory activity on histology nor serum ALT level influenced FT values independently.

Conclusion

Advanced fibrosis stage (F3–4) is the sole factor of discordance between FT and LB in Asian patients with CHB.     

Study on Post-Treatment Relapse in HBeAg Positive CHB Patients

Background

Many factors are associated with post-treatment relapse in CHB patients, and there are no effective factors to predict relapse. In this study, we investigate the influence factors associated with post-treatment relapse and their predictive value in HBeAg positive CHB (eP-CHB).

Methods

The factors associated with post-treatment relapse were analyzed firstly by a retrospective study in eP-CHB. Variables included age, sex, regimen, baseline HBeAg and HBV DNA level, total course of treatment as well as duration of consolidation therapy after HBeAg seroconversion. The predictive effects of the influence factors were evaluated in an eP-CHB prospective cohort.

Results

89 patients were enrolled in the retrospective study, 42(47.2%) relapsed after discontinuation of treatment. Factors related to post-treatment relapse were total course of treatment, duration of consolidation therapy and baseline HBV DNA level. Relapse rates in patients with total course >36 months, consolidation duration >12 months and baseline HBV DNA level < 1.0E+5IU/ml were lower than those of total course <24 months (P = 0.002), consolidation duration≤12 months (P = 0.011) and baseline HBV DNA level > 1.0E+7IU/ml (P = 0.01) respectively. Patients with HBV DNA≥1.0E+7IU/ml plus HBeAg<200COI at baseline had the highest relapse rate and cumulative relapse rate than the other three arms (P = 0.048 and 0.008 respectively). Logistic regression analysis demonstrated that baseline HBV DNA level, duration of consolidation therapy and combination of baseline HBV DNA and HBeAg (Ig^DNA/Ig^HBeAg) were independent factors to predict post-treatment relapse. The model based on baseline Ig^DNA/Ig^HBeAg and consolidation duration worked well in predicting post-treatment relapse in the prospective study and the accuracy, specificity, sensitivity, PPV and NPV for prediction were 80.3%, 81.1%, 79.2%, 73.1% and 85.7% respectively.

Conclusions

Virological factors including baseline HBV DNA, HBeAg and treatment course were major influence factors associated with post-treatment relapse in eP-CHB. Patients with higher HBV DNA and lower HBeAg levels at baseline, shorter total course as well as consolidation therapy were more likely to develop relapse after discontinuation of therapy. The antiviral therapy in eP-CHB patients should be individually managed at different levels. It is better to treat those with higher viral load and lower HBeAg levels at baseline for a longer course, especially longer consolidation duration so as to decrease the relapse rate.     

Serum Testosterone Levels and Androgen Receptor CAG Polymorphism Correlate with Hepatitis B Virus (HBV)-Related Acute Liver Failure in Male HBV Carriers

Background

Augmentation of androgen/androgen receptor (AR) pathway may influence chronic hepatitis B (CHB) more likely in males. AR activity is modulated by a polymorphic CAG repeat sequence in AR exon 1. This study aimed to investigate the relationship between serum testosterone levels, CAG repeat numbers and hepatitis B virus (HBV)-related acute liver failure (ALF).

Methods

Three hundred and seventy eight male CHB patients with ALF and 441 asymptomatic HBV carriers (AsCs) were recruited. AR CAG repeats numbers were analyzed. The serum testosterone levels of AsCs, ALFs and patients with hepatitis B flare groups, and sequential serum samples, were assessed quantitatively.

Results

The median CAG repeat (M-CAG) frequency was significantly higher in ALF patients than AsCs (P<0.001). Patients with M-CAG alleles (P<0.001, OR 3.0, 95% CI 2.1–4.2) had the highest risk for ALF. Serum testosterone levels were significantly higher (P<0.001) at hepatitis flare point (8.2±3.0 ng/mL) than inactive phase (6.4±2.0 ng/mL). CHB (8.30±2.71 ng/mL, P = 7.6×10⁻⁶) and ALF group (2.61±1.83 ng/mL, P = 1.7×10⁻¹⁷) had significantly different levels of testosterone in comparison with AsCs group (6.56±2.36 ng/mL). The serum testosterone levels sharply decreased from hepatitis flare phase to liver failure phase, and tended to be normal at the recovery phase. Male AsCs with M-CAG alleles had significantly lower serum testosterone levels (P<0.05).

Conclusions

There was a serum testosterone fluctuation during hepatitis B flare and HBV-related ALF, and the median CAG repeats in AR gene exon 1 were associated with lower serum testosterone levels in asymptomatic HBV carriers and an increased susceptibility to HBV-related ALF.     

Radiation-Induced Temporal Lobe Injury for Nasopharyngeal Carcinoma: A Comparison of Intensity-Modulated Radiotherapy and Conventional Two-Dimensional Radiotherapy

Background

To compare the radiation-induced temporal lobe injury (TLI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT) or two-dimensional conventional radiotherapy (2D-CRT).

Patients and Methods

1276 cases of NPC treated with IMRT or 2D-CRT were retrospectively reviewed. A diagnosis of TLI was made on follow-up magnetic resonance imaging (MRI).

Results

The crude incidence of TLI was 7.5% and 10.8% (P = 0.048), and the actuarial 5-year incidence was 16% and 34.9% (P<0.001) for the IMRT and 2D-CRT groups, respectively. Multivariate analysis revealed both T stage (P<0.001) and radiation technique (P<0.001) as independent predictors. Patients with T1, T2 and T3 disease had a significantly higher risk when treated with 2D-CRT (P = 0.005, 0.016, <0.001, respectively). This trend was not evident for T4 patients (P = 0.680). The 2D-CRT group had a longer latency for the development of TLI (P<0.001). Those with T4 disease had a shorter median time to TLI (P = 0.006, 0.042, <0.001 when compared with T1, T2 and T3, respectively).

Conclusions

IMRT is superior to 2DRT for the management of T1-T3 NPC in terms of sparing the temporal lobe. The high incidence of TLI in T4 disease needs to be addressed.     

High Expression of Heat Shock Protein 90 Is Associated with Tumor Aggressiveness and Poor Prognosis in Patients with Advanced Gastric Cancer

The heat shock protein 90 (HSP90) is overexpressed and highly associated with poor prognosis in many malignancies. However, the role of HSP90 in gastric cancer has not been thoroughly elucidated. The aim of this study is to investigate the relationship of HSP90 expression with clinicopathological parameters and prognosis in advanced gastric cancer, and estimate the alteration of HSP90 expression after neoadjuvant chemotherapy. HSP90 and matrix metallopeptidase 9 (MMP-9) antigen expression was evaluated by immunohistochemistry in 322 advanced gastric carcinoma samples. The relationships between HSP90 and clinicopathological parameters and prognosis were analyzed. The response of HSP90 level was assessed in chemotherapeutic effect in 54 patients received 1–2 cycles of neoadjuvant chemotherapy. The positive expression of HSP90 was found to be 69.6% in 322 advanced gastric carcinoma samples. HSP90 protein expression was significantly associated with depth invasion (P<0.001), lymph node metastasis (P<0.001) and stage of disease (P<0.001). The positive rates of HSP90 expression were higher in both prominent serosal invasion group (P<0.001) and lymph node metastasis group (P<0.001). Moreover, HSP90 was significantly correlated with MMP-9 among 322 gastric cancer tissues (P<0.001). In univariate and multivariate analyses, HSP90 was an independent prognostic factor for both recurrence-free survival (RFS) and overall survival (OS). These results suggested that HSP90 may play an important role on tumor invasion, metastasis and prognosis, and might act as a promising target for prognostic prediction.     

CXCL9 Associated with Sustained Virological Response in Chronic Hepatitis B Patients Receiving Peginterferon Alfa-2a Therapy: A Pilot Study

Background and Aims

There is lack of a practical biomarker to predict sustained virological response (SVR) in chronic hepatitis B (CHB) patients undergoing peginterferon alfa-2a (PEG-IFN). The aim of this pilot study was to identify immunological features associated with SVR.

Methods

Consecutive 74 CHB patients receiving 24 weeks (for hepatitis B e antigen (HBeAg)-positive) or 48 weeks (for HBeAg-negative) PEG-IFN, were prospectively enrolled. Serum HBV viral loads, hepatitis B surface antigen (HBsAg), CXCL9, IFN-γ-inducible protein 10 (IP-10), interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-β) were measured at baseline and week 12. SVR was defined as HBeAg seroconversion combined with viral load <2000 IU/mL in HBeAg-positive (n=36), and viral load <2000 IU/mL in HBeAg-negative patients (n=38) at 48 weeks after the end of treatment.

Results

Nineteen patients (25.7%), 7 in HBeAg-positive and 12 in HBeAg-negative, achieved SVR. There were significant declines of HBV DNA, HBsAg, IP-10 and IFN-γ levels at week 12. In multivariate analysis, pre-treatment CXCL9 >80 pg/mL, HBV DNA <2.5 x 10⁷ IU/mL and on-treatment HBV viral load, HBsAg decline >10% at week 12 were predictors of SVR. The performance of CXCL9 in predicting SVR was good in patients with HBV DNA <2.5 x 10⁷ IU/mL, particularly in HBeAg-negative CHB cases (positive predictive value, PPV= 64.3%).

Conclusions

Pre-treatment CXCL9 level has the potential to select CHB patients who can respond to PEG-IFN, especially in HBeAg-negative patients with low viral loads.     

Effect of Age on Survival Outcome in Operated and Non-Operated Patients with Colon Cancer: A Population-Based Study

Objective

To know the effect of age on survival outcome in operated and non-operated patients with colon cancer.

Methods

From the Surveillance, Epidemiology, and End Results database, we identified 123,356 patients with colon cancer who were diagnosed between 1996 and 2005, grouped them as older or younger than 40 years and analyzed their 5-year cancer-specific survival (CSS) data, along with some risk factors, using Kaplan–Meier methods and multivariable Cox regression models.

Results

The younger group had significantly higher pathological grades (P<0.001), more mucinous and signet-ring histology (P<0.001), advanced AJCC stage (P<0.001), and were more likely to undergo surgery (P<0.001). For surgically treated patients, age did not significantly affect 5-year CSS (younger: 66.7%; older: 67.3%; P = 0.86). Further analysis showed that age was an independent prognostic factor in stage I–IV disease (stage I: P = 0.001; P<0.001 for stages II–IV, in both uni- and multivariate analyses), but not for patients with unknown disease stage (P = 0.52). For non-surgically treated patients, age significantly affected 5-year CSS (younger: 16.2%; older: 12.9%; P<0.001) in univariate analysis; and was an independent prognostic factor (P<0.001) in multivariate analysis.

Conclusion

The CSS rate for younger CC patients was at least as high as for older patients, although they presented with higher proportions of unfavorable factors and more advanced disease.     

The Association of Platelet Count with Clinicopathological Significance and Prognosis in Renal Cell Carcinoma: A Systematic Review and Meta-Analysis

ObjectiveElevated platelet count (PC), a measure of systemic inflammatory response, is inconsistently reported to be associated with poor prognosis in patients with renal cell carcinoma (RCC). We conducted a systematic review and meta-analysis to clarify the significance of PC in RCC prognosis.MethodsPubMed, Embase, and Web of Science databases were searched to identify eligible studies to evaluate the associations of PC with patient survival and clinicopathological features of RCC.ResultsWe analyzed 25 studies including 11,458 patients in the meta-analysis and categorized the included articles into three groups based on RCC stage. An elevated PC level was associated with poor overall survival (OS, hazard ratio [HR] 2.24, 95% confidence interval [CI] 1.87-2.67, P<0.001) and cancer-specific survival (CSS, HR 2.59, 95% CI 1.92-3.48, P<0.001) when all stages were examined together; with poor CSS (HR 5.09, 95% CI 2.41-10.73, P<0.001) and recurrence-free survival (HR 6.68, 95% CI 3.35-13.34, P<0.001) for localized RCC; with poor OS (HR 2.00, 95% CI 1.75-2.28, P<0.001) for metastatic RCC; and with poor OS (HR 2.05, 95% CI 1.04-4.03, P = 0.038), CSS (HR 3.38, 95% CI 1.86-6.15, P<0.001), and PFS (HR 2.97, 95% CI 1.47-6.00, P = 0.002) for clear cell RCC. Furthermore, an elevated PC level was significantly associated with TNM stage (OR 3.11, 95% CI 1.59-6.06, P = 0.001), pathological T stage (OR 3.13, 95% CI 2.60-3.77, P<0.001), lymph node metastasis (OR 4.01, 95% CI 2.99-5.37, P<0.001), distant metastasis (OR 3.85, 95% CI 2.46-6.04, P<0.001), Fuhrman grade (OR 3.70, 95% CI 3.00-4.56, P<0.001), tumor size (OR 4.69, 95% CI 2.78-7.91, P<0.001) and Eastern Cooperative Oncology Group score (OR 5.50, 95% CI 3.26-9.28, P<0.001).ConclusionAn elevated PC level implied poor prognosis in patients with RCC and could serve as a readily available biomarker for managing this disease.     

Association of α-fetoprotein levels with liver stiffness measurement in outpatients with chronic hepatitis B

The association between α-fetoprotein (AFP) levels with the assessment of liver stiffness (LS) in chronic hepatitis B (CHB) patients were explored. A total of 283 outpatients with CHB were enrolled. Patient age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), AFP, platelet (PLT), total bilirubin (TB), direct bilirubin (DB), alkaline phosphatase (ALP), albumin (ALB), globulin, and albumin/globulin (A/G) levels were associated with LS values in the univariate model (P<0.05). Significant associations between AFP and PLT levels with LS values were observed when both variables were included in the multivariate analysis models. Receiver operation characteristic (ROC) analysis indicated that the combination of AFP and PLT levels could enhance the predictive performance of liver fibrosis (area under the curve (AUC) = 0.819, P<0.001) and that PLT levels (PLT < 100 × 10⁹/l) combined with high AFP levels (AFP > 8 ng/ml) significantly increased the prediction of liver fibrosis (OR = 11.216). More importantly, LS values associated with higher AFP levels (AFP > 8 ng/ml), independently of higher ALT or AST values, were significantly higher than those of low AFP level groups. In conclusion, in Chinese outpatients with CHB, AFP outperformed ALT and/or AST levels in terms of their association with LS. AFP and PLT levels were independently associated with LS, and their combined assessment could enhance the diagnostic and predictive performance of liver fibrosis among CHB patients.     

Association between CXCL10 and DPP4 Gene Polymorphisms and a Complementary Role for Unfavorable IL28B Genotype in Prediction of Treatment Response in Thai Patients with Chronic Hepatitis C Virus Infection

Pretreatment serum levels of interferon-γ-inducible protein-10 (IP-10, CXCL10) and dipeptidyl peptidase-4 (DPP IV) predict treatment response in chronic hepatitis C (CHC). The association between functional genetic polymorphisms of CXCL10 and DPP4 and treatment outcome has not previously been studied. This study aimed to determine the association between genetic variations of CXCL10 and DPP4 and the outcome of treatment with pegylated interferon-α (PEG-IFN-α) based therapy in Thai patients with CHC. 602 Thai patients with CHC treated using a PEG-IFN-α based regimen were genotyped for CXCL10 rs56061981 G>A and IL28B rs12979860 C>T. In addition, in patients infected with CHC genotype 1, DPP4 (rs13015258 A>C, rs17848916 T>C, rs41268649 G>A, and rs 17574 T>C) were genotyped. Correlations between single nucleotide polymorphisms, genotype, and treatment response were analyzed. The rate of sustained virologic response (SVR) was higher for the CC genotype of IL28B rs12979860 polymorphisms than for non-CC in both genotype 1 (60.6% vs. 29.4%, P < 0.001) and non-genotype 1 (69.4% vs. 49.1%, P < 0.05) CHC. SVR was not associated with the CXCL10 gene variant in all viral genotypes or DPP4 gene polymorphisms in viral genotype1. Multivariate analysis revealed IL28B rs12979860 CC genotype (OR = 3.12; 95% CI, 1.72–5.67; P < 0.001), hepatitis C virus RNA < 400,000 IU/ml (OR = 2.21; 95% CI, 1.22–3.99, P < 0.05), age < 45 years (OR = 2.03; 95% CI, 1.11–3.68; P < 0.05), and liver fibrosis stage 0–1 (OR = 1.64; 95% CI, 1.01–2.65, P < 0.05) were independent factors for SVR. Unfavorable IL28B rs12979860 CT or TT genotypes with the CXCL10 rs56061981 non-GG genotype were associated with a higher SVR than GG genotype (66.7% vs. 33.0%, P = 0.004) in viral genotype 1. In Thai CHC genotype 1 infected patients with an unfavorable IL28B rs12979860 CT/TT genotype, the complementary CXCL10 polymorphism strongly enhances prediction of treatment response.     

Differences in Clinical Outcomes According to Weaning Classifications in Medical Intensive Care Units

Background

Although the weaning classification based on the difficulty and duration of the weaning process has been evaluated in the different type of intensive care units (ICUs), little is known about clinical outcomes and validity among the three groups in medical ICU. The objectives of this study were to evaluate the clinical relevance of weaning classification and its association with hospital mortality in a medical ICU with a protocol-based weaning program.

Methods

All consecutive patients admitted to the medical ICU and requiring mechanical ventilation (MV) for more than 24 hours were prospectively registered and screened for weaning readiness by a standardized weaning program between July 2010 and June 2013. Baseline characteristics and outcomes were compared across weaning classifications.

Results

During the study period, a total of 680 patients were weaned according to the standardized weaning protocol. Of these, 457 (67%) were classified as simple weaning, 136 (20%) as difficult weaning, and 87 (13%) as prolonged weaning. Ventilator-free days within 28 days decreased significantly from simple to difficult to prolonged weaning groups (P < 0.001, test for trends). In addition, reintubation within 48 hours after extubation (P < 0.001) and need for tracheostomy during the weaning process (P < 0.001) increased significantly across weaning groups. Finally, ICU (P < 0.001), post-ICU (P = 0.001), and hospital (P < 0.001) mortalities significantly increased across weaning groups. In a multiple logistic regression model, prolonged weaning but not difficult weaning was still independently associated with ICU (adjusted OR 8.265, 95% CI 3.484–19.605, P < 0.001), and post-ICU (adjusted OR 3.180, 95% CI 1.349–7.497, P = 0.005), and hospital (adjusted OR 5.528, 95% CI 2.801–10.910, P < 0.001) mortalities.

Conclusions

Weaning classification based on the difficulty and duration of the weaning process may provide prognostic information for mechanically ventilated patients who undergo the weaning process.     

Increased Circulating Cathepsin K in Patients with Chronic Heart Failure

Cysteinyl cathepsin K (CatK) is one of the most potent mammalian collagenases involved in cardiovascular disease. Here, we investigated the clinical predictive value of serum CatK levels in patients with chronic heart failure (CHF). We examined 134 patients with CHF, measuring their serum CatK, troponin I, high-sensitive C-reactive protein, and pre-operative N-terminal pro-brain natriuretic peptide levels. The patients were divided into two groups: the 44 patients who showed a left ventricular (LV) ejection fraction (LVEF) < 40% (the “lowLVEF” group) and the 90 patients showing LVEF values ≥ 40% (the “highLVEF” group). The lowLVEF patients had significantly higher serum CatK levels compared to the highLVEF patients (58.4 ± 12.2 vs. 44.7 ± 16.4, P < 0.001). Overall, a linear regression analysis showed that CatK levels correlated negatively with LVEF (r = −0.4, P < 0.001) and positively with LV end-diastolic dimensions (r = 0.2, P < 0.01), LV end-systolic dimensions (r = 0.3, P < 0.001), and left atrial diameters (r = 0.3, P < 0.01). A multiple logistic regression analysis showed that CatK levels were independent predictors of CHF (odds ratio, 0.90; 95% confidence interval, 0.84–0.95; P < 0.01). These data indicate that elevated levels of CatK are closely associated with the presence of CHF and that the measurement of circulating CatK provides a noninvasive method of documenting and monitoring the extent of cardiac remodeling and dysfunction in patients with CHF.     

Prognostic Significance of Combination of Preoperative Platelet Count and Neutrophil-Lymphocyte Ratio (COP-NLR) in Patients with Non-Small Cell Lung Cancer: Based on a Large Cohort Study

IntroductionThe aim of this study was to investigate the prognostic significance of the combination of the preoperative platelet count and neutrophil-lymphocyte ratio (COP-NLR) for predicting postoperative survival of patients undergoing complete resection for non-small cell lung cancer (NSCLC).MethodsThe preoperative COP-NLR was calculated on the basis of data obtained.Patients with both an increased platelet count (>30.0×10⁴ mm^-3) and an elevated NLR (>2.3) were assigned a score of 2, and patients with one or neither were assigned as a score of 1 or 0, respectively.ResultsA total of 1238 NSCLC patients were enrolled in this analysis. Multivariate analysis using the 15 clinicolaboratory variables selected by univariate analyses demonstrated that the preoperative COP-NLR was an independent prognostic factor for DFS (HR: 1.834, 95%CI: 1.536 to 2.200, P<0.001) and OS (HR: 1.810, 95%CI: 1.587 to 2.056, P<0.001). In sub-analyses by tumor stage (I, II, IIIA), a significant association was found between DFS and OS and level of COP-NLR in each subgroup (P<0.001, P=0.002, P<0.001 for DFS, respectively; P<0.001, P=0.001, P<0.001 for OS). When the subgroup of patients with high-risk COP-NLR (score of 2) was analyzed, no benefit of adjuvant chemotherapy could be found (P=0.237 for DFS and P=0.165 for OS).ConclusionsThe preoperative COP-NLR is able to predict the prognosis of patients with NSCLC and divide these patients into three independent groups before surgery. Our results also demonstrate that high-risk patients based on the COP-NLR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.     

Does Nucleos(t)ide Analogues Treatment Affect Renal Function in Chronic Hepatitis B Patients Who Have Already Decreased eGFR? A Longitudinal Study

This study aimed to assess the renal function in chronic hepatitis B (CHB) patients who received nucleos(t)ide analogues (NAs) therapy using estimated glomerular filtration rate (eGFR) titer. We performed a longitudinal observational study of 37 tenofovir-, 42 telbivudine-, and 62 entecavir-naïve CHB patients, who had impaired renal function (eGFR, 90–30 ml/min/1.73m²) without history of diabetes, hypertension, and chemotherapy. Calculation and evaluation of eGFR was performed with the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Cockcroft-Gault formula at pretreatment, at baseline, and after the 1^st and 2^nd year of treatment. The eGFR was significantly increased in patients given telbivudine or entecavir (p = 0.003 and p = 0.012, respectively), but the eGFR was decreased in patients given tenofovir (p = 0.001) after 2 years of treatment. Of all patients, eGFR was stable one year prior to treatment. If we analyzed the renal function by change of chronic kidney disease (CKD) category with a change of 25% of eGFR, the proportion of uncertain drop (drop in CKD category with <25% decrease in eGFR) and certain drop (drop in CKD category with ≧25% decrease in eGFR) in tenofovir group was smaller (5.4%) than those of telbivudine (12.9%) or entecavir (6.5%). Furthermore, telbivudine had the lowest stable rate (76.2%), the highest certain rise rate (9.5%), and certain drop rate (7.1%) compared to the other groups (p = 0.049). In conclusion, in NAs-naïve CHB patients with impaired renal function, telbivudine and entecavir resulted in a significant increase in eGFR while tenofovir resulted in a significant decrease after a 2-year treatment. Interestingly, TDF had the lowest proportion of patients reclassified to certain and uncertain drop groups; in contrast, LdT had a higher proportion in both raise and drop groups. The outcomes of this renal effect remain to be determined.     

Abbott RealTime HBV Assay Is More Sensitive in Detection of Low Viral Load and Little Impacted by Drug Resistant Mutation in Chronic Hepatitis B Patients under Nucleot(s)ide Analogues Therapy

Background

Selection of drug-resistant strains may lead to failure of HBV antiviral therapy. There is little information whether there is detection difference in drug resistant mutations between different viral load assays of HBV.

Objectives

This study is aimed to investigate whether there is drug-resistant strains related detection difference between Abbott RealTime HBV (RealTime) and CobasAmpliPrep/CobasTaqMan HBV assays 2.0 (TaqMan).

Study Design

One hundred and thirty-four CHB patients who received HBV anti-viral therapy were enrolled. HBV virological markers were tested 3 months apart regularly. Serum HBV DNA levels were determined using the TaqMan and RealTime. YMDD (rt180M and rt204V) mutation was checked in patients who experienced virologic breakthrough (VBT).

Results

The correlation of HBV DNA observed between the RealTime and TaqMan was good for all 571 samples (R² = 0.797; P<0.001). However, the correlation in the 434 samples with HBV DNA level <3 log₁₀ IU/ml was not as good as in all samples (R² = 0.457). Overall, 21.5% of samples had a detection difference of ≥1 log₁₀ IU/ml with 91.9% of these having HBV DNA level <3 log₁₀ IU/ml. Twenty-four patients experiencedVBT. Three of these patients had acquired the YMDD mutation and exhibited discordant viral load results between the two methods tested. In each case, persistent HBV DNA was detected by RealTime and undetectable with TaqMan. Of the patients who experienced a VBT and had acquired YMDD mutation, 4.7% had undetectable HBV DNA by TaqMan while all were detectable with RealTime.

Conclusions

RealTime assay is more sensitive and is little impacted by the development of drug resistant mutation.     

The Efficacy and Safety of Nucleos(t)ide Analogues in Patients with Spontaneous Acute Exacerbation of Chronic Hepatitis B: A Systematic Review and Meta-Analysis

Background

Spontaneous acute exacerbation (AE) of chronic hepatitis B (CHB) is often detrimental but sometimes leads to sustained immune control and disease remission. The efficacy and safety of nucleos(t)ide analogues (NAs) in patients with spontaneous AE of CHB remains unclear.

Methods

We performed a systematic review and meta-analysis of NAs in patients with spontaneous AE of CHB. We calculated pooled effects of NAs in these patients of each study and conducted quantitative meta-analysis, displaying results using Forest plots.

Results

15 studies were included and substantial heterogeneity was noted in the inclusion/exclusion criteria and controls. Pooled data showed no benefit of lamivudine (LAM) vs. untreated controls for transplant-free survival in patients with spontaneous AE of CHB (OR = 0.98 (95% CI, 0.50–1.92; P = 0.956)), hepatic decompensation (OR = 0.94 (95% CI, 0.47–1.88; P = 0.862)) and liver failure owing to AE (OR = 2.30 (95% CI, 0.35–15.37; P = 0.387)) at 3 months. Entecavir achieved even higher short-term mortality than LAM. NAs led to rates of ALT normalization, undetectable HBV DNA, HBeAg loss, HBeAg seroconversion and drug resistance at 1 year in 88%, 61%, 46%, 35% and 5%. Pooled data also showed benefit favoring LAM vs. untreated controls for ALT normalization (OR = 1.98 (95% CI, 1.03–3.80; P = 0.039)) and undetectable HBV DNA (OR = 38.50 (95% CI, 7.68–192.99; P<0.001)) at 3 months. All NAs were relatively safe and well tolerated.

Conclusion

NAs had no obvious impact on short-term survival in patients with AE of CHB, despite of possible better antiviral responses. We suggest additional studies to evaluate the efficacy of other NAs and early introduction of immunosuppressant in combination with NAs. We highlight developing prognostic models to identify predictors of mortality and disease progression for AE of CHB.     

Hydroxyurea affects in vitro porcine oocyte maturation through increased apoptosis and oxidative stress

Hydroxyurea (HU) is an FDA-approved drug used to treat a variety of diseases, especially malignancies, but is harmful to fertility. We used porcine oocytes as an experimental model to study the effect of HU during oocyte maturation. Exposure of cumulus–oocyte complexes (COCs) to 20 µM (P<0.01) and 50 µM (P<0.001) HU reduced oocyte maturation. Exposure to 20 µM HU induced approximately 1.5- and 2-fold increases in Caspase-3 (P<0.001) and P53 (P<0.01) gene expression levels in cumulus cells, respectively, increased Caspase-3 (P<0.01) and P53 (P<0.001) protein expression levels in metaphase II (MII) oocytes and increased the percentage of apoptotic cumulus cells (P<0.001). In addition, HU decreased the mitochondrial membrane potential (Δφm) (P<0.01 and P<0.001) and glutathione (GSH) levels (P<0.01 and P<0.001) of both cumulus cells and MII oocytes, while increasing their reactive oxygen species (ROS) levels (P<0.001). Following parthenogenetic activation of embryos derived from MII oocytes, exposure to 20 µM HU significantly reduced total blastocyst cell numbers (P<0.001) and increased apoptosis of blastocyst cells (P<0.001). Moreover, HU exposure reduced the rate of development of two-celled, four- to eight-celled, blastocyst, and hatching stages after parthenogenetic activation (P<0.05). Our findings indicate that exposure to 20 µM HU caused significant oxidative stress and apoptosis of MII oocytes during maturation, which affected their developmental ability. These results provide valuable information for safety assessments of HU.     

Preoperative Neutrophil-to-Lymphocyte Ratio Is a Predictor of Recurrence following Thermal Ablation for Recurrent Hepatocellular Carcinoma: A Retrospective Analysis

Purpose

The aim of this study is to determine the predictive value of preoperative blood neutrophil-to-lymphocyte ratio (NLR) for recurrence in recurrent hepatocellular carcinoma (RHCC) patients following thermal ablation.

Material and Methods

This retrospective study enrolled 506 RHCC patients who underwent thermal ablation from April 2006 to April 2014. The clinicopathological parameters including NLR were evaluated to identify predictors of recurrence rate after thermal ablation. A Cox multiple regression analysis was performed to determine the parameters that predicted recurrence in RHCC patients. The best cutoff value of NLR was determined with time-dependent receiver operating characteristic (ROC) curve analysis. The recurrence-free survival (RFS) rate was determined in patients with high and low NLR.

Results

The multivariate Cox proportional hazard model analysis showed that NLR was a prognostic factor in recurrence-free survival. NLR ≥2.14 was evaluated (AUROC = 0.824; P<0.001), and 183 of 506 patients (36.2%) had a NLR of more than 2.14. During the follow-up period (12–96 months), the 1-, and 3- year recurrence rates were 20.7% and 31.6% in low NLR group, respectively. These recurrence rates were significantly less than those in the high NLR group (57.9% and 82.5%, respectively) (P<0.001). A recurrence-free survival analyses demonstrated that the RFS in the low NLR group (67.2%) was significantly higher than that in the high NLR group (13.1%) (P<0.001).

Conclusion

Our results show that preoperative NLR is a predictor for re-recurrence after thermal ablation in RHCC patients. Additionally, patients with NLR <2.14 have a lower recurrence rate, which may improve the clinical management of RHCC patients.