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Background and aims: The enhanced liver fibrosis (ELF) score is a blood test that combines three markers linked to liver fibrosis. The utility of the ELF score has been demonstrated primarily in Western countries, but whether it is useful in areas with a high number of elderly people suffering from chronic liver disease has yet to be determined. Methods: This is a prospective study that included 373 consecutive patients who underwent a liver biopsy and had their ELF score measured on the same day. The diagnostic accuracy of the ELF score for liver fibrosis and the effect of age on the ELF score were investigated. Results: The median (interquartile) ELF scores in F0, F1, F2, F3, and F4 are 8.7 (8.2–9.2), 9.3 (8.8–10.0), 10.1 (9.4–10.7), 10.7 (9.9–11.2), and 12.0 (11.2–12.7), respectively. ELF scores increased with increasing liver fibrosis stage (p < 0.001). The diagnostic accuracy of the ELF score and FIB-4 for significant fibrosis (F2–4) and advanced fibrosis (F3–4) was comparable, but the ELF score had a higher diagnostic accuracy for cirrhosis (F4) than FIB-4. When patients were stratified by age of 60 years, the median ELF score did not differ by age in F2, F3, and F4. However, the median FIB-4 increased in patients with ≥60 years compared to those with Conclusions: ELF score has high diagnostic accuracy for liver fibrosis, regardless of age, and it could be used as a primary screening method.

Abstract Background and Aim Hepatocellular carcinoma development can be decreased by achieving and maintaining complete virological response (CVR) in chronic hepatitis B. However, it is unclear whether switching from entecavir (ETV) to tenofovir alafenamide (TAF) could achieve and maintain CVR in patients with low‐level viremia (LLV; HBV DNA ≤ 3.3 log IU/mL) or occasional detectable HBV DNA during ETV treatment. Therefore, we aimed to examine whether the switching from ETV to TAF is effective in achieving CVR in patients with LLV or occasional detectable HBV DNA. Methods This study comprised 45 patients who switched from ETV to TAF. All patients received ETV and TAF for >2 years, and the HBV DNA levels were measured every 3 months. Maintaining undetectable HBV DNA during 2‐year period is defined as CVR. The primary endpoint is the CVR rate during ETV and TAF treatment. Results The CVR rate for each of the 2 years of ETV and TAF therapy was 33.3% (15/45) and 68.9% (31/45, P

Background: Early medical residents are expected to have a higher prevalence of burnout due to physical and psychological stressors. However psychological distress associated with burnout has not been adequately investigated in a longitudinal manner. We therefore examined the longitudinal trajectory of depression and its associated factors among early medical residents. Methods: In this cohort study, medical residents (n = 215) who started rotation at the University of Yamanashi Hospital during 2012 to 2018 were recruited and asked to complete the Brief Job Stress Questionnaire (BJSQ), Center for Epidemiologic Studies Depression Scale (CESD), Brief Scale for Coping Profile (BSCP) and Athens Insomnia Scale (AIS) at the time of exit from each clinical department for up to two years over seven years. Factors associated with the CES-D scores were statistically explored, with a cutoff score of 16 to denote depression. Results: The CES-D was completed by 205 residents. The average CES-D score was 10.3 ± 8.0 and the scores were lower in the 2nd versus 1st year of residency (11.3 ± 6.7 versus 9.2 ± 7.0). Multiple regression analysis of BJSQ/BSCP/AIS on CES-D revealed that insomnia had a significant impact on the CES-D scores. Apart from insomnia, avoidance and suppression and peer support had significant effects. Resilient residents, who showed the maximum CES-D score of under 16 consistently throughout the residency, was better in terms of changing a point of view, active solution and changing mood. Women were more likely to express emotions to others, while they reported more job control in the first year. Conclusions: Our results have high clinical relevance to challenge psychological burnout among early medical residents, offering some possible clues for prevention such as reduced burden, more flexibility during the first year and strengthening coworker support. Insomnia exerted moderate to strong effects on depression and monitoring of sleep appears indispensable in this specific population.

Key Clinical Message The liquid CGP was useful for detecting FGFR2 fusion and the patient experienced typical side effects (nail disorders, hyperphosphatemia, and taste disorders) of pemigatinib that required treatment.

Abstract Background and Aim Administration of tenofovir alafenamide (TAF) as prevention or treatment of hepatitis B virus (HBV) reactivation is not well known. The aim of this study is to reveal the efficacy and safety of TAF against HBV reactivation. Methods Entecavir (ETV) and TAF were given to 66 and 11 patients, respectively, as prophylaxis against or treatment of HBV reactivation during chemotherapy or immune suppression therapy from January 2010 to June 2020. The antiviral effects and safety were assessed. Results At week 24, the antiviral effects on patients receiving ETV and TAF were similar in terms of reduction of HBV DNA (−2.83 ± 1.45log IU/mL vs −3.05 ± 2.47log IU/mL; P = 0.857) and achieving undetectable levels of HBV DNA (78.8 vs 90.9%; P = 0.681). There was no significant difference in the decrease in the estimated glomerular filtration rate (eGFR) between the two groups (−0.62 ± 11.2 mL/min/1.73 m2 vs −3.67 ± 13.2 mL/min/1.73 m2; P = 0.291). Conclusion TAF is safe and effective against HBV reactivation.

Abstract Background Therapeutic strategies for unresectable hepatocellular carcinoma (u‐HCC) in geriatric patients are important for real‐world practice. However, there remain no established biomarkers or therapeutic strategies regarding the best second‐line agent after atezolizumab plus bevacizumab therapy. Aim In this study, we investigated the usefulness of modified Geriatric 8 (mG8) score in examining elderly patients (≥75 years old) with unresectable hepatocellular carcinoma (u‐HCC) using sorafenib or lenvatinib as first‐line therapy. Methods and results This study assessed 101 elderly patients with u‐HCC for their mG8 score (excluding elements of age from 8 items) and classified them into 2 groups according to their mG8 score: ≥11 as the high‐score group and ≤ 10 as the low‐score group. Among those taking sorafenib, no significant differences were noted in overall survival (OS) and progression free survival (PFS) between low and high mG8 score groups. Only modified albumin–bilirubin (ALBI) grade (2b/3 vs. 1/2a: HR 0.34; 95% CI, 0.17–0.69; p = .0029) was significantly associated with OS. Among those taking lenvatinib, patients with a high mG8 score (n = 26) had longer survival than those with a low mG8 score (n = 10) (20.0 months vs. 7.7 months: HR 0.31, 95% CI 0.11–0.89; p = .029). Intrahepatic tumor volume (

ABSTRACT This study aimed to calibrate hepatitis E virus (HEV) serological assays. We optimized the previously developed in-house HEV antibody enzyme-linked immunosorbent assay (ELISA) by setting the cutoff with an in-house serological performance panel consisting of broad HEV antibody titers and subtracting nonspecific background values for anti-HEV IgM, IgA, and IgG. We also compared the assay’s performance with that of commercial serological assay kits (four kits for IgM, one for IgA, and two for IgG). Although all serological assays readily detected HEV antibodies at high titers in the symptomatic hepatitis E population, considerable variations between assays were observed in the asymptomatic population. The in-house ELISA showed a higher sensitivity for HEV IgM, IgA, and IgG than the commercial kits and detected the seroconversion of HEV IgM and IgG earlier when testing a commercially available HEV seroconversion panel. The low sensitivity of the commercial kits was due to the high setting of the original cutoff, which was demonstrated by receiver operating characteristic analysis. However, the corrected cutoff value reduced assay specificity. Background subtraction is essential to achieve high specificity because the in-house ELISA without background subtraction reduced its specificity. These results indicate that asymptomatic specimens and background subtraction contribute to the optimization of HEV serological assays. IMPORTANCE Accurate diagnosis of hepatitis E virus (HEV) infection is essential for public health surveillance and for preventing HEV-contaminated blood transfusion. Anti-HEV IgM or IgA is used as a reliable marker of recent HEV infection. However, considerable variability in the sensitivity and specificity of HEV antibody detection is observed among several commercially available assay kits. In addition, none of the HEV antibody detection methods have been approved by the U.S. Food and Drug Administration (FDA). Here, we show that the in-house enzyme-linked immunosorbent assay (ELISA) could detect HEV IgM and IgA more sensitively than commercial kits in the asymptomatic population. We also suggest that the assay performance of commercial kits might be improved by optimizing the cutoff and reducing nonspecific background noise. A sensitive serological (IgM or IgA) assay in addition to HEV RNA testing will contribute to accurate diagnosis of acute HEV infection because HEV RNA-positive duration is relatively short.

Abstract Background Postoperative pancreatic fistula (POPF) is one of the most serious complications after pancreaticoduodenectomy (PD). Various factors have been reported as POPF risks, but the most serious of these is soft pancreas. To reduce POPF occurrences, many changes to the PD process have been proposed. This study evaluates short-term results of anastomosis technique for PD. Methods In total, 123 patients with soft pancreases who had undergone PD at Yamanashi University between January 2012 and August 2020 were retrospectively analyzed. We divided these patients into two groups depending on the time PD was performed: a conventional group (n = 67) and a modified group (n = 56). Results The rate of clinically relevant POPF was significantly lower in the modified group than that in the conventional group (5.4% vs 22.4%, p value

Background and Aim Loss of hepatitis B surface antigen (HBsAg) is an important goal in the treatment of chronic hepatitis B. We investigated whether switching from long‐term entecavir (ETV) administration to tenofovir (TFV) (tenofovir alafenamide [TAF] or tenofovir disoproxil fumarate [TDF]) could contribute to the reduction of HBsAg levels. Methods The degree of HBsAg reduction by 48 weeks in 30 patients following switching from ETV to TFV was compared with results from 147 patients who continued ETV as a control. Results TFV group switched to TFV after mean 6.79 years of ETV administration. HBV‐DNA levels remained below 1.0 log IU/mL in all cases in both groups during 48 weeks. Median HBsAg reduction at 48 weeks was 0.075 (−0.05 to 0.38) log/IU/mL in the TFV switch group, and 0.070 (−0.28 to 0.50) in the ETV continuation group, which was not statistically significant (p = 0.5). In a subgroup of hepatitis B e antigen negative patients whose HBsAg had not been reduced (HBsAg reduction ≤0 log IU/mL) in the 48 weeks prior to entry into the study, HBsAg reduction was significantly higher in the TFV switch group than in the ETV continuation group (0.15 [0.07–0.135] in TFV, 0.09 [−0.14 to 0.25] log IU/mL in ETV, p = 0.04). Conclusion Although HBsAg reduction is equivalent with ETV continuation and switching to TFV in all patients at 48 weeks, switching from ETV to TFV could provide an alternative therapeutic strategy toward HBsAg elimination in a specific subpopulation of patients.

Background and aim The long-term prognosis of hepatocellular carcinoma (HCC) treated at a very-early-stage (the Barcelona Clinical Liver Cancer (BCLC) classification stage 0) was unclear, especially in terms of background liver disease. Methods This single-center, retrospective study included 302 patients with BCLC stage 0 HCC treated with radiofrequency ablation (RFA) and followed for at least six months. We examined the impact of background liver disease on overall survival and recurrence. Results The median age was 72 (range; 36–91) years; the median tumor diameter was 15 (range; 8–20) mm. The etiologies of background liver disease were hepatitis B virus infection (HBV) in 24 cases, hepatitis C virus infection (HCV) in 195 cases, and non-viral (NBNC) in 83 cases. Among the patients with HCV, 63 had achieved sustained virological response (SVR) by antiviral therapy (HCV SVR) before developing HCC (n = 37) or after HCC treatment (n = 26), and 132 had active HCV infection (HCV non-SVR). The median overall survival was 85 (95% CI; 72–98) months, and the median recurrence-free survival was 26 (95% CI; 20–30) months. Active infection with hepatitis C virus negatively contributed to overall survival (HR 2.91, 95% CI 1.31–3.60, p = 0.003) and recurrence-free survival (HR 1.47, 95% CI 1.06–2.05, p = 0.011). Conclusions The prognosis of RFA treatment for very early-stage HCC was favorable. Achieving SVR in hepatitis C was important for further prognosis improvement.

Background & Aims: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. Methods: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. Results: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p

Lenvatinib is an approved first-line therapy for unresectable hepatocellular carcinoma (HCC), but the effect of dose modification on its efficacy is unclear. We analyzed the relationship between the relative dose intensity during the initial 4 weeks of therapy [4W-relative dose intensity (RDI)] and the efficacy of lenvatinib therapy in the real-world setting. A total of 48 consecutive patients with unresectable HCC who received lenvatinib therapy for more than 4 weeks were included. The 4W-RDI was calculated as the cumulative dose in the initial 4 weeks divided by the weight-based standard dose, and we evaluated its association with overall survival (OS) and best response by modified Response Evaluation Criteria in Solid Tumor (mRECIST). The baseline factors predicting high 4W-RDI were analyzed further. The median durations of follow-up and of therapy among the 48 participants were 7.6 and 6.6 months, respectively. The median OS was not reached. Drug interruption and/or dose reduction were necessary in 30 patients (62.5%) and the median 4W-RDI was 70% (range 22%-100%). Patients with 4W-RDI ≥70% had longer OS [hazard ratio (HR) 0.28, 95% confidential interval (CI):0.09-0.90, p = 0.03], and longer duration of lenvatinib therapy (HR 0.39, 95%CI:0.16-0.92, p = 0.03). Patients with 4W-RDI ≥70% showed higher disease control rate compared to those with 4W-RDI 3.4g/dL or ALBI score less than -2.171 were significantly associated with achieving 4W-RDI ≥70%. In conclusion, 4W-RDI of lenvatinib therapy is associated with favorable radiological response and longer OS.

Abstract Histological molecular classification of hepatocellular carcinoma (HCC) is clinically important for predicting the prognosis. However, a reliable serum marker has not been established. The aim of this study was to evaluate the diagnostic value of serum Wisteria Floribunda agglutinin-positive sialylated mucin 1 (WFA-sialylated MUC1), which is a novel biliary marker, as a marker of HCC with hepatic progenitor cell (HPC)/biliary features and of prognosis. A total of 144 consecutive patients who underwent complete radiofrequency ablation of primary HCC were enrolled. A serum WFA-sialylated MUC1 level of 900 μL/mL was determined as the optimal cutoff value for prediction of immunohistochemical staining for HPC/biliary features [sialylated MUC1 and cytokeratin 19 (CK19)]. Positive staining rate of sialylated MUC1 and CK19 was significantly higher in patients with WFA-sialylated MUC1 ≥900 than those with WFA-sialylated MUC1

Background and aimsThe present study aimed to report our real-life experience of the TPO receptor agonist lusutrombopag for cirrhotic patients with low platelet counts.MethodsWe studied platelet counts in 1,760 cirrhotic patients undergoing invasive procedures at our hospital between January 2014 and December 2017. In addition, we studied 25 patients who were administered lusutrombopag before invasive procedures between June 2017 and January 2018. Effectiveness of lusutrombopag to raise platelet counts and to avoid transfusion and treatment-related adverse events were analyzed.ResultsIn 1,760 cirrhotic patients without lusutrombopag prior to invasive procedures, proportion of patients whose platelet counts 30,000/μL (n = 17) (50,000 ± 20,000 vs 86,000 ± 26,000/μL, p = 0.002). Patients with a baseline platelet count ≤30,000/μL with spleen index (calculated by multiplying the transverse diameter by the vertical diameter measured by ultrasonography) ≥40 cm2 (n = 3) had a lower response rate to lusutrombopag compared to those with spleen index ConclusionsLusutrombopag is an effective and safe drug for thrombocytopenia in cirrhotic patients, and can reduce the frequency of platelet transfusions.

Abstract Radiofrequency ablation (RFA) is considered the most effective treatment for early‐stage hepatocellular carcinoma (HCC) patients unsuitable for resection. However, poor outcome after RFA has occasionally been reported worldwide. To predict such an outcome, we investigated imaging findings using contrast‐enhanced ultrasonography (CEUS) with Sonazoid and serum tumor markers before RFA. This study included 176 early‐stage HCC patients who had initially achieved successful RFA. Patients were examined using CEUS; their levels of alpha‐fetoprotein (AFP), Lens culinaris agglutinin‐reactive fraction of AFP (AFP‐L3), and des‐gamma‐carboxy prothrombin before RFA were measured. Sonazoid provided parenchyma‐specific contrast imaging and facilitated tumor vascular architecture imaging through maximum intensity projection (MIP). Kaplan–Meier analysis examined cumulative rates of local tumor progression, intrasubsegmental recurrence, and survival; factors associated with these were determined with Cox proportional hazards analysis. Local tumor progression (n = 15), intrasubsegmental recurrence (n = 46), and death (n = 18) were observed. Irregular pattern in MIP classification and serum AFP‐L3 level (>10%) before RFA were identified as independent risk factors for local tumor progression and intrasubsegmental recurrence. These two factors were independently associated with poor survival after RFA (irregular pattern in MIP: hazard ratio, (HR) = 8.26; 95% confidence interval, (CI) = 2.24–30.3; P = 0.002 and AFP‐L3 > 10%: HR = 2.94; 95% CI = 1.09–7.94; P = 0.033). Irregular MIP pattern by CEUS and high level of serum AFP‐L3 were independent risk factors for poor outcome after successful RFA. The Patients with these findings should be considered as special high‐risk group in early‐stage HCC.

Background: A test to narrow down patients who require esophagogastroduodenoscopy (EGD) with a high probability of having gastroesophageal varices (GEV) and a high-risk of liver-related events is an unmet need. Methods: The measurement of serum fibrosis markers and EGD was performed in 166 consecutive chronic hepatitis C patients. The correlation between the grades of GEV and fibrosis markers and the subsequent occurrence of liver-related and fibrosis markers were examined. Results: Wisteria floribunda agglutinin-positive human Mac-2 binding protein (WFA+−M2BP) levels increased according to the grade of GEV (3.4 (0.2−18.6) for no GEV, 7.9 (1.8−20.0) for small GEV, and 11.4 (4.0−20.0) for large GEV; p < 0.001). The diagnostic accuracy of the WFA+−M2BP was superior compared to other serum fibrosis markers, and WFA+−M2BP was an independent predictor of GEV in the multivariate analysis. Furthermore, the cumulative incidence of liver-related events at one year was 2.3% in patients with WFA+−M2BP levels ≤ 7.0 and 37.5% in patients with WFA+−M2BP levels > 7.0 (p < 0.001). WFA+−M2BP > 7.0 was a significant predictive factor for liver-related events (Hazard ratio 6.7, p = 0.004) independent of Child−Pughclass. Conclusions: WFA+−M2BP could be used to estimate the presence and grade of GEV and is linked to liver-related events in chronic hepatitis C patients.

BACKGROUND:The present study aimed to investigate the impact of pre-sarcopenia on the prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. METHODS:We enrolled 214 patients (71 ± 10 years old; 166 men and 48 women; 90% Child-Pugh grade A and 10% Child-Pugh grade B) treated with sorafenib in our hospital from July 2009 to August 2016. The muscle volume was measured from CT images just before sorafenib administration using software (SliceOmatic). Skeletal muscle mass index was calculated, and the presence of pre-sarcopenia was judged according to the standard (42 cm2/m2 for men and 38 cm2/m2 for women) proposed by the Japan Society of Hepatology. RESULTS:Pre-sarcopenia was found in 123 patients (57%). The overall survival (OS) in patients with pre-sarcopenia tended to be worse than in patients without pre-sarcopenia (median 252 vs. 284 days, respectively; p = 0.16). Multivariate Cox hazard analysis revealed a baseline serum albumin level of ≤3.5 g/dl [hazard ratio (HR) 1.9; p = 0.0006], a baseline alpha-fetoprotein(AFP) level of ≥100 ng/ml (HR 2.1; p = 0.002), presence of lesions in bilateral hepatic lobes (HR 1.7; p = 0.03), and presence of major portal vein invasion (HR 1.8; p = 0.01) to be independent prognostic factors. In the 68 patients who had three or more negative prognostic factors, the presence of pre-sarcopenia did not correlate with prognosis. Of the 146 patients who had two or less prognostic factors, OS was significantly worse in 84 patients (58%) with pre-sarcopenia than in 62 patients without pre-sarcopenia (median 417 vs. 562 days, respectively; p = 0.047), and Cox hazard analysis revealed pre-sarcopenia to be an important prognostic factor (HR 1.6; p = 0.047). CONCLUSION:In sorafenib treatment for advanced HCC, pre-sarcopenia is a significant prognostic factor in patients with two or less negative prognostic factors, and could be the target of intervention to improve prognosis.

BACKGROUND:Tolvaptan is vasopressin type 2 receptor antagonist that inhibits water reabsorption. It is used in combination with standard diuretics to treat ascites unresponsive to standard diuretic therapy or hyponatremia because of liver cirrhosis. This study evaluated the effectiveness and safety of tolvaptan in clinical practice and aimed to determine the factors related to its effectiveness. METHODS:Tolvaptan was administered to 88 consecutive cirrhotic patients with ascites unresponsive to standard diuretic therapy. An effective treatment response was a ≥2% reduction in body weight on day 7. The association of patient pretreatment characteristics with therapeutic effects was analyzed. RESULTS:Mean weight reduction on day 7 of tolvaptan therapy was -2.9% ± 3.2%, and treatment was effective in 52% of patients. Multivariate analysis revealed that spot urine Na/K ratio ≥2.5 at baseline was the only factor independently related to therapeutic effect, with an odds ratio of 7.85 (95% confidence interval 2.64-23.40, p = 0.0002). Weight reduction percentage on day 7 was -4.0% ± 2.8% in patients with spot urine Na/K ≥2.5, which was significantly greater than the 0.7% ± 2.7% loss in those with urine Na/K < 2.5 (p < 0.05). A spot urine Na/K ratio ≥2.5 had a sensitivity of 85% and specificity of 60% for predicting effective treatment. No adverse events of treatment led to treatment discontinuation. CONCLUSIONS:Baseline spot urine Na/K was predictive of an effective response to tolvaptan therapy. It is simple to perform and readily available and might serve as an indicator of optimal timing of tolvaptan administration in patients with inadequate response to conventional Na diuretic therapy.

We aimed to clarify the characteristics of resistance-associated substitutions (RASs) after treatment failure with NS5A inhibitor, daclatasvir (DCV) in combination with NS3/4A inhibitor, asunaprevir (ASV), in patients with chronic hepatitis C virus genotype 1b infection.This is a nationwide multicenter study conducted by the Japanese Red Cross Liver Study Group. The sera were obtained from 68 patients with virological failure after 24 weeks of DCV/ASV treatment. RASs in NS5A and NS3 were determined by population sequencing.The frequency of signature RASs at position D168 of NS3 was 68%, and at positions L31 and Y93 of NS5A was 79 and 76%, respectively. The frequency of dual signature RASs in NS5A (L31-RAS and Y93-RAS) was 63%. RASs at L28, R30, P32, Q54, P58, and A92 in addition to dual signature RAS were detected in 5, 5, 1, 22, 2, and 0 patients, respectively. In total, triple, quadruple, and quintuple RASs in combination with dual signature RAS were detected in 35, 10, and 1.5% patients, respectively. These RASs were detected in patients without baseline RASs or who prematurely discontinued therapy. Co-existence of D168 RAS in NS3 and L31 and/or Y93 RAS in NS5A was observed in 62% of patients.Treatment-emergent RASs after failure with DCV/ASV combination therapy are highly complex in more than 50% of the patients. The identification of complex RAS patterns, which may indicate high levels of resistance to NS5A inhibitors, highlights the need for RAS sequencing when considering re-treatment with regimens including NS5A inhibitors.

For patients receiving endoscopic submucosal dissection (ESD), there is urgent need pertaining to the prevention of postoperative bleeding. We conducted a retrospective propensity score-matched study that evaluated whether pre-ESD gastric lavage prevents postoperative bleeding after ESD for gastric neoplasms.From September 2002 to October 2015, the 760 consecutive patients receiving ESD for gastric neoplasm were enrolled and data regarding them were retrospectively analyzed. All patients received conventional preventive treatment against delayed bleeding after ESD, including the administration of proton pump inhibitor and preventive coagulation of visible vessels, at the end of the ESD procedure.Pre-ESD risk factors for postoperative bleeding included tumor size and no gastric lavage. Using multivariate analysis tumor size >2.0 cm (HR 2.90, 95% CI 1.65-5.10, p = 0.0002) and no gastric lavage (HR 3.20, 95% CI 1.13-9.11, p = 0.029) were found to be independent risk factors. Next, we evaluated the effect of gastric lavage on the prevention of post-ESD bleeding using a propensity score-matching method. A total of 284 subjects (142 per group) were selected. Adjusted odds ratio of gastric lavage for post-ESD bleeding was 0.25 (95% CI 0.071-0.886, p = 0.032).Pretreatment gastric lavage reduced postoperative bleeding in patients receiving ESD for gastric neoplasm.

[This corrects the article DOI: 10.1371/journal.pone.0154558.].

The fibrosis stage, which is evaluated by the distribution pattern of collagen fibers, is a major predictor for the development of hepatocellular carcinoma (HCC) for patients with hepatitis C. Meanwhile, the role of elastin fibers has not yet been elucidated. The present study was conducted to determine the significance of quantifying both collagen and elastin fibers.We enrolled 189 consecutive patients with hepatitis C and advanced fibrosis. Using Elastica van Gieson-stained whole-slide images of pretreatment liver biopsies, collagen and elastin fibers were evaluated pixel by pixel (0.46 μm/pixel) using an automated computational method. Consequently, fiber amount and cumulative incidences of HCC within 3 years were analyzed.There was a significant correlation between collagen and elastin fibers, whereas variation in elastin fiber was greater than in collagen fiber. Both collagen fiber (p = 0.008) and elastin fiber (p < 0.001) were significantly correlated with F stage. In total, 30 patients developed HCC during follow-up. Patients who have higher elastin fiber (p = 0.002) in addition to higher collagen fiber (p = 0.05) showed significantly higher incidences of HCC. With regard to elastin fiber, this difference remained significant in F3 patients. Furthermore, for patients with a higher collagen fiber amount, higher elastin was a significant predictor for HCC development (p = 0.02).Computational analysis is a novel technique for quantification of fibers with the added value of conventional staging. Elastin fiber is a predictor for the development of HCC independently of collagen fiber and F stage.

The assessment of individual risk of fibrosis progression in patients with chronic hepatitis C is an unmet clinical need. Recent genome-wide association studies have highlighted several genetic alterations as predictive risk factors of rapid fibrosis progression in chronic hepatitis C. However, most of these results require verification, and whether the combined use of these genetic predictors can assess the risk of fibrosis progression remains unclear. Therefore, genetic risk factors associated with fibrosis progression were analyzed in 176 chronic hepatitis C patients who did not achieve sustained virological response by interferon-based therapy and linked to the fibrosis progression rate (FPR). FPR was determined in all patients by paired liver biopsy performed before and after therapy (mean interval: 6.2 years). Mean FPR in patients with IL28B (rs8099917) TG/GG and PNPLA3 (rs738409) CG/GG were significantly higher than in those with IL28B TT (FPR: 0.144 vs. 0.034, P < 0.001) and PNPLA3 CC (FPR: 0.10 vs. 0.018, P = 0.005), respectively. IL28B TG/GG [hazard ratio (HR): 3.9, P = 0.001] and PNPLA3 CG/GG (HR: 3.1, P = 0.04) remained independent predictors of rapid fibrosis progression upon multivariate analysis together with average alanine aminotransferase after interferon therapy ≥40 IU/l (HR: 4.2, P = 0.002). Based on these data, we developed a new clinical score predicting the risk of fibrosis progression (FPR-score). The FPR-score identified subgroups of patients with a low (FPR: 0.005), intermediate (FPR: 0.103, P < 0.001), and high (FPR: 0.197, P < 0.001) risk of fibrosis progression. In conclusion, IL28B and PNPLA3 genotypes are associated with rapid fibrosis progression, and the FPR-score identifies patients who has a high risk of fibrosis progression and require urgent antiviral treatment.

The presence of resistance-associated variants (RAVs) of hepatitis C virus (HCV) attenuates the efficacy of direct acting antivirals (DAAs). The objective of this study was to characterize the susceptibility of RAVs to interferon-based therapy.Direct and deep sequencing were performed to detect Y93H RAV in the NS5A region. Twenty nine genotype 1b patients with detectable RAV at baseline were treated by a combination of simeprevir, pegylated interferon and ribavirin. The longitudinal changes in the proportion of Y93H RAV during therapy and at breakthrough or relapse were determined.By direct sequencing, Y93H RAV became undetectable or decreased in proportion at an early time point during therapy (within 7 days) in 57% of patients with both the Y93H variant and wild type virus at baseline when HCV RNA was still detectable. By deep sequencing, the proportion of Y93H RAV against Y93 wild type was 52.7% (5.8%- 97.4%) at baseline which significantly decreased to 29.7% (0.16%- 98.3%) within 7 days of initiation of treatment (p = 0.023). The proportion of Y93H RAV was reduced in 21 of 29 cases (72.4%) and a marked reduction of more than 10% was observed in 14 cases (48.7%). HCV RNA reduction was significantly greater for Y93H RAV (-3.65±1.3 logIU/mL/day) than the Y93 wild type (-3.35±1.0 logIU/mL/day) (p

BACKGROUND: Pancreatic islet endocrine cell-supporting architectures, including islet encapsulating basement membranes (BMs), extracellular matrix (ECM), and possible cell clusters, are unclear. PROCEDURES: The architectures around islet cell clusters, including BMs, ECM, and pancreatic acinar-like cell clusters, were studied in the non-diabetic state and in the inflamed milieu of fulminant type 1 diabetes in humans. RESULT: Immunohistochemical and electron microscopy analyses demonstrated that human islet cell clusters and acinar-like cell clusters adhere directly to each other with desmosomal structures and coated-pit-like structures between the two cell clusters. The two cell-clusters are encapsulated by a continuous capsule composed of common BMs/ECM. The acinar-like cell clusters have vesicles containing regenerating (REG) Iα protein. The vesicles containing REG Iα protein are directly secreted to islet cells. In the inflamed milieu of fulminant type 1 diabetes, the acinar-like cell clusters over-expressed REG Iα protein. Islet endocrine cells, including beta-cells and non-beta cells, which were packed with the acinar-like cell clusters, show self-replication with a markedly increased number of Ki67-positive cells. CONCLUSION: The acinar-like cell clusters touching islet endocrine cells are distinct, because the cell clusters are packed with pancreatic islet clusters and surrounded by common BMs/ECM. Furthermore, the acinar-like cell clusters express REG Iα protein and secrete directly to neighboring islet endocrine cells in the non-diabetic state, and the cell clusters over-express REG Iα in the inflamed milieu of fulminant type 1 diabetes with marked self-replication of islet cells.