Michele L. Johnson

A randomized comparative effectiveness trial of novel endoscopic techniques and approaches for Barrett's esophagus screening in the community.

Objectives:The objective of this study was to compare participation rates and clinical effectiveness of sedated esophagogastroduodenoscopy (sEGD) and unsedated transnasal endoscopy (uTNE) for esophageal assessment and Barrett’s esophagus (BE) screening in a population-based cohort.Methods:This was a prospective, randomized, controlled trial in a community population. Subjects ≥50 years of age who previously completed validated gastrointestinal symptom questionnaires were randomized (stratified by age, sex, and reflux symptoms) to one of three screening techniques (either sEGD or uTNE in a mobile research van (muTNE) or uTNE in a hospital outpatient endoscopy suite (huTNE)) and invited to participate.Results:Of the 459 subjects, 209 (46%) agreed to participate (muTNE n=76, huTNE n=72, and sEGD n=61). Participation rates were numerically higher in the unsedated arms of muTNE (47.5%) and huTNE (45.7%) compared with the sEGD arm (40.7%), but were not statistically different (P=0.27). Complete evaluation of the esophagus was similar using muTNE (99%), huTNE (96%), and sEGD (100%) techniques (P=0.08). Mean recovery times (min) were longer for sEGD (67.3) compared with muTNE (15.5) and huTNE (18.5) (P<0.001). Approximately 80% of uTNE subjects were willing to undergo the procedure again in future. Respectively, 29% and 7.8% of participating subjects had esophagitis and BE.Conclusions:Mobile van and clinic uTNE screening had comparable clinical effectiveness with similar participation rates and safety profile to sEGD. Evaluation time with uTNE was significantly shorter. Prevalence of BE and esophagitis in community subjects ≥50 years of age was substantial. Mobile and outpatient unsedated techniques may provide an effective alternative strategy to sEGD for esophageal assessment and BE screening.

Incidence and predictors of osteoporotic fractures in patients with Barrett's oesophagus: a population‐based nested case‐control study

Proton pump inhibitors (PPI) are inconsistently associated with osteoporotic fractures. Barretts oesophagus (BO) patients are treated with high PPI doses for prolonged periods, but there are limited data on the incidence of osteoporosis and fractures in this group pf patients.

Predictors of Progression in Barrett’s Esophagus with Low-Grade Dysplasia: Results from a Multicenter Prospective BE Registry

Objectives:Low-grade dysplasia (LGD) is a risk factor for progression in Barrett’s esophagus (BE). Progression estimates however vary and predictors of progression are not well established. We aimed to assess predictors of progression in a multicenter BE-LGD cohort.Methods:All subjects with LGD (diagnosed by a GI pathologist) in a prospective BE registry were identified. Progression was defined development of HGD/EAC more than 12 months after index date of LGD diagnosis. Clinical, endoscopic factors and impact of histologic review by an independent panel of two GI pathologists were assessed as predictors of progression. Cox proportional hazard models were used to assess their association with risk of progression.Results:244 BE-LGD subjects met inclusion criteria. Their mean age was 63.2 years. 205 (84%) were males. The median follow up was 4.8 years. Fifty six patients were diagnosed with HGD/EAC in less than 12 months, while 14 progressed to HGD/EAC after 12 months, with an overall annual risk of progression of 1.2%. 29% of LGD subjects were downgraded to non-dysplastic and the remaining re-confirmed as LGD or indefinite dysplasia. The risk of progression in the reconfirmed LGD group was eight fold higher (hazards ratio: 7.6, 95% CI: 1.5–139.4) in a propensity score stratified model.Conclusions:In this large BE-LGD cohort, progression risk increased substantially when an additional panel of two expert GI pathologists re-confirmed a LGD diagnosis. These BE subjects may be candidates for endoscopic therapy. LGD was a marker of prevalent HGD/EAC in 18% of patients.

Highly Discriminant Methylated DNA Markers for the Non-endoscopic Detection of Barrett’s Esophagus

BACKGROUND: Minimally invasive methods have been described to detect Barretts esophagus (BE), but are limited by subjectivity and suboptimal accuracy. We identified methylated DNA markers (MDMs) for BE in tissue and assessed their accuracy on whole esophagus brushings and capsule sponge samples. METHODS: Step 1: Unbiased whole methylome sequencing was performed on DNA from BE and normal squamous esophagus (SE) tissue. Discriminant MDM candidates were validated on an independent patient cohort (62 BE cases, 30 controls) by quantitative methylation specific PCR (qMSP). Step 2: Selected MDMs were further evaluated on whole esophageal brushings (49 BE cases, 36 controls). 35 previously sequenced esophageal adenocarcinoma (EAC) MDMs were also evaluated. Step 3: 20 BE cases and 20 controls were randomized to swallow capsules sponges (25 mm, 10 pores or 20 pores per inch (ppi)) followed endoscopy. DNA yield, tolerability, and mucosal injury were compared. Best MDM assays were performed on this cohort. RESULTS: Step 1: 19 MDMs with areas under the ROC curve (AUCs) >0.85 were carried forward. Step 2: On whole esophageal brushings, 80% of individual MDM candidates showed high accuracy for BE (AUCs 0.84‐0.94). Step 3: The capsule sponge was swallowed and withdrawn in 98% of subjects. Tolerability was superior with the 10 ppi sponge with minimal mucosal injury and abundant DNA yield. A 2‐marker panel (VAV3 + ZNF682) yielded excellent BE discrimination (AUC = 1). CONCLUSIONS: Identified MDMs discriminate BE with high accuracy. BE detection appears safe and feasible with a capsule sponge. Corroboration in larger studies is warranted. ClinicalTrials.gov number NCT02560623.

Comparative quality assessment of esophageal examination with transnasal and sedated endoscopy

Background Unsedated transnasal esophagoscopy (TNE) may offer a less expensive, mobile alternative to sedated esophagogastroduodenoscopy (EGD) for evaluations of reflux related complications. Comparisons of imaging quality by these methods are lacking. Methods Two reviewers evaluated videos of TNE and EGD procedures, performed during a community randomized study comparing endoscopic techniques. Subjects were randomized to EGD, TNE in endoscopy suite, or TNE in mobile research unit. Endoscopic quality was assessed using a validated scoring tool. Results In total, 115 videos (58 EGD, 28 endoscopy suite TNE, and 29 mobile TNE) were reviewed. Overall quality scores for TNE and EGD were excellent without a statistically significant difference (P = 0.30). There were no differences in gastroesophageal junction (GEJ) visualization scores, though EGD scored higher in esophageal passage (P < 0.05) and TNE scored higher in esophageal intubation (P < 0.05). There was no significant difference in any quality score between mobile TNE and gastrointestinal suite TNE. Conclusion Esophageal assessment with TNE or EGD was comparable in overall quality and GEJ visualization. TNE quality was not affected by procedure location. TNE is a feasible option for endoscopic assessment of reflux complications.

Influence of reflux and central obesity on intercellular space diameter of esophageal squamous epithelium

Background While central obesity increases gastroesophageal reflux (GER) by mechanically disrupting the anti-reflux barrier, limited data exist on pathways by which central obesity may potentiate esophageal injury by non-mechanical means. Obesity has been associated with an impaired epithelial intestinal barrier. Objective We aimed to assess the influence of central obesity and reflux on the squamous esophageal epithelial intercellular space diameter (ICSD). Methods The ICSD was measured using electron microscopy in esophageal biopsies from individuals who underwent ambulatory pH monitoring and endoscopy. Anthropometric measurements were obtained on all participants. Participants were classified into four groups: with and without central obesity and reflux. Results Sixteen individuals were studied with four in each study group. The mean ICSD was almost three-fold greater (p < 0.001) in the group with central obesity without reflux, compared to controls without central obesity and reflux. It was also comparable to the ICSD in groups with acid reflux only and those with both reflux and central obesity. Conclusions There is evidence of esophageal squamous ICSD increase in individuals with central obesity who do not have evidence of acid and nonacid reflux on ambulatory pH monitoring. This may reflect a mechanism by which central obesity potentiates reflux-induced esophageal injury and inflammation.

Obesity and GERD impair esophageal epithelial permeability through 2 distinct mechanisms

The mechanism by which obesity leads to damage independent of reflux is unclear. We aimed to determine the influence of obesity on mean nocturnal baseline impedance (MNBI), a functional measure of the epithelial barrier, in the presence and absence of acid reflux, using ambulatory pH impedance measurements.

Sa1074 Increased Number of Risk Factors Predicts Esophageal Injury and Metaplasia: Results From a Large Prospective Population-Based Study

modalities were included in this analysis. Patients who stopped EET and started surveillance prior to CE-IM were excluded. Complete eradication of intestinal metaplasia (CE-IM) was defined as having an endoscopy with no visible columnar lined epithelium in the tubular esophagus and biopsies of the neo-squamous mucosa showing no intestinal metaplasia. Patients were considered to have achieved CE-IM if they had done so with 2cm were less likely to achieve CE-IM compared to those with C extents ≤2cm (64.3% vs. 73.5%, p=0.027). Patients with M extents of > 3cm were less likely to achieve CE-IM compared to those with M extents ≤3cm (61.2% vs. 88.4%, p<0.001). Conclusions: Results of this multi-center effectiveness trial show that pre-treatment Barretts esophagus extent as measured by the Prague criteria is associated with the rate of achieving CE-IM with endoscopic eradication therapy. This was true for both the C and M extents of disease. This study provides the first validation of the Prague criteria with clinically relevant outcomes in the management of patients with Barretts esophagus.

Sa1071 Direct and Indirect Costs Associated With Barrett's Esophagus Screening: Results From a Community Randomized Controlled Trial

Background and Aims: Real costs associated with screening for Barretts esophagus (BE) are not known. Modeling studies concluding that screening for BE is cost effective have used estimates based on several assumptions. As part of a prospective randomized controlled trial assessing the comparative effectiveness of unsedated transnasal endoscopy (uTNE) and sedated endoscopy (sEGD), real direct and indirect costs associated with BE screening were prospectively collected and compared. Methods: Patients were randomly allocated to three screening techniques: sEGD or uTNE in a hospital setting (huTNE) versus uTNE in a mobile research van (muTNE). Following the procedure, patients were called at 1 and 30 days by a research coordinator to assess adverse effects, loss of work (for the screening procedure) and medical care sought after the BE screening procedure. Direct medical (initial screening test and medical costs within 30 days of test), indirect (loss of work for subject and caregiver) and total medical costs were extracted using the Olmsted County Healthcare Expenditure and Utilization Database (OCHEUD). This claims-based database contains details on healthcare utilization, associated charges, and inflation adjusted economic costs for patients in Olmsted County. Costs were analyzed descriptively and compared using multivariate regression. Covariates in the model included age, sex and comorbidities (measured using the Hwang method). To test whether the assumed cost affects results, sensitivity analyses were performed by varying costs from 50% to 300%. Results: 209 patients (46% males, mean age 65 years) were screened (61 with sEGD, 72 with huTNE and 76 with muTNE), out of 459 who were invited (participation rate 46%). Clinical effectiveness of uTNE screening was comparable to that of sEGD (Sami, AmJGastro 2014). 4 sEGD and 4 muTNE patients did not have follow-up interviews and were excluded from analyses. 30 day direct medical costs and indirect costs were higher in the sEGD than in huTNE and muTNE groups. Total costs (direct medical + indirect costs) were significantly higher in the sEGD group than in the uTNE groups (Table 1). muTNE had significantly lower costs than the huTNE group on univariate and multivariate analysis. (Table 2). Sensitivity analyses still resulted in significantly higher costs for sEGD compared to muTNE for both low and high values (results not shown). Conclusions: In our prospective randomized comparative effectiveness trial, we demonstrate for the first time that real short term direct medical, indirect and total costs of BE screening are significantly lower with uTNE compared with sEGD. Costs associated with mobile uTNE were lower than with huTNE, raising the possibility of mobile screening (which has comparable clinical effectiveness to sEGD and huTNE) as a novel method of screening for BE and esophageal adenocarcinoma. Table 1. Total costs (30 day direct medical + indirect costs) over the one-month period following screening, by study group. (Costs in US

Sa1067 Rates and Predictors of Progression in Barrett's Esophagus With Low Grade Dysplasia: Results From a Prospective U.S. Registry

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