Phase IV randomized clinical study: Peginterferon alfa-2a with adefovir or entecavir pre-therapy for HBeAg-positive chronic hepatitis B.

BACKGROUND: Efficacy of sequential therapy with nucleos(t)ide analogues and interferons versus monotherapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) remains unexplored. We aimed to assess efficacy and safety of sequential therapy with adefovir (ADV) or entecavir (ETV) followed by peginterferon (PEG-IFN) alfa-2a in Taiwanese patients with HBeAg-positive. METHODS: This randomized, placebo-controlled, double-blind trial was conducted at nine sites in Taiwan from April 2010 to October 2013. Patients (N = 280) were randomized 1:1:1 to receive placebo, ETV or ADV alone for four weeks, combined with PEG-IFN alfa-2a for two weeks, then PEG-IFN alfa-2a alone for 46 weeks. The primary efficacy end point was HBeAg seroconversion at 48 weeks post-treatment. RESULTS: No significant differences were observed among groups for HBeAg seroconversion (PEG-IFN alfa-2a+placebo, 36.3%; PEG-IFN alfa-2a+ETV, 29.5%; and PEG-IFN alfa-2a+ADV, 27.4%), HBeAg loss (37.4%, 32.2%, and 28.6%, respectively) or change in hepatitis B surface antigen (HBsAg) levels from baseline (-0.56 IU/mL, -0.60 IU/mL, and -0.41 IU/mL, respectively). However, hepatitis B virus DNA levels were higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa+ETV at week 64 (p = 0.0412), 76 (p = 0.0311), and 88 (p = 0.0113), and alanine aminotransferase (ALT) normalization rate was higher with PEG-IFN alfa-2a+placebo than PEG-IFN alfa-2a+ADV (p = 0.0283) or PEG-IFN alfa-2a+ETV (p = 0.0369) at week 88. Sub-analysis of results revealed an association between on-treatment HBsAg and ALT levels and efficacy 48 weeks post-treatment. Safety was comparable among treatment groups. CONCLUSION: Pre-therapy with ADV or ETV followed by PEG-IFN alfa-2a is not superior to PEG-IFN alfa-2a monotherapy in Taiwanese patients with HBeAg-positive CHB. CLINICAL TRIAL ID: NCT: 00922207.

Long-term Effects of Hepatitis B Immunization of Infants in Preventing Liver Cancer.

BACKGROUND & AIMS: The incidence of hepatocellular carcinoma (HCC) increases with age, but protective antibody responses decrease with time after infants are immunized against hepatitis B virus (HBV). We investigated whether immunization of infants against HBV prevents their developing HCC as adults. We also searched for strategies to maximize the cancer-preventive effects. METHODS: We collected data from 2 Taiwan HCC registry systems on 1509 patients (6-26 years old) diagnosed with HCC from 1983 through 2011. Data on history of HBV immunization and prenatal maternal levels of HBV antigens of all HCC patients born after July 1984 were retrieved from the HBV immunization data bank of the Taiwan Center for Disease Control. We collected data on birth cohort-specific populations (6-26 years old) of Taiwan using the National Household Registry System. Rates of HCC incidence per 10(5) person-years were derived by dividing the number of patients with HCC by the person-years of the general population. Relative risks (RR) for HCC were estimated by Poisson regression analysis in vaccinated vs unvaccinated birth cohorts. We stratified patients by age group to evaluate the association of birth cohorts and HCC risks. RESULTS: Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 10(5) person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6-9 years old, 10-14 years old, 15-19 years old, and 20-26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval [CI], 0.17-0.40), 0.34 (95% CI, 0.25-0.48), 0.37 (95% CI, 0.25-0.51), and 0.42 (95% CI, 0.32-0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992-2005 vs 1986-1992; P < .001 and 1986-1992 vs 1984-1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with development of HCC. CONCLUSIONS: Based on an analysis of 1509 patients with HCC in Taiwan, immunization of infants against HBV reduces their risk of developing HCC as children and young adults. Improving HBV vaccination strategies and overcoming risk factors could reduce the incidence of liver cancer.

Restriction fragment length polymorphism effectively identifies exon 1 mutation of UGT1A1 gene in patients with Gilbert's Syndrome.

BACKGROUND & AIMS: Gilbert's syndrome causes pharmacological variation in drug glucuronidation and unexpected toxicity from therapeutic agents. The two common genotypes of Gilbert's syndrome are a dinucleotide polymorphism (TA)7 in TATA-Box as well as the 211G>A mutation in the coding exon 1, particularly in Asians, of human UGT1A1 gene. In this study, we aimed to establish an effective method to detect the 211G>A mutation. METHODS: The coding exon 1 sequence of human UGT1A1 gene was analysed by Vector NTI software. The 211G>A mutation in the coding exon 1 of UGT1A1 gene was determined by restriction fragment length polymorphism (RFLP) method. Serum total bilirubin level was measured as well. RESULTS: A newly identified BsmBI site was located in the coding exon 1 of UGT1A1 gene. The 211G>A mutation in the coding exon 1 of UGT1A1 gene was determined by DNA RFLP. Furthermore, we reported our present work on genetic analysis of mutations of UGT1A1 gene, and the correlation of UGT1A1 mutations with serum total bilirubin levels in Taiwanese population. The results showed that 15 subjects carried 211G>A mutation in 23 subjects related with Gilbert's syndrome. The homozygous 211G>A mutant as well as simultaneously heterozygous mutants both in TATA-Box and 211G>A significantly increased the risk of Gilbert's syndrome similar to subjects carrying homozygous TATA-Box mutant. CONCLUSIONS: BsmBI RFLP is an effective method to detect 211G>A mutation in the coding exon 1 of UGT1A1 gene. The common 211G>A mutation is one of the causes of Gilbert's syndrome in Taiwanese population.

Nuclear factor κB down-regulates human UDP-glucuronosyltransferase 1A1: a novel mechanism involved in inflammation-associated hyperbilirubinaemia.

Jaundice or hyperbilirubinaemia is a common complication of sepsis. UGT1A1 (UDP-glucuronosyltransferase 1A1) is a critical gene for bilirubin metabolism and irinotecan detoxification. However, the molecular pathogenesis of hyperbilirubinaemia during inflammation needs to be further clarified. Human hepatic UGT1A1 expression was analysed by RT (reverse transcription)-PCR, qRT-PCR (quantitative real-time PCR) and Western blotting in response to LPS (lipopolysaccharide) stimulation. Transcription regulatory elements in the upstream promoter region of the human UGT1A1 gene were determined using EMSA (electrophoretic mobility-shift assay) and ChIP (chromatin immunoprecipitation). The important role of the transcription regulatory element was examined using a luciferase assay, and was determined by qRT-PCR using a transcription factor activation inhibitor. LPS down-regulated the UGT1A1 mRNA expression in human hepatoma cell lines. A newly identified NF-κB (nuclear factor κB)-binding site was located on the upstream promoter region (-725/-716) of the human UGT1A1 gene. LPS-induced NF-κB activation and specific binding to the NF-κB-binding site can suppress human UGT1A1 promoter activity and human UGT1A1 expression. We demonstrated that LPS mediates the suppression of human UGT1A1 expression through specific binding of NF-κB to this newly identified NF-κB-binding site in the upstream promoter of the human UGT1A1 gene. The present study may partly explain the molecular pathogenesis of inflammation-associated hyperbilirubinaemia.

Peginterferon alfa-2a plus ribavirin for hemophilic patients with chronic hepatitis C virus infection in Taiwan.

BACKGROUND/PURPOSE: Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in patients with hemophilia. However, the efficacy and safety of pegylated interferon (PEG-IFN) plus ribavirin (RBV) for hemophilic patients with chronic HCV infection in Taiwan are still unknown. The aim of this study is to report the efficacy and safety of PEG-IFN plus RBV in a single center in Taiwan. METHODS: In an open-label single-treatment one-arm cohort study, 12 hemophilic patients with elevated alanine aminotransferase level more than two times the upper limit of normal for more than 3 months received 180 µg/week of PEG-IFN-α-2a plus RBV 1000-1200 mg/day at a cut-off value of 75 kg. The duration of treatment was 48 weeks for patients with HCV Genotype 1/4 infection and 24 weeks for patients with HCV Genotype 2/3 infection. Efficacy of therapy was expressed as sustained virological response (SVR). RESULTS: Eight patients achieved SVR (66.7%). The SVR rates were 57%, 100%, 100%, and 0% for patients with HCV Genotypes 1, 2, 3, and 4 infection, respectively. Adverse events (AEs) developed in 10 patients (83.3%). Severe thrombocytopenia developed in one patient. However, the patient did not suffer from severe bleeding. CONCLUSION: Our study shows that the SVR rates are similar in hemophilic and nonhemophilic patients with chronic HCV infection who receive PEG-IFN-α-2a plus RBV in Taiwan. The rate of AEs also resembled other studies in nonhemophilic patients in Taiwan. No patient suffered from severe bleeding. However, large-scale, well-conducted studies are still needed to verify the treatment efficacy and safety.

Carbon dioxide insufflation does not reduce pain scores during colonoscope insertion in unsedated patients: a randomized, controlled trial.

BACKGROUND: CO(2) is rapidly absorbed from the colon and eliminated via the lung. Insufflation of CO(2) instead of air during colonoscopy can reduce distention-induced pain. OBJECTIVE: This study aimed to evaluate the effects of CO(2) insufflation on pain during intubation and extubation and to identify predictors of pain and discomfort during colonoscope insertion. DESIGN: Prospective, randomized, controlled trial. SETTING: Single tertiary medical center in Taiwan. PATIENTS: A total of 193 patients enrolled from September 2010 through June 2011. INTERVENTIONS: Colonoscope insertion with either air or CO(2) insufflation. CO(2) was used for extubation in both groups. MAIN OUTCOME MEASUREMENTS: The main outcome measurement was pain, recorded on a 10-point visual analog scale (VAS) for left-sided colonoscope insertion and right-sided colonoscope insertion and at 1, 3, 6, and 24 hours post-procedure. Colonoscope cecal intubation time and extubation time, completeness of intubation, and loop formation were also assessed. RESULTS: CO(2) insufflation during colonoscope intubation was used in 98 patients and air in 97 patients. The mean pain scores during intubation were low (2-3) for patients undergoing air insufflation and were not reduced further in patients receiving CO(2). A mean pain score of 0 was reported by both groups for all postprocedure time points. Multivariate analysis identified sex, loop formation of the sigmoid colon, time to reach the transverse colon, and requested sedation as factors that significantly affect VAS pain scores. LIMITATIONS: This study was limited in scope to a single medical center with experienced endoscopists. CONCLUSIONS: We detected no significant benefit to the use of CO(2) insufflation compared with air insufflation during intubation for colonoscopy performed by experienced colonoscopists. The absence of postprocedure pain in both groups supports previous observations that CO(2) insufflation during extubation is effective in reducing postprocedure pain. Female sex and loop formation were identified as key factors influencing pain scores on colonoscope insertion. ( CLINICAL TRIAL REGISTRATION NUMBER: TSGHIRB-099-05-081.).

Hepatitis C virus infection in patients with primary biliary cirrhosis.

BACKGROUND AND AIM: The aim of this study is to evaluate the role of hepatitis C virus (HCV) infection in patients with primary biliary cirrhosis (PBC). MATERIAL AND METHODS: On the basis of a retrospective review of medical records, all patients consecutively diagnosed with PBC or HCV infection between 1999 and 2011 and who had a regular follow-up of at least 3 years were included in the study. Clinical characteristics, especially the severity of cirrhosis, were analyzed in PBC patients with HCV infection (PBC-HCV), PBC patients without HCV infection (PBC-only), and patients with only HCV infection (HCV-only). RESULTS: A total of 76 patients with PBC, including 9 patients with HCV infection, were analyzed. Of the PBC-HCV patients, 7 (7/9, 77.8%) were women with a mean age of 55.11 ± 14.29 years. Age- and sex-matched PBC-only patients (n = 36) and HCV-only patients (n = 36) were used as control groups. In comparison to the PBC-only controls, PBC-HCV patients had a greater severity of cirrhosis based on Child-Pugh (p = 0.019) and Model for End-Stage Liver Disease (MELD) (p = 0.01) scores. However, no significant difference in the severity of cirrhosis was found between the PBC-HCV and HCV-only control patients (p = 0.94 in Child-Pugh scores; p = 0.64 in MELD scores). CONCLUSIONS: In PBC patients with concomitant HCV infection, aggressive management may be warranted in view of the associated more severe liver cirrhosis.

Association between chronic hepatitis C virus infection and bone mineral density.

Whether chronic hepatitis C virus (HCV) infection is a risk factor for the development of bone disease has long been controversial. For this reason, chronic HCV-infected participants (n = 69) were recruited into a prospective cohort study and underwent dual-energy X-ray absorptiometry for determination of bone mineral density (BMD). Fibrosis staging was evaluated according to the noninvasive index FIB-4. T scores at the femoral neck and lumbar spine were used as the primary outcome variables to assess the association between degree of liver disease and BMD. The study cohort was 41 % male with a mean age of 53.6 years. The mean BMD, Z score, and T score values of lumbar spine in chronic hepatitis C (CHC) patients were significantly lower than those in healthy controls (p < 0.001). The rate of osteoporosis for CHC patients aged 45-54 years was significantly higher than that of the control group (p = 0.011). Bone alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen levels were also significantly higher in CHC patients with reduced BMD. Patients with more advanced liver fibrosis had significantly lower BMD. In conclusion, reduced BMD is common in this population of chronic HCV-infected patients and associated with liver disease severity. This extrahepatic manifestation is probably secondary to increased bone turnover in osteodystrophy pathogenesis.

Locoregional therapy-induced tumor necrosis as a predictor of recurrence after liver transplant in patients with hepatocellular carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) often undergo locoregional therapy before liver transplant either to downstage the tumor or as bridge therapy. Our goal was to assess the risk factors for posttransplant tumor recurrence, specifically the extent of necrosis induced by locoregional therapy. METHODS: We conducted a hospital-based retrospective analysis of 100 patients with HCC who received a liver transplant, 86 of whom had received pretransplant locoregional therapy. We evaluated various patient- and tumor-related parameters to determine the risk factors for recurrence. Furthermore, we grouped patients by the degree of tumor necrosis after locoregional therapy and identified the factors that were associated with a favorable tumor response. RESULTS: Initial tumor extent beyond the University of San Francisco (UCSF) criteria, microvascular invasion, and attainment of less than 90% tumor necrosis after locoregional therapy were independent risk factors for tumor recurrence. In addition, there was a significant correlation between the tumor necrosis percentage and disease-specific survival rate. Among patients whose tumors initially exceeded the UCSF criteria, those with extensive locoregional therapy-induced tumor necrosis had lower recurrence rates. All recurrences after transplant occurred within 3 years, and recurrence rates in patients with extensive tumor necrosis at 1, 2, and 3 years were 3%, 6%, and 10%, respectively. Female gender and a solitary tumor were independently associated with extensive tumor necrosis. CONCLUSIONS: In HCC patients who are transplant candidates and undergo pretransplant locoregional therapy, the degree of induced tumor necrosis affects both tumor recurrence and survival rate.

Endoscopic submucosal dissection with the pulley method for early-stage gastric cancer (with video).

BACKGROUND: Using EMR techniques, physicians frequently remove tumors >15 mm by piecemeal resection, which is associated with an increased rate of disease recurrence and difficulty in histologically evaluating the specimen. Endoscopic submucosal dissection (ESD) of early-stage gastric cancer improves the rate of successful en bloc resection, but it is associated with more complications, such as bleeding and perforation, than conventional EMR. OBJECTIVE: To describe a simple technique that uses the pulley method to facilitate ESD procedures in the excision of large early-stage gastric cancers. DESIGN: Case series. SETTING: Tertiary medical center in Taiwan. PATIENTS AND METHODS: Eleven patients with early-stage gastric cancers or adenomas >20 mm underwent ESD. INTERVENTIONS: The pulley method with standard clips and dental floss was used to provide traction to improve visualization of the dissection plane during ESD. MAIN OUTCOME MEASUREMENT: Proportion with complete en bloc resection. RESULTS: En bloc resection of the lesion was achieved in 11 patients. No perforation or emergent surgery was noted. LIMITATIONS: One endoscopist performed all procedures, and only 11 patients were studied in an uncontrolled manner. CONCLUSIONS: The pulley method seems to facilitate en bloc ESD of early-stage gastric cancers >20 mm.

Modified Mallampati classification as a clinical predictor of peroral esophagogastroduodenoscopy tolerance.

BACKGROUND: Unsedated esophagogastroduodenoscopy (EGD) is simpler and safer than sedated EGD; however, approximately 40% of patients cannot tolerate it. Early identification of patients likely to poorly tolerate unsedated EGD is valuable for improving compliance. The modified Mallampati classification (MMC) has been used to evaluate difficult tracheal intubation and laryngoscope insertion. We tried to assess the efficacy of MMC to predict the tolerance of EGD in unsedated patients. METHODS: Two hundred patients who underwent an unsedated diagnostic EGD were recruited. They were stratified according to the view of the oropharynx as either MMC class I + II (good view) or class III + IV (poor view). EGD tolerance was assessed in three ways: gag reflex by endoscopist assessment, patient satisfaction by interview, and the degree of change in vital signs. RESULTS: MMC was significantly correlated to gag reflex (P < 0.001), patient satisfaction (P = 0.028), and a change of vital signs (P = 0.024). Patients in the poor view group had a 3.87-fold increased risk of gag reflex (P < 0.001), a 1.78-fold increased risk of unsatisfaction (P = 0.067), and a 1.96-fold increased risk of a change in vital signs (P = 0.025) compared to those in the good view group. CONCLUSIONS: MMC appears to be a clinically useful predictor of EGD tolerance. Patients with poor view of oropharynx by MMC criteria may be candidates for sedated or transnasal EGD.

Minocycline attenuates 5-fluorouracil-induced small intestinal mucositis in mouse model.

Minocycline exerts anti-inflammatory and anti-apoptotic effects distinct from its antimicrobial function. In this study we investigated the effect of this drug on chemotherapy-induced gut damage. Body weight loss results, diarrhea scores, and villi measurements showed that minocycline attenuated the severity of intestinal mucositis induced by 5-fluorouracil (5-FU). Minocycline repressed the expression of TNF-alpha, IL-1beta, and iNOS, decreased the apoptotic index, and inhibited poly(ADP-ribose) polymerase-1 (PARP-1) activity in the mouse small intestine. In vitro experiments showed that minocycline suppressed the upregulation of PARP-1 activity in enterocyte IEC-6 cells treated with 5-FU. In addition, minocycline treatment appeared to enhance the antitumor effects of 5-FU in tumor CT-26 xenograft mice. Our results indicate that minocycline protects mice from gut injury induced by 5-FU and enhances the antitumor effects of 5-FU in xenograft mice. These observations suggest that minocycline treatment may benefit patients undergoing standard cancer chemotherapy by alleviating chemical-associated intestinal mucositis.

Minocycline attenuates experimental colitis in mice by blocking expression of inducible nitric oxide synthase and matrix metalloproteinases.

In addition to its antimicrobial activity, minocycline exerts anti-inflammatory effects in several disease models. However, whether minocycline affects the pathogenesis of inflammatory bowel disease has not been determined. We investigated the effects of minocycline on experimental colitis and its underlying mechanisms. Acute and chronic colitis were induced in mice by treatment with dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS), and the effect of minocycline on colonic injury was assessed clinically and histologically. Prophylactic and therapeutic treatment of mice with minocycline significantly diminished mortality rate and attenuated the severity of DSS-induced acute colitis. Mechanistically, minocycline administration suppressed inducible nitric oxide synthase (iNOS) expression and nitrotyrosine production, inhibited proinflammatory cytokine expression, repressed the elevated mRNA expression of matrix metalloproteinases (MMPs) 2, 3, 9, and 13, diminished the apoptotic index in colonic tissues, and inhibited nitric oxide production in the serum of mice with DSS-induced acute colitis. In DSS-induced chronic colitis, minocycline treatment also reduced body weight loss, improved colonic histology, and blocked expression of iNOS, proinflammatory cytokines, and MMPs from colonic tissues. Similarly, minocycline could ameliorate the severity of TNBS-induced acute colitis in mice by decreasing mortality rate and inhibiting proinflammatory cytokine expression in colonic tissues. These results demonstrate that minocycline protects mice against DSS- and TNBS-induced colitis, probably via inhibition of iNOS and MMP expression in intestinal tissues. Therefore, minocycline is a potential remedy for human inflammatory bowel diseases.

A prospective trial of variable stiffness colonoscopes with different tip diameters in unsedated patients.

OBJECTIVES: Few data exist comparing the clinical versatility of variable stiffness (VS) colonoscopes with different tip diameters and stiffness ranges. We compared the intubation time and success rate, maneuvering ease, and patient comfort of three colonoscopes: pediatric VS (PVSC), nonmagnifying adult VS (AVSC), and magnifying VS (MVSC). METHODS: Two hundred sixteen consecutive patients scheduled for routine colonoscopy were randomized to undergo colonoscopy with one of the three different colonoscopes (PVSC N = 72, AVSC N = 72, MVSC N = 72). Outcome measurements included time required for cecal intubation, success rate for cecal intubation, maneuvering ease, and patient comfort. RESULTS: The overall success rate for cecal intubation was 95.83%. Intubation time was significantly different among the groups (PVSC 12.88 +/- 7.11 min, AVSC 9.25 +/- 5.16 min, MVSC 9.62 +/- 5.55 min; P < 0.01). Intubation time with PVSC required about 3 min more when compared with AVSC or MVSC. Multivariate analyses revealed that colonoscopy with AVSC required 3 min less when compared with PVSC (P= 0.03). Age greater than 55 yr, waist circumference, prior hysterectomy, and pain experienced by patients were also factors affecting intubation time. CONCLUSIONS: In this study, a PVSC might not decrease patient discomfort or intubation time. The ideal colonoscope is the AVSC that has a modest diameter and stiffness range and thus is capable of achieving both a short intubation time and an acceptable comfort level. We also should bear in mind that MVSC has an additional function of magnifying observation.

Spontaneous intracranial hemorrhage in cirrhotic patients.

OBJECTIVE: The major characteristics of spontaneous intracranial hemorrhage (SICH) in cirrhotic patients have not been completely defined. Cirrhotic patients with SICH were thus analyzed in an effort to better understand the risk factors for SICH and predict patient outcomes. PATIENTS AND METHODS: From 1997 to 2006, 4515 hospitalized cirrhotic patients were recruited, with a focus on 36 cirrhotic patients with SICH who had no history of cerebral vascular accidents, head injuries, or cerebral arteriovenous malformations. The patient characteristics, severity of cirrhosis, location of the hematoma, and prognosis were analyzed. RESULTS: Of the patients, 78% were males, 72% consumed alcohol, and 81% had a mild-to-moderate degree of cirrhosis. The overall incidence of SICH was related to the etiology of cirrhosis as follows: virus-related cirrhosis (0.3%), alcohol-related cirrhosis (1.9%), and combined virus- and alcohol-related cirrhosis (3%). The outcome of patients with SICH was associated with the size of the hematoma (P<0.005), the initial Glasgow Coma Scale score (P<0.05), the Child-Pugh classification (P=0.05), and the serum total bilirubin level (P<0.05). CONCLUSION: SICH occurs primarily in young males with mild-to-moderate alcoholic cirrhosis of the liver. The etiology of cirrhosis is related to the incidence of SICH, but not to the patient outcome. The severity of liver cirrhosis is associated with patient outcome, but not the incidence of SICH.

Association of Renal Function and Direct-Acting Antiviral Agents for HCV: A Network Meta-Analysis.

The effectiveness and safety of direct-acting antiviral agents (DAAs) in hepatitis C virus (HCV) patients with renal insufficiency remain controversial. Therefore, this network meta-analysis aims to assess effectiveness and safety of DAAs in populations with different renal function. The pooled data were obtained from Cochrane Library, EMBASE, PubMed, and Web of Science. Thirteen studies recruited 6884 patients with hepatitis C infection and reported their outcomes in relation to different levels of renal function after treatment with DAAs. The results showed no difference in the virologic responses among patients with different renal function. Regarding safety, whereas in patients without chronic kidney disease (CKD) or with early CKD DAAs were associated with a risk ratio (RR) of 0.14 (95% confidence interval (CI), 0.04 to 0.43) for renal disorder, increased risk of renal function deterioration was found in advanced-CKD patients, though this effect may be related to the natural course of advanced CKD. Similarly, patients without CKD or with early CKD showed a lower risk of anemia (RR, 0.34; 95% CI, 0.20 to 0.57) and discontinuation (RR, 0.41; 95% CI, 0.39 to 0.56) than patients with advanced CKD. The efficacy of DAAs for HCV treatment was comparable in patients with advanced CKD and in those with early CKD or without CKD. However, the safety of DAAs should be verified in future studies.

Identification and preclinical evaluation of the small molecule, NSC745887, for treating glioblastomas via suppressing DcR3-associated signaling pathways.

The small-molecule naphtha [2,3-f]quinoxaline-7,12-dione (NSC745887) can effectively inhibit the proliferation of various cancers by trapping DNA-topoisomerase cleavage. The aim of this study was to elucidate cellular responses of NSC745887 in human glioblastoma multiforme (GBM, U118MG and U87MG cells) and investigate the underlying molecular mechanisms. NSC745887 reduced the cell survival rate and increased the sub-G1 population in dose- and time-dependent manners in GBM cells. Moreover, NSC745887 increased expression of γH2AX and caused DNA fragmentation leading to DNA damage. Furthermore, Annexin V/propidium iodide and Br-dTP staining showed the apoptotic effect of NSC745887 in GBM cells. DNA repair proteins of ataxia-telangiectasia mutated (ATM), ATM and Rad3-related, and decoy receptor 3 also decreased with NSC745887 treatment. In addition, NSC745887 caused apoptosis by the caspase-8/9-caspase-3-poly(ADP-ribose) polymerase cascade. An in vivo study indicated that NSC745887 suppressed the [18F]-FDG-specific uptake value in brain tumors. Histological staining also indicated a decrease in Ki-67 and increases in γH2AX and cleaved caspase-3 in the brain tumor area. These data provide preclinical evidence for NSC745887 as a potential new small molecule drug for managing glioblastomas.

Emergency endoscopic management of dietary foreign bodies in the esophagus.

OBJECTIVE: We report our experience of endoscopy in the emergency management of dietary foreign bodies. METHODS: One hundred thirty-six patients were admitted to the emergency department (ED) between January 1997 and October 2006 for the endoscopic removal of esophageal dietary foreign bodies. They had a mean age of 47.7 years, and 91 (67%) were women. RESULTS: Most of the ingested materials (98.5%) were successfully extracted using either flexible or rigid endoscope. The objects most frequently ingested were fish bones (48%) and chicken bones (46%). Most of the objects (84%) were lodged in the upper esophagus. Two patients with irretrievable foreign bodies or complicated perforations were taken to surgery. CONCLUSION: Because most of these foreign bodies lodged in the upper esophagus, physicians should take care of this area to avoid secondary injury or complications, especially with sharp bones.