Cumulative risk of developing a new symptom in patients with primary biliary cholangitis and its impact on prognosis.

Background and Aim: Symptoms of primary biliary cholangitis (PBC) frequently impair one's quality of life (QOL). Nonetheless, with improved treatment, the prognosis of PBC also improves. QOL plays an important role in patients with PBC. In this study, we aimed to reevaluate the transition of new symptom development in PBC and its predictive factors. Methods: This retrospective multicenter study enrolled 382 patients with PBC for symptom analysis. The impact of a newly developed symptom on PBC prognosis was investigated by Kaplan-Meier analysis with propensity score matching and logistic progression analysis. Results: The cumulative risk of developing a new symptom after 10 and 20 years of follow-up was 7.6 and 28.2%, and specifically that of pruritus, which was the most common symptom, was 6.7 and 23.3%, respectively. In Cox hazard risk analysis, serum Alb level (hazard ratio [HR], 1.097; 95% confidence interval [CI], 1.033-1.165; P = 0.002), the serum D-Bil level (HR, 6.262; 95% CI, 2.522-15.553, P < 0.001), and Paris II criteria (HR, 0.435; 95% CI, 0.183-1.036; P = 0.037) were significant independent predictors of a new symptom. Kaplan-Meier analysis showed that the overall survival and liver-related death were not significant between patients with and without a new symptom. Conclusion: The cumulative risk of new symptom development is roughly 30% 20 years after diagnosis and could be predicted by factors including serum albumin levels, serum D-Bil level, and Paris II criteria.

Hemorrhagic Colitis Caused by Everolimus in a Patient with Nonfunctional Pancreatic Neuroendocrine Neoplasms: A Case Report.

A 60-year-old woman was diagnosed with nonfunctional pancreatic neuroendocrine neoplasm with multiple liver metastases and was administered everolimus. Due to persistent epigastric pain and diarrhea, a colonoscopy was performed on the 14th day after the start of everolimus administration, which revealed small bleeding ulcers in the ileocecal region, transverse colon, and rectum. These adverse effects were attributed to the everolimus; it was immediately discontinued, and the patient's clinical symptoms and imaging findings improved. We concurred that the administration of calcium channel blockers resulted in the inhibition of everolimus metabolism and the disease onset. The everolimus was discontinued. There was no subsequent recurrence of hemorrhagic colitis.

Clinical Differences in c-Myc Expression in Early-Stage Gastric Neoplasia: A Retrospective Study Based on the WHO Classification.

c-Myc is an oncogene that is dysregulated in various cancers. Early gastric neoplasia with c-Myc expression has been reported as a more malignant lesion. This study clarifies the differences in c-Myc expression in early gastric neoplasia based on the WHO classification. Samples from 100 patients with differentiated-type early gastric neoplasia, who underwent endoscopic submucosal dissection between March 2020 and January 2021, were stained for c-Myc. One hundred lesions were classified as low-grade dysplasia, high-grade dysplasia, or intramucosal adenocarcinoma. The staining intensity and extent were scored. A hierarchical cluster analysis for a clinicopathological analysis among the groups, the chi-square test, Bonferroni correction, and residual analysis were performed. Subgroup one and two consisted of 39 patients; while subgroup three consisted of 22. Significant differences among various characteristics were observed between these subgroups. The frequency of low-grade dysplasia was significantly higher, while that of high-grade dysplasia was significantly lower in subgroup three. The frequency of intramucosal adenocarcinoma was significantly higher in subgroup one. The c-Myc positivity rate was significantly higher in subgroup one compared with that in subgroup three. c-Myc expression distinctly differed in early gastric neoplasia. c-Myc-negative low-grade dysplasia may be separately categorized from c-Myc-positive low-grade dysplasia, high-grade dysplasia, and intramucosal adenocarcinoma.

Changes in disease characteristics of primary biliary cholangitis: An observational retrospective study from 1982 to 2016.

AIM: Disease characteristics of primary biliary cholangitis have changed recently. However, detailed studies on the subject have been limited. Therefore, we aimed to clarify disease characteristics of patients with recent primary biliary cholangitis using the cohort from Niigata University and 21 affiliated hospitals. METHODS: Overall, 508 patients were enrolled in this study from 1982 to 2016, divided into three cohorts according to their year of diagnosis: ≤1999, 2000-2009 and ≥2010. We compared differences in clinical characteristics, response to ursodeoxycholic acid and prognosis. RESULTS: The male-to-female ratio increased incrementally from 1:16.4 (≤1999) to 1:3.8 (≥2010) (P < 0.001). In women, the median age at diagnosis increased incrementally from 54.0 years (≤1999) to 60.5 years (≥2010) (P < 0.001) and serum albumin decreased gradually (P = 0.001), which might have affected the increase in the Fibrosis-4 Index and albumin-bilirubin score. The ursodeoxycholic acid response rate according to the Barcelona criteria increased incrementally from 26.7% (≤1999) to 78.4% (≥2010) (P < 0.010), and those according to other criteria (Paris-I, Rotterdam and Toronto) were approximately ≥80% in all cohorts. Ten-year survival rate in the ≤1999 and 2000-2009 cohorts were 98.6% and 95.6%, respectively. These earlier cohorts were also characterized by a higher rate of asymptomatic state and mild histology (83.5% [≤1999] and 84.7% [2000-2009], and 93.6% [≤1999] and 91.1% [2000-2009]). CONCLUSIONS: Patients with primary biliary cholangitis were characterized by older age at diagnosis and an increase in male to female ratio as well as higher response rates of ursodeoxycholic acid and longer survival, resulting from the early recognition of primary biliary cholangitis.

Factors associated with hepatocellular carcinoma occurrence after HCV eradication in patients without cirrhosis or with compensated cirrhosis.

The present study aimed to investigate the incidence of hepatocellular carcinoma (HCC) and factors related to HCC occurrence after direct-acting antiviral (DAA) treatment in the Fukushima Liver Academic Group (FLAG). We conducted a multicenter retrospective cohort study of 1068 patients without cirrhosis (NC) or with compensated liver cirrhosis (LC) who achieved a sustained virologic response (SVR). First, we compared the cumulative HCC incidence and survival rates in NC (n = 880) and LC (n = 188) patients without a history of HCC treatment. Second, we performed multivariate analysis of factors related to HCC occurrence after DAA treatment. Overall, the average age was 65 years, and the male/female ratio was 511/557. Thirty-nine (4%) patients developed HCC. The cumulative 4-year HCC incidence and survival rates were 3.0% and 99.8% in NC patients and 11.5% and 98.5% in LC patients, respectively. The independent factors affecting HCC occurrence identified by multivariate analysis were the serum albumin (ALB) level before SVR for NC patients and the ALBI score, platelet count, and diabetes before SVR for LC patients. The factors related to HCC occurrence differed between NC and LC patients. Careful surveillance of post-SVR patients with these risk factors is needed.

Ceftriaxone-associated Pseudolithiasis in the Gallbladder and Bile Duct of an Elderly Patient.

A 78-year-old man had been undergoing treatment with Cefamezin for pyogenic spondylitis. Because of complication of a urinary tract infection, the medication was switched to ceftriaxone (CTRX) 2 g/day. On day 18 after starting CTRX, the patient began experiencing abdominal pain. Computed tomography (CT) and endoscopic ultrasound led to the identification of calculi in the gallbladder and extrahepatic bile duct with a peculiar formation. We suspected CTRX-associated pseudo-cholecystolithiasis and pseudo-choledocholithiasis, although CT performed at admission had shown no such findings. Therefore, CTRX was discontinued. By day 17 after CTRX cessation, both the pseudo-cholecystolithiasis and pseudo-choledocholithiasis had disappeared.

Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C.

AIM: To evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODS: The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTS: Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSION: Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.

Idiopathic perforation of acalculous gallbladder after insertion of a transpapillary pancreatic stent.

BACKGROUND AND STUDY AIMS: Endoscopic retrograde pancreatocholangiography (ERCP) is associated with many types of adverse events (AEs) but idiopathic perforation of the gallbladder (IPGB) is very rare. Pancreatobiliary reflux is one of the factors involved with occurrence of IPGB 1. Here we present a case of acalculous gallbladder perforation as an AE following the insertion of an indwelling endoscopic nasal pancreatic drainage (ENPD) tube (a pancreatic stent) to obtain pancreatic fluid. In this case, acute pancreatobiliary reflux might have been caused by the insertion of the ENPD-tube.

Failure to achieve 2-log10 viral decrease in first four weeks of peg-IFNalpha-2b plus ribavirin therapy for chronic hepatitis C with genotype 1b and high viral titer is useful in predicting non-response: evaluation of response-guided therapy.

BACKGROUND/AIMS: To clarify clinical parameters predicting sustained viral response (SVR) during 48 weeks pegylated-interferon (peg-IFN)alpha-2b plus ribavirin therapy for Japanese patients with chronic hepatitis C [CH(C)] genotype 1b and high viral titers. METHODOLOGY: One hundred and fifty-one (151) patients receiving peg-IFNalpha-2b plus ribavirin therapy for 48 weeks were enrolled. SVR and clinical parameters were evaluated. The relationship between virological parameters (substitutions in the core and NS5A) and the degree of early viral decrease was also studied. RESULTS: Seventy (46.4%) patients achieved SVR (per protocol analysis). Negative predictive value (NPV) of <2-log10 decrease after 4 weeks of therapy for SVR was 78.0%; similar to that for failing to achieve early viral response (EVR) at 12 weeks (82.2%). CONCLUSIONS: Failure to achieve 2- log10 decrease in the first 4 weeks may be an important predictor of non-SVR during 48 weeks of peg-IFNalpha-2b plus ribavirin therapy; thus, therapeutic plans should be reassessed at that point.

Characterization of elevated alanine aminotransferase levels during pegylated-interferon α-2b plus ribavirin treatment for chronic hepatitis C.

AIM: Elevation of alanine aminotransferase (ALT) levels during pegylated-interferon (peg-IFN) plus ribavirin therapy in patients with chronic hepatitis C [CHC] is a problem that cannot be disregarded. The aim of this study is to assess the frequency and to characterize clinical parameters of this phenomenon. METHODS: Two hundred and thirty-five (235) CHC patients with genotype 1b receiving peg-IFN α-2b plus ribavirin therapy were analyzed. Clinical parameters that may be associated with abnormal ALT values during treatment and therapy outcomes were evaluated statistically. One hundred and sixteen (116) patients treated with peg-IFN α-2a plus ribavirin were also included for partial analysis. RESULTS: Abnormal ALT values during treatment were observed in 23.0% of patients. It was observed in 14.5% of those with sustained virological response (SVR) and 17.8% of those with relapse, in whom viral clearance was observed during therapy. Multivariate logistic regression analysis revealed that pretreatment ALT values, therapy outcome, and body mass index (BMI) were significant factors related to abnormal ALT values during treatment. Abnormal ALT values during treatment became normal in SVR patients at 6 months after the completion of treatment, but not in NR (non-response) patients. Mean ALT values were significantly higher at some time points during treatment in patients treated with α-2a when compared to those treated with α-2b. CONCLUSION: Abnormal ALT values during peg-IFN plus ribavirin treatment are observed relatively frequently, even in patients without detectable HCV RNA. Direct or indirect involvement of drugs is considered as one possible cause.

Successful treatment with lamivudine may correlate with reduction of serum ferritin levels in the patients with chronic hepatitis and liver cirrhosis type B.

PURPOSE: To study the changes in serum ferritin levels in lamivudine (LAM)-treated patients with chronic hepatitis and liver cirrhosis type B and determine whether successful treatment with LAM results in a reduction of serum ferritin levels. METHODS: Thirty patients with chronic hepatitis B virus (HBV) infection were followed prospectively during their treatment with LAM for 12 months. Serum HBV DNA, ferritin levels, and emergence of YMDD mutants were monitored. A case of severe liver cirrhosis with hepatic hemosiderosis that was treated successfully with LAM also is shown as a representative case. RESULTS: Serum alanine aminotransferase and ferritin levels decreased significantly more in the patients treated with LAM without YMDD mutants (n = 23) than those with mutants (n = 7). Hepatic hemosiderosis along with serum iron markers improved greatly in the representative patient. CONCLUSION: Successful treatment with LAM may reduce serum ferritin levels and improve hepatic siderosis in a subset of patients with chronic HBV infection.

Absence of pretreatment markers that predict the emergence of YMDD mutants during lamivudine treatment--the results of a prospective multi-center study.

BACKGROUND/AIMS: The emergence of YMDD mutants in patients who are treated with lamivudine may determine the clinical prognosis. However, currently there are no clinical or virological factors that predict specifically the emergence of the mutants. METHODOLOGY: To define these factors, we analyzed 69 patients with chronic hepatitis B infection who were treated with lamivudine (LAM) and followed prospectively for at least 12 months. RESULTS: Of the 69 patients, 12 (17.4%) developed YMDD mutants up to 12 months after the start of LAM. The incidence of YMDD mutants was slightly higher in those who were younger, had higher HBV DNA titers, lower ALT levels, genotype C, and mutations in the core promoter before treatment. However, we could not find any significant factors that correlated with the appearance of the mutants. CONCLUSIONS: Currently, using conventional virological assays, it is difficult to predict the development of mutants before LAM treatment. Management of flare-ups of hepatitis, due to the appearance of mutants, should always be envisaged when LAM treatment is started.

What is an appropriate indication for endoscopic papillary balloon dilation?

OBJECTIVE: There are a number of views on the indication for endoscopic papillary balloon dilation (EPBD) in the management of bile duct stones. In this study, we have evaluated the efficacy and safety of EPBD compared with endoscopic sphincterotomy (EST). DESIGN: Prospective randomized trial. SETTING: One university hospital and one general hospital. PARTICIPANTS AND MAIN OUTCOME MEASURES: One hundred and forty patients were randomly allocated to EPBD or EST. Outcomes and complications were observed for a median period of 30 months. RESULTS: Both treatment approaches finally achieved similar success rates and needed similar numbers of treatment sessions for patients with stones less than 10 mm in diameter. However, for patients with stones of 10 mm or more, EPBD required a significantly greater mean number of treatment sessions than EST (2.4 vs 1.6, P < 0.01). Early complications occurred in seven EPBD (four pancreatitis, two cholangitis and one basket impaction) and eight EST (three pancreatitis, two bleeding and three cholangitis) patients. Late complications occurred in four EPBD (three recurrent bile duct stones and one cholecystitis) and six EST (three recurrent stones and three cholecystitis) patients. CONCLUSIONS: EPBD has little risk of bleeding. The technique removed small bile duct stones just as easily as did EST. These two procedures had approximately the same risk of pancreatitis and incidence of recurrent bile duct stones. Therefore, both procedures appear to be appropriate treatments for small bile duct stones. Whether or not EPBD becomes an established treatment will depend on further long-term studies.