HtrA-Dependent E-Cadherin Shedding Impairs the Epithelial Barrier Function in Primary Gastric Epithelial Cells and Gastric Organoids.

Impaired E-cadherin (Cdh1) functions are closely associated with cellular dedifferentiation, infiltrative tumor growth and metastasis, particularly in gastric cancer. The class-I carcinogen Helicobacter pylori (H. pylori) colonizes gastric epithelial cells and induces Cdh1 shedding, which is primarily mediated by the secreted bacterial protease high temperature requirement A (HtrA). In this study, we used human primary epithelial cell lines derived from gastroids and mucosoids from different healthy donors to investigate HtrA-mediated Cdh1 cleavage and the subsequent impact on bacterial pathogenesis in a non-neoplastic context. We found a severe impairment of Cdh1 functions by HtrA-induced ectodomain cleavage in 2D primary cells and mucosoids. Since mucosoids exhibit an intact apico-basal polarity, we investigated bacterial transmigration across the monolayer, which was partially depolarized by HtrA, as indicated by microscopy, the analyses of the transepithelial electrical resistance (TEER) and colony forming unit (cfu) assays. Finally, we investigated CagA injection and observed efficient CagA translocation and tyrosine phosphorylation in 2D primary cells and, to a lesser extent, similar effects in mucosoids. In summary, HtrA is a crucially important factor promoting the multistep pathogenesis of H. pylori in non-transformed primary gastric epithelial cells and organoid-based epithelial models.

Novel technique of flexible endoscopic therapy of Zenker's diverticulum using a pulsed Holmium laser-a retrospective single-center analysis.

BACKGROUND: In recent years, flexible endoscopic therapy of Zenker's diverticulum seems to become the standard approach. The aim of this study was to assess the safety, efficacy and short-term outcome of flexible endoscopic diverticulotomy of Zenker's diverticulum with a pulsed Holmium laser (PHL). PATIENTS AND METHODS: All patients treated with endoscopic laser-diverticulotomy using a PHL between February 2013 and November 2021 at the University Hospital Salzburg were extracted from our prospectively maintained endoscopic database. Demographic data, size of Zenker's diverticulum, procedure duration, complications, short-term outcome and rate of recurrence were evaluated. RESULTS: In the study period, 45 procedures in 36 patients were performed. Mean depth of the Zenker diverticulum was 21 mm (10-60 mm), mean procedure time was 31 min (15-60 min), intraprocedural adverse events occurred in 2 out of 45 patients (5%) which were both managed endoscopically, post-procedural stenosis occurred in 1 patient (2%). In the follow-up examinations (mean follow-up after 6.4 months), 27 out of 36 patients (75%) were symptom-free, 6 patients (17%) reported an improvement of dysphagia. 3 patients (9%) suffered from persistent dysphagia. After initial symptom relief, a recurrent diverticulum occurred in 5 patients. Endoscopic re-intervention with PHL was done in these cases. CONCLUSIONS: Flexible endoscopic treatment of primary and recurrent Zenker's diverticulum using a PHL is a promising, safe and effective treatment with, in our opinion, technical advantages in comparison to the CO2 laser. Further controlled prospective trials are needed.

Real-life Indications and Outcome of Electrocautery-enhanced Lumen-apposing Metal Stents in a Tertiary Center.

PURPOSE: Electrocautery-enhanced lumen-apposing stents (EC-LAMS) were originally designed for the drainage of the gallbladder, bile duct, and pancreas pseudocysts. Throughout the years, several off-label indications were established. This study aims to evaluate the indication, safety, efficacy, and outcome of all LAMS implanted in a single tertiary referral center. METHODS: From April 2016 to April 2022, all patients undergoing LAMS placement in a single tertiary center were included. We present a detailed analysis of indications, success rates, and complications based on a retrospective analysis of our prospectively maintained database. RESULTS: A total of 86 stents were placed in 77 patients between April 2016 and April 2022. Indications were walled-off pancreatic necrosis (25.6%), bile duct obstructions (16.3%), acute cholecystitis (15.1%), pancreas pseudocysts (15.1%), postoperative collections (10.5%), postoperative pancreatic fistulas (9.3%), and gastro-gastrostomy/jejunostomy (8.1%) to enable to perform an endoscopic retrograde cholangiopancreatography in patients with gastric bypass. Technical success was 97.7% (84 out of 86). A total of 10 (11.7%) adverse events were observed. In 3 patients (3.5%), severe complications occurred, which required acute surgery; one displacement was closed through clips. In 7 patients (8.2%), bleedings occurred during necrosectomy or from mucosal erosions at the stent side, respectively, that were treated with endoclips. CONCLUSIONS: EC-LAMS are safe and show a high technical success rate in all indications. In everyday clinical practice, the main indications are hepato-pancreato-biliary, and therefore an hepato-pancreato-biliary-surgical department should have EC-LAMS in their armamentarium.

Body composition dynamics and impact on clinical outcome in gastric and gastro-esophageal junction cancer patients undergoing perioperative chemotherapy with the FLOT protocol.

PURPOSE: Perioperative chemotherapy with FLOT constitutes a standard of care approach for locally advanced, resectable gastric or gastro-esophageal junction (GEJ) cancer. We aimed at investigating anthropometric, CT-based and FDG-PET-based body composition parameters and dynamics during this multidisciplinary approach and the impact on clinical outcomes. METHODS: This retrospective, single-center study was based on medical records and (FDG-PET)-CT images among gastric/GEJ cancer patients undergoing perioperative FLOT chemotherapy. RESULTS: Between 2016 and 2021, 46 gastric/GEJ cancer patients started perioperative FLOT at our tertiary cancer center (Salzburg, Austria). At a median follow-up of 32 months median PFS was 47.4 months and median OS was not reached. The skeletal muscle index (SMI, cm2/m2) turned out to be the only body composition parameter with a statistically significant decrease during pre-operative FLOT (51.3 versus 48.8 cm2/m2, p = 0.02). Neither pre-FLOT body mass index (BMI), nor SMI had an impact on the duration of pre-operative FLOT, the time interval from pre-operative FLOT initiation to surgery, the necessity of pre-operative or post-operative FLOT de-escalation or the likelihood of the start of postoperative chemotherapy. Pre-FLOT BMI (overweight versus normal, HR: 0.11, 95% CI: 0.02-0.65, p = 0.02) and pre-FLOT SMI (sarcopenia versus no sarcopenia, HR: 5.08, 95% CI: 1.27-20.31, p = 0.02) were statistically significantly associated with PFS in the multivariable analysis. CONCLUSION: The statistically significant SMI loss during pre-operative FLOT and the meaningful impact of baseline SMI and BMI on PFS argue for the implementation of a nutritional screening and support program prior to the initiation of pre-operative FLOT in clinical routine.