Lightdale, Charles J.

INTRODUCTION: Reflux bile acids are believed to promote esophageal adenocarcinoma (EAC), but the role of systemic bile acids is unknown. This study aimed to assess associations between systemic bile acids and stages of Barrett's esophagus (BE) progression. METHODS: Subjects with and without BE were enrolled in this multicenter cross-sectional study. Targeted serum bile acid profiling was performed, and a subset of subjects completed a validated food frequency questionnaire. RNA sequencing was performed on BE or gastric cardia tissue to assess bile acid associations with gene expression. RESULTS: A total of 141 subjects were enrolled with serum bile acids profiled (49 non-BE; 92 BE: 44 no dysplasia, 25 indefinite/low grade dysplasia, 23 high-grade dysplasia/EAC). Lower Healthy Eating Index score, older age, higher body mass index, and no proton pump inhibitor use were associated with increased levels of multiple bile acids. Global bile acid pools were distinct between non-BE and stages of BE neoplasia ( P = 0.004). Increasing cholic acid was associated with high-grade dysplasia/EAC compared with non-BE, even after adjusting for EAC risk factors (adjusted odds ratio 2.03, 95% confidence interval 1.11–3.71) as was the combination of unconjugated primary bile acids (adjusted odds ratio 1.81, 95% confidence interval 1.04–3.13). High cholic acid levels were associated with tissue gene expression changes including increased DNA replication and reduced lymphocyte differentiation genes. DISCUSSION: Alterations in serum bile acids are independently associated with advanced neoplasia in BE and may contribute to neoplastic progression. Future studies should explore associated gut microbiome changes, proneoplastic effects of bile acids, and whether these bile acids, particularly cholic acid, represent potential biomarkers or viable therapeutic targets for advanced neoplasia in BE.

INTRODUCTION: Ablation of Barrett's esophagus (BE) is the preferred approach for the treatment of neoplasia without visible lesions. Limited data on cryoballoon ablation (CBA) suggest its potential clinical utility. We evaluated the safety and efficacy of CBA in a multicenter study of patients with neoplastic BE. METHODS: In a prospective clinical trial, 11 academic and community centers recruited consecutive patients with BE of 1–6 cm length and low-grade dysplasia, high-grade dysplasia (HGD), or intramucosal adenocarcinoma (ImCA) confirmed by central pathology. Patients with symptomatic pre-existing strictures or visible BE lesions had dilation or endoscopic mucosal resection (EMR), respectively, before enrollment. A nitrous oxide cryoballoon focal ablation system was used to treat all visible columnar mucosa in up to 5 sessions. Study end points included complete eradication of all dysplasia (CE-D) and intestinal metaplasia (CE-IM) at 1 year. RESULTS: One hundred twenty patients with BE with ImCA (20%), HGD (56%), or low-grade dysplasia (23%) were enrolled. In the intention-to-treat analysis, the CE-D and CE-IM rates were 76% and 72%, respectively. In the per-protocol analysis (94 patients), the CE-D and CE-IM rates were 97% and 91%, respectively. Postablation pain was mild and short lived. Fifteen subjects (12.5%) developed strictures requiring dilation. One patient (0.8%) with HGD progressed to ImCA, which was successfully treated with EMR. Another patient (0.8%) developed gastrointestinal bleeding associated with clopidogrel use. One patient (0.8%) had buried BE with HGD in 1 biopsy, not confirmed by subsequent EMR. DISCUSSION: In patients with neoplastic BE, CBA was safe and effective. Head-to-head comparisons between CBA and other ablation modalities are warranted (clinicaltrials.gov registration NCT02514525).

AbstractVolumetric laser endomicroscopy (VLE) has been shown to improve detection of early neoplasia in Barrett’s esophagus (BE). However, diagnostic performance using histopathology-correlated VLE regions of interest (ROIs) has not been adequately studied. We evaluated the diagnostic accuracy of VLE assessors for identification of early BE neoplasia in histopathology-correlated VLE ROIs. In total, 191 ROIs (120 nondysplastic and 71 neoplastic) from 50 BE patients were evaluated in a random order using a web-based module. All ROIs contained histopathology correlations enabled by VLE laser marking. Assessors were blinded to endoscopic BE images and histology. ROIs were first scored as nondysplastic or neoplastic. Level of confidence was assigned to the predicted diagnosis. Outcome measures were: (i) diagnostic performance of VLE assessors for identification of BE neoplasia in all VLE ROIs, defined as accuracy, sensitivity, and specificity; (ii) diagnostic performance of VLE assessors for only high level of confidence predictions; and (iii) interobserver agreement. Accuracy, sensitivity, and specificity for BE neoplasia identification were 79% (confidence interval [CI], 75–83), 75% (CI, 71–79), and 81% (CI, 76–86), respectively. When neoplasia was identified with a high level of confidence, accuracy, sensitivity, and specificity were 88%, 83%, and 90%, respectively. The overall strength of interobserver agreement was fair (k = 0.29). VLE assessors can identify BE neoplasia with reasonable diagnostic accuracy in histopathology-correlated VLE ROIs, and accuracy is enhanced when BE neoplasia is identified with high level of confidence. Future work should focus on renewed VLE image reviewing criteria and real-time automatic assessment of VLE scans.

Abstract Background Volumetric laser endomicroscopy (VLE) allows for near-microscopic imaging of the superficial esophageal wall and may improve detection of early neoplasia in Barrett’s esophagus (BE). Interpretation of a 6-cm long, circumferential VLE “full scan” may however be challenging for endoscopists. We aimed to evaluate the accuracy of VLE experts in correctly diagnosing VLE full scans of early neoplasia and non-dysplastic BE (NDBE). Methods 29 VLE full scan videos (15 neoplastic and 14 NDBE) were randomly evaluated by 12 VLE experts using a web-based module. Experts were blinded to the endoscopic BE images and histology. The 15 neoplastic cases contained a subtle endoscopically visible lesion, which on endoscopic resection showed high grade dysplasia or cancer. NDBE cases had no visible lesions and an absence of dysplasia in all biopsies. VLE videos were first scored as “neoplastic” or “NDBE.” If neoplastic, assessors located the area most suspicious for neoplasia. Primary outcome was the performance of VLE experts in differentiating between non-dysplastic and neoplastic full scan videos, calculated by accuracy, sensitivity, and specificity. Secondary outcomes included correct location of neoplasia, interobserver agreement, and level of confidence. Results VLE experts correctly labelled 73 % (95 % confidence interval [CI] 67 % – 79 %) of neoplastic VLE videos. In 54 % (range 27 % – 66 %) both neoplastic diagnosis and lesion location were correct. NDBE videos were consistent with endoscopic biopsies in 52 % (95 %CI 46 % – 57 %). Interobserver agreement was fair (kappa 0.28). High level of confidence was associated with a higher rate of correct neoplastic diagnosis (81 %) and lesion location (73 %). Conclusions Identification of subtle neoplastic lesions in VLE full scans by experts was disappointing. Future studies should focus on improving methodologies for reviewing full scans, development of refined VLE criteria for neoplasia, and computer-aided diagnosis of VLE scans.

Abstract Background and study aims Little is known about the learning curve for image interpretation in volumetric laser endomicroscopy (VLE) in Barrett’s esophagus (BE). The goal of this study was to calculate the learning curve, competence of image interpretation, sensitivity, specificity, and accuracy of VLE among novice users. Methods 31 novice users viewed 96 VLE images electronically at three academic institutions after a brief training session. There were 24 images of each histologic type: normal gastric cardia, normal esophageal squamous epithelium, non-neoplastic BE, and neoplastic BE. The users were asked to identify the correct tissue type and level of confidence. The cumulative summation (CUSUM) technique was used to construct a learning curve. Results 22 (71 %) of the physicians achieved VLE interpretation competency during their 96-slide review. Half of the physicians achieved competency at 65 images (95 % confidence interval [CI] 45 – 85). There was a statistically significant association between confidence in diagnosis and selecting the correct histologic tissue type (P < 0.001). The median accuracy for esophageal squamous epithelium, normal gastric cardia, non-neoplastic BE, and neoplastic BE was 96 % (95 %CI 95 % – 96 %), 95 % (95 %CI 94 % – 96 %), 90 % (95 %CI 88 % – 91 %), 96 % (95 %CI 95 % – 96 %). The overall accuracy was 95 % (95 %CI 93 % – 95 %). Conclusion The majority of novice users achieved competence in image interpretation of VLE for BE, using a pre-selected image set, with a favorable learning curve after a brief training session. An electronic review of VLE images, prior to real-time use of VLE, is encouraged.

83 Background: Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity and mortality. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study was to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal cancer. Methods: This study includes patients enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from twelve academic and community practices. Endoscopic spray cryotherapy was performed until local tumor eradication was confirmed by biopsy or until treatment was halted due to progression of disease, patient withdrawal or co-morbidities. Results: One-hundred and eight patients (median age 75.5, 79.6% male, 93.5% adenocarcinoma, mean length 5.2 cm) underwent 442 treatments (mean 4.2 per patient). Tumor stages included 40 with T1a, 27 with T1b, 10 with unspecified T1, 15 with T2, and 16 with no T stage reported. One-hundred and six patients completed treatment with complete response of intraluminal disease in 54.7%, including complete response in 74.4% for T1a, 50% for T1b, 65.3% for all T1, 6.7% for T2, and 50% for those with no T stage reported. Mean follow-up was 17.3 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 11 of 108 patients (10.2%) but were present before spray cryotherapy in 3 of 11. Conclusions: This study suggests that endoscopic spray cryotherapy is safe, well tolerated and effective for early esophageal cancer in patients who are not candidates for conventional therapy.