Search

Importance: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven., Objective: To compare the survival of patients with surveillance-detected PDAC with US national data., Design, Setting, and Participants: This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023., Exposures: Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment., Main Outcomes and Measures: Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted., Results: A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%])., Conclusions and Relevance: These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

Purpose: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance., Materials and Methods: Using a training/validation study design, FUT2 / FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay., Results: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUC PR ) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2., Conclusion: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.

Purpose: Inherited cancer susceptibility is often not suspected in the absence of a significant cancer family history. Pathogenic germline variants in pancreatic cancer are well-studied, and routine genetic testing is recommended in the guidelines. However, data on rare periampullary cancers other than pancreatic cancer are insufficient. We compared the prevalence of germline susceptibility variants in patients with pancreatic cancer and nonpancreatic periampullary cancers., Materials and Methods: Six hundred and eight patients who had undergone pancreaticoduodenal resection at a tertiary referral hospital were studied, including 213 with pancreatic ductal adenocarcinoma, 172 with ampullary cancer, 154 with distal common bile duct cancer, and 69 with duodenal adenocarcinoma. Twenty cancer susceptibility and candidate susceptibility genes were sequenced, and variant interpretation was assessed by interrogating ClinVar and PubMed., Results: Pathogenic or likely pathogenic, moderate- to high-penetrant germline variants were identified in 46 patients (7.7%), including a similar percentage of patients with pancreatic (8.5%) and nonpancreatic periampullary cancer (7.1%). Low-penetrant variants were identified in an additional 11 patients (1.8%). Eighty-nine percent of the moderate- to high-penetrant variants involved the major cancer susceptibility genes BRCA2 , ATM , BRCA1 , CDKN2A , MSH2 / MLH1 , and PALB2 ; the remaining 11% involved other cancer susceptibility genes such as BRIP1 , BAP1 , and MSH6 . Almost all pathogenic variant carriers had a family history of cancer., Conclusion: Patients with pancreatic and nonpancreatic periampullary cancer have a similar prevalence of pathogenic cancer susceptibility variants. Germline susceptibility testing should be considered for patients with any periampullary cancer.

Background: Cancer antigen 19-9 (CA19-9) is widely used as a marker of pancreatic cancer tumor burden and response to therapy. Synthesis of CA19-9 and its circulating levels are determined by variants encoding the fucosyltransferases, FUT2 and FUT3. Individuals can be grouped into one of four functional FUT groups (FUT3-null, FUT-low, FUT-intermediate, FUT-high), each with its own CA19-9 reference range based on its predicted capacity to produce CA19-9. The authors hypothesized that a FUT variant-based CA19-9 tumor marker gene test could improve the prognostic performance of CA19-9., Methods: Preoperative and pre-treatment CA19-9 levels were measured, and FUT variants were determined in 449 patients who underwent surgery for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2010 and 2020, including 270 patients who underwent neoadjuvant therapy. Factors associated with recurrence-free and overall survival were determined in Cox proportional hazards models., Results: Higher preoperative CA19-9 levels were associated with recurrence and mortality for patients in the higher-FUT groups (FUT-intermediate, FUT-high for mortality, with adjustment for other prognostic factors; hazard ratio [HR], 1.34 and 1.58, respectively; P < 0.001), but not for those in the lower-FUT groups (FUT3-null, FUT-low). As a tumor marker, CA19-9 levels of 100 U/ml or lower after neoadjuvant therapy and normalization of CA19-9 based on FUT group were more sensitive but less specific predictors of evidence for a major pathologic response to therapy (little/no residual tumor) and of early recurrence (within 6 months)., Conclusion: Among patients undergoing pancreatic cancer resection, a CA19-9 tumor marker gene test modestly improved the prognostic performance of CA19-9., (© 2024. Society of Surgical Oncology.)

Goals: To better understand the characteristics, treatment approaches, and outcomes of patients with esophageal lichen planus (ELP)., Background: ELP is a rare, often unrecognized and misdiagnosed disorder. Data on this unique patient population are currently limited to small, single-center series., Study: A multicenter, retrospective descriptive study was conducted of adults diagnosed with ELP over a 5-year period, between January 1, 2015, and October 10, 2020, from 7 centers across the United States., Results: Seventy-eight patients (average age 65 y, 86% female, 90% Caucasian) were included. Over half had at least 1 extraesophageal manifestation. Esophageal strictures (54%) and abnormal mucosa (50%) were frequent endoscopic findings, with the proximal esophagus the most common site of stricture. Approximately 20% had normal endoscopic findings. Topical steroids (64%) and/or proton pump inhibitors (74%) dominated management; endoscopic response favored steroids (43% vs. 29% respectively). Almost half of the patients required switching treatment modalities during the study period. Adjunctive therapies varied significantly between centers., Conclusions: Given its at times subtle clinical and endoscopic signs, a high index of suspicion and biopsy will improve ELP diagnosis, especially in those with extraesophageal manifestations. Effective therapies are lacking and vary significantly. Prospective investigations into optimal treatment regimens are necessary., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Factors that influence the pancreas microbiome are not well understood. Regular proton pump inhibitor (PPI) use induces significant alterations in the gut microbiome, including an increase in the abundance of Streptococcus, and may be associated with pancreatic cancer risk. The aim of this study was to examine whether PPI use is associated with pancreatic and duodenal tissue microbiomes. We compared 16S rRNA microbiome profiles of normal pancreatic and duodenal tissue from 103 patients undergoing pancreatic surgery for non-malignant indications, including 34 patients on PPIs, accounting for factors including age, smoking, body mass index and the presence of main pancreatic duct dilation. Histologically normal tissue from the pancreatic head had higher alpha diversity and enrichment of Firmicutes by phylum-level analysis and Streptococcus species compared to normal pancreas body/tail tissues (16.8 % vs 8.8 %, P = .02, and 5.9 % vs 1.4 %, P = .03, respectively). Measures of beta diversity differed significantly between the pancreas and the duodenum, but in subjects with main pancreatic duct dilation, beta diversity of pancreatic head tissue was more similar to normal duodenal tissue than those without pancreatic duct dilation. Duodenal tissue of PPI users had significant enrichment of Firmicute phyla (34.7 % vs. 14.1 %, P = .01) and Streptococcus genera (19.5 % vs. 5.2 %, P = .01) compared to non-users; these differences were not evident in pancreas tissues. By multivariate analysis, PPI use was associated with alpha diversity in the duodenum, but not in the pancreas. However, some differences in pancreas tissue beta diversity were observed between PPI users and non-users. In summary, we find differences in the microbiome profiles of the pancreas head versus the pancreatic body/tail and we find PPI use is associated with alterations in duodenal and pancreatic tissue microbiome profiles., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of the study is to assess the relationship between magnetic resonance imaging (MRI)-based estimation of pancreatic fat and histology-based measurement of pancreatic composition., Materials and Methods: In this retrospective study, MRI was used to noninvasively estimate pancreatic fat content in preoperative images from high-risk individuals and disease controls having normal pancreata. A deep learning algorithm was used to label 11 tissue components at micron resolution in subsequent pancreatectomy histology. A linear model was used to determine correlation between histologic tissue composition and MRI fat estimation., Results: Twenty-seven patients (mean age 64.0 ± 12.0 years [standard deviation], 15 women) were evaluated. The fat content measured by MRI ranged from 0% to 36.9%. Intrapancreatic histologic tissue fat content ranged from 0.8% to 38.3%. MRI pancreatic fat estimation positively correlated with microanatomical composition of fat (r = 0.90, 0.83 to 0.95], P < 0.001); as well as with pancreatic cancer precursor ( r = 0.65, P < 0.001); and collagen ( r = 0.46, P < 0.001) content, and negatively correlated with pancreatic acinar ( r = -0.85, P < 0.001) content., Conclusions: Pancreatic fat content, measurable by MRI, correlates to acinar content, stromal content (fibrosis), and presence of neoplastic precursors of cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC)., Experimental Design: A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19-9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19-9 alone versus with the gene test., Results: Applying the CA19-9 standard cutoff (<36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19-9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19-9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P < 0.001)., Conclusions: Using a tumor marker gene test to personalize an individual's CA19-9 reference range significantly improves diagnostic accuracy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Revision of a failed laparoscopic fundoplication carries higher risk of complication and lower chance of success compared to the original surgery. Transoral incisionless fundoplication (TIF) may be an endoscopic alternative for select GERD patients without need of a moderate/large hiatal hernia repair. The aim of this study was to assess feasibility, efficacy, and safety of TIF 2.0 after failed laparoscopic Nissen or Toupet fundoplication (TIFFF)., Methods: This is a multicenter retrospective cohort study of patients who underwent TIFFF between September 2017 and December 2020 using TIF 2.0 technique (EsophyX Z/Z+) performed by gastroenterologists and surgeons. Patients were included if they had (1) recurrent GERD symptoms, (2) pathologic reflux based upon pH testing or Grade C/D esophagitis or Barrett's esophagus, and (3) hiatal hernia ≤ 2 cm. The primary outcome was improvement in GERD Health-Related Quality of Life (GERD-HRQL) post-TIFFF. The TIFFF cohort was also compared to a similar surgical re-operative cohort using propensity score matching., Results: Twenty patients underwent TIFFF (median 4.1 years after prior fundoplication) and mean GERD-HRQL score improved from 24.3 ± 22.9 to 14.75 ± 21.6 (p = 0.014); mean Reflux Severity Index (RSI) score improved from 14.1 ± 14.6 to 9.1 ± 8.0 (p = 0.046) with 8/10 (80%) of patients with normal RSI (< 13) post-TIF. Esophagitis healed in 78% of patients. PPI use decreased from 85 to 55% with 8/20 (45%) patients off of PPI. Importantly, mean acid exposure time decreased from 12% ± 17.8 to 0.8% ± 1.1 (p = 0.028) with 9/9 (100%) of patients with normalized pH post-TIF. There were no statistically significant differences in clinical efficacy outcomes between TIFFF and surgical revision, but TIFFF had significantly fewer late adverse events., Conclusion: Endoscopic rescue with TIF is a safe and efficacious alternative to redo laparoscopic surgery in symptomatic patients with appropriate anatomy and objective evidence of persistent or recurrent reflux., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk., Methods: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress., Results: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant., Conclusion: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2022 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer., Methods: Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated., Results: Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%., Conclusion: Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies., Methods: Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I v higher-stage). Overall survival was determined using the Kaplan-Meier method., Results: Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio [95% CI]; 0.13 [0.03 to 0.50], P = .003)., Conclusion: Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.

Objective: Patients with laryngopharyngeal reflux (LPR) symptoms may not respond to proton pump inhibitors (PPI) if they have an alternative laryngeal diagnosis or high-volume reflux. Transoral incisionless fundoplication (TIF) or TIF with concomitant hiatal hernia repair (cTIF) are effective in decreasing symptoms of gastroesophageal reflux disease (GERD) but are not well studied in patients with LPR symptoms. This prospective multicenter study assessed the patient-reported and clinical outcomes after TIF/cTIF in patients with LPR symptoms and proven GERD., Methods: Patients with refractory LPR symptoms (reflux symptom index [RSI] > 13) and with erosive esophagitis, Barrett's esophagus, and/or pathologic acid reflux by distal esophageal pH testing were evaluated before and after a minimum of 6 months after TIF/cTIF. The primary outcome was normalization of RSI. Secondary outcomes were >50% improvement in GERD-Health-Related Quality of Life (GERD-HRQL), normalization of esophageal acid exposure time, discontinuation of PPI, and patient satisfaction., Results: Forty-nine patients had TIF (n = 26) or cTIF (n = 23) with at least 6 months follow-up. Mean pre- and post TIF/cTIF RSI were 23.6 and 5.9 (mean difference: 17.7, P  < .001). Post TIF/cTIF, 90% of patients had improved GERD-HQRL score, 85% normalized RSI, 75% normalized esophageal acid exposure time, and 80% discontinued PPI. No serious procedure-related adverse events occurred. Patient satisfaction was 4% prior to TIF/cTIF and 73% after TIF/cTIF ( P  < .001)., Conclusion: In patients with objective evidence of GERD, TIF, or cTIF are safe and effective in controlling LPR symptoms as measured by normalization of RSI and improvement in patient satisfaction after TIF/cTIF., Level of Evidence: Level 4.

Gene variants that encode pancreatic enzymes with impaired secretion can induce pancreatic acinar endoplasmic reticulum (ER) stress, cellular injury and pancreatitis. The role of such variants in pancreatic cancer risk has received little attention. We compared the prevalence of ER stress-inducing variants in CPA1 and CPB1 in patients with pancreatic ductal adenocarcinoma (PDAC cases), enrolled in the National Familial Pancreas Tumor Registry, to their prevalence in noncancer controls in the Genome Aggregation Database (gnomAD). Variants of unknown significance were expressed and variants with reduced secretion assessed for ER stress induction. In vitro assessments were compared with software predictions of variant function. Protein variant software was used to assess variants found in only one gnomAD control ("n-of-one" variants). A meta-analysis of prior PDAC case/control studies was also performed. Of the 1385 patients with PDAC, 0.65% were found to harbor an ER stress-inducing variant in CPA1 or CPB1, compared to 0.17% of the 64 026 controls (odds ratio [OR]: 3.80 [1.92-7.51], P = .0001). ER stress-inducing variants in the CPA1 gene were identified in 4 of 1385 PDAC cases vs 77 of 64 026 gnomAD controls (OR: 2.4 [0.88-6.58], P = .087), and variants in CPB1 were detected in 5 of 1385 cases vs 33 of 64 026 controls (OR: 7.02 [2.74-18.01], P = .0001). Meta-analysis demonstrated strong associations for pancreatic cancer and ER-stress inducing variants for both CPA1 (OR: 3.65 [1.58-8.39], P < .023) and CPB1 (OR: 9.51 [3.46-26.15], P < .001). Rare variants in CPB1 and CPA1 that induce ER stress are associated with increased odds of developing pancreatic cancer., (© 2021 UICC.)

Background & Aims: The tumor microbiome of patients with pancreas ductal adenocarcinoma (PDAC) includes bacteria normally present in the upper gastrointestinal tract. If the predominant source of intratumoral bacteria in patients with PDAC is retrograde migration from the duodenum, duodenal fluid could be a representative biospecimen for determining microbiome profiles of patients with PDAC or at risk of developing PDAC., Methods: We performed a case-control study comparing bacterial and fungal (16S and 18S rRNA) profiles of secretin-stimulated duodenal fluid collections from 308 patients undergoing duodenal endoscopy including 134 normal pancreas control subjects, 98 patients with pancreatic cyst(s) and 74 patients with PDAC., Results: Alterations in duodenal fluid microbiomes with diminished alpha diversity were significantly associated with age >70 and proton pump inhibitor use. Patients with PDAC had significantly decreased duodenal microbial alpha diversity compared with age-matched control subjects with normal pancreata and those with pancreatic cyst(s). There was evidence of enrichment of Bifidobacterium genera in the duodenal fluid of patients with PDAC compared with control subjects and those with pancreatic cyst(s). There were also enrichment of duodenal fluid Fusobacteria and Rothia bacteria among patients with PDAC with short-term survival. Duodenal fluid microbiome profiles were not significantly different between control subjects and patients with pancreatic cyst(s)., Conclusion: Patients with PDAC have alterations in their duodenal fluid microbiome profiles compared with patients with pancreatic cysts and those with normal pancreata. ClinicalTrials.gov, Number: NCT02000089., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and study aims  Transoral incisionless fundoplication (TIF) is a safe and effective minimally invasive endoscopic technique for treating gastroesophageal reflux disease (GERD). The learning curve for this technique has not been reported. We studied the learning curve for TIF when performed by a gastroenterologist by identifying the threshold number of procedures needed to achieve consistent technical success or proficiency (consistent creation of TIF valve ≥ 270 degrees in circumference, ≥ 2 cm long) and efficiency after didactic, hands-on and case observation experience. Patients and methods  We analyzed prospectively collected data from patients who had TIF performed by a single therapeutic endoscopist within 17 months after basic training. We determined thresholds for procedural learning using cumulative sum of means (CUSUM) analysis to detect changes in achievement rates over time. We used breakpoint analysis to calculate procedure metrics related to proficiency and efficiency. Results  A total of 69 patients had 72 TIFs. The most common indications were refractory GERD (44.7 %) and proton pump inhbitor intolerance (23.6 %). Proficiency was achieved at the 18 th to 20 th procedure. The maximum efficiency for performing a plication was achieved after the 26 th procedure, when mean time per plication decreased to 2.7 from 5.1 minutes (P < 0.0001). TIF procedures time varied until the 44 th procedure, after which it decreased significantly from 53.7 minutes to 39.4 minutes (P < 0.0001). Conclusions  TIF can be safely, successfully, and efficiently performed in the endoscopy suite by a therapeutic endoscopist. The TIF learning curve is steep but proficiency can be achieved after a basic training experience and 18 to 20 independently performed procedures., Competing Interests: Competing interests Dr. Ngamruengphong is a consultant for Boston Scientific. Dr. Kumbhari is a consultant for Medtronic, Pentax Medical (USA), Boston Scientific, FujiFilm, Apollo Endosurgery, and received research support from Erbe USA, and Apollo Endosurgery. Dr. Khashab is a consultant for Boston Scientific, Medtronic, Olympus, GI Supply, and Triton. Dr. Murray is a consultant for Endogastric Solutions. PJ is a consultant for Endogastric solutions, Ethicon/J&J, and Olympus. Dr. Ihde is a consultant for Endogastric solutions, and Microline Medical. Dr. Chang is a consultant for Apollo Endosurgery, Cook, Erbe USA, Endogastric solutions, Mauna Kea, Mederi, Medtronic, Olympus, Ovesco and Pentax Medical (USA). Dr. Thosani is a consultant for Boston Scientific, Medtronic, Pentax Medical (USA), received research support from Pentax Medical (USA), royalties from UpToDate, and is on the advisory board of ColubrisMX. Dr. Canto received research grants from Endogastric solutions and Pentax Medical (USA), and royalties from UpToDate., (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/).)

Background: There is growing interest in developing impedance planimetry as a tool to enhance the clinical outcomes for endoscopic and surgical management of achalasia. The primary aim of this study was to determine whether impedance planimetry measurements can predict clinical response and reflux following peroral endoscopic myotomy (POEM)., Methods: A multicenter cohort study of patients with achalasia undergoing POEM was established from prospective databases and retrospective chart reviews. Patients who underwent impedance planimetry before and after POEM were included. Clinical response was defined as an Eckardt score of ≤ 3. Tenfold cross-validated area under curve (AUC) values were established for the different impedance planimetry measurements associated with clinical response and reflux development., Results: Of the 290 patients included, 91.7 % (266/290) had a clinical response and 39.4 % (108/274) developed reflux following POEM. The most predictive impedance planimetry measurements for a clinical response were: percent change in cross-sectional area (%ΔCSA) and percent change in distensibility index (%ΔDI), with AUCs of 0.75 and 0.73, respectively. Optimal cutoff values for %ΔCSA and %ΔDI to determine a clinical response were a change of 360 % and 272 %, respectively. Impedance planimetry values were much poorer at predicting post-POEM reflux, with AUCs ranging from 0.40 to 0.62., Conclusion: Percent change in CSA and distensibility index were the most predictive measures of a clinical response, with a moderate predictive ability. Impedance planimetry values for predicting reflux following POEM showed weak predictive capacity., Competing Interests: B. Joseph Elmunzer is a consultant for Takeda Pharmaceuticals. Mouen A. Khashab is a consultant for Boston Scientific, Olympus, and Medtronic, and is also on the medical advisory board for Boston Scientific and Olympus. Vivek Kumbhari is a consultant for Apollo Endosurgery, Boston Scientific, Medtronic, and ReShape Life Science. Bu Hayee is a consultant for Apollo Endosurgery, Boston Scientific, Fuji, Medtronic, Obalon, Pentax Medical, and ReShape Life Sciences. All other authors declare that they have no conflicts of interest., (Thieme. All rights reserved.)

Background: Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (ERCP; EDGE) is an alternative to enteroscopy- and laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass anatomy. Although short-term results are promising, the long-term outcomes are not known. The aims of this study were: (1) to determine the rates of long-term adverse events after EDGE, with a focus on rates of persistent gastrogastric or jejunogastric fistula; (2) to identify predictors of persistent fistula; (3) to assess the outcomes of endoscopic closure when persistent fistula is encountered., Methods: This was a multicenter retrospective study involving 13 centers between February 2015 and March 2019. Adverse events were defined according to the ASGE lexicon. Persistent fistula was defined as an upper gastrointestinal series or esophagogastroduodenoscopy showing evidence of fistula., Results: 178 patients (mean age 58 years, 79 % women) underwent EDGE. Technical success was achieved in 98 % of cases (175/178), with a mean procedure time of 92 minutes. Periprocedural adverse events occurred in 28 patients (15.7 %; mild 10.1 %, moderate 3.4 %, severe 2.2 %). The four severe adverse events were managed laparoscopically. Persistent fistula was diagnosed in 10 % of those sent for objective testing (9/90). Following identification of a fistula, 5 /9 patients underwent endoscopic closure procedures, which were successful in all cases., Conclusions: The EDGE procedure is associated with high clinical success rates and an acceptable risk profile. Persistent fistulas after lumen-apposing stent removal are uncommon, but objective testing is recommended to identify their presence. When persistent fistulas are identified, endoscopic treatment is warranted, and should be successful in closing the fistula., Competing Interests: A.L. Chang has received consultancy fees and research support from Boston Scientific; T.E. Kowalski has received consultancy fees from Boston Scientific and Medtronic; T.H. Baron has received consultancy fees from Boston Scientific, Cook Endoscopy, W.L. Gore, Medtronic, and Olympus America, and speaker’s fees from Medtronic; J. Nieto has received consultancy fees from Boston Scientific and Olympus America, and speaker’s fees from AbbVie; J.Y. Nasr has received consultancy fees from Boston Scientific; H.S. Khara has received consultancy fees from Boston Scientific and speaker’s fees from Olympus America, Covidien, Gyrus ACMI, Inc., and US Endoscopy; S. Irani has received research support from Boston Scientific; R.J. Law has received consultancy fees from Boston Scientific, Olympus America, and ERBE, and research support from Cook Medical; D.E. Loren has received consultancy fees from Boston Scientific and Olympus America; D.L. Diehl has received consultancy fees from Boston Scientific, Cook Endoscopy, Olympus America, Pentax Medical, Lumendi, US Endoscopy, and C2 Therapeutics, and speaker’s fees from Boston Scientific and Olympus America; M.A. Al-Haddad has received consultancy fees and research support from Boston Scientific; D.K. Pleskow has received consultancy fees from Boston Scientific, Olympus, Fuji, Nine Point Medical, and Medtronic; M. Huggett has received consultancy fees from Boston Scientific and Cook Endoscopy, and speaker’s fees from Boston Scientific, Cook Endoscopy, and Olympus; A.J. Trindade has received consultancy fees from Olympus America, C2 Therapeutics, and Pentax Medical; V. Kumbhari has received consultancy fees from Apollo Endosurgery, Boston Scientific, Medtronic, Pentax Medical, and ReShape Lifescience, and research support from ERBE, C2 Therapeutics, and Ovesco; M.A. Khashab has received consultancy fees from and is on the advisory board of Boston Scientific and Olympus America, and has received consultancy fees from Medtronic. The remaining authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain., Methods: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals., Results: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed., Conclusions: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: Objectives: Pancreatic cysts are frequently detected in high-risk individuals (HRI) undergoing surveillance for pancreatic cancer. The International Cancer of the Pancreas Screening (CAPS) Consortium developed consensus recommendations for surgical resection of pancreatic cysts in HRI that are similar to the Fukuoka guidelines used for the management of sporadic cysts. We compared the performance characteristics of CAPS criteria for pancreatic cyst management in HRI with the Fukuoka guidelines originally designed for the management of cysts in non-HRI., Methods: Using prospectively collected data from CAPS studies, we determined for each patient with resected screen-detected cyst(s) whether Fukuoka guidelines or CAPS consensus statements would have recommended surgery. We compared sensitivity, specificity, PPV, NPV, and Receiver Operator Characteristics (ROC) curves of these guidelines at predicting the presence of high-grade dysplasia or invasive cancer in pancreatic cysts., Results: 356/732 HRI had ≥ one pancreatic cyst detected; 24 had surgery for concerning cystic lesions. The sensitivity, specificity, PPV, and NPV for the Fukuoka criteria were 40%, 85%, 40%, and 85%, while those of the CAPS criteria were 60%, 85%, 50%, 89%, respectively. ROC curve analyses showed no significant difference between the Fukuoka and CAPS criteria., Conclusions: In HRI, the CAPS and Fukuoka criteria are moderately specific, but not sufficiently sensitive for detecting advanced neoplasia in cystic lesions. New approaches are needed to guide the surgical management of cystic lesions in HRI., Competing Interests: Declaration of competing interest Dr. Hruban has the right to receive royalty payments from Thrive Earlier Detection for the GNAS invention through a relationship managed by Johns Hopkins University. All other authors disclose no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background and Aims: EMR is the preferred endoscopic therapy for duodenal adenomas (DAs) but is associated with an overall adverse event rate of 26%. Cryotherapy using a Cryoballoon Focal Ablation System (CbFAS) can safely and effectively eradicate esophageal intestinal metaplasia. We report our first experience with cryoballoon ablation for treatment of flat DAs., Methods: This was an American, multicenter, retrospective study involving 5 centers. DAs (Paris 0-IIa and 0-IIb) were treated with nitrous oxide for 5 to 12 seconds using CbFAS. Follow-up EGD was performed at 3 to 12 months., Results: Seventeen DAs (mean size, 22.7 ± 14.3 mm; 12 tubular, 5 tubulovillous) from 13 patients (mean age, 66.5 ± 9.99 years; 61.5% males) were included in the study. Thirteen of 17 DAs (76.5%) had failed previous treatment, and 4 of 17 (23.5%) were treatment naÏve. All procedures were technically successful and achieved a >50% decrease in size after cryoballoon ablation There was no increase in size or progression of disease for any lesions. Overall, treatment was completed in 15 of 17 patients, and recurrence-free survival was achieved in 12 of 17 (71%) after a median follow-up of 15.5 months (interquartile range [IQR], 6.8-19.4). The median cryoablation time per polyp was 4 minutes (IQR, 1-7.5 minutes), and the median total procedure time was 25 minutes (IQR, 22-30.5 minutes). There were no intra- or postprocedural adverse events., Conclusions: Nitrous oxide cryoballoon ablation of nonpolypoid DAs is feasible, with promising safety and efficacy., (Copyright © 2021 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The newest addition in the management of achalasia and esophagogastric junction outflow obstruction (EGJOO) is a 30-mm hydrostatic balloon dilator that uses impedance planimetry technology. It allows for the measurement of the diameter and cross-sectional area to determine effective dilation. We aimed to (1) determine the clinical success (defined as a decrease in Eckardt score to ≤3) in the treatment of esophageal motility disorders and (2) report the safety (rate/severity of adverse events)., Methods: This retrospective multicenter study involved 4 centers. Patients with esophageal motility disorders who underwent hydrostatic balloon dilation between January 2015 and October 2018 were included., Results: Fifty-one patients (mean age, 54.1 years; women, 49%) underwent hydrostatic dilation for achalasia (n = 37) or EGJOO (n = 14) during the study period. Forty-seven patients had a median baseline Eckardt score of 5 (range, 3-8; achalasia, n = 35, 6 [range, 3-8]; EGJOO, n = 12, 4 [range, 3.25-6.5]). Clinical success was achieved in 60% of cases (achalasia vs EGJOO: 68.4% vs 33.3%, P = .18). Dilation resulted in a significant decrease in the median Eckardt score from 5 (range, 3-8) to 1.5 (range, 1-4.75; P < .001). Patients with achalasia had a decrease in Eckardt score from 6 (range, 3-8) to 1 (range, 1-4; P < .001), whereas those with EGJOO experienced no significant change. One patient had mild postprocedure chest pain., Conclusions: The hydrostatic balloon dilator is a new tool in our armamentarium to treat esophageal motility disorders. This is the first multicenter study showing the device to be safe and moderately efficacious., (Copyright © 2020 American Society for Gastrointestinal Endoscopy. All rights reserved.)

Background & Aims: Levels of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA-125) in blood are used as markers to determine the response of patients with cancer to therapy, but are not used to identify patients with pancreatic cancer., Methods: We obtained blood samples from 504 patients undergoing pancreatic surveillance from 2002 through 2018 who did not develop pancreatic cancer and measured levels of the tumor markers CA19-9, CEA, CA-125, and thrombospondin-2. Single-nucleotide polymorphisms (SNPs) in FUT3, FUT2, ABO, and GAL3ST2 that have been associated with levels of tumor markers were used to establish SNP-defined ranges for each tumor marker. We also tested the association between additional SNPs (in FUT6, MUC16, B3GNT3, FAM3B, and THBS2) with levels of tumor markers. To calculate the diagnostic specificity of each SNP-defined range, we assigned the patients under surveillance into training and validation sets. After determining the SNP-defined ranges, we determined the sensitivity of SNP-adjusted tests for the tumor markers, measuring levels in blood samples from 245 patients who underwent resection for pancreatic ductal adenocarcinoma (PDAC) from 2010 through 2017., Results: A level of CA19-9 that identified patients with PDAC with 99% specificity had 52.7% sensitivity. When we set the cut-off levels of CA19-9 based on each SNP, the test for CA19-9 identified patients with PDAC with 60.8% sensitivity and 98.8% specificity. Among patients with FUT3 alleles that encode a functional protein, levels of CA19-9 greater than the SNP-determined cut-off values identified 66.4% of patients with PDAC, with 99.3% specificity. In the validation set, levels of CEA varied among patients with vs without SNP in FUT2, by blood group, and among smokers vs nonsmokers; levels of CA-125 varied among patients with vs without the SNP in GAL3ST2. The use of the SNPs to define the ranges of CEA and CA-125 did not significantly increase the diagnostic accuracy of the assays for these proteins. Combining data on levels of CA19-9 and CEA, CA19-9 and CA-125, or CA19-9 and thrombospondin-2 increased the sensitivity of detection of PDAC, but slightly reduced specificity., Conclusions: Including information on SNPs associated with levels of CA19-9, CEA, and CA-125 can improve the diagnostic accuracy of assays for these tumor markers in the identification of patients with PDAC. Clinicaltrials.gov no: NCT02000089., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Multiple studies have examined the use of lumen-apposing metal stents (LAMSs) for the drainage of peripancreatic fluid collections. Data on the use of LAMSs for postoperative fluid collections (POFCs) are scarce. POFCs may lead to severe complications without appropriate treatment. We aimed to study the outcomes (technical success, clinical success, rate/severity of adverse events, length of stay, recurrence) of the use of LAMSs for the drainage of POFCs., Methods: This international, multicenter, retrospective study involved 19 centers between January 2012 and October 2017. The primary outcome was clinical success. Secondary outcomes included technical success and rate/severity of adverse events using the ASGE lexicon., Results: A total of 62 patients were included during the study period. The most common etiology of the POFCs was distal pancreatectomy (46.8 %). The mean (standard deviation) diameter was 84.5 mm (30.7 mm). The most common indication for drainage was infection (48.4 %) and transgastric drainage was the most common approach (82.3 %). Technical success was achieved in 60/62 patients (96.8 %) and clinical success in 57/62 patients (91.9 %) during a median (interquartile range) follow-up of 231 days (90 - 300 days). Percutaneous drainage was needed in 8.1 % of patients. Adverse events occurred intraoperatively in 1/62 patients (1.6 %) and postoperatively in 7/62 (11.3 %). There was no procedure-related mortality., Conclusion: This is the largest study on the use of LAMSs for POFCs. It suggests good clinical efficacy and safety of this approach. The use of LAMSs in the management of POFCs is a feasible alternative to percutaneous and surgical drainage., Competing Interests: Dr. Amrita Sethi is a Consultant for Olympus and Boston Scientific. Dr. Reem Z. Sharaiha is a consultant for Boston Scientific and Apollo Endosurgery. Dr. Thomas Kowalski is a consultant for Boston Scientific and Medtronic. Dr. Jose Nieto is a consultant for Boston Scientific. Dr. Sachin Wani is a consultant for and received grant support from Boston Scientific and Medtronic, and grant support from Cook. Dr. Mihir S. Wagh has served as a consultant for Boston Scientific and Medtronic. Dr. Ali Mir Ahmed is a consultant for Boston Scientific and Cook Medical. Dr. Andrea Anderloni is a consultant for Boston Scientific. Dr. Douglas G. Adler is a consultant for Boston Scientific. Dr. Nikhil A. Kumta is a consultant for Apollo Endosurgery, Boston Scientific and Olympus. Dr. Frank P. Vleggaar is a consultant for Boston Scientific Dr. Isaac Raijman is a consultant for Boston Scientific. Dr. Shayan Irani is a consultant for Boston Scientific. Dr. Vivek Kumbhari is a consultant for ReShape Lifesciences, Apollo Endosurgery, Boston Scientific and Medtronic. Dr. Vikesh Singh is consultant for Abbvie, Novo Nordisk, and Ariel and advisory board participant for Nordmark. Dr. Douglas Pleskow is a consultant for Boston Scientific, Olympus, Nine Point and CSA. Dr. Mouen A. Khashab is a consultant for Boston Scientific, Olympus and Medtronic and is on the medical advisory board for Boston Scientific and Olympus, (© Georg Thieme Verlag KG Stuttgart · New York.)

Background and study aims  EUS-guided gastroenterostomy (GE) is a novel, minimally invasive endoscopic procedure for the treatment of gastric outlet obstruction (GOO). The direct-EUS-GE (D-GE) approach has recently gained traction. We aimed to report on a large cohort of patients who underwent DGE with focus on long-term outcomes. Patients and methods  This two-center, retrospective study involved consecutive patients who underwent D-GE between October 2014 and May 2018. The primary outcomes were technical and clinical success. Secondary outcomes were adverse events (AEs), rate of reintervention, procedure time, time to resume oral diet, and post-procedure length of stay (LOS). Results  A total of 57 patients (50.9 % female; median age 65 years) underwent D-GE for GOO. The etiology was malignant in 84.2 % and benign in 15.8 %. Technical success and clinical success were achieved in 93 % and 89.5 % of patients, respectively, with a median follow-up of 196 days in malignant GOO and 319.5 days in benign GOO. There were 2 (3.5 %) AEs, one severe and one moderate. Median procedure time was 39 minutes (IQR, 26 - 51.5 minutes). Median time to resume oral diet after D-GE was 1 day (IQR 1 - 2 days). Median post D-GE LOS was 3 days (IQR 2 - 7 days). Rate of reintervention was 15.1 %. Conclusions  D-GE is safe and effective in management of both malignant and benign causes of GOO. Clinical success with D-GE is durable with a low rate of reintervention based on a long-term cohort.