Trindade, Arvind J.

Abstract Aberrant DNA methylation and copy-number alterations (CNA) drive Barrett’s esophagus progression to esophageal adenocarcinoma; however, their combined utility for early detection is unclear. We aimed to identify and validate methylated DNA markers (MDM) and CNAs to distinguish esophageal adenocarcinoma/high-grade dysplasia (HGD) from nondysplastic Barrett’s esophagus (NDBE). In this multiphase, multicenter study, we discovered and validated MDMs and quantified CNAs utilizing whole-genome methylation sequencing of esophageal brushings. DNA biomarkers identified from discovery were further validated in independent patients with paired esophageal brushing and swallowed capsule sponge samples. MDMs were filtered against a reduced representation bisulfite sequencing dataset obtained from independent tissue samples to advance only concordant candidates. CNA burden was quantified using ichorCNA-derived aneuploidy scores (AS). Two hundred MDMs discovered in HGD (N = 18) and esophageal adenocarcinoma (N = 18) versus NDBE brushing samples (N = 18) were tested in independent samples (N = 146). A 52-MDM panel achieved a cross-validated AUC of 0.88 [95% confidence interval (CI), 0.82–0.95]; the addition of AS improved discrimination of HGD/esophageal adenocarcinoma from NDBE to 0.91 (95% CI, 0.86–0.97) AUC. At 80% specificity, the combined model detected 93% of esophageal adenocarcinoma and 88% of HGD cases. In paired capsule sponge samples, a 58-MDM panel achieved a cross-validated AUC of 0.77 (95% CI, 0.66–0.88); a combined 58-MDM and AS model achieved AUC 0.80 (95% CI, 0.7–0.9). MDMs and AS discerned HGD/esophageal adenocarcinoma from normal esophagus/NDBE in endoscopic brushing and capsule sponge samples. This approach may improve Barrett’s esophagus surveillance. Prevention Relevance: This study demonstrates that combining epigenetic and genomic biomarkers across minimally invasive sampling methods can accurately distinguish HGD/esophageal adenocarcinoma from nondysplastic Barrett’s esophagus, offering promising, less invasive strategies to improve BE surveillance and enable endoscopic therapy for esophageal adenocarcinoma prevention and treatment.

AbstractEndoscopic eradication therapy (EET) is recommended for the management of dysplastic Barrett’s esophagus (BE) and intramucosal adenocarcinoma. Both radiofrequency (RFA) and cryoballoon ablation (CBA) can induce complete remission of intestinal metaplasia (CRIM). We aimed to compare long-term durability following CRIM in patients treated with RFA vs. CBA.We conducted a retrospective cohort study to analyze patient outcomes following EET with RFA or CBA at two referral centers. We measured and compared the recurrence rate of BE, with or without dysplasia, after CRIM, using Cox proportional hazard models and propensity score-matched analyses. Our secondary aim was to identify predictors of recurrence.681 patients who achieved CRIM were included (RFA 610; CBA 71), with median follow-up of 4.1 years and 4.4 years following RFA and CBA, respectively. A multivariable model revealed a higher risk of any recurrence with RFA (hazard ratio [HR] 2.19, 95%CI 1.18–4.06; P = 0.01), but not dysplastic recurrence (HR 0.88, 95%CI 0.39–1.97; P = 0.75). However, a comparable risk of “any recurrence” was observed after excluding intestinal metaplasia of the gastroesophageal junction (HR 1.18, 95%CI 0.61–2.30; P = 0.62). Propensity score-matched analysis (54 cases in each group) showed that the two groups had comparable recurrence risk. Baseline maximum BE length was associated with a higher risk of any recurrence (HR 1.07; P<0.001) and dysplastic recurrence (HR 1.11; P = 0.001).The rates of any BE recurrence and dysplastic recurrence were comparable with the two modalities in this nonrandomized study.

AbstractEUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS.A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure.A total of 109 patients were included. Technical success was achieved in 108 of 109 (99.1%) and initial clinical success in 106 of 109 (97.2%). Long-term clinical success was achieved in 98 of 109 (89.9%) over a median follow-up of 140 days (range 30–1188). On multivariable analysis (MVA), acalculous cholecystitis (odds ratio [OR] 15.93, 95% confidence interval [CI] 1.22–208.52, P = 0.04) and the occurrence of a LAMS-specific AE (OR 63.60, 95% CI 5.08–799.29, P <0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not.EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.

Background Methods: The question prompt list content was derived through a modified Delphi process consisting of 3 rounds. In round 1, experts provided 5 answers to the prompts “What general questions should patients ask when given a new diagnosis of Barrett’s esophagus” and “What questions do I not hear patients asking, but given my expertise, I believe they should be asking?” Questions were reviewed and categorized into themes. In round 2, experts rated questions on a 5-point Likert scale. In round 3, experts rerated questions modified or reduced after the previous rounds. Only questions rated as “essential” or “important” were included in Barrett’s esophagus question prompt list (BE-QPL). To improve usability, questions were reduced to minimize redundancy and simplified to use language at an eighth-grade level (Fig. 1). Results: Twenty-one esophageal medical and surgical experts participated in both rounds (91% males; median age 52 years). The expert panel comprised of 33% esophagologists, 24% foregut surgeons, and 24% advanced endoscopists, with a median of 15 years in clinical practice. Most (81%), worked in an academic tertiary referral hospital. In this 3-round Delphi technique, 220 questions were proposed in round 1, 122 (55.5%) were accepted into the BE-QPL and reduced down to 76 questions (round 2), and 67 questions (round 3). These 67 questions reached a Flesch Reading Ease of 68.8, interpreted as easily understood by 13 to 15 years olds. Conclusions: With multidisciplinary input, we have developed a physician-derived BE-QPL to optimize patient-physician communication. Future directions will seek patient feedback to distill the questions further to a smaller number and then assess their usability.

Abstract Background and study aims Optical coherence tomography (OCT) is a new technology available for evaluation of indeterminate biliary strictures. It allows under-the-surface visualization and preliminary studies have confirmed standardized characteristics associated with malignancy. The aim of this study is to evaluate the first interobserver agreement in identifying previously agreed upon OCT criteria and diagnosing of malignant versus benign disease. Patients and methods Fourteen endoscopists were asked to review an atlas of reference clips and images of eight criteria derived from expert consensus A total of 35 de-identified video clips were then evaluated for presence of the eight criteria and for final diagnosis of malignant versus benign using the atlas as reference Intraclass correlation (ICC) analysis was done to evaluate interrater agreement. Results Clips of 23 malignant lesions and 12 benign lesions were scored. Excellent interobserver agreement was seen with dilated hypo-reflective structures (0.85) and layering effacement (0.89); hyper-glandular mucosa (0.76), intact layering (0.81), and onion-skin layering (0.77); fair agreement was seen with scalloping (0.58), and thickened epithelium (0.4); poor agreement was seen with hyper-reflective surface (0.36). The diagnostic ICC for both neoplastic (0.8) and non-neoplastic (0.8) was excellent interobserver agreement. The overall diagnostic accuracy was 51 %, ranging from 43 % to 60 %. Conclusions Biliary OCT is a promising new modality for evaluation of indeterminate biliary strictures. Interobserver agreement ranged from fair to almost perfect on eight previously identified criteria. Interobserver agreement for malignancy diagnosis was substantial (0.8). Further studies are needed to validate this data.

Abstract Background and study aims En bloc endoscopic mucosal resection (EMR) is preferred over piecemeal resection for polyps ≤ 20 mm. Data on colorectal EMR training are limited. We aimed to evaluate the en bloc EMR rate of polyps ≤ 20 mm among advanced endoscopy trainees and to identify predictors of failed en bloc EMR. Methods This was a multicenter prospective study evaluating trainee performance in EMR during advanced endoscopy fellowship. A logistic regression model was used to identify the number of procedures and lesion cut-off size associated with an en bloc EMR rate of ≥ 80 %. Multivariate analysis was performed to identify predictors of failed en bloc EMR. Results Six trainees from six centers performed 189 colorectal EMRs, of which 104 (55 %) were for polyps ≤ 20 mm. Of these, 57.7 % (60/104) were resected en bloc. Trainees with ≥ 30 EMRs (OR 6.80; 95 % CI: 2.80–16.50; P = 0.00001) and lesions ≤ 17 mm (OR 4.56;95 CI:1.23–16.88; P = 0.02) were more likely to be associated with an en bloc EMR rate of ≥ 80 %. Independent predictors of failed en bloc EMR on multivariate analysis included: larger polyp size (OR:6.83;95 % CI:2.55–18.4; P = 0.0001), right colon location (OR:7.15; 95 % CI:1.31–38.9; P = 0.02), increased procedural difficulty (OR 2.99; 95 % CI:1.13–7.91; P = 0.03), and having performed < 30 EMRs (OR: 4.87; 95 %CI: 1.05–22.61; P = 0.04). Conclusions In this pilot study, we demonstrated that a relatively low proportion of trainees achieved en bloc EMR for polyps ≤ 20 mm and identified procedure volume and lesion size thresholds for successful en bloc EMR and independent predictors for failed en bloc resection. These preliminary results support the need for future efforts to define EMR procedure competence thresholds during training.

INTRODUCTION: Studies have shown that dysplasia in Barrett's esophagus (BE) has a predilection for the right hemisphere. There is limited information on the longitudinal distribution. The aim was to determine both the longitudinal and circumferential distributions of dysplasia and early neoplasia from 3 prospective studies. METHODS: This is a pooled analysis from 3 prospective studies of patients with treatment-naive BE. Both circumferential and longitudinal locations (for BE segments greater than 1 cm) of dysplastic and early neoplastic lesions were recorded. RESULTS: A total of 177 dysplastic and early neoplastic lesions from 91 patients were included in the pooled analysis; of which 59.3% (n = 105) were seen on high-definition white light endoscopy, 29.4% (n = 52) on advanced imaging, and 11.2% (n = 20) with random biopsies. The average Prague score was C3M5. Of 157 lesions within BE segments greater than 1 cm, 49 (34.8%) lesions were in the proximal half, whereas 92 lesions (65.2%) were in the distal half ( P < 0.001). The right hemisphere of the esophagus contained 55% (86/157) of the total lesions compared with 45% (71/157) for the left hemisphere ( P = 0.02). This was because of the presence of high-grade dysplasia being concentrated in the right hemisphere compared with the left hemisphere (60% vs 40%, P = 0.002). DISCUSSION: In this pooled analysis of prospective studies, both low-grade dysplasia and high-grade dysplasia are more frequently found in the distal half of the Barrett's segment. This study confirms that the right hemisphere is a hot spot for high-grade dysplasia. Careful attention to these locations is important during surveillance endoscopy.

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).