PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to hepatitis B surface antigen (HBsAg) clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse up to week 96. METHODS: In this multicenter randomized-controlled clinical trial, 180 non-cirrhotic patients with HBeAg-negative chronic hepatitis B on continuous NUC therapy for ≥2.5 years, with HBV DNA levels <60 IU/ml, were randomized to discontinue NUC therapy (n = 90) or receive 48 weeks of PegIFN-α-2a treatment (n = 90). Patients were followed up for up to 96 weeks. The primary endpoint was the virological relapse rate up to week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, p <0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, p = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, p = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and leads to higher HBsAg loss rates than NUC treatment cessation alone in patients with HBeAg-negative chronic hepatitis B. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimized scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized-controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse up to week 96 in patients with HBeAg-negative chronic hepatitis B. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, p <0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, p = 0.03) than the NUC cessation group up to week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.

Synthesis and evaluation of L-quebrachitol derivatives against platelet aggregation.

Thrombosis plays an important role in the occurrence and development of cardiovascular and cerebrovascular diseases that contribute to high mortality and morbidity in patients. L-(-)-Quebrachitol (QCT), a natural product, was first isolated from quebracho bark. It can inhibit PAF receptor and decrease gastric damage induced by indomethacin, as a drug against platelet aggregation. Here, five QCT derivatives were synthesized and investigated for their inhibitory effects on platelet aggregation. Among them, compound 3a showed anticoagulant effects comparable to aspirin, while compound 4b showed dose-independent inhibitory activities in rats that were stronger than aspirin.

Kinetics changes in total cholesterol predict HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon-alfa.

There is no satisfactory standard for predicting HBeAg seroconversion during Pegylated interferon alpha (PegIFNα) treatment. Studies have shown that IFNα therapy in chronic hepatitis C patients could alter serum lipid profiles. However, there have been no studies on lipid changes that predict the outcome of PegIFNα monotherapy in treated-naive chronic hepatitis B (CHB) patients. This retrospective study included 130 treated-naive HBeAg-positive CHB patients receiving PegIFNα monotherapy. The relationship between serum lipid changes and HBeAg seroconversion was analysed. The TC-ALT-HBsAg-HBeAg-Genotype-Age (CASEGA) model was established to predict HBeAg seroconversion after PegIFN-α monotherapy. Among 130 patients, 33 achieved HBeAg seroconversion (SR) and 97 did not achieve HBeAg seroconversion (NR). The decrease in serum total cholesterol (TC) in the NR group was significantly higher than in the SR group at Week 24 (-9.59% vs. -0.31%, p < 0.001). Multivariate logistic regression analysis showed that the change in TC at Week 24 (odds ratio = 1.065, p = 0.009) was an independent predictor of HBeAg seroconversion. The area under the receiver operating characteristic curve for the CASEGA model was 0.883. The model score at the maximum Youden index was 90, and the specificity, sensitivity, positive predictive value and negative predictive value were 0.727, 0.794, 0.546 and 0.895, respectively. The HBeAg seroconversion rate at Week 72 in patients with scores >90 was significantly higher than that in patients with scores <90 (54.55% vs. 10.47%, p < 0.001). This study indicated that the change in the TC level at 24 weeks in CHB patients treated with PegIFNα was associated with HBeAg seroconversion. The CASEGA prediction model based on the TC change rate of 24 weeks has good predictive efficiency for HBeAg seroconversion.

Thyroid dysfunction incidence and risk factors in Chinese chronic hepatitis B patients treated with pegylated interferon alpha: A long-term follow-up study.

The long-term impact, incidence and risk factors of thyroid dysfunction in chronic hepatitis B (CHB) patients receiving pegylated interferon (IFN) alpha (PegIFN-alpha) therapy remain unclear. We aim to investigate the long-term safety of thyroid dysfunction in CHB patients receiving PegIFN-alpha. A retrospective observational study of 425 CHB patients with normal baseline thyroid function was carried out. Patients were followed up over 10 years to assess thyroid function after receiving IFN. At the end of the IFN therapy, 67 patients (15.8%) had developed thyroid dysfunction, 31 patients (46.3%) had hyperthyroidism and 64.4% presented with subclinical thyroid dysfunction. In follow-up of thyroid dysfunction patients, 37 patients (74.0%) spontaneously regained normal thyroid function. Pretreatment thyroid-stimulating hormone (TSH) level, thyroid peroxidase antibody (TPOAb) positivity and free thyroxine (FT4) were independent risk factors associated with thyroid dysfunction incidence. High TSH level (OR = 9.866, 95%CI, 3.245-29.998) was associated with a greater likelihood of hypothyroidism. High FT4 levels (OR = 0.464, 95%CI, 0.248-0.868) indicate a low likelihood of thyroid dysfunction. Thyroid dysfunction is a common but acceptable side effect of IFN therapy for CHB. Most thyroid dysfunction is reversible. Pretreatment TSH level and TPOAb positivity are risk factors for thyroid dysfunction development during IFN therapy. A high TSH level predicts an increased incidence of hypothyroidism. Moreover, FT4 may be a protective factor for thyroid dysfunction.

STAT4 genetic polymorphism significantly affected HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving Peginterferon-α therapy: A prospective cohort study in China.

A variant in signal transducer and activator of transcription 4 (STAT4) was reported to correlate with the response of interferon-α (IFN-α) in a retrospective study in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (CHB) patients. Here, we conducted a prospective study to analyze the effect of STAT4 genetic polymorphism on the response of pegylated interferon-α-2a (PegIFN-α-2a) in HBeAg-positive patients. A prospective, multicenter, open-label, parallel cohort study was performed. One hundred and fifty treatment-naïve and 156 nucleos(t)ide analog (NA)-experienced HBeAg-positive CHB patients were enrolled, respectively. All patients received PegIFN-α-2a treatment for 48 weeks and 24-week follow-up post PegIFN-α-2a treatment. Before treatment, STAT4 genetic polymorphism was determined by PCR and DNA sequencing. Serological markers, serum HBV DNA levels, and adverse events were collected at each visit. We observed a larger reduction of HBV DNA load and a significantly higher HBeAg seroconversion rate in the GT/TT group than in the GG group at week 72 (p = 0.002 and p = 0.023) in treatment-naïve patients. In NA-experienced patients, the HBeAg seroconversion rate in the GT/TT group was higher than that in the GG group at week 72 (p = 0.005). STAT4 rs7574865 gene polymorphism was the strongest independent predictor of HBeAg seroconversion in both paralleled cohorts. Also, patients in the GT/TT group had a higher hepatitis B surface antigen loss rate than in the GG group in the study. There was no significant difference in adverse events between GG and GT/TT groups. This prospective cohort study confirmed that STAT4 rs7574865 gene polymorphism is associated with HBeAg seroconversion and HBsAg loss irrespective of naïve and NA-experienced HBeAg-positive CHB patients treated with PegIFN-α-2a.

Development and Validation of a New Integrative Score Based on Various Systemic Inflammatory and Nutritional Indicators in Predicting Prognosis in Patients With Resectable Esophageal Squamous Cell Carcinoma: A Retrospective Cohort Study.

BACKGROUND: Recent studies revealed that various inflammatory and nutritional indexes were associated with prognosis in esophageal cancer (EC). However, these studies only evaluated one or two indexes, and the prognostic value of these indexes individually or in combination is unclear. This study aimed to construct an integrative score based on various inflammatory and nutritional indexes for prognosis in resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 421 consecutive patients were randomly divided into either a training or validation cohort at a ratio of 7:3 for retrospective analysis. Using logic regression analyses, independent risk factors from peripheral blood indexes were screened to construct an integrative score. The associations regarding the integrative score, clinical characteristics, cancer-specific survival (CSS), and overall survival (OS) were analyzed. RESULTS: Out of 20 indexes, hemoglobin (HB), C-reactive protein to albumin ratio (CAR), and platelet to lymphocyte ratio (PLR) were independent risk factors based on logical regression analyses. Then, an integrative score with the optimal cut-off value of .67 was established according to the Combination Of HB, CAR, and PLR (COHCP). The area under the curve (AUC) indicated higher predictive ability of COHCP on prognosis than other indicators. Multivariate analyses revealed that COHCP serves as an independent prognostic score. Patients with COHCP low group (≤.67) had better 5-year CSS (57.3% vs 13.5%, P < .001) and OS (51.1% vs 12.3%, P < .001) than those with high group, respectively. Finally, the nomogram based on COHCP was established and validated regarding CSS and OS, which can accurately and effectively predict individual survival in resected ESCC. CONCLUSION: The COHCP was a novel, simple, and useful predictor in resectable ESCC. The COHCP-based nomogram may accurately and effectively predict survival.

Baseline serum exosome-derived miRNAs predict HBeAg seroconversion in chronic hepatitis B patients treated with peginterferon.

This study aimed to explore the value of baseline serum exosome-derived miRNAs for predicting HBeAg seroconversion in chronic hepatitis B (CHB) patients treated with peginterferon (Peg-IFN). A total of 120 treatment-naïve HBeAg-positive CHB patients who received Peg-IFN therapy (48 weeks) were enrolled. Next-generation sequencing was performed to screen the serum exosomal miRNAs that were associated with Peg-IFN treatment outcome, and qRT-PCR was used to validate them. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the predictive efficacy of biomarkers. Thirty-three patients (27.5%) achieved HBeAg seroconversion (response group), and 87 patients (72.5%) did not achieve HBeAg seroconversion (nonresponse group). In the identification cohort, 40 serum exosome-derived miRNAs were differentially expressed between the response group (four patients) and the nonresponse group (four patients). In the confirmation cohort, the expression levels of serum exosomal miR-194-5p (p < .001) and miR-22-3p (p < .001) were significantly downregulated in the response group (29 patients) compared to the nonresponse group (83 patients). Multivariate analysis identified baseline serum exosomal miR-194-5p, miR-22-3p, alanine aminotransferase (ALT), and HBV DNA as independent predictors of HBeAg seroconversion (all p < .05). The AUROCs of serum exosomal miRNAs (0.77 and 0.75 for miR-194-5p and miR-22-3p, respectively) were higher than that of ALT (0.70) and HBV DNA (0.69). The combination of exosomal miR-194-5p and miR-22-3p further improved the predictive performance with an AUROC of 0.82. Baseline serum exosomal miR-194-5p and miR-22-3p may serve as novel biomarkers to predict HBeAg seroconversion in CHB patients treated with Peg-IFN.

A Stepwise Evaluation of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure to Optimize the Indication for Urgent Liver Transplantation.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a dynamic but reversible disease. AIM: We aimed to clarify whether the change in Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) grade in HBV-ACLF patients can be used to predict prognosis, and to explore the appropriate conditions for performing urgent liver transplantation. METHODS: We assessed the COSSH-ACLF grades of HBV-ACLF patients at different time points from June 2013 to May 2019 at Huashan Hospital in Shanghai, China, and analyzed the relationship between the change in grade and patient prognosis. RESULTS: A total of 207 HBV-ACLF patients were enrolled, of which 79 underwent urgent liver transplantation. Their COSSH-ACLF grades were calculated at diagnosis, 3-7 days after diagnosis, and on the final day. Most of the final ACLF grades were consistent with their corresponding grades at days 3-7 after diagnosis (62.5%), while only 44.5% were in accordance with the initial grades at diagnosis. In patients who had a poor prognosis (initial ACLF-3 and ACLF-2 or -3 at days 3-7), the 28-day survival rate was 93.3% in those who underwent transplantation and 6.8% in those who did not (P < 0.0001). However, in patients who had a good prognosis (ACLF-0 or ACLF-1 at days 3-7), the 28-day survival rate was 100% in transplanted patients and 91.5% in non-transplanted patients (P = 0.236). CONCLUSIONS: Reevaluation of the COSSH-ACLF grade 3-7 days after diagnosis could potentially show an indication for urgent liver transplantation.

Final report of a prospective randomized study on thoracic radiotherapy target volume for limited-stage small cell lung cancer with radiation dosimetric analyses.

BACKGROUND: The thoracic radiotherapy (TRT) target volume for limited-stage small-cell lung cancer (SCLC) has been controversial for decades. In this report, the final results of a prospective randomized trial on the TRT target volume before and after induction chemotherapy are presented. METHODS: After 2 cycles of etoposide and cisplatin, patients arm were randomized to receive TRT to the postchemotherapy or prechemotherapy tumor volume in a study arm and a control arm. Involved-field radiotherapy was received in both arms. TRT consisted of 1.5 grays (Gy) twice daily in 30 fractions to up to a total dose of 45 Gy. Lymph node regions were contoured, and intentional and incidental radiation doses were recorded. RESULTS: The study was halted early because of slow accrual. Between 2002 and 2017, 159 and 150 patients were randomized to the study arm or the control arm, respectively; and 21.4% and 19.1% of patients, respectively, were staged using positron emission tomography/computed tomography (P = .31). With a median follow-up of 54.1 months (range, 19.9-165.0 months) in survivors, the 3-year local/regional progression-free probability was 58.2% and 65.5% in the study and control arms, respectively (P = .44), and the absolute difference was -7.3% (95% CI, -18.2%, 3.7%). In the study and control arms, the median overall survival was 21.9 months and 26.6 months, respectively, and the 5-year overall survival rate was 22.8% and 28.1%, respectively (P = .26). Grade 3 esophagitis was observed in 5.9% of patients in the study arm versus 15.5% of those in the control arm (P = .01). The isolated out-of-field failure rate was 2.6% in the study arm versus 4.1% in the control arm (P = .46), and all such failures were located in the supraclavicular fossa or contralateral hilum. The regions 7, 3P, 4L, 6, 4R, 5, and 2L received incidental radiation doses >30 Gy. CONCLUSIONS: TRT could be limited to the postchemotherapy tumor volume, and involved-field radiotherapy could be routinely applied for limited-stage SCLC.

Long-term follow-up of patients treated with entecavir and peginterferon add-on therapy for HBeAg-positive chronic hepatitis B infection: ARES long-term follow-up.

Addition of peginterferon alpha (PEG-IFN add-on) to entecavir (ETV) treatment after a short lead-in phase results in more response than ETV monotherapy in HBeAg-positive chronic hepatitis B infection (CHB). This study is the first to assess long-term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG-IFN add-on in a global trial (ARES study) and completed follow-up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG-IFN add-on and 48 patients treated with ETV monotherapy were included. The median follow-up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non-responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10  HBsAg decline in 59% vs 28% (P = 0.02) for PEG-IFN add-on and ETV monotherapy, respectively. In 41 initial non-responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG-IFN add-on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow-up, rates of serological response became comparable between PEG-IFN add-on and ETV monotherapy. Although in this LTFU study initial non-responders were overrepresented in the add-on arm, PEG-IFN add-on possibly leads rather to accelerated HBeAg loss than to increased long-term HBeAg loss rates.

Roles of sphingosine-1-phosphate signaling in cancer.

The potent pleiotropic lipid mediator sphingosine-1-phosphate (S1P) participates in numerous cellular processes, including angiogenesis and cell survival, proliferation, and migration. It is formed by one of two sphingosine kinases (SphKs), SphK1 and SphK2. These enzymes largely exert their various biological and pathophysiological actions through one of five G protein-coupled receptors (S1PR1-5), with receptor activation setting in motion various signaling cascades. Considerable evidence has been accumulated on S1P signaling and its pathogenic roles in diseases, as well as on novel modulators of S1P signaling, such as SphK inhibitors and S1P agonists and antagonists. S1P and ceramide, composed of sphingosine and a fatty acid, are reciprocal cell fate regulators, and S1P signaling plays essential roles in several diseases, including inflammation, cancer, and autoimmune disorders. Thus, targeting of S1P signaling may be one way to block the pathogenesis and may be a therapeutic target in these conditions. Increasingly strong evidence indicates a role for the S1P signaling pathway in the progression of cancer and its effects. In the present review, we discuss recent progress in our understanding of S1P and its related proteins in cancer progression. Also described is the therapeutic potential of S1P receptors and their downstream signaling cascades as targets for cancer treatment.

Serum hepatitis B virus RNA levels as a predictor of HBeAg seroconversion during treatment with peginterferon alfa-2a.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion represents an endpoint of treatment of chronic hepatitis B virus (HBV) infections. METHODS: We have studied whether levels of serum hepatitis B virus ribonucleic acid (HBV RNA) during pegylated interferon alfa-2a treatment might be helpful for predicting HBeAg seroconversion. 61 HBeAg-positive chronic hepatitis B (CHB) patients treated with pegylated interferon alfa-2a alone or in combination with adefovir (10 mg/day) for 48 weeks were included in this retrospective analysis. Response was defined as HBeAg seroconversion at 24 weeks posttreatment. Receiver operating characteristic analyses were used to identify baseline and on-treatment HBV RNA levels associated with response. RESULTS: Twenty-two of 61 (36.1%) patients achieved a response. Baseline HBV RNA levels were lower in responders than in nonresponders (4.55 ± 1.19 and 5.90 ± 1.13 copies/mL, respectively, P = 0.001). Baseline HBV RNA cut off level (200,000 copies/mL) provided a positive predictive value (PPV) of 56.0% and a negative predictive value (NPV) of 77.8%. HBV RNA level (3000 copies/mL) at week 12 provide a PPV of 75.0% and a NPV of 82.8%. Moreover, HBeAg seroconversion rates at 24 weeks posttreatment were significantly higher in patients with HBV RNA ≤ 200,000 copies/mL at baseline and HBV RNA ≤ 3000 copies/mL at week 12 (92.9%) versus others (12.5%) (All P < 0.05). CONCLUSIONS: In Conclusions, serum HBV RNA levels may serve as a novel tool for prediction of HBeAg seroconversion during therapy with pegylated interferon alfa-2a in HBeAg-positive CHB patients.

Transarterial Infusion of iRGD-Modified ZrO2 Nanoparticles with Lipiodol Improves the Tissue Distribution of Doxorubicin and Its Antitumor Efficacy.

PURPOSE: To evaluate the effect of transarterial infusion of iRGD-modified and doxorubicin-loaded zirconia-composite nanoparticles (R-DZCNs) with lipiodol in the improvement of the distribution of doxorubicin (DOX) in liver tumors and its antitumor efficacy. MATERIALS AND METHODS: The effect of R-DZCNs was evaluated in vitro by tumor cellular uptake and cytotoxicity assays. For the in vivo study, DOX distribution and antitumor efficiency were assessed. In the DOX distribution study, VX2 tumor-bearing rabbits received transarterial infusion of lipiodol with DOX, doxorubicin-loaded zirconia-composite nanoparticles (DZCNs), or R-DZCNs, respectively. DOX distribution was assessed by immunofluorescence. In the antitumor study, tumor-bearing rabbits received transarterial infusions of lipiodol with DOX, DZCNs, R-DZCNs, or saline respectively. Tumor volume was measured using magnetic resonance imaging, and the expression of apoptosis-related factors (caspase-3, Bax, Bcl-2) was analyzed by immunohistochemistry and Western blotting. RESULTS: R-DZCNs increased cellular uptake and caused stronger cytotoxicity. Compared with the DOX + lipiodol or DZCNs + lipiodol group, the R-DZCNs + lipiodol group showed more DOX fluorescence spots (2,449.15 ± 444.14 vs. 3,464.73 ± 632.75 or 5,062.25 ± 585.62, respectively; P < .001) and longer penetration distance (117.58 ± 19.36 vs 52.64 ± 8.53 or 83.37 ± 13.76 µm, respectively; P < .001). In the antitumor study, the R-DZCNs + lipiodol group showed smaller tumor volumes than the DOX + lipiodol or DZCNs + lipiodol group (1,223.87 ± 223.58 vs. 3,695.26 ± 666.25 or 2281.06 ± 457.21 mm3, respectively; P = .005).The greatest extent of tumor cell apoptosis was observed in R-DZCNs + lipiodol group immunohistochemistry and Western blotting results. CONCLUSIONS: Transarterial infusion of R-DZCNs with lipiodol improved the distribution of DOX and enhanced its antitumor efficacy.

Validation and comparison of seventeen noninvasive models for evaluating liver fibrosis in Chinese hepatitis B patients.

BACKGROUND & AIMS: To avoid liver biopsy, many noninvasive models comprised of serum markers for liver fibrosis assessment have been developed. Given that most of them were developed in hepatitis C cohorts and few of them have been validated in Chinese hepatitis B patients, we aim to conduct this validation and compare their diagnostic accuracies in such a population. METHODS: A total of 937 HBV-infected patients who underwent liver biopsy were included in this single-centre retrospective study. The diagnostic accuracies of the 17 noninvasive models were assessed by areas under the receiver-operating characteristic curves (AUROCs), using histologically evaluated fibrotic stages of the biopsy specimens as standards. To compare efficiencies of the models, a grading system based on AUROC levels was developed. RESULTS: For discriminating significant fibrosis in all patients, the best three noninvasive models were King's score (AUROC = 0.756), Virahep-C model (AUROC = 0.756) and GPR (AUROC = 0.744); and for diagnosing cirrhosis, Lok index (AUROC = 0.832), FI (AUROC = 0.820) and FIB-4 (AUROC = 0.818) got the first three places. AUROCs in HBeAg-positive group were generally higher than those in HBeAg-negative group. In addition, based on the grading system, Virahep-C and GPR outstood others in evaluating liver fibrosis in all patients. CONCLUSIONS: In Chinese HBV-infected patients, Virahep-C models and GPR had high accuracies in diagnosing liver fibrosis and cirrhosis, while the most discussed models like APRI and FIB-4 did not outstand. Assessment should take into account the HBeAg sero-status, since these noninvasive models were more appropriate for HBeAg-positive patients than HBeAg-negative ones.

Neutrophil gelatinase-associated lipocalin accurately predicts renal tubular injury in patients with chronic hepatitis B treated with nucleos(t)ide analogs.

AIM: Little is known about the impact of long-term use of nucleos(t)ide analogs on tubular function in patients with chronic hepatitis B. Previous studies showed that neutrophil gelatinase-associated lipocalin (NGAL) elevation was associated with renal tubular injury. We evaluated renal function markers and bone mineral density in patients treated long-term with adefovir dipivoxil (ADV) or entecavir (ETV). METHODS: In this cross-sectional study, we enrolled 78 patients (ADV, 36; ETV: 42), and 21 patients matched for age, observation time, and baseline estimated glomerular filtration rate from each group. RESULTS: Patients treated with ADV showed a significant increase in serum creatinine and urine ß2 -microglobulin, and decreased estimated glomerular filtration rate and bone mineral density. Furthermore, the median levels of NGAL in patients treated with ADV were significantly higher than those of ETV (12.5 ng/mL vs. 2.5 ng/mL, P = 0.020). The proportions of patients with proteinuria and phosphate <1 mmol/L in the ADV group were higher than those in the ETV group. Additionally, age, ß2 -microglobulin, phosphate, and ADV use were associated with altered NGAL levels on multivariate analysis. Among the commonly used biomarkers, NGAL was the most useful (odds ratio = 5.72; P = 0.005) and specific (92% specificity at 18.1 ng/mL cut-off) in predicting low bone mass. CONCLUSIONS: Patients with chronic hepatitis B treated long-term with ADV showed elevated urinary NGAL levels. Neutrophil gelatinase-associated lipocalin was more specific in predicting low bone mass during therapy compared with ß2 -microglobulin, phosphate, and creatinine. In general, this analysis examined the value of NGAL as a renal tubular injury indicator, resulting from ADV use.

Role of quantitative hepatitis B core antibody levels in predicting significant liver inflammation in chronic hepatitis B patients with normal or near-normal alanine aminotransferase levels.

AIM: Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti-HBc) during CHB management. In this cross-sectional study, we evaluated the utility of qAnti-HBc in identifying significant liver inflammation in CHB patients. METHODS: A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti-HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed. RESULTS: In the training set, qAnti-HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721-0.810; P < 0.001) and in patients with normal or near-normal ALT levels (AUROC = 0.767; 95% CI, 0.697-0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti-HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768-0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732-0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814-0.942) and 0.867 (95% CI, 0.749-0.943) in all patients and patients with normal ALT levels, respectively. CONCLUSIONS: The qAnti-HBc level predicts significant liver inflammation well, even in patients with normal or near-normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non-invasive biomarker for significant liver inflammation in CHB patients.

Pegylated Interferon Alfa-2b Add-on Treatment in Hepatitis B Virus Envelope Antigen-Positive Chronic Hepatitis B Patients Treated with Nucleos(t)ide Analogue: A Randomized, Controlled Trial (PEGON).

Background: We studied whether 48 weeks of pegylated interferon alfa-2b (peginterferon) add-on therapy increases serological response in hepatitis B virus (HBV) envelope antigen (HBeAg)-positive patients receiving nucleos(t)ide analogue (NA) therapy, compared with continued NA monotherapy. Methods: This randomized trial included HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of <2000 IU/mL. Patients were randomly assigned in a 1:1 ratio to 48 weeks of peginterferon add-on therapy (n = 39) or continued NA monotherapy (n = 38). Response (defined as HBeAg seroconversion with an HBV DNA load of <200 IU/mL) was assessed at week 48, with responders discontinuing NA therapy at week 72. Results: The primary end point (response at week 96) was achieved in 18% of patients who were assigned peginterferon add-on therapy versus 8% of patients assigned NA monotherapy (P = .31). Among 58 interferon-naive patients, add-on therapy led to a greater frequency of HBeAg seroconversion (30% vs 7%; P = .034) and response (26% vs 7%; P = .068) at week 96, compared with monotherapy. Among 8 responders at week 48 who discontinued NA therapy at week 72, 6 patients (75%) maintained a response until week 96 (4 of 6 [67%] in the add-on therapy group vs 2 of 2 [100%] in the monotherapy group; P = 1.00). Adverse events were mainly related to peginterferon. Conclusion: The primary end point was negative, but peginterferon add-on therapy appeared to result in a greater frequency of HBeAg seroconversion, compared with NA monotherapy, in interferon-naive patients receiving NA therapy. Clinical Trials Registration: NCT01532843.

Durability of Response After Hepatitis B Surface Antigen Seroclearance During Nucleos(t)ide Analogue Treatment in a Multiethnic Cohort of Chronic Hepatitis B Patients: Results After Treatment Cessation.

In 70 chronic hepatitis B patients with hepatitis B surface antigen seroclearance during nucleos(t)ide analogue therapy, response was sustained in all 54 patients who discontinued treatment. Clinically significant relapses as indicated by high hepatitis B virus DNA and ALT levels were not observed. Anti-HBs positivity may not be required to ensure sustained off-treatment response.

Prognostic and predictive significance of tumor length in patients with esophageal squamous cell carcinoma undergoing radical resection.

BACKGROUND: The objective of this study was to investigate the prognostic and predictive significance of tumor length in patients with esophageal squamous cell carcinoma undergoing radical resection. METHODS: Tumor length and other clinicopathological variables were retrospectively evaluated in 1435 patients with squamous cell carcinoma treated with radical resection between 2003 and 2010. Tumor length was analyzed as categorical and continuous variable. Associations with overall survival were assessed with Cox proportional hazards models. Model-based nomograms were constructed. Predictive accuracy was measured with C-index. Decision curve analysis was used to evaluate clinical usefulness of prediction models. RESULTS: Both categorically and continuously coded tumor length were independent prognostic factors in multivariable analysis. Adding categorically and continuously coded tumor length to TNM staging model increased predictive accuracy by 0.2 and 0.4 % respectively. Decision curve analysis revealed that the models built by the addition of categorically or continuously coded tumor length did not perform better than TNM staging model. CONCLUSIONS: Tumor length is an independent prognostic factor in patients with esophageal squamous cell carcinoma treated with radical resection. It increases predictive accuracy of TNM staging system for overall survival in these patients. But it does not increase clinical usefulness of TNM staging system as a prediction model.

Novel experimental model of enlarging abdominal aortic aneurysm in rabbits.

OBJECTIVE: This study tested the hypothesis that an experimental model of abdominal aortic aneurysm in rabbits results in progressive enlargement when induced by a combination of periaortic elastase administration and aortic coarctation. METHODS: Male New Zealand white rabbits were randomly divided into four groups: (A) stenosis (n = 12), (B) elastase (n = 12), (C) aneurysm (n = 15), and (D) control (n = 12). The stenosis group received an extrinsic coarctation below the right renal artery, the elastase group received a 10-minute administration of 60 µL elastase (1 U/µL) in a 1.5-cm aortic segment, the aneurysm group received stenosis and elastase, and a sham operation was performed in the control group. The aortic diameter was measured after 1, 2, 4, 8, and 16 weeks, and animals were subsequently euthanized for histopathologic and immunohistochemical studies. RESULTS: All animals in the aneurysm group developed aneurysm by 2 weeks after treatment, with average diameters of 5.21 ± 0.74 mm by 2 weeks, 6.23 ± 1.10 mm by 4 weeks, 7.87 ± 0.50 mm by 8 weeks, and 9.40 ± 0.36 mm by 16 weeks. Aortic diameter dilated progressively, and all aneurysms developed by 4 weeks in the stenosis group (4.17 ± 0.22 mm). Only one aneurysm was seen in the elastase group by week 1 (3.60 ± 0.64 mm), and no aneurysm formed in the control group by week 8 (2.47 ± 0.38 mm). The aneurysm group exhibited less media thickness, elastin content, and endothelial recovery, but stronger expression of matrix metalloproteinase 2 and 9 and rabbit macrophage compared with the control group. CONCLUSIONS: This novel rabbit abdominal aortic aneurysm model with a gradually enlarging diameter is simply and reliably induced, appropriately mimicking human aortic aneurysm disease.