United European Gastroenterology Journal

Probiotics are commonly used for the prevention of antibiotic-associated diarrhea (AAD). However, the optimum regimen remains controversial.

The objective of this article is to compare and rank the relative efficacy and tolerability among all available probiotic agents for AAD through a network meta-analysis.

Eligible studies were identified by searching PubMed, Embase, Medline, Cochrane library and Web of Science for randomized controlled trials (RCTs) that examined the efficacy of probiotic therapy for AAD. A random-effects model was applied within a frequentist framework. Quality of evidence was performed by the GRADE approach. The project was prospectively registered with PROSPERO (CRD 42016050776).

Fifty-one articles (60 comparisons, 9569 participants), including 10 probiotic interventions, were identified. Lactobacillus rhamnosus GG (LGG) had the highest probability of being ranked best both in effectiveness (odds ratio (OR), 95% confidence interval (CI) = 0.28 (0.17, 0.47)) and tolerance (0.44 (0.23, 0.84)) on prevention of AAD. With regard to reducing Clostridium difficile infection rate, Lactobacillus casei (L. casei) was considered better efficacy (0.04 (0.00, 0.77)) and medium tolerance (0.56 (0.19, 1.66)). Strain combination reported no superiority over single strain in either efficacy or tolerability.

LGG is probably the best option to consider when AAD is indicated. L. casei appears to be the most efficacious choice when associated with severe C. difficile-related cases.

Citrulline has been described as a marker of intestinal function or absorption but evidence varies according to clinical settings.

The objective of this article is to examine the evidence of plasma citrulline as a marker of intestinal function and absorption in various clinical settings.

Studies were examined for p values, means and standard deviations, correlation coefficients or other metrics depicting the association of citrulline with intestinal function. A random effects model was used to produce a pooled estimate. A hierarchical summary receiver operating curve model was fitted for diagnostic accuracy measures.

Citrulline levels are correlated strongly with small bowel length in short bowel syndrome patients (r = 0.67). Citrulline is strongly negatively correlated (r = –0.56) with intestinal disease severity with regards to enteropathies (coeliac disease, tropical enteropathy, Crohn’s disease, mucositis, acute rejection in intestinal transplantation). Citrulline cut-off levels have an overall sensitivity and specificity of 80% and 84% respectively. Citrulline levels in untreated coeliac patients compared to controls were reduced by 10 µmol/l. Citrulline levels increase with gluten-free diet and with improvement of enteropathy. Citrulline is decreased in critical illness and sepsis.

These findings allow us to advocate quite reasonably that citrulline is a marker of acute and chronic intestinal insufficiency.

Endoscopic screening for gastric cancer is debatable in countries with an intermediate risk.

The objective of this article is to determine the cost-utility of screening strategies for gastric cancer in a European country.

We conducted a cost-utility analysis using a Markov model comparing three screening strategies versus no screening: stand-alone upper endoscopy, endoscopy combined with a colorectal cancer screening colonoscopy after a positive faecal occult blood test or pepsinogens serologic screening. Clinical data were collected from systematic reviews, costs from published national data and utilities as quality-adjusted life years (QALY). The primary outcome was the incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were performed. The threshold was set at €37,000 (2016 prices).

Upper endoscopy combined with screening colonoscopy (every 10 or 5 years) had an ICER of 15,407/QALY and €30,908/QALY respectively, stand-alone endoscopic screening (every five years) an ICER of €70,693/QALY and pepsinogens screening an ICER of €143,344/QALY. Sensitivity analyses revealed that only endoscopic costs <€75, a provision of only three endoscopies per patient or a gastric cancer risk >25/100,000 would make stand-alone endoscopic screening cost-effective.

Endoscopic gastric cancer screening in Europe can be cost-effective if combined with a screening colonoscopy in countries with a gastric cancer risk ≥10 per 100,000.

Endoscopic submucosal dissection (ESD) allows “en bloc” resection of superficial gastric lesions.

The aim of this study is to report “en bloc" resection rate, procedure results, post resection features, analysis of complications, and relapses at mid–long term follow-up on an Italian center case series of patients with superficial gastric neoplastic lesions treated with ESD.

This is a retrospective evaluation of a prospectively collected series of patients diagnosed with gastric superficial lesions who underwent ESD between November 2007 and May 2015. The analysis included demographic, clinical, endoscopic, and histological data. In detail, the following features were analyzed: (1) “en bloc” resection rate; (2) R0, R1, and RX rate; (3) complication rate; and (4) neoplastic recurrence during follow-up. A comparison was performed between lesions treated according to standard and to extended criteria.

In the analysis, therefore, 70 superficial lesions and 70 endoscopic procedures were considered.

Overall, 53 (76%) procedures were performed according to the extended-ESD criteria. The remaining 17 (24%) cases were performed according to standard criteria. In 68/70 (97%) procedures “en bloc” resection was successful. Forty-four (65.6%) patients had a R0 resection, while 15 (22%) patients had a R1 and the remaining 8 (12.4%) patients were RX. Two patients (2.8%) experienced a major complication. Overall, 7 patients (10.4%) required surgery: in two cases because of local recurrence, in one case for an intraprocedural complication not amenable to endoscopic treatment, in three patients with R1 vertical margins, and in the last patient because of an aggressive pathology (i.e. signet ring cell adenocarcinoma). The mean follow-up of patients with neoplastic lesions was 36.6 ± 13.1 months.

ESD for early gastric cancer is a safe and effective technique when performed by experienced Endoscopists also in Western setting. When comparing the outcomes of the ESD in patients with standard and extended indication there is no significant difference in terms of complete resection, complications and local recurrence rates. Larger Western studies are needed to clearly define the role and the outcomes of ESD in regions at low incidence for gastric neoplasia.

In pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%.

The objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study.

The German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician.

A total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24–1.43); p < 0.001), negatively associated with presence of liver cirrhosis (OR 0.71 (0.56–0.89); p < 0.003) and positively associated with female gender (OR 1.52 (1.21–1.91); p < 0.001).

Data from this real-world registry show SVR12 rates close to those obtained in clinical studies. Discontinuation rates are low, confirming good tolerance of the regimens and good adherence of patients (Trial registration number DRKS00009717, German Clinical Trials Register, DRKS).

Direct antiviral agents (DAAs) have led to high sustained virological responses (SVR) in hepatitis C virus (HCV) patients. However, genotype 3 patients respond to treatment in a suboptimal way. This study aims to identify which of the several treatment schedules recommended for genotype 3 would constitute the best option.

Twenty-four Italian centers were involved in this real-life study of HCV genotype 3 patients treated with DAAs. To expand the number of cases, we conducted a systematic review of the literature on the outcome of genotype 3 patients treated with DAAs.

A total of 233 patients with HCV genotype 3 were enrolled. Cirrhotic patients accounted for 83.7%. Overall, the SVR12 rate was achieved by 205 patients (88.0%); the SVR rates were 78.8% after sofosbuvir/ribavirin, 92.5% after sofosbuvir/daclatasvir ± ribavirin, and 100% after sofosbuvir/ledipasvir (seven patients). No difference in rate of SVR was observed in cirrhotic and non-cirrhotic patients (92.2 vs 94.4) using a combination regimen of NS5A and NS5B inhibitors.

The systematic review of the literature provided data of 3311 patients: The mean weighted SVR12 rate was 84.4% (CI: 80.4–87.8); the rates varied from 79.0% (CI: 70.9–85.3) with sofosbuvir/ribavirin, to 83.7% (CI: 66.2–93.1) with sofosbuvir/ledispavir, and to 88.2% (CI: 83.3–91.7) with sofosbuvir/daclatasvir.

Our results reinforce the concept that patients with HCV genotype 3 should no longer be considered difficult-to-treat individuals. The optimal therapeutic regimen for these patients appears to be the combination sofosbuvir/daclatasvir, administered for 12 weeks without the use of RBV in non-cirrhotic patients. In cirrhotics the meta-analytic approach suggests extending therapy to 24 weeks.

Sorafenib is the recommended treatment for advanced hepatocellular carcinoma (HCC), but transarterial chemoembolization (TACE) is performed in individual cases with limited extrahepatic spread. The aim of this study was to compare the outcome of patients with HCC and extrahepatic disease (EHD) treated with sorafenib and TACE.

A total of 172 patients with HCC and EHD treated with sorafenib (n = 98) or TACE (n = 74) at three German referral centers (Hannover, Mainz and Hamburg) were included in this study. In order to reduce selection bias, patients were matched for significant demographic differences using a propensity score analysis.

Patients with liver cirrhosis, higher extrahepatic tumor burden and/or infiltration of adjacent organs/structures were significantly more often treated with sorafenib. Median overall survival (OS) was similar for sorafenib- and TACE-treated patients (7 versus 8 months, p = 0.312). In a propensity score analysis matched for demographic differences, median OS remained similar with 4 versus 8 months for sorafenib versus TACE (p = 0.613).

Treatment with TACE is not inferior to treatment with sorafenib in patients with limited EHD of HCC. TACE represents an effective therapeutic option in selected patients with EHD.

Several years ago the International Autoimmune Hepatitis Group simplified the previous revised original scoring system for diagnosis of autoimmune hepatitis (AIH) into a scoring system based on only four instead of 13 parameters.

We aimed to evaluate the suitability of the simplified AIH score for diagnosis of AIH in a German cohort with chronic liver diseases.

In this retrospective single-center study, we compared the accuracy of both AIH scores in 70 patients with AIH and 211 patients with chronic liver diseases (PBC (n = 52), PSC (n = 27), NASH (n = 67), DILI (n = 15), CHB/C (n = 50)). Sensitivity, specificity and predictability of each scoring system were calculated.

Using the simplified AIH score, the sensitivity and specificity of detecting a probable AIH (scores ≥ 6) were 96% and 97% with a positive and negative predictive value of 92% and 99%, respectively. For diagnosis of definite AIH (scores ≥ 7), the sensitivity and specificity were 43% and 100% with a positive and negative predictive value of 97% and 84%, respectively. The concordance with the revised original criteria was 63%. The specificity for excluding AIH was excellent in both scoring system.

The simplified diagnostic criteria allow a reliable diagnosis of AIH in a German cohort.

The median age of diagnosis of primary sclerosing cholangitis (PSC) is ∼30–40 years.

We aimed to analyse disease progression and liver-dependent survival in patients diagnosed with PSC after 50 years of age.

Patients with PSC were analysed with regard to their age at diagnosis. Patients with a first diagnosis of PSC after the age of 50 years were considered as the late-onset group.

A total of 32/215 (14.9%) patients were diagnosed with PSC after 50 years of age. The proportion of females was significantly higher among patients with late-onset PSC (48.4 vs. 27.3%; p = 0.02). Patients with later diagnosis required dilatation therapy more often due to dominant stenosis (84.2 vs. 53.1%; p = 0.01) and suffered from recurrent cholangitis more often (48.3 vs. 21.0%; p = 0.003). Patients with late-onset PSC had reduced transplantation-free survival (10.5 ± 0.6 years vs. 20.8 ± 1.7 years, p < 0.0001), with progredient liver failure and cholangiocarcinoma as the leading causes of death.

Patients with later age at diagnosis of PSC displayed a different clinical phenotype with a different sex ratio, immune status and an increased risk for progressive liver failure and biliary malignancies.

Perihilar cholangiocarcinomas are often considered incurable. Late diagnosis is common. Advanced disease therefore frequently causes questioning of curative surgical outcome.

This study aimed to develop a prediction model of curative surgery in patients suffering from perihilar cholangiocarcinomas based on preoperative endosonography and computer tomography.

A cohort of 81 patients (median age 67 (54–75) years, 62% male) with perihilar cholangiocarcinoma was retrospectively analyzed. Multivariate logistic regression analysis of staging variables taken from the European Staging System was performed and applied to ROC analysis.

The correlation of predicted rates of eligibility for surgery with actual rates reached AUC values between 0.652 and 0.758 for endosonography and computer tomography (p < 0.05 each). Best prediction for curative surgical option was achieved by combining endosonography and computer tomography (AUC: 0.787; 95% CI 0.680–0.893, p < 0.0001). A predictive model (pSurg) was developed using multivariate analysis.

Our predictive web-based model pSurg with inclusion of T, N, M, B, PV, HA and V stage of the recently published European Staging System for perihilar cholangiocarcinoma results in highly significant predictability for curative surgery when combining preoperative endosonography and computer tomography, thus allowing for better patient selection in terms of possibility of curative surgery.

Altered immune homeostasis and involvement of T cells has been reported in chronic pancreatitis (CP). We evaluated the role of Bach2 (BTB and CNC homology basic leucine zipper transcription factor 2), a key regulator of immune homeostasis in the chronicity of CP.

Expression of Bach2 and T-cell transcription factors, enumeration of BACH2+/CD4+ T-lymphocytes were performed by qRT-PCR and flow cytometry respectively. Bach2silenced human CD4+ T-lymphocytes were exposed to CP tissue extract to assess T-cell lineage commitment. Aryl hydrocarbon receptor (Ahr) and Deubiquitinase enzyme A (DUBA/OTUD5gene) were evaluated as markers of persistent Th17 cell differentiation. Bach2 gene (exons) was sequenced to identify risk variants and functionally validated.

Decrease in Bach2 (p < 0.0001) and increase (p < 0.001) in TBX21, RORC, Ahr, PRDM1, IL23R mRNA were noted in pancreatic tissues, while BACH2+/CD4+ T-lymphocytes were decreased (p < 0.01) in circulation and tissues. Exposure of Bach2 silenced CD4+ T-lymphocytes to CP tissue extract showed increased Ahr, decreased OTUD5, and enhanced Th17 cell differentiation. Sequencing of Bach2 gene revealed association of novel variant (rs9111 in 5′-UTR) with advanced disease and luciferase assay confirmed its role in Bach2 repression.

Bach2 repression mediates Th17 cell induced inflammation and rs9111-TT in individuals with primary genetic susceptibility to CP is associated with clinical features of advanced disease.

A split-dose (SD) regimen is crucial for colonoscopy quality. Compliance with SD for early morning colonoscopy is generally poor. The present study evaluated whether pre-colonoscopy counselling, in addition to a dedicated leaflet, might increase SD uptake.

Consecutive 50–69-year-old patients undergoing screening colonoscopy before 10 a.m. were randomized to either receive written information only on bowel preparation (Written Group, WG) or written and oral instructions (Written and Oral Group, WaOG). The leaflet strongly encouraged SD adoption. The primary endpoint was the number of patients adopting SD in each group. The secondary endpoints were predictors of SD uptake, compliance with preparation schemes and cleansing adequacy.

A total of 286 patients (143 WG, 143 WaOG) were enrolled (mean age 59.6 ± 6.1 years, men 49.3%). SD was adopted by 114 and 125 patients in the WG and WaOG, respectively (79.7% versus 87.4%, p = 0.079). No significant differences were observed for the proportion of patients with full compliance with preparation scheme (97.9% versus 97.2%, p = 0.99) and of procedures with adequate bowel cleansing (95.6% versus 95.1%, p = 0.77). At multivariate analysis, a > 1 h travel time to the endoscopy service was inversely correlated with SD uptake (odds ratio (OR) 0.30, 95% confidence interval (CI) 0.09–0.98).

Our leaflet guaranteed satisfactory uptake of SD and excellent adherence to the preparation scheme for early morning colonoscopy. Its use might marginalize the need for additional oral instructions, particularly in open-access settings.

Current surveillance strategies for colorectal cancer following polypectomy are determined by endoscopic and histopathological factors. Such a distinction has been challenged. The present study was designed to identify molecular parameters in colonic polyps potentially defining new sub-groups at risk.

One hundred patients were enrolled in this multicentre study. Polyps biopsies underwent formalin-free processing (PAXgene, PreAnalytiX) and targeted next generation sequencing (38 genes (QIAGEN), NextSeq 500 platform (Illumina)). Genetic and histopathological analyses were done blinded to other data.

In 100 patients, 224 polyps were removed. Significant associations of genetic alterations with endoscopic or histological polyp characteristics were observed for BRAF, KRAS, TCF7L2, FBXW7 and CTNNB1 mutations. Multivariate analysis revealed that polyps ≥ 10 mm have a significant higher relative risk for harbouring oncogene mutations (relative risk 3.467 (1.742–6.933)). Adenomas and right-sided polyps are independent risk factors for CTNNB1 mutations (relative risk 18.559 (2.371–145.245) and 12.987 (1.637–100.00)).

Assessment of the mutational landscape of polyps can be integrated in the workflow of current colonoscopy practice. There are distinct genetic patterns related to polyp size and location. These results suffice to optimise individual risk calculation and may help to better define surveillance intervals.

Psychological states may interfere with visceral sensitivity. Here we investigate associations between psychosocial factors and visceral sensitivity in irritable bowel syndrome (IBS).

Two IBS patient cohorts (Cohort 1: n = 231, Rome II; Cohort 2: n = 141, Rome III) underwent rectal barostat testing, and completed questionnaires for anxiety, depression, somatization, and abuse. The associations between questionnaire measures and visceral sensitivity parameters were analyzed in three-step general linear models (step1: demographic and abuse variables; step 2: anxiety and depression; step 3: somatization).

Cohort 1. Pain threshold was positively associated with age and female gender, and negatively with adult sexual abuse and somatization. Pain referral area was negatively associated with age and positively with somatization and GI-specific anxiety, the latter effect mediated by somatization. Cohort 2. Pain threshold was positively associated with age and male gender, and negatively with adult sexual abuse. Pain intensity ratings were positively associated with somatization, female gender and depression, the latter effect mediated by somatization.

Somatization is associated with most visceral sensitivity parameters, and mediates the effect of some psychological factors on visceral sensitivity. It may reflect a psychobiological sensitization process driving symptom generation in IBS. In addition, abuse history was found to independently affect some visceral sensitivity parameters.

In clinical practice, treatment sequences of biologicals are applied for active fistulising Crohn’s disease, however underlying health economic analyses are lacking.

The purpose of this study was to analyse the cost-effectiveness of different biological sequences including infliximab, biosimilar-infliximab, adalimumab and vedolizumab in nine European countries.

A Markov model was developed to compare treatment sequences of one, two and three biologicals from the payer’s perspective on a five-year time horizon. Data on effectiveness and health state utilities were obtained from the literature. Country-specific costs were considered. Calculations were performed with both official list prices and estimated real prices of biologicals.

Biosimilar-infliximab is the most cost-effective treatment against standard care across the countries (with list prices: €34684–€72551/quality adjusted life year; with estimated real prices: €24364–€56086/quality adjusted life year). The most cost-effective two-agent sequence, except for Germany, is the biosimilar-infliximab–adalimumab therapy compared with single biosimilar-infliximab (with list prices: €58533–€133831/quality adjusted life year; with estimated prices: €45513–€105875/quality adjusted life year). The cost-effectiveness of the biosimilar-infliximab–adalimumab–vedolizumab three-agent sequence compared wit biosimilar-infliximab –adalimumab is €87214–€152901/quality adjusted life year.

The suggested first-choice biological treatment is biosimilar-infliximab. In case of treatment failure, switching to adalimumab then to vedolizumab provides meaningful additional health gains but at increased costs. Inter-country differences in cost-effectiveness are remarkable due to significant differences in costs.

Patients with ulcerative colitis (UC) have an increased risk of colorectal cancer. Scarce data regarding the development of adenomas in these patients are available both for normal and colitic mucosa.

The objective of this article is to evaluate the prevalence of adenomatous polyps and associated risk factors in patients with UC.

Patients with UC were identified from the databases of two tertiary referral centers. Medical, endoscopic and histologic reports were reviewed.

A total of 403 patients were included (53% male; 33% extensive colitis) and 1065 colonoscopies (median per patient, 2) were recorded and analyzed. Seventy-four adenomas in 47 patients (11.7%) and three cases of colorectal cancer were found during a median follow-up of 6.3 years. The cumulative risk of colorectal adenoma was 4.7%, 16.7%, 23.6% and 34.4% at 10, 20, 30 and 40 years from UC diagnosis, respectively. The cumulative risk of developing metachronous colorectal adenoma was 66.7%, 87.9%, and 90.9% at 5, 10, and 15 years from first adenoma detection. Older age at UC diagnosis and longer disease duration were independent risk factors for colorectal adenoma development.

The prevalence of colorectal adenomas among UC patients seems to be higher than previously reported, although lower than in the background population.