We analyzed the transcriptomes and genetic regulatory profiles of gastric corpus and for the first time also of antrum mucosa in 431 healthy individuals. Through tissue-specific gene expression and eQTL analyses, we uncovered unique and common physiological processes across both primary gastric sites. Notably, our findings reveal that stomach-specific eQTLs are enriched in loci associated with metabolic traits and diseases, highlighting the pivotal role of gene expression regulation in gastric physiology and potential pathophysiology.

BACKGROUND:Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.METHODS:We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.FINDINGS:Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.INTERPRETATION:Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.FUNDING:German Research Foundation (DFG).

ABSTRACT Background & Aims Non‐selective β‐blockers (NSBBs) and endoscopic variceal‐ligation (EVL) have similar efficacy preventing first variceal bleeding. Compensated and decompensated cirrhosis are markedly different stages, which may impact treatment outcomes. We aimed to assess the efficacy of NSBBs vs EVL on survival in patients with high‐risk varices without previous bleeding, stratifying risk according to compensated/decompensated stage of cirrhosis. Methods By systematic review, we identified RCTs comparing NSBBs vs EVL, in monotherapy or combined, for primary bleeding prevention. We performed a competing‐risk, time‐to‐event meta‐analysis, using individual patient data (IPD) obtained from principal investigators of RCTs. Analyses were stratified according to previous decompensation of cirrhosis. Results Of 25 RCTs eligible, 14 failed to provide IPD and 11 were included, comprising 1400 patients (656 compensated, 744 decompensated), treated with NSBBs ( N = 625), EVL ( N = 546) or NSBB+EVL ( N = 229). Baseline characteristics were similar between groups. Overall, mortality risk was similar with EVL vs. NSBBs (subdistribution hazard‐ratio (sHR) = 1.05, 95% CI = 0.75–1.49) and with EVL + NSBBs vs either monotherapy, with low heterogeneity ( I 2 = 28.7%). In compensated patients, mortality risk was higher with EVL vs NSBBs (sHR = 1.76, 95% CI = 1.11–2.77) and not significantly lower with NSBBs+EVL vs NSBBs, without heterogeneity ( I 2 = 0%). In decompensated patients, mortality risk was similar with EVL vs. NSBBs and with NSBBs+EVL vs. either monotherapy. Conclusions In patients with compensated cirrhosis and high‐risk varices on primary prophylaxis, NSBBs significantly improved survival vs EVL, with no additional benefit noted adding EVL to NSBBs. In decompensated patients, survival was similar with both therapies. The study suggests that NSBBs are preferable when advising preventive therapy in compensated patients.

Summary: Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett’s oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

Background and aims Adenoma detection rate (ADR) in colon cancer screening is most important for cancer prophylaxis. This work is the first three-armed randomised controlled clinical trial aimed at comparing a head-to-head setting standard colonoscopy (SC) with Endocuff-assisted colonoscopy (EC) and cap-assisted colonoscopy (CAC) for improvement of ADR. Methods Patients from Poland and Germany with independent indication for colonoscopy were randomised into three arms of this trial: EC, CAC and SC. Exclusion criteria were age <18 years, active Crohn's disease or ulcerative colitis, known stenosis and post-colonic resection status. Results A total of 585 patients (195 SC, 189 EC and 186 CAC) were enrolled in this study. Indications were not different between the groups (colorectal cancer screening 51%, diagnostic colonoscopy in 31% and post-polypectomy follow-up in 18%; p = 0.94). Withdrawal time was a mean of 7 min in all groups (p = 0.658), and bowel preparation did not differ between the groups. The time to reach the caecum was significantly reduced when using the cap (a mean of 6 min for CAC vs. 7 min for SC; p = 0.0001). There was no significant difference in the primary outcome of the ADR between the groups (EC 32%, CAC 30%, SC 30%; p = 0.815). EC proved to be superior (EC vs. SC) in the sigmoid colon and transverse colon for polyp detection. Conclusion The use of EC increased the total number of polyps seen during colonoscopy. In contrast to recent studies, no significant improvement of the ADR was detected.

ZusammenfassungDie Leitlinie Komplikationen der Leberzirrhose der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) ersetzt die Leitlinie aus dem Jahr 2011. Sie basiert auf den Empfehlungen der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF) für eine evidenzbasierte Konsensus-Leitlinie der Entwicklungsstufe S2k und wurde interdisziplinär unter Beteiligung aller relevanten Fachgesellschaften und der Patientenvertretung erstellt. Neben den in der Vorgängerversion behandelten Kapiteln Aszites, spontan bakterielle Peritonitis, hepatorenales Syndrom, hepatischer Hydrothorax und hepatopulmonales Syndrom wurden die Kapitel Diagnostik und Therapie der Hepatischen Enzephalopathie neu aufgenommen.

Adenoma detection rate (ADR) in colon cancer screening is most important for cancer prophylaxis. Recent studies suggest a benefit of endoscopic devices attached to the distal tip of the colonoscope for improving the ADR. This work is the first three arm randomized controlled trial comparing standard colonoscopy with Endocuff and Cap. 569 patients from Poland and Germany were randomized into three arms of this study: Endocuff assisted (EC), Cap assisted (CC) and Standard colonoscopy (SC). Indications for colonoscopy were screening, diagnostic colonoscopy and post interventional care. The examiners had at least an experience of 3000 colonoscopies as professional gastroenterologists. Exclusion criteria were age under 18, active morbus Crohn or ulcerative colitis, known stenosis and status post colonic resection. The study was as approved by the local Ethics committee. Registered Clinical trials number NCT02331836. Among the groups, no significant differences were seen according to age, gender distribution, withdrawal time (mean SC 7.52 min, EC 8.13 min, CA 7.46 min, p= 0.658) and bowel preparation (p=0.15). The time to reach the coecum was significantly reduced when using the Cap (mean CC 6.34 min vs. SC 8.39 min, p= 0.0001). Neoplastic polyp detection did not differ between the arms (p=0.95). In SC, polyp detection rate (PDR) was 48%, ADR was 31.2%, in EC, PDR was 4.4%, ADR was 29.3% and in CA PDR was 51.6% and ADR was 28%. No significant differences were seen in all three arms. However, regarding to the mean number of polyps detected, the EC proofed superior to SC and CA (mean SC 2 polyps vs. EC polyps 2.45, p= 0.009). The use of EC increased the total number of polyps seen during colonoscopy. The use of a Cap significantly reduced the examination time without losing screening quality. In contrast to recent studies, no significant improvement of the ADR was detected.

Background: Altered liver function tests are a common finding in clinical practice. Our retrospective study aimed to identify the diagnoses in a non-selected cohort of patients with altered liver tests and to investigate whether alpha-1 antitrypsin genotyping should be part of the diagnostic workup.Patients and Methods: 501 patients who were admitted to our outpatient clinic for further evaluation of altered liver function tests were included in the study. The patients underwent a standardized diagnostic program with history taking, physical examination, laboratory tests and ultrasonography. Liver biopsy was performed if appropriate.Results: More than 50% of the patients had nonalcoholic fatty liver disease. Alcoholic and drug-induced liver injury were found in 8.6% and 7% of patients, respectively. Chronic hepatitis B and C, autoimmune liver disease and inherited causes of liver disease made up for approximately 16% of the diagnoses. The remaining patients were diagnosed with kryptogenic liver disease or had miscellaneous diagnoses. In 3.7% of the genotyped patients, the alpha-1 antitrypsin genotype PiMZ was found.Conclusion: Nonalcoholic fatty liver disease is nowadays the most frequent cause of altered liver tests. Alcoholic liver disease might be underrepresented in our study since these patients less often seek medical attention or the diagnosis is already made by the primary care physician. Drug-induced liver injury was found in more patients than expected and might therefore be underdiagnosed in practice. The alpha-1 antitrypsin genotype PiMZ was found in absence of other possible causes of liver disease, indicating that the PiMZ genotype is itself a risk factor for liver disease. Genotyping for alpha-1 antitrypsin should therefore be done when other causes for altered liver function tests have been ruled out.

BACKGROUND & AIMSPatients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis.METHODSWe performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures.RESULTSA significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups.CONCLUSIONSPlacement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

GOALS AND BACKGROUND:Screening colonoscopy for colorectal cancer has proven to reduce mortality rates. Recently the Endocuff (EC), an attachment to the distal tip of the colonoscope, was introduced. The aim of our study was to compare EC-assisted colonoscopies with standard colonoscopies for the detection of colonic polyps.STUDY:This study is a randomized prospective 2-center trial. The study was conducted at 2 tertiary care centers.PARTICIPANTS:A total of 498 patients [249 males; median age 67 y; interquartile range (IQR), 56-75 y] for colon adenoma screening purposes were included. All patients underwent standard colonoscopy with or without the use of EC. Overall polyp detection rate, the number of colonic polyps, and the polyp distribution in the colon were measured. Difference in recognition of polyps with or without the use of EC was assessed. Statistical analysis was applied.RESULTS:In the EC group, the number of polyps detected per patient was 63% higher [2.00 (IQR, 1.00-4.00) vs. 1.00 (IQR, 1.00-2.25), P<0.0001]. The polyp detection rate in patients increased by 14% with the use of EC (56% vs. 42%, P=0.001). For polyp detection, superiority by use of EC could be observed in the sigmoid (P=0.001) and cecum (P=0.002) for polyps <1 cm in diameter. In the EC group, the number of adenomas detected per patient significantly increased by 86% (P=0.002). No major complications occurred in both groups.CONCLUSIONS:The use of the EC is feasible and safe with significantly higher polyp detection rates, especially for those located in the sigmoid region. The cuff system has the potential to improve the accuracy of screening colonoscopies.

Hintergrund/Einleitung: Der Rho-Kinase Signalweg ist wichtig zur intrazelluären Kalziumsensibilisierung bei der Konstriktion glatter Gefäßmuskelzellen. Der spezifische Rho-Kinase Inhibitor Y-27632 wird in Tiermodellen als antihypertensive Substanz eingesetzt (Circ Res 2003;92:411) und hat intrahepatisch antifibrogenetische Eigenschaften (J Hepatol 2001;35:474).

Einleitung: Patienten mit unbehandelten Ösophagusvarizen bei Leberzirrhose haben innerhalb von 2 Jahren nach Diagnose ein Blutungsrisiko von etwa 40%, das durch die Gabe von Propranolol (P), nicht jedoch durch eine Sklerosierungstherapie, etwa halbiert wird. Es wurde spekuliert, dass die endoskopische Ligatur (L) gleich effektiv oder noch effektiver als P sein könnte. Dies prüften wir in einer randomisierten Studie.

Objectives The Endocuff is a device mounted on the tip of the colonoscope to help flatten the colonic folds during withdrawal. This study aimed to compare the adenoma detection rates between Endocuff-assisted (EC) colonoscopy and standard colonoscopy (SC). Methods This randomized prospective multicenter trial was conducted at four academic endoscopy units in Germany. Participants: 500 patients (235 males, median age 64[IQR 54–73]) for colon adenoma detection purposes were included in the study. All patients were either allocated to EC or SC. The primary outcome measure was the determination of the adenoma detection rates (ADR). Results The ADR significantly increased with the use of the Endocuff compared to standard colonoscopy (35.4%[95% confidence interval{CI} 29–41%] vs. 20.7%[95%CI 15–26%], p<0.0001). Significantly more sessile polyps were detected by EC. Overall procedure time and withdrawal time did not differ. Caecal and ileum intubation rates were similar. No major adverse events occurred in both groups. In multivariate analysis, age (odds ratio [OR] 1.03; 95%[CI] 1.01–1.05), male sex (OR 1.74; 95%CI 1.10–2.73), withdrawal time (OR 1.16; 95%CI 1.05–1.30), procedure time (OR 1.07; 95%CI 1.04–1.10), colon cleanliness (OR 0.60; 95%CI 0.39–0.94) and use of Endocuff (OR 2.09; 95%CI 1.34–3.27) were independent predictors of adenoma detection rates. Conclusions EC increases the adenoma detection rate by 14.7%(95%CI 6.9–22.5%). EC is safe, effective, easy to handle and might reduce colorectal interval carcinomas. Trial Registration ClinicalTrials.gov NCT02034929.

Die Einführung von Vorsorgekoloskopien zur Detektion kolorektaler Karzinome und deren Vorstufen hat zu einer deutlichen Reduktion von Morbidität und Mortalität geführt. Kürzlich wurde der EndoCuff, eine neuartige Aufsatzkappe mit Seitenärmchen für das Koloskop entwickelt, der zu einer Verbesserung der Inspektion von Darmfalten während einer Koloskopie führen soll.

Hintergrund: Nach einer akuten Ösophagusvarizenblutung ist wegen des hohen Rezidivblutungsrisikos eine sekundäre Blutungsprophylaxe mittels der Kombination von Ligatur und Propranolol Standard. Viele Patienten zeigen jedoch keinen ausreichenden Abfall des Portaldrucks auf Propranolol. Kürzlich wurde die frühe Anlage eines intrahepatischen Shunts (TIPS) zur Behandlung der Varizenblutung erneut propagiert. Bisher wurde der Effekt einer hämodynamisch kontrollierten medikamentösen Therapie und alleinige Ligatur bei unzureichender medikamentöser Portaldrucksenkung nicht mit elektivem TIPS verglichen.