Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Glucagon-Like Peptide Receptor Agonists Use Before Endoscopy Is Associated With Low Retained Gastric Contents: A Multicenter Cross-Sectional Analysis.

INTRODUCTION: While ubiquity of glucagon-like peptide receptor agonists (GLP1-RAs) is rising, guidance from the gastroenterology societies and American Society of Anesthesiologist (ASA) remains in conflict on recommendations regarding preoperative holding before endoscopy. The aim of this study was to address this by evaluating the effect of GLP1-RAs on gastric retention during upper endoscopy. METHODS: This multicenter cross-sectional study included patients on confirmed GLP1-RAs receiving an endoscopy from 2021 to 2023. Demographics, prescribing practices, and procedure outcomes were captured. GLP1-RA management of preoperative holding was retroactively classified per ASA guidance. Multivariable logistic regression was performed to assess factors influencing retained gastric contents. RESULTS: Of 815 patients, 70 (8.7%) had retained gastric contents on endoscopy of whom 65 (93%) had type 2 diabetes mellitus. Only 1 (1.4%) of these patients required unplanned intubation, and none had aspiration events. Those with GLP1-RA held per ASA guidance (406, 49.8%) were less likely to have retained contents (4.4% vs 12.7%, P < 0.001), but there were no significant differences to intubation (0% vs 2%, P = 0.53) or aborting procedure rates (28% vs 18%, P = 0.40) due to gastric retention. On multivariable analysis, likelihood of food retention increased 36% (95% confidence interval 1.15-1.60) for every 1% increase in hemoglobin A1C after adjusting for GLP1-RA type and preoperative medication hold. DISCUSSION: In this multicenter study, very low rates of retained gastric contents were seen during endoscopy in patients on GLP1-RAs and most were in patients with type 2 diabetes mellitus. Our findings suggest an individualized approach rather than universal preoperative holding of medications before endoscopy.

EUS-guided coil injection therapy in the management of gastric varices: the first U.S. multicenter experience (with video).

BACKGROUND AND AIMS: Despite the significant morbidity associated with gastric variceal bleeding, there is a paucity of high-quality data regarding optimal management. EUS-guided coil injection therapy (EUS-COIL) has recently emerged as a promising endoscopic modality for the treatment of gastric varices (GV), particularly compared with traditional direct endoscopic glue injection. Although there are data on the feasibility and safety of EUS-COIL in the management of GV, these have been limited to select centers with particular expertise. The aim of this study was to report the first U.S. multicenter experience of EUS-COIL for the management of GV. METHODS: This retrospective analysis included patients with bleeding GV or GV at risk of bleeding who underwent EUS-COIL at 10 U.S. tertiary care centers between 2018 and 2022. Baseline patient and procedure-related information was obtained. EUS-COIL entailed the injection of .018 inch or .035 inch hemostatic coils using a 22-gauge or 19-gauge FNA needle. Primary outcomes were technical success (defined as successful deployment of coil into varix under EUS guidance with diminution of Doppler flow), clinical success (defined as cessation of bleeding if present and/or absence of bleeding at 30 days' postintervention), and intraprocedural and postprocedural adverse events. RESULTS: A total of 106 patients were included (mean age 60.4 ± 12.8 years; 41.5% female). The most common etiology of GV was cirrhosis (71.7%), with alcohol being the most common cause (43.4%). Overall, 71.7% presented with acute GV bleeding requiring intensive care unit stay and/or blood transfusion. The most common GV encountered were isolated GV type 1 (60.4%). A mean of 3.8 ± 3 coils were injected with a total mean length of 44.7 ± 46.1 cm. Adjunctive glue or absorbable gelatin sponge was injected in 82% of patients. Technical success and clinical success were 100% and 88.7%, respectively. Intraprocedural adverse events (pulmonary embolism and GV bleeding from FNA needle access) occurred in 2 patients (1.8%), and postprocedural adverse events occurred in 5 (4.7%), of which 3 were mild. Recurrent bleeding was observed in 15 patients (14.1%) at a mean of 32 days. Eighty percent of patients with recurrent bleeding were successfully re-treated with repeat EUS-COIL. No significant differences were observed in outcomes between high-volume (>15 cases) and low-volume (<7 cases) centers. CONCLUSIONS: This U.S. multicenter experience on EUS-COIL for GV confirms high technical and clinical success with low adverse events. No significant differences were seen between high- and low-volume centers. Repeat EUS-COIL seems to be an effective rescue option for patients with recurrent bleeding GV. Further prospective studies should compare this modality versus other interventions commonly used for GV.

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Structured training program on confocal laser endomicroscopy for pancreatic cystic lesions: a multicenter prospective study among early-career endosonographers (with video).

BACKGROUND AND AIMS: Data on how to teach endosonographers needle-based confocal laser endomicroscopy (nCLE)-guided histologic diagnosis of pancreatic cystic lesions (PCLs) are limited. Hence, we developed and tested a structured educational program to train early-career endosonographers in nCLE-guided diagnosis of PCLs. METHODS: Twenty-one early-career nCLE-naïve endosonographers watched a teaching module outlining nCLE criteria for diagnosing PCLs. Participants then reviewed 80 high-yield nCLE videos, recorded diagnoses, and received expert feedback (phase 1). Observers were then randomized to a refresher feedback session or self-learning at 4 weeks. Eight weeks after training, participants independently assessed the same 80 nCLE videos without feedback and provided histologic predictions (phase 2). Diagnostic performance of nCLE to differentiate mucinous versus nonmucinous PCLs and to diagnose specific subtypes were analyzed using histopathology as the criterion standard. Learning curves were determined using cumulative sum analysis. RESULTS: Accuracy and diagnostic confidence for differentiating mucinous versus nonmucinous PCLs improved as endosonographers progressed through nCLE videos in phase 1 (P < .001). Similar trends were observed with the diagnosis of PCL subtypes. Most participants achieved competency interpreting nCLE, requiring a median of 38 assessments (range, 9-67). During phase 2, participants independently differentiated PCLs with high accuracy (89%), high confidence (83%), and substantial interobserver agreement (κ = .63). Accuracy for nCLE-guided PCL subtype diagnoses ranged from 82% to 96%. The learned nCLE skills did not deteriorate at 8 weeks and were not impacted by a refresher session. CONCLUSIONS: We developed a practical, effective, and durable educational intervention to train early-career endosonographers in nCLE-guided diagnosis of PCLs.

Magnitude and Time-Trend Analysis of Postendoscopy Esophageal Adenocarcinoma: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Identification of postendoscopy esophageal adenocarcinoma (PEEC) among Barrett's esophagus (BE) patients presents an opportunity to improve survival of esophageal adenocarcinoma (EAC). We aimed to estimate the proportion of PEEC within the first year after BE diagnosis. METHODS: Multiple databases (Medline, Embase, Scopus, and Cochrane databases) were searched until September 2020 for original studies with at least 1-year follow-up evaluation that reported EAC and/or high-grade dysplasia (HGD) in the first year after index endoscopy in nondysplastic BE, low-grade dysplasia, or indefinite dysplasia. The proportions of PEEC defined using EAC alone and EAC+HGD were calculated by dividing EAC or EAC+HGD in the first year over the total number of EAC or EAC+HGD, respectively. RESULTS: We included 52 studies with 145,726 patients and a median follow-up period of 4.8 years. The proportion of PEEC (EAC) was 21% (95% CI, 13-31) and PEEC (EAC+HGD) was 26% (95% CI, 19-34). Among studies with nondysplastic BE only, the PEEC (EAC) proportion was 17% (95% CI, 11-23) and PEEC (EAC+HGD) was 14% (95% CI, 8-19). Among studies with 5 or more years of follow-up evaluation, the PEEC (EAC) proportion was 10% and PEEC (EAC+HGD) was 19%. Meta-regression analysis showed a strong inverse relationship between PEEC and incident EAC (P < .001). The PEEC (EAC) proportion increased from 5% in studies published before 2000 to 30% after 2015. Substantial heterogeneity was observed for most analyses. CONCLUSIONS: PEEC accounts for a high proportion of HGD/EACs and is proportional to reduction in incident EAC. Using best endoscopic techniques now and performing future research on improving neoplasia detection through implementation of quality measures and educational tools is needed to reduce PEEC.

Prognostic Value of Hypochloremia in Critically Ill Patients With Decompensated Cirrhosis.

OBJECTIVES: Cirrhosis is frequently complicated by electrolyte disturbances, with prior studies primarily focused on the importance of hyponatremia. Emerging evidence on patients with chronic heart failure and chronic kidney disease has identified hypochloremia as an independent predictor for mortality. This study aimed to investigate the prognostic value of serum chloride and its association with mortality in cirrhotic patients. DESIGN: Retrospective cohort study. SETTING: The medical ICU at Parkland Memorial Hospital, a tertiary care public health system in Dallas, Texas. PATIENTS: Adult patients with confirmed diagnosis of decompensated cirrhosis who were admitted to the ICU between March 2015 and March 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Kaplan-Meier analysis and multivariable Cox proportional hazard ratio models were performed to determine the impact of hypochloremia on 180-day mortality. Of the 389 enrolled patients, 133 (34.2%) died within 180 days of ICU admission. Patients with hypochloremia had higher 180-day mortality than those with normochloremia (45.2% vs 26.7%; p < 0.0001). Cumulative survival via the Kaplan-Meier method was significantly lower in the hypochloremic group. Serum chloride was independently associated with 180-day mortality with multivariable adjustment (hazard ratio, 0.95; 95% CI, 0.93-0.98; p = 0.001) or after adjusting for Model for End-stage Liver Disease or Sequential Organ Failure Assessment. Contrarily, the inverse association between serum sodium and mortality no longer existed in all multivariable models. CONCLUSIONS: Serum chloride is independently and inversely associated with short-term mortality in critically ill cirrhotic patients. Hypochloremia, but not hyponatremia, remained associated with mortality with multivariable analyses, suggesting that hypochloremia may account for the mortality risk previously attributed to hyponatremia. These findings signify the prognostic value of serum chloride and potential inclusion of chloride into future cirrhosis prognostic scores.

Endoscopic repair of surgically transected bile duct using overlapping covered metal stents.

Video 1Endoscopic repair of surgically transected bile duct using overlapping covered metal stents.

How I do It: Zenker's Per Oral Endoscopic Myotomy with Partial Mucosal Septum Division Modification.

We describe our current approach for flexible endoscopic management of Zenker's diverticulum. This approach utilizes the latest techniques in flexible Zenker's surgery including submucosal division of the muscular common wall, partial mucosal wall division, and watertight closure. Laryngoscope, 2024.

Epidemiology and Risk Factors for Upper Gastrointestinal Bleeding.

Although the incidence of nonvariceal upper gastrointestinal bleeding (UGIB) has been decreasing worldwide, nonvariceal UGIB continues to be a significant problem. Even with the advent of advanced endoscopic procedures and potent medications to suppress acid production, UGIB carries significant morbidity and mortality. Some of the most common risk factors for nonvariceal UGIB include Helicobacter pylori infection, nonsteroidal antiinflammatory drugs (NSAIDs), aspirin, selective serotonin reuptake inhibitors, and other antiplatelet and anticoagulant medications. In patients with cardiovascular disease and kidney disease, UGIB tends to be more severe and has greater morbidity. Many of the newer NSAIDs have been removed from the market.