Trending Topics in Gastroenterology | GastroAGI

Ivonescimab Plus Gemcitabine–Cisplatin in Biliary Tract Cancer (BTC): Journal of Hepatology | July 2026

Introduction: Advanced biliary tract cancer (BTC) carries a poor prognosis, with limited improvements in survival despite the addition of immune checkpoint inhibitors to standard gemcitabine–cisplatin chemotherapy. This phase II trial evaluated ivonescimab, a novel PD-1/VEGF bispecific antibody, combined with chemotherapy as first-line treatment. Why was this study needed? • Current first-line immunochemotherapy provides only modest survival benefit. • Advanced BTC continues to have poor long-term outcomes. • More effective first-line treatment strategies are urgently needed. • Biomarkers predicting treatment response remain poorly defined. • Novel immunotherapy combinations require prospective evaluation. Results: • Ivonescimab plus gemcitabine–cisplatin demonstrated impressive antitumor activity, achieving a 66.7% objective response rate, 100% disease control rate, and a median overall survival of 16.8 months. • The combination showed a manageable safety profile, with predominantly expected hematologic toxicities and no treatment-related deaths. • MAP2K7 emerged as a potential biomarker of resistance, suggesting a future role in patient selection and development of combination therapies. Clinical Impact: This study suggests that ivonescimab-based immunochemotherapy may improve outcomes beyond current first-line standards for advanced biliary tract cancer. Although these encouraging findings require confirmation in randomized phase III trials, they highlight the promise of dual PD-1/VEGF blockade and biomarker-driven precision therapy. Bottom Line: Ivonescimab plus gemcitabine–cisplatin demonstrated encouraging efficacy and acceptable safety as first-line therapy for advanced biliary tract cancer. If confirmed in larger trials, it may become a new treatment option, with MAP2K7 serving as a potential biomarker to personalize therapy.

GLP-1 Receptor Agonists and Gallbladder Disease: UEG Journal | June 2026

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become a cornerstone in the management of type 2 diabetes because of their excellent glycemic, cardiovascular, and weight-loss benefits. However, concerns remain regarding their potential association with gallbladder and biliary diseases. Why was this study needed? Previous studies suggested a possible increase in gallbladder complications with GLP-1 RAs, but long-term real-world data evaluating individual biliary outcomes and differences between specific GLP-1 agents have been limited. What did the study show? • This large real-world cohort included over 156,000 patients with type 2 diabetes, with follow-up extending to three years. • GLP-1 RA therapy was associated with higher risks of cholelithiasis, choledocholithiasis, cholecystitis, and subsequent cholecystectomy. • No significant increase was observed in acute pancreatitis or the need for ERCP. • The biliary risk varied among individual agents, with semaglutide and dulaglutide showing a higher risk of gallstones, whereas liraglutide and exenatide were not significantly associated with increased risk. • Steatotic liver disease, obesity, and alcohol use independently increased the likelihood of gallbladder and biliary complications. Clinical Impact: The overall benefits of GLP-1 RAs continue to outweigh these modest biliary risks for most patients. Clinicians should remain vigilant in individuals with pre-existing gallstones, steatotic liver disease, obesity, or heavy alcohol use, and promptly evaluate new biliary symptoms during treatment. Take-Home Message: GLP-1 receptor agonists remain highly effective therapies for type 2 diabetes, but they are associated with a modest increase in gallbladder and biliary complications. Careful patient selection, counseling, and monitoring can help maximize benefits while minimizing biliary adverse events.

Remnant Duct Dilatation Rarely Signals IPMN Recurrence : Ann Surg | Jun 2026

Introduction: Patients undergoing pancreatoduodenectomy for non invasive intraductal papillary mucinous neoplasm (IPMN) require long-term surveillance because of the risk of disease recurrence in the pancreatic remnant. New pancreatic duct (PD) dilatation is commonly detected during follow-up imaging, but its clinical significance remains uncertain, often creating a dilemma regarding further investigation or completion pancreatectomy. Problem Statement: Although main pancreatic duct dilatation is a recognized radiological hallmark of IPMN, postoperative duct dilatation may also result from benign causes such as anastomotic changes, aging, pancreatitis, or physiological postoperative remodeling. Distinguishing benign ductal dilatation from true IPMN recurrence is essential to avoid unnecessary surgery while ensuring timely detection of invasive disease. Summary: This international multicenter study evaluated the natural history of remnant pancreatic duct dilatation following pancreatoduodenectomy for non invasive IPMN. During long-term surveillance, more than one-quarter of patients developed new pancreatic duct dilatation, making it a frequent postoperative finding. Older age and longer duration of follow-up were the only factors associated with duct enlargement, whereas the original IPMN subtype and preoperative duct diameter did not predict its development. Importantly, although duct dilatation frequently raised suspicion for recurrent IPMN, progression to invasive pancreatic cancer was exceptionally uncommon. Only a very small proportion of patients ultimately required completion pancreatectomy for invasive carcinoma, and most of these patients had high-grade dysplasia in the original surgical specimen, suggesting that initial pathological severity may be more informative than postoperative duct dilatation alone. The findings indicate that remnant pancreatic duct dilatation is often a physiological consequence of long-term postoperative changes rather than evidence of recurrent neoplasia. Clinically, these results support a cautious, surveillance-based approach rather than immediate surgical intervention when isolated duct dilatation is identified after pancreatoduodenectomy. Overall, the study provides reassuring evidence that new remnant duct dilatation is common but rarely represents clinically significant IPMN recurrence, helping refine postoperative surveillance strategies and reducing the risk of unnecessary completion pancreatectomy.

Post-Pancreatectomy Chyle Leak: Annals of Surgery | June 2026

• This study evaluated 1,063 patients undergoing pancreatic surgery; 11% developed conventionally defined chyle leak. • Most clinically relevant cases were grade B, while no grade C leaks were reported. • A minimally invasive surgical approach was independently associated with a higher likelihood of chyle leak. • Maximum daily drain output was also strongly associated with clinically relevant leakage. • The key finding was that triglyceride-rich drainage was frequently not milky. • More than one-third of patients had drain triglycerides ≥1.2 mmol/L despite the absence of classic milky-colored fluid. • Patients with high-volume drainage ≥300 mL/day and elevated triglycerides had prolonged hospitalisation, even when the drainage appeared clear or non-milky. • Their length of stay was comparable to that of patients with high-volume, triglyceride-rich, visibly milky drainage. • In contrast, low-volume triglyceride-rich drainage had less clinical impact. • These findings challenge reliance on drain appearance when diagnosing post-pancreatectomy chyle leak. • Measuring both drain triglyceride concentration and daily output volume may identify clinically important lymphatic leakage more accurately. • The current International Study Group for Pancreatic Surgery definition may therefore underestimate clinically relevant cases that lack a milky appearance. • As this was an observational single-centre study, external validation is needed before formal diagnostic criteria are changed. Bottom line: After pancreatic surgery, high-volume triglyceride-rich drainage should be managed as a clinically relevant chyle leak even when it is not milky.

Immediate Necrosectomy Accelerates Recovery in Walled-Off Necrosis : Gastroenterology | Jul 2026

Introduction: Endoscopic ultrasound (EUS)-guided drainage has become the preferred minimally invasive treatment for symptomatic necrotizing pancreatitis. However, the optimal timing of direct endoscopic necrosectomy (DEN) following drainage remains uncertain. While the conventional step-up approach reserves necrosectomy for patients who fail to improve after drainage alone, some experts advocate earlier intervention to accelerate resolution of infected or symptomatic necrosis. Problem Statement: Although the step-up strategy minimizes procedural interventions, delayed necrosectomy may prolong inflammation, hospital stay, and recovery. Whether immediate DEN following EUS-guided drainage improves clinical outcomes without increasing complications has not been established in prospective randomized trials. Summary: The WONDER-01 trial is the first randomized study to directly compare immediate DEN with a drainage-oriented step-up strategy in patients undergoing endoscopic treatment for symptomatic necrotizing pancreatitis. The study demonstrated that immediate necrosectomy significantly shortened the time to clinical success, resulting in faster reduction of necrotic collections and earlier resolution of systemic inflammation. Patients receiving immediate DEN achieved recovery approximately two weeks earlier than those managed with the conventional step-up approach. Importantly, this benefit was achieved without an increase in procedure-related adverse events, mortality, or technical failure. As expected, all patients in the immediate intervention arm underwent necrosectomy, whereas less than half of patients in the step-up group ultimately required the procedure, highlighting the trade-off between faster recovery and greater procedural utilization. The findings suggest that early removal of necrotic debris may accelerate disease resolution in appropriately selected patients while maintaining a favorable safety profile. However, because many patients managed with drainage alone avoided necrosectomy altogether, treatment decisions should remain individualized. Overall, this landmark trial provides evidence that immediate DEN after EUS-guided drainage can shorten recovery time without compromising safety. The results challenge the traditional step-up paradigm and support consideration of earlier necrosectomy in selected patients with symptomatic walled-off necrosis, while emphasizing the need to balance procedural burden against potential clinical benefit.

Fatty Pancreas: A Hidden Burden in T2DM : Diabetes Res Clin Pract | June 2026

Introduction: Fatty pancreas disease (FPD), also known as intrapancreatic fat deposition, has emerged as an important metabolic condition closely linked to obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). Although ectopic fat accumulation in the liver has been extensively studied, pancreatic steatosis has received comparatively less attention despite growing evidence suggesting a role in β-cell dysfunction and metabolic deterioration. Problem Statement: The true prevalence of fatty pancreas in patients with T2DM remains uncertain because individual studies have reported highly variable estimates, influenced by differences in population characteristics, imaging modalities, and diagnostic criteria. A comprehensive assessment is needed to clarify the burden of FPD in diabetes and its potential clinical implications. Summary: This meta-analysis evaluated the prevalence of fatty pancreas disease among individuals with T2DM by pooling data from observational studies across diverse populations. The analysis demonstrated that fatty pancreas is highly prevalent in patients with T2DM, affecting approximately one-half of individuals with the disease. This finding highlights pancreatic steatosis as a common but often underrecognized component of the diabetic phenotype. Subgroup analyses suggested variability in prevalence across geographic regions and study settings, although the overall burden remained consistently high. Importantly, the prevalence was not significantly influenced by differences in imaging techniques or study period, indicating that the association between T2DM and pancreatic fat accumulation is robust across methodologies. These results support the concept that ectopic pancreatic fat may represent an important metabolic abnormality accompanying diabetes, potentially contributing to insulin resistance, impaired insulin secretion, and disease progression. The findings also reinforce growing interest in the pancreas as a target organ in metabolic disease, analogous to the liver in metabolic dysfunction–associated steatotic liver disease. From a clinical perspective, the study underscores the need for greater awareness of fatty pancreas in patients with T2DM and highlights the importance of future research to determine its prognostic significance, role in diabetes progression, relationship with pancreatitis and pancreatic cancer, and potential responsiveness to lifestyle and pharmacological interventions.

Selective Use of Biliary Drainage Supported in pCCA : BJS | Jun 2026

Introduction: Preoperative biliary drainage (PBD) is frequently used in patients with perihilar cholangiocarcinoma (pCCA) to relieve biliary obstruction before surgery. The proposed benefits include improved liver function, reduced jaundice, and optimization of the future liver remnant before major hepatectomy. However, biliary drainage is also associated with procedure-related complications, infection, and potential delays to definitive surgery. As a result, its routine use remains controversial. Problem Statement: Current practice varies widely because there is no clear consensus regarding which patients with resectable pCCA truly benefit from preoperative biliary drainage. Determining whether drainage improves or worsens postoperative outcomes is critical for optimizing perioperative management and reducing surgical risk. Summary: This large international multicenter study evaluated the impact of preoperative biliary drainage on postoperative outcomes in patients undergoing resection for perihilar cholangiocarcinoma. After adjustment for important baseline differences, the investigators found that patients who underwent biliary drainage experienced higher rates of major postoperative complications and, most notably, a significantly increased risk of posthepatectomy liver failure. When additional multivariable analyses were performed, the association with posthepatectomy liver failure remained robust, suggesting that biliary drainage may contribute to adverse postoperative liver-related outcomes in selected patients. These findings challenge the traditional assumption that preoperative drainage is universally beneficial before major liver resection for pCCA. Importantly, the study does not imply that biliary drainage should be abandoned altogether. Rather, it highlights that a subset of patients with resectable disease may proceed safely to surgery without routine drainage. The results support a more individualized approach in which decisions are guided by factors such as bilirubin levels, cholangitis, anticipated future liver remnant volume, and planned extent of resection. Given the retrospective nature of the analysis, definitive conclusions regarding causality cannot be drawn. Nevertheless, this represents one of the largest studies addressing this question and provides important evidence that routine preoperative biliary drainage should be carefully reconsidered. Future prospective studies are needed to better define which patients derive genuine benefit from drainage before surgery for perihilar cholangiocarcinoma.

Pancreatic Plasticity in Development and Disease : Nat Rev Gastroenterol Hepatol | May 2026

Introduction The pancreas represents one of the most dynamic models of cellular plasticity in human biology, where developmental fate decisions, tissue maintenance and regenerative responses are orchestrated through tightly regulated transcriptional and microenvironmental interactions. Recent advances in single-cell sequencing, spatial transcriptomics and lineage-tracing technologies have transformed understanding of pancreatic ontogeny, uncovering previously unrecognized cellular heterogeneity and transient developmental states. Pancreatic Cancer and Diabetes have increasingly been linked to dysregulated cellular plasticity pathways that recapitulate embryonic developmental programs. Problem Statement Despite major progress in defining pancreatic cell lineages, the mechanisms governing lineage commitment, dedifferentiation and regeneration remain incompletely understood. The relationship between developmental plasticity and pathological reprogramming in adult pancreatic tissue is particularly important, as injury-induced or disease-associated plasticity may contribute both to tissue repair and malignant transformation. Understanding how pancreatic cell identity is established and destabilized is critical for advancing regenerative medicine, stem-cell–based therapies and novel therapeutic strategies for pancreatic diseases. Summary This review provides an integrated overview of pancreatic development and cellular plasticity across embryogenesis, tissue homeostasis and disease. Pancreatic organogenesis is presented as a highly coordinated process involving reciprocal signalling between pancreatic endoderm and surrounding mesenchymal, endothelial, neural and immune compartments. These interactions are integrated through complex gene regulatory networks governed by lineage-defining transcription factors that determine endocrine, acinar and ductal cell fates. Single-cell and spatial analyses have identified substantial cellular diversity within pancreatic tissue, including rare and transient intermediate states that appear critical for lineage specification and adaptive remodelling. The review highlights how developmental plasticity mechanisms persist into adulthood, where they may become reactivated during injury, inflammation and neoplastic transformation. In particular, adult pancreatic cells can undergo dedifferentiation and lineage conversion in response to stress, resembling embryonic transcriptional programs. Such plasticity may support tissue regeneration but can also facilitate tumorigenesis in pancreatic cancer. Importantly, insights derived from developmental biology have enabled the generation of pancreatic cell types from human pluripotent stem cells, advancing the field of regenerative therapeutics for diabetes and pancreatic disorders. Emerging in vitro systems that better reproduce pancreatic microenvironmental niches and multicellular interactions are now providing increasingly physiologic platforms for disease modelling and therapeutic development. Overall, the review positions cellular plasticity as a central biological principle linking pancreatic development, regeneration and disease pathogenesis, with major implications for future translational strategies.

Rethinking Antibiotic Strategy in Infected Necrotizing Pancreatitis | Journal of Antimicrobial Chemotherapy

Introduction Infected necrotizing pancreatitis remains one of the most severe complications of acute pancreatitis and is associated with substantial morbidity, organ failure and mortality. Management relies on timely antimicrobial therapy combined with delayed, minimally invasive source control strategies. However, optimal antibiotic selection remains controversial because treatment is frequently empirical and microbiological confirmation is often unavailable early in the disease course. Problem Statement Traditional management has favored carbapenems because of presumed superior pancreatic penetration, yet increasing antimicrobial resistance and prolonged antibiotic exposure are reshaping the microbiology of infected pancreatic necrosis. At the same time, uncertainty persists regarding the true role of anaerobes, enterococci and fungal pathogens, while inappropriate empirical therapy remains common and may contribute to worse outcomes and multidrug resistance. Summary This comprehensive review highlights the evolving microbiological and pharmacokinetic landscape of infected necrotizing pancreatitis and challenges several long-standing assumptions regarding antimicrobial therapy. The microbiology is predominantly enteric, with Gram-negative organisms such as Escherichia coli and Klebsiella species remaining the dominant pathogens, although prolonged hospitalization and cumulative antibiotic exposure increasingly select for multidrug-resistant organisms, enterococci and fungal infections. Importantly, the review emphasizes that prophylactic antibiotics do not prevent infected necrosis or improve mortality and therefore should not be routinely used. The authors also question the traditional preference for carbapenems, noting that pharmacokinetic studies demonstrate that piperacillin-tazobactam and advanced-generation cephalosporins can achieve adequate penetration into necrotic pancreatic tissue, particularly when administered using extended infusion strategies. Molecular diagnostic studies further suggest that anaerobic organisms are substantially underrecognized by conventional culture techniques, supporting the rationale for empirical anaerobic coverage despite low reported culture yields. The review advocates for more individualized antimicrobial selection based on local resistance patterns, previous antibiotic exposure and evolving disease phase, while reserving carbapenems for multidrug-resistant infections or clinical failure. Overall, this work supports a more stewardship-focused, pharmacokinetically informed approach to antimicrobial therapy in infected necrotizing pancreatitis.

GCAL Score Helps Triage EUS in Unexplained Bile Duct Dilatation | Indian Journal of Gastroenterology

Introduction Unexplained common bile duct (CBD) dilatation is a frequent and often challenging clinical finding in gastroenterology practice. Although cross-sectional imaging may fail to identify a cause, endoscopic ultrasound (EUS) can detect clinically significant biliary and periampullary pathology that may require intervention. The challenge lies in identifying which patients are most likely to benefit from EUS while avoiding unnecessary procedures in low-risk individuals. Problem Statement Not all patients with isolated CBD dilatation harbor clinically meaningful pathology, yet routine EUS for all such patients is resource-intensive and may not be justified. A practical and validated clinical tool is needed to identify patients with a high likelihood of actionable findings and better guide EUS utilization in this increasingly common diagnostic scenario. Summary This study presents the development and prospective validation of the GCAL score, a practical risk stratification tool designed to identify patients with unexplained CBD dilatation who are most likely to benefit from EUS. The score incorporates five readily available clinical variables—gallbladder status, CBD diameter, age and liver function abnormalities—to predict the likelihood of actionable findings requiring endoscopic or surgical intervention. In both derivation and validation cohorts, EUS identified actionable pathology in approximately half of patients, underscoring its diagnostic value in this setting. The GCAL score demonstrated strong predictive performance and reliably distinguished patients at higher risk of clinically significant findings from those less likely to benefit from further invasive evaluation. Importantly, the model performed particularly well in prospective validation, supporting its clinical applicability in routine practice. These findings provide a simple and clinically relevant framework for triaging EUS in patients with unexplained bile duct dilatation and may help optimize procedural selection, improve diagnostic efficiency and reduce unnecessary investigations.