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Background and Aims: Factors predicting the need for step-up procedures after EUS-guided drainage (EUS-FCD) of peripancreatic fluid collections (PFCs) were explored in retrospective studies restricted to Walled-Off Necrosis (WON) and Lumen Apposing Metal Stents (LAMS)., Methods: All consecutive candidates for EUS-FCD between 2020-2024 were included in a Prospective Registry of Therapeutic EUS (PROTECT, NCT04813055), with prospective monthly follow-up evaluating clinical success, adverse events and recurrences. Prospectively assessed baseline clinical and morphological factors, including the Quadrant-Necrosis-Infection (QNI) classification, were included in a stepwise logistic regression model to predict the need for step-up. The agreement between EUS and Radiology in assessing the extent of necrosis was compared with Cohen's kappa., Results: Seventy patients (29 post-surgical collections, 21 pseudocysts, and 20 WONs) were treated with double-pigtail plastic stents (DPPS) in 59% of cases and LAMS in 41%. Clinical success was 92.9%, with a need for step-up (mostly endoscopic necrosectomy) in 35.7% of cases. Necrosis ≥60% (OR=7.7, 95%CI 1.4-43) and being in the high-risk QNI group (OR=4.6, 95%CI 1.4-15) were the only independent predictors of any step-up. The same factors predicted the endoscopist's decision to allocate PFCs to LAMS vs. DPPS. The high-risk QNI group was associated with a significantly longer hospital stay (12 days vs. 4 days, p=0.004). EUS tended to upscale the necrotic content compared to preprocedural Radiology (κ=0.31) CONCLUSIONS: The extent of necrosis and the QNI classification strongly correlated with the need for step-up and allocation to LAMS vs. DPPS drainage, proposing a central role in treatment personalization., (Copyright © 2025 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID rs9604789 variant with an increased risk of developing the disease (OR Meta  = 1.31, p = 9.67 × 10 -6 ). We also confirmed the association of TP63 rs1515496 and TP63 rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10 -8 and OR = 1.16, p = 2.74 × 10 -5 ). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63 rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10 -4 and p = 1.56 × 10 -3 ), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10 -4 ). These results were in agreement with research suggesting that the TP63 rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Malignant Distal Biliary Obstruction (MBDO) is a common event occurring along the natural history of both pancreatic cancer and cholangiocarcinoma. Epidemiological and biological features make MBDO one of the key elements of the clinical management of patients suffering for of pancreatic cancer or cholangiocarcinoma. The development of dedicated biliary lumen-apposing metal stents (LAMS) is changing the clinical work up of patients with MBDO. i-EUS is an Italian network of clinicians and scientists with a special interest in biliopancreatic endoscopy, EUS in particular., Methods: The scientific methodology was chosen in line with international guidance and in a fashion similar to those applied by broader scientific associations. PICO questions were elaborated and subsequently voted by a broad panel of experts within a simplified Delphi process., Results and Conclusions: The manuscripts describes the results of a consensus conference organized by i-EUS with the aim of providing an evidence based-guidance for the appropriate use of the techniques in patients with MBDO., (© 2024. The Author(s).)

Pancreatic fluid collections (PFCs), including pancreatic pseudocysts (PPs) and walled-off pancreatic necrosis (WON), are common complications of pancreatitis and pancreatic surgery. Historically, the treatment of these conditions has relied on surgical and radiological approaches. The treatment of patients with PFCs has already focused toward an endoscopy-based approach, and with the development of dedicated lumen-apposing metal stents (LAMS), it has almost totally shifted towards interventional Endoscopic Ultrasound (EUS)-guided procedures. However, there is still limited consensus on several aspects of PFCs treatment within the multidisciplinary management. The interventional endoscopy and ultrasound (i-EUS) group is an Italian network of clinicians and scientists with special interest in biliopancreatic interventional endoscopy, especially interventional EUS. This manuscript focuses on the second part of the results of a consensus conference organized by i-EUS, with the aim of providing evidence-based guidance on several intra- and post-procedural aspects of PFCs drainage, such as clinical management and follow-up., Competing Interests: Conflict of Interest There is no financial support to this study. Chiara Coluccio: Lecturer per steris. Cecilia Binda: Lecturer fees for Fujifilm, Steris, Q3 Medical, Boston Scientific. Andrea Lisotti received consultancy from Boston Scientific. Giuseppe Vanella: lecture fees from Boston Scientific and travel grants from Euromedical. Carlo Fabbri: consultant per Boston scientific, Lecturer per steris e Q3 medical All the other authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10 -5 ). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association., (© 2024 UICC.)

Background and study aims Although outcomes of lumen-apposing metal stents (LAMS) placement in native anatomy have been reported, data on LAMS placement in surgically altered anatomy (SAA) are sparse. We aimed to assess outcomes of LAMS placement in patients with SAA for different indications. Patients and methods This was an international, multicenter, retrospective, observational study at 25 tertiary care centers through November 2023. Consecutive patients with SAA who underwent LAMS placement were included. The primary outcome was technical success defined as correct placement of LAMS. Secondary outcomes were clinical success and safety. Results Two hundred and seventy patients (125 males; average age 61 ± 15 years) underwent LAMS placement with SAA. Procedures included EUS-directed transgastric ERCP (EDGE) and EUS-directed transenteric ERCP (EDEE) (n = 82), EUS-guided entero-enterostomy (n = 81), EUS-guided biliary drainage (n = 57), EUS-guided drainage of peri-pancreatic fluid collections (n = 48), and EUS-guided pancreaticogastrostomy (n = 2). Most cases utilized AXIOS stents (n = 255) compared with SPAXUS stents (n = 15). Overall, technical success was 98%, clinical success was 97%, and the adverse event (AE) rate was 12%. Using AGREE classification, five events were rated as Grade II, 21 events as Grade IIIa, and six events as IIIb. No difference in AEs were noted among stent types ( P = 0.52). Conclusions This study shows that placement of LAMS is associated with high technical and clinical success rates in patients with SAA. However, the rate of AEs is noteworthy, and thus, these procedures should be performed by expert endoscopists at tertiary centers., Competing Interests: Conflict of Interest Benedetto Mangiavillano has no conflict of interest regarding this paper but is consultant for Taewoong medical., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objectives: Malignant double obstruction, defined as the simultaneous presence of biliary and gastric outlet obstruction, represents a challenging clinical scenario. Previous retrospective experiences have demonstrated shorter dysfunction-free survival (DyFS) of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) versus EUS-hepaticogastrostomy (EUS-HGS) in this setting, but no prospective evidence is available., Methods: Twenty consecutive patients with malignant double obstruction, treated with EUS-gastroenterostomy (and EUS-guided biliary drainage, following a previously failed ERCP, were enrolled in a prospective observational study (ClinicalTrials.gov NCT04813055) comparing EUS-CDS versus EUS-HGS. Efficacy and safety were evaluated, with Biliary Dysfunctions as the primary outcome and DyFS using Kaplan-Meier estimates as a primary measure., Results: Twenty patients (75% with pancreatic cancer, 50% with metastatic disease) with EUS-gastroenterostomy were included (seven EUS-CDS and 13 EUS-HGS). No significant difference was detected at baseline. Technical success was 100% in both groups. EUS-CDS compared to EUS-HGS showed similar clinical success (100% vs. 92.3%, p = 0.5), a higher rate of post-procedural adverse events (42.9% vs. 7.7%, p = 0.067, mostly related to severe/fatal cholangitis in the EUS-CDS group) and a higher rate of biliary dysfunctions during follow-up (71.4% vs. 16.7%, p = 0.002).DyFS was significantly shorter in the EUS-CDS group (39 [15-62] vs. 268 [192-344] days, p = 0.0023), with a 30-days DyFS probability of 57.1% vs. 100% (hazard ratio = 7.8 [1.4-44.2])., Conclusions: In this prospective comparison of patients with malignant double obstruction undergoing EUS-gastroenterostomy, treating jaundice with EUS-CDS versus EUS-HGS resulted in a reduced probability of survival without biliary events and an increased risk of biliary dysfunctions (number needed to harm = 1.8), with detection of severe/fatal cholangitis., Competing Interests: Giuseppe Vanella reports lecture fees from Boston Scientific and travel grants from Euromedical. Michiel Bronswijk received grant support from Boston Scientific. Roy LJ van Wanrooij holds a consultancy agreement with Boston Scientific. Schalk van der Merwe has consultancy agreements with Cook Medical, Pentax, and Olympus and chairs the Boston Scientific board in Therapeutic Biliopancreatic Endoscopy and the Cook Medical board in Interventional endoscopy. All other authors declare no conflict of interest., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Pancreatic fluid collections (PFCs), including pancreatic pseudocysts (PPs) and walled-off pancreatic necrosis (WON), are common complications of pancreatitis and pancreatic surgery. Historically, the treatment of these conditions has relied on surgical and radiological approaches; however, it has later shifted toward an endoscopy-based approach. With the development of dedicated lumen-apposing metal stents (LAMS), interventional Endoscopic Ultrasound (EUS)-guided procedures have become the standard approach for PFC drainage. However, there is still limited consensus on several aspects of the multidisciplinary management of PFCs. The interventional endoscopy and ultrasound (i-EUS) group is an Italian network of clinicians and scientists with special interest in biliopancreatic interventional endoscopy, especially interventional EUS. This manuscript describes the first part of the results of a consensus conference organized by i-EUS with the aim of providing evidence-based guidance on aspects such as indications for treating PFCs, the timing of intervention, and different technical strategies for managing patients with PFCs., Competing Interests: Conflict of Interest There is no financial support to this study. Chiara Coluccio: Lecturer per steris Cecilia Binda: Lecturer fees for Fujifilm, Steris, Q3 Medical, Boston Scientific. Andrea Lisotti received consultancy from Boston Scientific Giuseppe Vanella: lecture fees from Boston Scientific and travel grants from Euromedical Carlo Fabbri: consultant per Boston scientific, Lecturer per steris e Q3 medical All the other authors have no conflict of interest to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Endoscopic ultrasound (EUS) is the most sensitive method for diagnosing chronic pancreatitis (CP) in its early stages, and Rosemont Classification (RC) is used for its evaluation. Data on the correlation between EUS features and pancreatic exocrine insufficiency (PEI) are limited. We investigated the correlation between the EUS findings and PEI., Methods: This was a retrospective, monocentric cohort study involving patients prospectively enrolled from 2018 to 2022, with definite or probable CP according to the M-ANNHEIM criteria. All the patients underwent EUS and exocrine function investigations within 12 months of diagnosis. PEI was diagnosed using fecal elastase (FE) or when overt steatorrhea was reversed by pancreatic enzyme replacement therapy. Logistic regression analyses, rank correlation, ROC curve, and area under the curve (AUROC) were performed to evaluate the association between EUS features and PEI, and the accuracy of RC in predicting PEI., Results: Among 128 patients examined (63.3 % male; mean age, 47 years), 69.5 % were diagnosed with PEI. In multivariate logistic regression among all the RC criteria, only lithiasis in the main pancreatic duct (MPD) was associated with increased risk of PEI (OR 2.92, 95 % CI 1.29-6.61; p = 0.01). Rank analysis showed a weak inverse correlation between RC and FE (Spearman's rho = -0.02; p = 0.03). The accuracy of RC was moderate (AUROC 0.62, p = 0.014)., Conclusions: Among RC EUS features, lithiasis in the MPD is helpful for predicting the risk of PEI, while other findings are of limited utility in evaluating exocrine function., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Malignant gastric outlet obstruction (mGOO) is a major condition affecting patients with periampullary tumors, including pancreatic cancer. The current treatment options include surgical gastroenterostomy, endoscopic stenting and more recently EUS-guided gastroenterostomy. Most studies comparing the outcomes of the three procedures focus on technical success, clinical success and safety. Several "occult" outcomes relevant to the patient's viewpoints and perspective may ultimately impact on cancer-related and overall survival, such as body mass composition, nutritional biomarkers, chemotherapy tolerance and patient-reported quality of life. The aim of this review is to provide an overview of potential key outcomes that should be explored in future comparative research around mGOO treatment options., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Cost-effectiveness of surveillance for branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) is debated. We combined different categories of risks of IPMN progression and of IPMN-unrelated mortality to improve surveillance strategies., Design: Retrospective analysis of 926 presumed BD-IPMNs lacking worrisome features (WFs)/high-risk stigmata (HRS) under surveillance. Charlson Comorbidity Index (CACI) defined the severity of comorbidities. IPMN relevant changes included development of WF/HRS, pancreatectomy or death for IPMN or pancreatic cancer. Pancreatic malignancy-unrelated death was recorded. Cumulative incidence of IPMN relevant changes were estimated using the competing risk approach., Results: 5-year cumulative incidence of relevant changes was 17.83% and 1.6% developed pancreatic malignancy. 5-year cumulative incidences for IPMN relevant changes were 13.73%, 19.93% and 25.04% in low-risk, intermediate-risk and high-risk groups, respectively. Age ≥75 (HR: 4.15) and CACI >3 (HR: 3.61) were independent predictors of pancreatic malignancy-unrelated death. 5-year cumulative incidence for death for other causes was 15.93% for age ≥75+CACI >3 group and 1.49% for age <75+CACI ≤3. 5-year cumulative incidence of IPMN relevant changes were 13.94% in patients with age <75+CACI ≤3 compared with 29.60% in those with age ≥75+CACI >3. In this group 5-year rate of malignancy-free patients was 95.56% with a 5-year survival of 79.51%., Conclusion: Although it is not uncommon the occurrence of changes considered by current guidelines as relevant during surveillance of low risk BD-IPMNs, malignancy rate is low and survival is significantly affected by competing patients' age and comorbidities. IPMN surveillance strategy should be tailored based on these features and modulated over time., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Malignant Gastric Outlet Obstruction (mGOO) has been standardly treated by surgical Gastrojejunostomy (S-GJ) or Endoscopic Stenting (ES). Recently, EUS-Gastrojejunostomy (EUS-GJ) has emerged as an alternative, despite its worldwide diffusion is heterogeneous. The aim of this survey was to assess clinical decision-making around mGOO and to explore current opinions regarding EUS-GJ., Methods: An online survey, spread through social networks and EPC newsletter, was created exploring opinions regarding indications, contraindications, benefits/risks, availability of mGOO treatments; 2 case vignettes explored clinical decision-making in different scenarios., Results: Overall, 290 pancreatologists from 44 countries responded, of whom 35% surgeons and 65% gastroenterologists. The most common treatment for mGOO was ES (86%), followed by laparoscopic GJ (76%). EUS-GJ was accessible to 59% of respondents, with 10% proficient in this technique. Gold-standard treatment for mGOO varied by specialty; 45% of gastroenterologists preferred ES, 20% EUS-GJ, and 10% surgical GJ, while among surgeons, these were 24%, 8%, and 25%, respectively. A higher annual volume of mGOO treated correlated with increased EUS-GJ adoption and reduced surgical advice. For 51%, EUS-GJ will become the primary treatment for mGOO, notably higher among gastroenterologists and high-volume centers. For 14%, EUS-GJ spread will be limited in the future, or used only when ES fails (19%). Life expectancy, disease stage and patient's frailty are the main decision driver in therapeutic choice, whereas future surgical resectability does not contraindicate any treatment for 75%. EUS-GJ's main advantages were its minimally invasive nature and clinical efficacy, offset by its steep learning curve., Conclusions: This survey revealed significant differences in the management of mGOO, depending on specialties, local expertise and treatment volume, suggesting the lack of standardized algorithms. Life expectancy and patients' frailty are the main decision drivers. Regarding EUS-GJ, its availability remains suboptimal, with learning curve as the main perceived barrier., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this 14th document in a series of papers entitled " Controversies in Endoscopic Ultrasound " we discuss various aspects of EUS-guided biliary drainage that are debated in the literature and in practice. Endoscopic retrograde cholangiography is still the reference technique for therapeutic biliary access, but EUS-guided techniques for biliary access and drainage have developed into safe and highly effective alternative options. However, EUS-guided biliary drainage techniques are technically demanding procedures for which few training models are currently available. Different access routes require modifications to the basic technique and specific instruments. In experienced hands, percutaneous transhepatic cholangiodrainage is also a good alternative. Therefore, in this paper, we compare arguments for different options of biliary drainage and different technical modifications.

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: A genetic predisposition seems to be involved in biliary tract cancer, but the prevalence of germline mutations in BTC remains unclear, and the therapeutic role of the germline pathologic variants is still unknown., Area Covered: The aim of the present work is to systematically review the data available on the hereditary predisposition of biliary tract cancer by a specific research on PubMed, in order to highlight the most important critical points and to define the current possible role of germinal testing and genetic counseling in this setting of patients., Expert Opinion: Basing on data already available, we decided to start in our institution a specific genetic protocol focused on biliary tract cancer patients, which includes genetic counseling and, if indicated, germline test. The inclusion criteria are: 1) Patient with personal history of oncologic disease other than BTC, 2) Patient with familiar history of oncologic disease (considering relatives of first and second grade), 3) Patient with ≤ 50 years old, 4) Patient presenting a somatic mutation in genes involved in DNA damage repair pathways and mismatch repair. The aim of the presented protocol is to identify germline pathogenic variants with prophylactic and therapeutic impact, and to collect and integrate a significant amount of clinical, familial, somatic, and genetic data.