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Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values

Background: Transoral incisionless fundoplication (TIF) with Medigus Ultrasonic Surgical Endostapler (MUSE) is a new intervention for treatment of gastro-esophageal reflux disease (GERD). We aimed at assessing the clinical, functional, and endoscopic effects of TIF by MUSE. Methods: Forty-six patients underwent TIF. Proton pump inhibitor (PPI) consumption, GERD-health-related quality of life (HRQL) and reflux symptom index (RSI) questionnaires, upper gastrointestinal (GI) endoscopy, esophageal 24-h pH-impedance recording, and high-resolution manometry (HRM) were done before TIF and scheduled 6 and 12months later (HRM only at 6-month). PPI consumption and symptoms were then assessed yearly. Data up to 3years are reported in this study (PP- and ITT-analysis). Results: TIF was successfully performed in 45/46 patients; in one patient esophageal intubation was impossible. Perforation occurred in two cases. One patient required surgery within 6 months. Clinical follow-up was available for 42 patients at 6 months and 1 year, 35 patients at 2 years, and 31 patients at 3 years. At 1, 2, and 3 years, PPI consumption was stopped, respectively, in 64.3%, 62.9%, and 74.2% of cases (ITT-analysis: 58.7%, 56.4%, and 65.7%). GERD-HRQL and RSI scores decreased at least 50%, respectively, in 71.5% and 76.2%, 71.4% and 68.6%, and 67.7% of cases (ITT-analysis: 65.2% and 69.6%, 64.1% and 61.5%, and 60%). A significant improvement of both scores was observed up to 3 years. 6-month and 1-year functional follow-up were possible in 31 and 20 patients. HRM showed significant increase of the median lower esophageal sphincter length and rate of peristaltic waves. Esophageal pH-impedance recording found significantly fewer acid, proximal and total refluxes, and percentage of esophageal pH < 4 total time at 6 months, but not at 1 year. Conclusion: TIF by MUSE significantly improved symptoms and PPIs consumption up to 3 years. However, esophagitis still persisted in one-third of cases at 1 year and functional improvement at 6 months was not confirmed at 1 year. Severe complications requiring surgery occurred in two cases. ClinicalTrials.Gov: ID: NCT03669874.

Contains fulltext : 229360.pdf (Publisher’s version ) (Closed access) BACKGROUND: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10(-5)) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.

Aims: A higher SGLT1 and GLUT2 gene expression was shown in the intestine of subjects with type 2 diabetes, while no data have been reported in type 1 diabetes (T1D). The purpose of our study was to evaluate the expression of glucose transporters in duodenal mucosa of subjects with T1D, compared to healthy controls (CTRL) and to patients with celiac disease (CD), as gut inflammatory disease control group. Materials and methods: Gene expression of GLUT1, GLUT2, SGLT1 and SGLT2 was quantified on duodenal mucosa biopsies of subjects with T1D (n = 19), CD (n = 16), T1D and CD (n = 6) and CTRL (n = 12), recruited at San Raffaele Hospital (Milan, Italy), between 2009 and 2018. SGLT2 expression was further evaluated by immunohistochemical and immunofluorescence staining. Results: The expression of all four glucose transporters was detected in duodenal mucosa of all groups. A reduced GLUT2, SGLT1 and SGLT2 expression was observed in CD in comparison with T1D and CTRL, as expected; GLUT1 was significantly more expressed in T1D compared to CTRL. SGLT2 expression was quantified at much lower levels than other transporters, with no differences between groups. SGLT2 expression was confirmed by immunohistochemistry in a restricted number of enterocytes lining in the mucosa of intestinal villi, also shown on immunofluorescence. Conclusions: Our results show that glucose transporters expression in duodenal mucosa of subjects with T1D, except an increased GLUT1, is not different from that observed in healthy controls. The expression of SGLT2 in human duodenal mucosa, although at low intensity, represents a novel finding.

Objectives Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia. Methods Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes. Results We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet. Conclusions Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.

Anastomotic dehiscence is one of the most morbidity related and deadly complication after foregut oncologic surgery. The aim of the study is to evaluate the effectiveness of double layer stents (Niti-S™ Beta™ Esophageal Stent) in the management of dehiscences after upper gastrointestinal oncologic surgery. We retrospectively studied consecutive patients who underwent Niti-S™ Beta™ esophageal stent placement from June 2014 to September 2019 for the treatment of anastomotic leaks/fistula following esophagectomy or gastrectomy for cancer. Univariate two-sided logistic regression analysis was used to evaluate possible predictors of successful anastomotic leak/fistula closure. A total of 37 patients were studied and 75 stents were positioned in these patients during the endoscopic procedures. Effective leak/fistula closure was obtained in 23/37 (62.2%). No technical endoscopic failure or complications ensued during the placing of the devices. Regarding delayed complications, migration was observed in 17/75 (22.7%) procedures and stent leaking in 29/75 (38.6%). Three variables significantly favoured stent treatment failure, namely previous neoadjuvant therapy (OR 9.3, P = 0.01), fistula (instead of leak) (OR 6.5, P = 0.01), and stent leak (OR 17.0, P = 0.01). Placement of Beta Niti-S esophageal stent is a safe and effective method that could be considered for the management of leaks and fistula after upper gastrointestinal cancer. Crucial points in the management of post-surgical leaks with this technique are the prompt recognition of leaks and fistula, the prompt endoscopic/radiologic drain of collection and the choice of adequate size of the stent.

© 2019 by the authors., Early-onset colorectal cancer (EOCRC) is an increasing and worrisome entity. The aim of this study was to analyze its association with polyps concerning prognosis and surveillance. EOCRC cases were compared regarding the presence or absence of associated polyps (clinical and molecular features), during a minimum of 7 years of follow-up. Of 119 cases, 56 (47%) did not develop polyps (NP group), while 63 (53%) did (P group). The NP group showed a predominant location of the CRC in the rectum (50%), of sporadic cases (54%), and diagnosis at advanced stages: Only P53 and SMARCB1 mutations were statistically linked to this group. The P group, including mainly early-diagnosed tumors, was linked with the most frequent and differential altered chromosomal regions in the array comparative genomic hybridization. The two most frequent groups according to the follow-up were the NP group (40%), and patients developing polyps in the first 5 years of follow-up (P < 5FU) (34%) (these last groups predominantly diagnosed at the earliest stage and with adenomatous polyps (45%)). EOCRC with polyps that developed during the entire follow-up (PDFU group) were mainly located in the right colon (53%), diagnosed in earlier stages, and 75% had a familial history of CRC. Patients developing polyps after the first 5 years (P > 5FU) showed a mucinous component (50%). Our results show that the absence or presence of polyps in EOCRC is an important prognostic factor with differential phenotypes. The development of polyps during surveillance shows that it is necessary to extend the follow-up time, also in those cases with microsatellite-stable EOCRC, This work was funded by the Spanish Ministry of Health and Consumer Affairs and FEDER, grant number PI10/00683 and PI16/01650 to J.P.G., PI16/01920 to R.G.S., and PI14/00459 to M.U., and by the National Cancer Institute, National Institutes of Health, grant number R01 CA72851, CA18172, CA184792 and U01 CA187956 to A.G.