Amitabh Chak

Background: Pancreatic surveillance commonly detects pancreatic cysts, most of which are presumed intraductal papillary mucinous neoplasms (IPMN). FUT2, the gene responsible for secretor status, has been implicated in IPMN development, although not with pancreatic cancer risk. Methods: We evaluated the association between inactivating variants in FUT2, FUT3, and ABO and pancreatic cysts in 1,865 patients in the multicenter Cancer of the Pancreas Screening (CAPS) cohort. Multivariable logistic regression was performed to estimate adjusted odds for presumed IPMN prevalence. A Johns Hopkins surgical cohort of 1,582 patients with IPMN, pancreatic ductal adenocarcinoma (PDAC), or carcinoma arising from IPMN was analyzed to examine trend in variant proportion by malignant progression. Results: In the CAPS cohort, older age [OR per year, 1.06 (1.05–1.07); P < 0.001], being FUT2 null [nonsecretors; OR, 1.66 (1.30–2.12); P < 0.001], non-O blood group [OR, 1.31 (1.06–1.62); P = 0.012], having familial-only versus genetic/familial risk [OR, 1.49 (1.20–1.85); P < 0.001], and participating site [OR, 2.20 (1.78–2.73); P < 0.001] were associated with having pancreatic cysts. There were no significant FUT2/ABO-presumed IPMN prevalence interactions. In the combined cohort, the proportion of FUT2-null patients with IPMN without carcinoma (by imaging or pathology) was 319 (27.4%) of 1,162, 57 (24.3% of 234) with IPMN and carcinoma, and 225 (22.5%) of 998 with PDAC alone (P = 0.009 for trend). Conclusions: IPMN is more prevalent in FUT2-null patients under pancreas surveillance, but the increased FUT2-null prevalence is not observed in patients with IPMN with carcinoma. Impact: Pancreatic cancer risk conferred by having IPMN may be lower in FUT2-null compared with FUT2-intact individuals.

The molecular underpinnings contributing to the onset of Barrett’s esophagus (BE) remain elusive. By studying familial clusters of the disease, here we identify a significant association between genetic variants in the V-set and Immunoglobulin Domain Containing 10 Like (VSIG10L) gene and BE predisposition. Using mammalian tissues and patient-derived organoids, we show VSIG10L is selectively expressed in the suprabasal squamous cells of the esophageal mucosa and is essential for epithelial maturation and homeostasis. Mice carrying human-orthologous germline mutations in Vsig10l exhibit loss of desmosomes, concomitant with disrupted epithelial differentiation programs, in the squamous mucosa. Upon long-term exposure to a bile acid (deoxycholate) supplemented diet, Vsig10l-mutant mice develop overt BE-like lesions in the forestomach. Furthermore, loss of esophageal VSIG10L expression is observed frequently in patients with chronic gastroesophageal reflux disease, a known risk factor for BE. Collectively, our study uncovers a fundamental link between VSIG10L, esophageal homeostasis, and BE predisposition.

INTRODUCTION: Upper endoscopy (EGD) is generally recommended in those with chronic gastroesophageal reflux disease (GERD). To evaluate nonendoscopic screening in those without GERD symptoms. METHODS: EsoCheck/Esoguard (LucidDx) was performed in recruited patients without chronic GERD who had ≥3 other BE risk factors. RESULTS: The EsoGuard assay was positive in 34 of 120 patients. BE was identified in 9 of 27 who had follow-up EGD, positive predictive value = 33% (17%–54%). EGD performed in 22 of 86 subjects with negative assays found no BE, negative predictive value = 100% (85%–100%). DISCUSSION: Nonendoscopic BE detection is effective in patients without chronic GERD.

Background Screening efforts for Barrett’s Esophagus (BE) predominantly focus on performing upper endoscopy (EGD) on patients with gastroesophageal reflux disease (GERD) symptoms who have additional risk factors for BE. However, cost and invasiveness preclude EGD in those who have no prior GERD symptoms, despite having other risk factors, representing missed opportunities for BE screening in individuals who account for approximately 40% of the patients who eventually develop esophageal adenocarcinoma (EAC). Aim The aim of this study was to evaluate if non-endoscopic methods can enable BE detection in an at-risk population without GERD symptoms. Methods Patients presenting for colonoscopy who had not undergone previous EGD plus had ≥3 BE risk factors (from among age >50 years, male sex, white race, smoking history, family history of BE/EAC, or central obesity) without chronic GERD symptoms were prospectively recruited for non-endoscopic screening. Trained nurses administered the EsoCheck (Lucid Diagnostics) encapsulated balloon. Samples were assayed with the EsoGuard BE detection methylated DNA marker panel (Lucid Diagnostics). Patients with a positive result were offered standard-of-care EGD, while patients with a negative EG result were offered free of cost research EGD. Positive predictive value (PPV), negative predictive value (NPV), and BE prevalence were calculated. Results The mean age of the 132 study subjects was 60.7 years, 129 (98%) were white, 124 (94%) were male, 71 (54%) had a prior smoking history, 46 (35%) were centrally obese, and 5 (4%) reported a family history. EsoCheck was successfully administered in 124 (94%) and the EsoGuard methylated DNA marker panel could be assayed in 120 (97%) of the samples. Thirty-four assays were positive of which 27 underwent a follow-up EGD and BE was identified in 9, PPV = 33% [17%, 54%] subjects. EGD was also performed in 22 of the 86 subjects whose assays were negative and none of them had BE, NPV = 100% [85%, 100%]. A logistic regression model fitted to impute the presence of BE estimated the PPV as 27% [13%, 44%], NPV as 98% [92%, 100%], and BE prevalence as 8.4% [4.5%, 14.3%]. Conclusion Patients without chronic GERD who have ≥3 BE risk factors have a moderately high prevalence of BE. Non-endoscopic detection can effectively identify BE, enabling expansion of screening to this larger at-risk population. Those with a negative EG assay have a low likelihood of BE.

Objective Sphincter of Oddi disorders (SOD) are contentious conditions in patients whose abdominal pain, idiopathic acute pancreatitis (iAP) might arise from pressurisation at the sphincter of Oddi. The present study aimed to measure the benefit of sphincterotomy for suspected SOD. Design Prospective cohort conducted at 14 US centres with 12 months follow-up. Patients undergoing first-time endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy for suspected SOD were eligible: pancreatobiliary-type pain with or without iAP. The primary outcome was defined as the composite of improvement by Patient Global Impression of Change (PGIC), no new or increased opioids and no repeat intervention. Missing data were addressed by hierarchal, multiple imputation scheme. Results Of 316 screened, 213 were enrolled with 190 (89.2%) of these having a dilated bile duct, abnormal labs, iAP or some combination. By imputation, an average of 122/213 (57.4% (95% CI 50.4% to 64.4%)) improved; response rate was similar for those with complete follow-up (99/161, 61.5% (54.0% to 69.0%)); of these, 118 (73.3%) improved by PGIC alone. Duct size, elevated labs and patient characteristics were not associated with response. AP occurred in 37/213 (17.4%) at a median of 6 months post ERCP and was more likely in those with a history of AP (30.9% vs 2.9%, pConclusion Nearly 60% of patients undergoing ERCP for suspected SOD improve, although the contribution of a placebo response is unknown. Contrary to prevailing belief, duct size and labs are poor response predictors. AP recurrence was common and like observations from prior non-intervention cohorts, suggesting no benefit of sphincterotomy in mitigating future AP episodes.

INTRODUCTION: Prophylactic pancreatic stent placement (PSP) is effective for preventing pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk cases, but the optimal technical approach to this intervention remains uncertain. METHODS: In this secondary analysis of 787 clinical trial patients who underwent successful stent placement, we studied the impact of (i) whether pancreatic wire access was achieved for the sole purpose of PSP or naturally during the conduct of the case, (ii) the amount of effort expended on PSP, (iii) stent length, (iv) stent diameter, and (v) guidewire caliber. We used logistic regression models to examine the adjusted association between each technical factor and post-ERCP pancreatitis (PEP). RESULTS: Ninety-one of the 787 patients experienced PEP. There was no clear association between PEP and whether pancreatic wire access was achieved for the sole purpose of PSP (vs occurring naturally; odds ratio [OR] 0.82, 95% confidence interval [CI] 0.37–1.84), whether substantial effort expended on stent placement (vs nonsubstantial effort; OR 1.58, 95% CI 0.73–3.45), stent length (>5 vs ≤5 cm; OR 1.01, 95% CI 0.63–1.61), stent diameter (≥5 vs post hoc subgroup analysis, these findings may have important implications in procedural decision making and suggest that the benefit of PSP is robust to variations in technical approach.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway (P = 0.01), amplifications of oncogenes (P = 0.01), and deletions of tumor suppressor genes (P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

INTRODUCTION: Although rates of esophageal adenocarcinoma (EAC) in the United States continue to rise, many patients at risk of disease are not screened. EsoCheck (EC), a nonendoscopic esophageal balloon sampling device coupled with EsoGuard (EG), a DNA-based screening assay, is an US Food and Drug Administration-approved minimally invasive alternative to the traditional screening method of upper endoscopy. The objective of this study was to prospectively determine the diagnostic accuracy, tolerance, and acceptability of the EC/EG test in a screening population. METHODS: We recruited veterans who met the American College of Gastroenterology Guideline criteria for endoscopic Barrett's esophagus (BE) and EAC screening at the Louis Stokes Cleveland Veterans Affairs Medical Center. All study participants completed unsedated EC-guided distal esophageal sampling followed by a sedated esophagogastroduodenoscopy (EGD). Diagnostic yield of the EG assay and EGD was recorded and used in calculation of sensitivity and specificity of EC/EG in prospective screening. The abbreviated Spielberger State-Trait Anxiety Inventory questionnaire was administered before and after completion of EC. Overall tolerance of EC sampling was evaluated on a 10-point Likert scale. RESULTS: Esophageal cancer screening was accepted by 130 of 782 eligible veterans (16.6%), and we analyzed results of those who completed both screening tests (N = 124). Prevalence of BE/EAC among studied veterans was 12.9% (16/124), based on EGD. Sensitivity and specificity of EC/EG for EGD-detected BE/EAC were 92.9% (95% confidence interval [CI] 66.1–99.8) and 72.2% (95% CI 62.1–80.8), respectively. Positive and negative predictive values were 32.5% (95% CI 18.6–49.1) and 98.6% (95% CI 92.4–100), respectively. Baseline Spielberger State-Trait Anxiety Inventory-6 scores were reflective of notable levels of anxiety among veterans in the periprocedural setting. The mean postprocedure acceptability score for the EC test was 7.23 (SD 2.45). DISCUSSION: Our data suggest excellent sensitivity and negative predictive value of EC/EG in a screening population of veterans, making this modality a powerful screening tool for BE and EAC.

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