Adverse Events Associated With Endoscopic Retrograde Cholangiopancreatography: Systematic Review and Meta-Analysis.
Gastroenterology
BACKGROUND & AIMS:Endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events (AEs) are associated with morbidity, mortality, and health care expenditure. We aimed to assess incidences and comparisons of ERCP AEs. METHODS:We included studies performed after 2000 reporting on ERCP AEs from database inception through March 12, 2024. Outcomes included pancreatitis, bleeding, cholangitis, cholecystitis, perforation, and death. DerSimonian and Laird random effects meta-analyses were performed to calculate incidences of AEs. Subgroup and pairwise meta-analyses were performed. Meta-regression was performed on median recruitment year to assess temporal trends in pancreatitis incidence. RESULTS:A total of 380 studies were included. The incidence of death attributable to ERCP was 0.2% (95% confidence interval [CI], 0.1%-0.3%; I, 44%; n = 47,258) in all-comers. The overall incidence of pancreatitis was 4.6% (95% CI, 4.0%-5.1%; I, 96%; n = 293,378) among all-comers and 6.5% (95% CI, 5.9%-7.1%, I, 89%; n = 88,809) among first-time patients. Pancreatitis incidence remained stable between 2000 and 2023 (average annual percent change 0.06, 95% CI, -0.27 to 0.39). The overall incidences of the following AEs for all-comers were: bleeding (1.5%; 95% CI, 1.2%-1.7%; I, 93%; n = 229,655), cholangitis (2.5%; 95% CI, 1.9%-3.3%; I, 96%; n = 121,619), cholecystitis (0.8%; 95% CI, 0.5%-1.2%; I, 39%; n = 7799), and perforation (0.5%; 95% CI, 0.4%-0.6%; I, 90%; n = 306,378). CONCLUSIONS:ERCP-associated AEs remain common. Incidence of post-ERCP pancreatitis remained static despite improvements in techniques, prevention, and recognition. These results are important to patients, endoscopists, and policy makers to inform consent and to encourage implementation of available risk mitigation strategies.
10.1053/j.gastro.2024.10.033
Phase 3 Validation of Prognostic Liver Secretome Signature With α-Fetoprotein Plus Age, Male Sex, Albumin-Bilirubin, and Platelets for Hepatocellular Carcinoma Risk Stratification in Cirrhosis.
Gastroenterology
BACKGROUND & AIMS:Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis. METHODS:Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events. RESULTS:Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection. CONCLUSIONS:PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.
10.1053/j.gastro.2024.10.035
Creeping Fat-Derived Free Fatty Acids Induce Hyperplasia of Intestinal Muscularis Propria Muscle Cells: A Novel Link Between Fat and Intestinal Stricture Formation in Crohn's Disease.
Gastroenterology
BACKGROUND & AIMS:In Crohn's disease, wrapping of mesenteric fat around the bowel wall, so-called "creeping fat," is highly associated with strictures. The strongest contributor to luminal narrowing in strictures is a thickening of the human intestinal muscularis propria (MP). We investigated creeping fat-derived factors and their effect on mechanisms of human intestinal MP smooth muscle cell (HIMC) hyperplasia. METHODS:Free fatty acids (FFAs) in creeping fat or noncreeping mesenteric fat organ cultures were measured via lipidomic mass spectrometry. Primary HIMCs were exposed to FFAs and cell proliferation was assessed. Intracellular FFA metabolism pathways and reactive oxygen species were functionally evaluated. Muscle thickness was investigated in dextran sodium sulfate colitis with small molecule inhibition of FFA transport and a novel fat deletion mouse model. RESULTS:Subserosal creeping fat is associated with a markedly thickened MP. Experimental deletion of mesenteric fat (FAT-ATTAC [fat apoptosis through targeted activation of caspase 8] mouse) reduced MP thickness. Human creeping fat-conditioned medium strongly up-regulated HIMC proliferation. Creeping fat released higher amounts of 5 long-chain FFAs, including palmitate. Inhibition of HIMC long-chain FFA metabolism or FFA uptake into mitochondria through carnitine palmitoyltransferase-1 reduced the palmitate-induced HIMC proliferation. Blockade of conversion of palmitate into phospholipids reduced HIMC proliferation. Prophylactic inhibition of carnitine palmitoyltransferase-1 in experimental dextran sodium sulfate colitis did not ameliorate inflammation, but reduced MP thickness. CONCLUSIONS:Creeping fat-released long-chain FFAs induce a selective proliferative response by HIMC. These results point to creeping fat as a novel contributor to stricture formation in Crohn's disease.
10.1053/j.gastro.2024.10.034
AGA Clinical Practice Update on Endoscopic Enteral Access: Commentary.
Gastroenterology
DESCRIPTION:The purpose of this American Gastroenterological Association (AGA) Clinical Practice Update is to facilitate understanding and improve the clinical practice of endoscopic enteral access. METHODS:This expert commentary was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology.
10.1053/j.gastro.2024.09.043
AGA Clinical Practice Update on Nonampullary Duodenal Lesions: Expert Review.
Gastroenterology
DESCRIPTION:Nonampullary duodenal polyps are found in up to 5% of all upper endoscopies; the vast majority are identified incidentally in asymptomatic patients. Although most are benign, adenomas are estimated to account for 10%-20% of these lesions. Most international guidelines recommend that all duodenal adenomas should be considered for endoscopic resection; this may be associated with a near 15% adverse event rate (predominantly bleeding and perforation) in prospective studies, with substantial local recurrence on surveillance. The aim of this American Gastroenterological Association (AGA) Clinical Practice Update Expert Review was to describe how individuals should be evaluated and risk-stratified for duodenal polyps, the best approaches to endoscopic resection and surveillance, and management of complications, highlighting opportunities for future research to fill gaps in the existing literature. METHODS:This expert review was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Non-neoplastic duodenal lesions (eg, metaplastic foveolar epithelium and gastric heterotopia) may mimic neoplastic adenomatous pathology. Careful optical evaluation and pathologic correlation may be necessary to exclude dysplasia. Nondysplastic lesions do not require endoscopic resection unless they are symptomatic or bleeding. BEST PRACTICE ADVICE 2: Ideal duodenal endoscopic inspection includes identification of the major and minor papilla with photodocumentation to ensure no involvement by the lesion. Adding a clear distal attachment device to a forward-viewing gastroscope improves visualization of the papilla and the medial wall. A side-viewing duodenoscope should be used when the major and minor papilla are not visible with the gastroscope and for most lesions on the medial wall of the duodenum within 5 cm of the ampulla. BEST PRACTICE ADVICE 3: All duodenal polyps should be described according to their size, Paris morphology, suspected histologic layer of origin (mucosal lesion or subepithelial lesion), duodenal location (D1-4) and orientation (anterior, posterior, medial, or lateral wall), and proximity/relationship to the major papilla to facilitate therapeutic planning and subsequent surveillance. BEST PRACTICE ADVICE 4: Given the high frequency of concomitant colonic adenomas in patients with duodenal adenomas, on identification of a duodenal adenoma, a colonoscopy should be performed if a high-quality examination has not been performed in the last 3 years. BEST PRACTICE ADVICE 5: Routine small bowel investigation (ie, capsule endoscopy) is not advised in patients with sporadic and nonsporadic duodenal adenomas. Periodic small bowel inspection with capsule endoscopy may be of benefit in patients with Peutz-Jeghers syndrome. BEST PRACTICE ADVICE 6: Definitive treatment of duodenal adenomas by endoscopic resection is less morbid, resource-intensive, and expensive than surgery and is therefore the preferred treatment option. BEST PRACTICE ADVICE 7: Due to the risk of malignant transformation, all sporadic duodenal adenomas should be considered for endoscopic resection. However, in comparison with colonic adenomas, the time course to malignant transformation may be more prolonged, and the risk of resection-related morbidity much greater. Therefore, the comorbidities and anticipated longevity of the patient must be carefully factored into the decision-making process. BEST PRACTICE ADVICE 8: The approach to endoscopic duodenal resection (ie, hot vs cold and conventional vs underwater endoscopic mucosal resection) should be individualized to reduce bleeding risk, based on lesion size, morphology, patient comorbidities, and endoscopist comfort level with specific techniques. Piecemeal cold snare resection for flat duodenal adenomas mitigates postprocedural bleeding risk and, for lesions <20 mm, is effective and carries a minimal risk of recurrence. In patients with comorbidities with flat nonbulky lesions measuring < 20 mm, cold snare resection can be considered. BEST PRACTICE ADVICE 9: Currently, duodenal adenomas >20 mm or with large Paris subtype Is components should be removed by conventional hot snare endoscopic mucosal resection. Thermal ablation of the post-endoscopic mucosal resection margin to mitigate the risk of recurrence to <2%-5% is safe and effective and should be considered. BEST PRACTICE ADVICE 10: Endoscopists performing duodenal polyp resection should be aware of the increased risk of postprocedural bleeding (compared with elsewhere in the gastrointestinal tract), which usually occurs in the first 48 hours after the procedure, with the risk proportional to the lesion size. For lesions >3 cm, bleeding risk is >25% and may be life-threatening and associated with hemodynamic compromise; however, after resuscitation, endoscopic hemostasis is generally effective. BEST PRACTICE ADVICE 11: Evaluation of the postpolypectomy/endoscopic mucosal resection defect is critical to identify concerns for postprocedural duodenal perforation, which, if unrecognized and left untreated, may be life-threatening and often mandates surgery. BEST PRACTICE ADVICE 12: Initial endoscopic surveillance for a completely resected duodenal adenoma should be undertaken at an interval of 6 months. Although usually diminutive, recurrence is often scarred and not amenable to conventional snare resection and may require avulsion techniques to achieve cure. BEST PRACTICE ADVICE 13: Nonampullary duodenal adenomas associated with familial adenomatous polyposis should be considered for endoscopic resection based on size (≥1 cm), morphologic characteristics, advanced histology (ie, high-grade dysplasia), and/or based on Spiegelman criteria.
10.1053/j.gastro.2024.10.008
Hypoxic and acidic tumor microenvironment-driven AVL9 promotes chemoresistance of pancreatic ductal adenocarcinoma via the AVL9-IκBα-SKP1 complex.
Gastroenterology
BACKGROUND & AIMS:Gemcitabine combined with albumin-paclitaxel (AG) is a crucial therapeutic option for pancreatic ductal adenocarcinoma (PDAC). However, the response to chemotherapy is relatively poor, with rapid development of resistance. The aim of this study was to explore the mechanism of resistance to AG and to develop strategies that can sensitize the AG regimen. METHODS:We utilized organoid models, patient-derived xenografts (PDX), and genetically engineered mouse models (GEMM) in our study. Chromatin-Immunoprecipitation (Ch-IP), double luciferase assay, Co-immunoprecipitation (Co-IP), and far-western blotting analysis were performed to investigate the mechanism. The AVL9 inhibitors were identified through protein structure analysis and molecular docking analysis, and their efficacy was verified in PDX, PDOX, and KPC models. RESULTS:Through multi-strategy screening, we identified AVL9 as a key target for AG resistance in PDAC. Its tumor-promoting effects were confirmed in our clinical cohorts. Mechanistically, HIF-1α, a hypoxia-related transcription factor, drives the expression of AVL9. AVL9 acts as a scaffold that facilitates the binding of IκBα to SKP1, leading to enhanced ubiquitination and degradation of IκBα, which further activates the NF-κB pathway. The potential AVL9-targeting inhibitor, Edotecarin, was shown to reverse AG chemo-resistance in PDAC. CONCLUSION:AVL9 expression is driven by HIF1α in PDAC. The physical interaction of AVL9, IκBα, and SKP1 provides a novel molecular mechanism for the abnormal activation of the NF-κB pathway. Therefore, the AVL9-targeting drug Edotecarin could be a promising therapeutic strategy for sensitizing PDAC to AG.
10.1053/j.gastro.2024.10.042
AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis.
Gastroenterology
BACKGROUND & AIMS:This American Gastroenterological Association (AGA) living guideline is intended to support practitioners in the pharmacological management of moderate-to-severe ulcerative colitis (UC). METHODS:A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to prioritize clinical questions, identify patient-centered outcomes, conduct an evidence synthesis, and develop recommendations on the pharmacological management of moderate-to-severe UC. RESULTS:The AGA guideline panel made 14 recommendations. In adult outpatients with moderate-to-severe UC, the AGA recommends the use of infliximab, golimumab, vedolizumab, tofacitinib, upadacitinib, ustekinumab, ozanimod, etrasimod, risankizumab, and guselkumab, and suggests the use of adalimumab, filgotinib, and mirikizumab over no treatment. In patients who are naïve to advanced therapies, the AGA suggests using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (eg, golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication (eg, adalimumab). In patients who have previously been exposed to 1 or more advanced therapies, particularly tumor necrosis factor (TNF)-α antagonists, the AGA suggests using a higher-efficacy medication (eg, tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy medication (eg, filgotinib, mirikizumab, risankizumab, and guselkumab) rather than a lower-efficacy medication (eg, adalimumab, vedolizumab, ozanimod, and etrasimod). In adult outpatients with moderate-to-severe UC, the AGA suggests against using thiopurine monotherapy for induction of remission, but suggests using thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission. The AGA suggests against using methotrexate monotherapy, for induction or maintenance of remission. In adult outpatients with moderate-to-severe UC, the AGA suggests the use of infliximab, adalimumab, and golimumab in combination with an immunomodulator over corresponding monotherapy. However, the AGA makes no recommendation in favor of, or against, the use of non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologic alone. In patients with UC who are in corticosteroid-free clinical remission for at least 6 months on combination therapy of TNF antagonists and an immunomodulator, the AGA suggests against withdrawal of TNF antagonists, but makes no recommendation in favor of, or against, withdrawing immunomodulators. In adult outpatients with moderate-to-severe UC, who have failed 5-aminosalicylates, and have escalated to therapy with immunomodulators or advanced therapies, the AGA suggests stopping 5-aminosalicylates. Finally, in adult outpatients with moderate-severe UC, the AGA suggests early use of advanced therapies and/or immunomodulator therapy, rather than gradual step-up after failure of 5-aminosalicylates. The panel also proposed key implementation considerations for optimal use of these medications and identified several knowledge gaps and areas for future research. CONCLUSIONS:This guideline provides a comprehensive, patient-centered approach to the pharmacological management of patients with moderate-to-severe UC.
10.1053/j.gastro.2024.10.001
A pan-genotypic hepatitis E virus replication inhibitor with high potency in a rat infection model.
Gastroenterology
BACKGROUND & AIMS:Hepatitis E virus (HEV) constitutes a substantial public health burden with ∼20 million human infections annually, including 3.3 million symptomatic cases. Appropriate treatment options for, in particular, HEV-infected immunocompromised patients and pregnant women are lacking, underscoring the urgent need for potent and safe antiviral drugs. METHODS:HEV subgenomic replicon systems were used to screen a small library of pre-selected nucleoside analogues, originally developed in a hepatitis C virus (HCV) antiviral program. Antiviral activity of the selected hit on HEV infection was evaluated in a variety of cell culture systems; the efficacy of the compound was assessed in the athymic nude rat HEV infection model. RESULTS:Compound JNJ-9117 exerts pan-genotype antiviral activity against HEV in different cell types as well as in primary human hepatocytes. A high level of conservation is observed between three crucial motifs in the catalytic domain of the HCV and HEV polymerases. This suggests a mechanism of action that is identical to that of the molecule against HCV, whereby the 5'-triphosphate of JNJ-9117 acts as a chain terminator during viral RNA synthesis. JNJ-9117 has a favorable pharmacokinetic and safety profile in rats and results in a pronounced antiviral effect in a chronic rat HEV infection model, both in a prophylactic and therapeutic setting. The combination of JNJ-9117 and ribavirin (each at an intentionally selected suboptimal/inactive dose) was in infected rats highly effective in lowering viral RNA load in liver and feces to (almost) undetectable levels. CONCLUSIONS:JNJ-9117 has a profile that holds promise for the treatment of life-threatening HEV infections in humans. Phase 1 studies with JNJ-9117 have been initiated in healthy human volunteers.
10.1053/j.gastro.2024.10.043