BACKGROUND AND AIMS:Carbohydrate sulfotransferase 15 [CHST15] biosynthesizes sulphated matrix glycosaminoglycans and is implicated in intestinal inflammation and fibrosis. Here, we evaluate the efficacy and safety of the double-stranded RNA oligonucleotide GUT-1, a specific blocker of CHST15, as induction therapy in patients with ulcerative colitis [UC].METHODS:In this randomized, double-blind, placebo-controlled, phase 2a study, we enrolled endoscopically active UC patients, refractory to conventional therapy, in five hospital centres across Germany. Patients were randomized 1:1:1 using a block randomized technique to receive a single dosing of 25 nM GUT-1, 250 nM GUT-1, or placebo by endoscopic submucosal injections. The primary outcome measure was improvement of endoscopic lesions at weeks 2 or 4. The secondary outcome measures included clinical and histological responses. Safety was assessed in all patients who received treatment.RESULTS:Twenty-eight patients were screened, 24 were randomized, and 21 were evaluated. Endoscopic improvement at weeks 2 or 4 was achieved by 71.4% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 28.6% in the placebo group. Clinical remission was shown by 57.1% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 14.3% in the placebo groups. Histological improvement was shown by 42.9% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 0% in the placebo groups. GUT-1 250 nM reduced CHST15 expression significantly and suppressed mucosal inflammation and fibrosis. GUT-1 application was well tolerated.CONCLUSION:Single dosing by submucosal injection of GUT-1 repressed CHST15 mucosal expression and may represent a novel induction therapy by modulating tissue remodelling in UC.

Polyps of the gastrointestinal tract encompass a variety of epithelial and non-epithelial tumour-like conditions. The most common polyps are epithelial lesions. In the upper gastrointestinal tract, reactive inflammatory changes and hyperplastic polyps dominate, whereas true neoplastic polyps, like adenomas, are much more common in the colorectum. In addition to neoplasias such as adenomas, non-neoplastic polyps such as hyperplastic polyps of the stomach may also be associated with an increased risk of malignancy. The risk of malignancy is determined by the histological subtype of polyp, as well as the size, presence and degree of dysplasia. The term "dysplasia" has been reintroduced for adenomas in the current 2019 World Health Organization (WHO) classification and replaces "intraepithelial neoplasia". A further change is the term "sessile serrated lesion" with and without dysplasia, which was formerly known as sessile serrated adenoma.

Summary Background To evaluate medical versus interventional treatment (transjugular thrombus fragmentation, local thrombolysis with or without stent implantation) in patients with acute non‐cirrhotic, non‐malignant portal vein thrombosis (PVT). Methods This prospective, observational study enrolled 65 patients with acute (<28 days since begin of symptoms, no cavernoma) PVT in nine centres. Thirty patients received medical treatment and 35 patients received interventional treatment. PVT was graded into grade 1: short thrombosis and incomplete occlusion of the vessel lumen and grade 2: extended thrombosis or complete occlusion. Treatment response was classified as partial or complete, if thrombosis was reduced by one grade or to <25% of the vessel diameter respectively. Results Partial and complete response rates were 7% and 30% in the medical compared to 17% and 54% ( P < 0.001) in the interventional treatment group. In the multivariate analysis, interventional treatment showed a strong positive (OR 4.32, P < 0.016) and a myeloproliferative aetiology a negative (OR 0.09, P = 0.006) prediction of complete response. Complications were rare in the medical group and consisted of septicaemia and upper gastrointestinal bleeding of unknown origin in one patient each. Interventional treatment was accompanied by mild and self‐limiting bleeding complications in nine patients, moderate intra‐abdominal bleeding requiring transfusions (2 units) in one patient and peritoneal bleeding requiring surgical rescue in one patient. Four patients in each group developed intestinal gangrene requiring surgery. One patient died 52 days after unsuccessful interventional treatment. Conclusions Compared to medical treatment alone, interventional treatment doubled response rates at the cost of increased bleeding complications.

Acute pancreatitis is a severe systemic disease triggered by a sterile inflammation and initial local tissue damage of the pancreas. Immune cells infiltrating into the pancreas are main mediators of acute pancreatitis pathogenesis. In addition to their antimicrobial potency, macrolides possess anti-inflammatory and immunomodulatory properties which are routinely used in patients with chronic airway infections and might also beneficial in the treatment of acute lung injury. We here tested the hypothesis that the macrolide antibiotic azithromycin can improve the course of acute experimental pancreatitis via ameliorating the damage imposed by sterile inflammation, and could be used as a disease specific therapy. However, our data show that azithromycin does not have influence on caerulein induced acute pancreatitis in terms of reduction of organ damage, and disease severity. Furthermore Infiltration of immune cells into the pancreas or the lungs was not attenuated by azithromycin as compared to controls or ampicillin treated animals with acute experimental pancreatitis. We conclude that in the chosen model, azithromycin does not have any beneficial effects and that its immunomodulatory properties cannot be used to decrease disease severity in the model of caerulein-induced pancreatitis in mice.

Abstract The relevance of gastrointestinal manifestations of cystic fibrosis (CF) is increasing due to an improved life expectancy. We report on 2 adult patients with prior lung transplantation who presented with a severe inflammatory disorder of the ileocecal region. One patient underwent ileocecal resection; the second patient died after emergency surgery for intestinal perforation. Both cases did not show typical signs of CF-related distal intestinal obstruction syndrome or extensive fibrosing colonopathy. However, the clinical and histopathological findings revealed CF-induced inflammatory alterations of the intestinal mucosa. Thus, these cases illustrate a further CF-related bowel disorder, which can be especially relevant in long-term CF survivors.

Caustic ingestion in adults is a rare but potentially life-threatening problem. It remains controversial whether endoscopic findings and mortality differ between acid and alkali ingestion. We compared ingestion of these agents and evaluated prediction parameters for survival and complications. Adult patients who presented with caustic ingestion were analyzed from 2005 to 2016. Mucosal injury was graded endoscopically by Zargar's score. Age, gender, intent of ingestion, caustic agents, comorbidities, management, complications, and mortality were examined. Thirty-one patients met inclusion criteria and were divided into acid (n=10) and alkali group (n=21). Ingestion of alkali resulted in higher grades (>= III) of esophageal (56% vs 24%, P=.01) and stomach injuries (43% vs 13%, P=.05) and was mostly done with suicidal intent (76% vs 30%, P=.003). Patients in the alkali group received more often surgical interventions, mechanical ventilation and tracheotomy. Overall complications including Zargar's-score >= grade III, mediastinitis, and aspiration pneumonia were higher in alkali group but all showed no statistical significance (P=.73). Mortality (acid: 1 (10%), alkali: 4 (19%), P=.52), age, gender, comorbidities, and intensive care management did not differ significantly between the groups. Chronic renal failure and mediastinitis were promising prediction parameters for mortality but did not reach statistical significance. No independent risk factors for the development of esophageal stenosis were identified. Alkaline agents caused a higher mucosal injury severity and were more often used in suicidal intent. Mediastinitis and chronic renal failure might be potential prediction parameters for survival but need to be evaluated in larger studies.

Background and study aims Patients with malignant tumors of the upper gastrointestinal tract are at risk of weight loss. Early supportive nutrition therapy is therefore recommended and usually requires placement of a percutaneous endoscopic gastrostomy (PEG). The aim of this study was to compare adverse events and usage characteristics of the direct puncture technique with those of the traditional pull technique when used in patients with endoscopically passable tumors. The primary endpoint was the rate of inflammatory adverse events (AEs) at the gastrostomy fistula. The secondary endpoint was the long-term rate of puncture-site metastases. Patients and methods One hundred twenty patients (median age 56; IQR 36, 86 years) were randomized and treated per protocol in this prospective open randomized single-center study. Follow-ups were conducted on the third and seventh post-interventional days, after 1, 3 and 6 months and the last follow-up 5 years after intervention. Results Within the short-term follow-up period of 6 months after PEG placement, AEs were noted in 47 patients (39.2%). These included 22 inflammations and 16 device dislocations and were mainly found in the puncture group (33 vs. 14 in the pull group) with a significantly increased incidence in the first month after PEG insertion (P = 0.001). Evaluation of the 5-year data did not reveal any significant differences. The gastrostomy tube was used in 101 patients (84.2%) (range 18 days to 5 years). Conclusions Our results favor the pull technique for patients with endoscopically passable tumors of the upper gastrointestinal tract due to less short-term adverse events. Both systems contributed equally to secure long-term use.

BACKGROUND/OBJECTIVES:Acute pancreatitis (AP) is one of the most common gastrointestinal disorders often requiring hospitalization. Frequent aetiologies are gallstones and alcohol abuse. In contrast to chronic pancreatitis (CP) few robust genetic associations have been described. Here we analysed whether common variants in the CLDN2-MORC4 and the PRSS1-PRSS2 locus that increase recurrent AP and CP risk associate with AP.METHODS:We screened 1462 AP patients and 3999 controls with melting curve analysis for SNPs rs10273639 (PRSS1-PRSS2), rs7057398 (RIPPLY), and rs12688220 (MORC4). Calculations were performed for the overall group, aetiology, and gender sub-groups. To examine genotype-phenotype relationships we performed several meta-analyses.RESULTS:Meta-analyses of all AP patients depicted significant (p-value < 0.05) associations for rs10273639 (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.81-0.97, p-value 0.01), rs7057398 (OR 1.27, 95% CI 1.07-1.5, p-value 0.005), and rs12688220 (OR 1.32, 95% CI 1.12-1.56, p-value 0.001). For the different aetiology groups a significant association was shown for rs10273639 (OR 0.76, 95% CI 0.63-0.92, p-value 0.005), rs7057398 (OR 1.43, 95% CI 1.07-1.92, p-value 0.02), and rs12688220 (OR 1.44, 95% CI 1.07-1.93, p-value 0.02) in the alcoholic sub-group only.CONCLUSIONS:The association of CP risk variants with different AP aetiologies, which is strongest in the alcoholic AP group, might implicate common pathomechanisms most likely between alcoholic AP and CP.

Anastomotic leakage is a frequent complication after gastrointestinal (GI) surgery and is associated with high morbidity and mortality. Endoluminal therapy offers numerous advantages compared to surgical revision. We present the case of a 74-year-old female patient with anastomotic leakage after esophagogastrostomy. The defect was closed using the OverStitch endoscopic suturing system with immediate technical and clinical success. Hereby, an example of the feasibility of this novel technique in a case of anastomotic leakage is presented and provides an outlook for the rising importance of endoscopic therapy.

Background p8 was initially described as being overexpressed in acute pancreatitis and encoding a ubiquitous stress protein. Analysis of insulin sensitivity and glucose tolerance in p8-knockout and haplodeficient mice revealed counterintuitive results. Thus, we determined glycemic control of p8 in mice fed with standard (SD) and high-fat diet (HFD). Methods p8-/- and wild type (p8+/+) mice were used for analysis of glucagon (immunohistochemistry), insulin levels (ELISA) and beta cell mass. Hyperinsulinemic- euglycemic glucose clamp technique, i.p. glucose tolerance test (ipGTT), i.p. insulin tolerance test (ipITT) and metabolic chamber analysis were performed in SD (4% fat) and HFD (55% fat) groups. Results p8-/- mice showed no differences in glucagon or insulin content but higher insulin secretion from pancreatic islets upon glucose stimulation. p8 deficiency resulted in elevated beta cell mass but was not associated with increased insulin resistance in ipGTT or ipITT. Glucose clamp tests also revealed no evidence of association of p8 deficiency with insulin resistance. Metabolic chamber analysis showed equal energy expenditure in p8-/- mice and wild type animals. Conclusion p8 depletion may contribute to glucose metabolism via stress-induced insulin production and elevated beta cell mass. Nevertheless, p8 knockout showed no impact on insulin resistance in SD and HFD-fed mice.

Solid pancreatic lesions found on imaging procedures are suspicious for malignancy and, therefore, demand immediate diagnostic evaluation and therapy. In the case of indeterminate histology, a primary resection should be considered in order to preserve the possibility of curative surgery, although rare entities may be initially disregarded. We present here the case of a 48-year-old female patient with a hypoechoic lesion of the pancreatic head, which was clearly delineated from the surrounding pancreatic tissue. The challenging diagnosis of metastatic leiomyosarcoma could only be established by considering the long-term clinical history and former histology specimens.

Objective Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results We replicated previously reported risk loci CLDN2-MORC4 , CTRC , PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956 . The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.

Background Necrotising pancreatitis, and particularly infected necrosis, are still associated with high morbidity and mortality. Since 2011, a step-up approach with lower morbidity rates compared to initial open necrosectomy has been established. However, mortality and complication rates of this complex treatment are hardly studied thereafter. Methods The German Pancreatitis Study Group performed a multicenter, retrospective study including 220 patients with necrotising pancreatitis requiring intervention, treated at 10 hospitals in Germany between January 2008 and June 2014. Data were analysed for the primary endpoints "severe complications" and "mortality" as well as secondary endpoints including "length of hospital stay", "follow up", and predisposing or prognostic factors. Results Of all patients 13.6% were treated primarily with surgery and 86.4% underwent a step-up approach. More men (71.8%) required intervention for necrotising pancreatitis. The most frequent etiology was biliary (41.4%) followed by alcohol (29.1%). Compared to open necrosectomy, the step-up approach was associated with a lower number of severe complications (primary composite endpoint including sepsis, persistent multiorgan dysfunction syndrome (MODS) and erosion bleeding: 44.7% vs. 73.3%), lower mortality (10.5% vs. 33.3%) and lower rates of diabetes mellitus type 3c (4.7% vs. 33.3%). Low hematocrit and low blood urea nitrogen at admission as well as a history of acute pancreatitis were prognostic for less complications in necrotising pancreatitis. A combination of drainage with endoscopic necrosectomy resulted in the lowest rate of severe complications. Conclusion A step-up approach starting with minimal invasive drainage techniques and endoscopic necrosectomy results in a significant reduction of morbidity and mortality in necrotising pancreatitis compared to a primarily surgical intervention.

Background Carboxyl-ester lipase (CEL) contributes to fatty acid ethyl ester metabolism, which is implicated in alcoholic pancreatitis. The CEL gene harbours a variable number of tandem repeats (VNTR) region in exon 11. Variation in this VNTR has been linked to monogenic pancreatic disease, while conflicting results were reported for chronic pancreatitis (CP). Here, we aimed to investigate a potential association of CEL VNTR lengths with alcoholic CP. Methods Overall, 395 alcoholic CP patients, 218 patients with alcoholic liver cirrhosis (ALC) serving as controls with a comparable amount of alcohol consumed, and 327 healthy controls from Germany and the United Kingdom (UK) were analysed by determination of fragment lengths by capillary electrophoresis. Allele frequencies and genotypes of different VNTR categories were compared between the groups. Results Twelve repeats were overrepresented in UK ACP patients (P = 0.04) compared to controls, whereas twelve repeats were enriched in German ALC compared to alcoholic CP patients (P = 0.03). Frequencies of CEL VNTR lengths of 14 and 15 repeats differed between German ALC patients and healthy controls (P = 0.03 and 0.008, respectively). However, in the genotype and pooled analysis of VNTR lengths no statistical significant association was depicted. Additionally, the 16–16 genotype as well as 16 repeats were more frequent in UK ALC than in alcoholic CP patients (P = 0.034 and 0.02, respectively). In all other calculations, including pooled German and UK data, allele frequencies and genotype distributions did not differ significantly between patients and controls or between alcoholic CP and ALC. Conclusions We did not obtain evidence that CEL VNTR lengths are associated with alcoholic CP. However, our results suggest that CEL VNTR lengths might associate with ALC, a finding that needs to be clarified in larger cohorts.