Dysplastic Barrett's Esophagus Research Articles

S576 Radiofrequency Ablation and Cryoablation for Dysplastic Barrett's Esophagus: A Potential Cause of Esophageal Mucosal Eosinophilia

S576 Radiofrequency Ablation and Cryoablation for Dysplastic Barrett's Esophagus: A Potential Cause of Esophageal Mucosal Eosinophilia

789. EFFICACY AND SAFETY OF CRYOBALLOON-180 ABLATION FOR THE TREATMENT OF DYSPLASTIC BARRETT ESOPHAGUS: PRELIMINARY RESULTS FROM A PROSPECTIVE MULTICENTER STUDY

Abstract Background Cryoballoon-ablation is a relatively novel method for the eradication of dysplastic Barrett esophagus (BE). While the focal cryoballoon-ablation system has shown to be efficacious for BE of limited extent, the cryoballoon180-ablation system (CBAS180) is developed to treat longer BE segments by semi-circumferential ablation over 3cm, in a single step. A first-in-human study demonstrated the feasibility of CBAS180 treatment, yet the optimal dose needs to be determined. The current prospective, multicenter study, investigates CBAS180 at lower dosages for patients with dysplastic BE. Methods A total of 62 patients with ablation naïve BE (C≤3 and M≥1) will be enrolled in six Dutch Barrett expert centers. Treatment consists of a full circumferential ablation over 3 cm of length, using two semi-circumferential ablations at a dose of 1.2 mm/sec. Follow-up consisted of phone calls at days 1, 7 and 30, a symptom diary during 14 days, and an endoscopy after 3 months. Outcomes included (1) technical success rate; (2) BE regression percentage at follow-up scored by an independent adjudication committee; (3) incidence of adverse events; (4) post-procedural pain (scored on a scale of 0-10); and (5) post-procedural dysphagia (scored on a validated scale of 0-4). Follow-up treatment consisted of focal cryoballoon-ablation until complete eradication of visible BE was achieved, confirmed by biopsies from the neo-Z-line. Results So far, 25 patients (80% male; mean age 67) with a median BE length of C0M2 (p25-p75 C0-1M2-4) were included. Technical success rate was 92% (23/25; 95% CI 74-99%). In two patients, treatment was technically unsuccessful due to unstable positioning of the balloon (n=1) or a device malfunction (n=1). Median procedure time was 14 (p25-p75 11-16) 4) minutes and median ablation time was 5 (p25-p75 3-5) minutes. All 23 successfully treated patients completed follow-up endoscopy at 3 months. Median BE regression was 90% (p25-p75 75%-100%) evaluated by the independent adjudication committee. Overall, CBAS180 adverse event rate was 8% (2/23); one patient developed esophageal stricture (1/23; 4% [95% CI 1-16%]) resolved after a single endoscopic dilation. Another patient (1/23; 4% [95% CI 1-16%]) experienced post-procedural bleeding, with re-endoscopy without intervention. The CBAS180 procedure was well tolerated with low post-procedural pain (median 2 [p25-p75 1-4] at day 1 and 0 [p25-p75 0-1] at day 7) and dysphagia (56% and 70% of patients with score 0 at days 1 and 7, respectively) scores. So far, 22/23 (95%) patients were additionally treated with focal cryoballoon-ablation and 18/22 (82%) achieved a complete endoscopis and histologic eradication of BE after median 1 (p25-p75 1-3) treatment, the other 4 are still under treatment. After focal cryoballoon-ablation, 2/22 patients developed strictures, resolved after 1 and 2 endoscopic dilatations. Conclusion Based on these preliminary results, circumferential ablation with CBAS180 at 1.2 mm/sec, followed by focal cryoballoon-ablation, emerges as an effective and safe procedure for dysplastic BE eradication in the hands of expert endoscopists. Further avenues for exploration should encompass the assessment of multiple CBAS180 ablations stacked on top of each other in larger segments and the validation of outcomes in a larger patient cohort.

Efficacy and Safety of Cryoablation in Barrett's Esophagus and Comparison with Radiofrequency Ablation: A Meta-Analysis.

The mainstay approach in endoscopic eradication therapy (EET) for dysplastic Barrett's esophagus (BE) includes the endoscopic resection of visible lesions, accompanied by ablation of the residual metaplastic epithelium. Cryoablation therapy is one such emerging ablation technique in this field. This systematic review with a meta-analysis aims to accumulate pooled data on cryoablation performance in the treatment of patients with BE and to compare this technique to the standard of care radiofrequency ablation (RFA). The MEDLINE, Cochrane, and Scopus databases were searched until June 2024 for studies evaluating BE management using cryoablation for cumulative results. The primary outcome was the complete eradication of dysplasia (CED) and intestinal metaplasia (CEIM) in BE compared to RFA, while secondary outcomes included the respective pooled rates using cryoablation, recurrence, and adverse events, with a separate analysis for strictures. The meta-analyses were based on a random-effects model, and the results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses by type of cryoablation were also performed. Twenty-three studies (1604 patients) were finally included, four of which were comparative. CED and CEIM did not differ significantly between cryoablation and RFA [OR= 0.95 (95%CI: 0.50-1.81) and OR = 0.57 (95%CI: 0.20-1.63), respectively)]. The pooled rates of CED, CEIM, and recurrence after cryoablation were 84.2% (95%CI: 79.1-89.3), 64.1% (95%CI: 49.2-79.0), and 8.3% (95%CI: 4.7-11.9), accompanied by high rates of heterogeneity. Adverse events were noted in 14.5% (95%CI: 9.9-19.2) of cases, and 6.5% (95%CI: 4.1-9.0) developed strictures. In the subgroup analysis, the cryoballoon achieved a reduction in heterogeneity in CED, adverse events, and stricture formation, whereas spray catheters provided homogenous results in terms of recurrence. Cryoablation provides equal outcomes compared to RFA in the treatment of patients with BE, with the cryoballoon achieving relatively homogenous rates of CED and adverse events.

GRAIL1 Stabilizes Misfolded Mutant p53 through a Ubiquitin Ligase-Independent, Chaperone Regulatory Function.

Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's esophagus progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL-gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But, how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here, we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for heat shock protein 40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain or a cell-permeable peptide (Pep-J) encoding the above 10 amino acids can bind and inhibit DNAJ-Hsp70 co-chaperone activity, thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic Barrett's esophagus and EAC cells and inhibit the growth of patient-derived organoids of dysplastic Barrett's esophagus in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J are comparable with simvastatin, a cholesterol-lowering drug that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. Implications: We identified a novel ubiquitin ligase-independent, chaperone-regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential.

Update on applications of endoscopic cryotherapy in the gastrointestinal tract.

Endoscopic cryotherapy has emerged as a minimally invasive procedure for targeted tissue ablation within the gastrointestinal tract. This review aims to provide a comprehensive overview of current clinical applications of EC with a review of the pertinent literature. Endoscopic cryotherapy has demonstrated safety and efficacy for various gastrointestinal conditions. Recent studies have highlighted the efficacy of endoscopic cryotherapy, including both liquid nitrogen-based spray cryotherapy and the novel cryoballoon focal ablation system, in achieving complete eradication of dysplasia and neoplasia in Barrett's esophagus. Endoscopic cryotherapy has also shown promise as a second-line treatment option for patients with dysplastic Barrett's esophagus refractory to radiofrequency ablation and as an alternative to surgical resection for duodenal adenomas, when endoscopic resection is not feasible. Innovative applications for the treatment of gastrointestinal bleeding and management of benign refractory esophageal strictures have also been reported. Endoscopic cryotherapy represents a safe, effective, and well tolerated therapeutic option for various clinical scenarios in gastrointestinal endoscopy, including challenging disease states such as refractory Barrett's esophagus and advanced esophageal cancer. Advancements in cryotherapy technology and ongoing research continue to explore additional clinical indications and expand the role of endoscopic cryotherapy in patient care with an aim toward improved patient outcomes.

Rates of Recurrent Intestinal Metaplasia and Dysplasia After Successful Endoscopic Therapy of Barrett's Neoplasia by Endoscopic Mucosal Resection vs Endoscopic Submucosal Dissection and Ablation: A Large North American Multicenter Cohort.

Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51-1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56-1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Liquid nitrogen spray cryotherapy for eradication of dysplastic Barrett’s esophagus: results from a multicenter prospective registry

Liquid nitrogen spray cryotherapy (SCT) is an alternative to radiofrequency ablation (RFA) for eradication of dysplastic Barrett's esophagus (BE). We aimed to assess the safety, efficacy, and durability of SCT in a multicenter U.S. registry. This is a multicenter prospective registry of adults with BE treated with truFreeze Spray Cryotherapy (Steris, Mentor, Ohio, USA) (4 community and 11 academic sites, 2013-2022). Complete eradication of intestinal metaplasia (CEIM) and dysplasia (CED) were assessed in BE with dysplasia or intramucosal adenocarcinoma. Kaplan-Meier analysis of CEIM and CED was performed. Hazard ratios for CEIM stratified by baseline risk factors were calculated. Among 138 subjects with low-grade dysplasia (24%), high-grade dysplasia (49%), and intramucosal adenocarcinoma (27%), 34% received prior RFA therapy. Subjects received a median of 2 SCT sessions. Adverse events were uncommon, with 5.5% reporting strictures and 0.7% a perforation. Rates of CEIM and CED, respectively, were 66% and 84% after 2 years and 67% and 92% after 3 years. In RFA-naïve patients, CEIM was 77% and CED was 96% at 3 years. Increasing BE length (per centimeter: adjusted hazard ratio, 0.90; 95% confidence interval, 0.83-0.96) and prior treatment with RFA (adjusted hazard ratio, 0.39; 95% confidence interval, 0.22-0.69) were associated with a lower rate of CEIM. Recurrence occurred in 8.8% (n= 6) at a mean follow-up of 2.5 years after CEIM. In this largest reported prospective cohort, liquid nitrogen SCT was safe and effective for the treatment of dysplastic and neoplastic BE. Response was lower in those with prior failed RFA; in that cohort, approximately 50% attained CEIM at 3 years.

Cryotherapy versus radiofrequency ablation in the treatment of dysplastic Barrett's esophagus with or without early esophageal neoplasia: a systematic review and meta-analysis.

Radiofrequency ablation (RFA) is the first-line therapy for dysplastic Barrett's esophagus (BE). Therefore, cryotherapy has emerged as an alternative treatment option. This study aimed to compare the efficacies of these two techniques based on the rates of complete eradication of intestinal metaplasia (CE-IM) and dysplasia (CE-D). Adverse events and recurrence have also been reported. An electronic search was conducted using the Medline (PubMed), Embase, LILACS, and Google Scholar databases until December 2022. Studies were included comparing cryotherapy and RFA for treating dysplastic BE with or without early esophageal neoplasia. This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Three retrospective cohort studies involving 627 patients were included. Of these, 399 patients underwent RFA, and 228 were treated with cryotherapy. There was no difference in CE-IM (risk difference [RD], -0.03; 95% confidence interval [CI], -0.25 to 0.19; p=0.78; I2=86%) as well as in CE-D (RD, -0.03; 95% CI, -0.15 to 0.09; p=0.64; I2=70%) between the groups. The absolute number of adverse events was low, and there was no difference in the recurrence rate. Cryotherapy and RFA were equally effective in treating dysplastic BE, with or without early esophageal neoplasia.

ANPEP/CD13 Expression as a Marker of Lymphovascular Invasion and Survival in Esophageal Adenocarcinoma

BackgroundThe presence of lymphovascular invasion (LVI) in early esophageal adenocarcinoma (EAC) is associated with more aggressive disease. Molecular markers associated with LVI are still largely unknown. Using a combination of transcriptomic analysis and validation experiments, we sought to describe markers for LVI and survival. MethodsWe performed NanoString expression profiling using RNA from 60 EAC specimens collected from surgery-only cases between 2000 and 2012. Differentially expressed genes (DEGs) were correlated with pathologic characteristics (T and N status and presence of LVI). Kaplan-Meier and Cox regression analyses were used to correlate gene expression with overall survival. Expression of alanyl aminopeptidase, membrane (ANPEP)/CD13 was validated by immunohistochemistry (IHC) in EAC tissue microarray and in EAC cell lines. ResultsWe identified >20 up-regulated DEGs in tumor samples containing LVI. Multivariable analysis showed depth of invasion and ANPEP/CD13 expression were independently associated with overall survival, whereas nodal status was not. IHC analysis demonstrated overexpression of the ANPEP/CD13 protein in dysplastic Barrett esophagus and EAC tumors. Kaplan-Meier analysis showed that patients with higher RNA expression and strongly positive ANPEP/CD13 membrane IHC-Histoscore staining have shorter survival (P = .002). Down-regulation of ANPEP/CD13 expression by short hairpin RNA vector reduces colony formation, migration, and invasion of FLO-1 EAC cells. Overexpression of CD13 in SKGT4 EAC cells increases colony formation, motility, and invasion in vitro. ConclusionsElevated expression of ANPEP/CD13 indicates shorter survival of EAC patients and a more invasive phenotype of cancer cells in vitro. Validation in a larger sample group is required to better understand the clinical significance of ANPEP/CD13 and other candidate genes.

Endoscopic Management of Dysplastic Barrett's Oesophagus and Early Oesophageal Adenocarcinoma.

Barrett's oesophagus is a pathological condition whereby the normal oesophageal squamous mucosa is replaced by specialised, intestinal-type metaplasia, which is strongly linked to chronic gastro-oesophageal reflux. A correct endoscopic and histological diagnosis is pivotal in the management of Barrett's oesophagus to identify patients who are at high risk of progression to neoplasia. The presence and grade of dysplasia and the characteristics of visible lesions within the mucosa of Barrett's oesophagus are both important to guide the most appropriate endoscopic therapy. In this review, we provide an overview on the management of Barrett's oesophagus, with a particular focus on recent advances in the diagnosis and recommendations for endoscopic therapy to reduce the risk of developing oesophageal adenocarcinoma.

Multi-focal dysplasia is associated with high recurrence rates after successful ablation of dysplastic Barrett's esophagus

Background & AimsBarrett's esophagus (BE) might recur after complete eradication of intestinal metaplasia (CEIM). We investigated factors associated with recurrence of BE after successful Radiofrequency ablation (RFA). MethodsA longitudinal study of BE patients with dysplasia treated with RFA from 2014 to 2021 in two large referral centers. Recurrence was identified in histologic specimens. Factors associated with post-RFA recurrence were analyzed using Cox regression analysis. ResultsA total of 728 patients with BE were identified, 118 had underwent RFA, and 113 had sufficient follow up time. Mean age was 63.7 (±11.7) years, 73.5% were males, 59.3% had long segment of BE, and 30.1% had multifocal dysplasia. During 340.8 patient-years of follow-up, 15 patients (13.3%) had recurrence of BE, which represent an incidence rate of 4.41% per patient-year. Incidence rate of recurrence with dysplasia was 1.17% per patient-year. Multifocal dysplasia, number of RFA sessions, and endoscopic resection before RFA were associated with risk of recurrence in univariate analysis. However, in cox regression analysis only multifocal dysplasia (HR 10.99; 95% CI 2.83–22.62, p = 0.001) was associated with post-RFA recurrence. ConclusionTotal recurrence rates after CEIM are low, and multifocal dysplasia before the ablative therapy is significantly associated with BE recurrence after CEIM. Patients with multifocal dysplasia should be monitored rigorously after successful ablation.

Location and appearance of dysplastic Barrett’s esophagus recurrence after endoscopic eradication therapy: no additional yield from random biopsy sampling neosquamous mucosa

Surveillance after complete remission of intestinal metaplasia (CRIM) is essential. Current recommendations are to sample visible lesions first, followed by random 4-quadrant biopsy sampling of the original Barrett's esophagus (BE) length. To inform post-CRIM surveillance protocols, we aimed to identify the anatomic location, appearance, and histology of BE recurrences. We performed an analysis of 216 patients who achieved CRIM after endoscopic eradication therapy for dysplastic BE at a Barrett's Referral Unit between 2008 and 2021. The anatomic location, recurrence histology, and endoscopic appearance of dysplastic recurrences were evaluated. After a median of 5.5 years (interquartile range, 2.9-7.2) of follow-up after CRIM, 57 patients (26.4%) developed nondysplastic BE (NDBE) recurrence and 18 patients (8.3%) developed dysplastic recurrence. From 8158 routine surveillance biopsy samplings of normal-appearing tubular esophageal neosquamous epithelium, the yield for recurrent NDBE or dysplasia was 0%. One hundred percent of dysplastic tubular esophageal recurrences were visible and in BE islands, whereas 77.8% of gastroesophageal junction dysplastic recurrences were nonvisible. Four distinct endoscopic features suspicious for recurrent advanced dysplasia or neoplasia were identified: buried or subsquamous BE, irregular mucosal pattern, loss of vascular pattern, and nodularity or depression. The yield of routine surveillance biopsy sampling of normal-appearing tubular esophageal neosquamous epithelium was zero. BE islands with indistinct mucosal or loss of vascular pattern, nodularity or depression, and/or signs of buried BE should raise clinician suspicion for advanced dysplasia or neoplasia recurrence. We suggest a new surveillance biopsy sampling protocol with a focus on meticulous inspection, followed by targeted biopsy sampling of visible lesions and random 4-quadrant biopsy sampling of the gastroesophageal junction.

Radio frequency ablation of dysplastic Barrett's esophagus: Outcomes of a single-center registry.

Barrett's esophagus (BE) is associated with an increased risk of esophageal adenocarcinoma. The use of radio frequency ablation (RFA) for complete eradication of BE with confirmed low-grade dysplasia (LGD) or high-grade dysplasia (HGD) has been promising in multicenter trials. Our aim was to evaluate the safety and efficacy outcomes associated with RFA for patients with BE and LGD/HGD in a single-center setting. This was a retrospective single-center study conducted at Department of Surgery and Transplantation, Rigshospitalet, Denmark. Data were collected from all patients who had undergone RFA for LGD or HGD from January 2014 to December 2018. Effectiveness outcomes were based on histology: complete eradication of dysplasia (CE-D), defined as all esophageal biopsies being negative for dysplasia at the last biopsy session, and complete eradication of intestinal metaplasia (CE-IM) defined as esophageal biopsies being without intestinal metaplasia. Safety outcomes were based on the proportion of complications to the RFA treatment. A total of 107 patients were identified during the follow-up period (75% men, median age = 65 years); 83% had LGD and 17% had HGD. The median follow-up was 25 months. After the last RFA treatment, CE-D was achieved in 89%. CE-D and CE-IM were achieved in 60%. Complications occurred in 6.5% of the patients. In patients with BE and confirmed LGD or HGD, RFA was associated with a high rate of CE-D and a low risk of complications. The observed safety and efficacy outcomes were comparable with those previously reported in multicenter trials, showing that the Danish treatment of BE with LGD and HGD is comparable with those of larger European expert centers.

OGBN O05 Safety and efficacy of endoscopic self-expanding stent insertion for benign oesophageal strictures – retrospective review of a single-centre case series

Abstract Background Benign oesophageal strictures (BOS) are common and are most often managed with endoscopic balloon or bougie dilation. While self-expanding stents (SES) are a key tool for managing malignant strictures, their role in management of BOS is less well defined, usually being reserved for refractory strictures. Potential benefits include reduced frequency of intervention to stabilise nutritional status, and risks include migration, perforation or erosion. We conducted a single-centre retrospective review of our experience using SES for BOS to evaluate their safety and efficacy. Methods All patients undergoing SES insertion at a tertiary oesophago-gastric surgery unit between November 2015 and November 2020 were retrospectively identified using cross-referencing across 3 internal software systems. Patients undergoing primary SES insertion for BOS were identified, records were retrieved and reviewed. Data was collected on pre-insertion stricture management, post-procedure complications and outcomes including further interventions within the next year. Results During the study period, 425 oesophageal SES were inserted. From these cases, 18 patients underwent primary SES insertion for BOS. 14/18 (78%) of patients were male with a mean age of 68 years. Causes of BOS were reflux (7, 39%), 360 degree radiofrequency ablation of dysplastic Barrett's oesophagus (7, 39%), radiotherapy for squamous cell carcinoma (2, 11%), post-achalasia treatment stricture (1, 6%) and anastomotic stricture (1, 6%). In the 12 months prior to SES insertion, patients underwent a median of 3 (IQR 2–4) balloon dilations. During the immediate preceding month, patients underwent a median of 1 (IQR 0–1) dilations. There were no cases of perforation, bleeding or erosion associated with SES insertion. 5 of 18 (28%) stents migrated. Median interval to the next endoscopy was just over 5 weeks (36 days (IQR 27.25–48). During the following 12 months after stent insertion, patients underwent a median of 5 (IQR 3–9.5) further endoscopies after primary stent insertion. Conclusions Stent insertion for BOS is safe and can provide a period of several weeks before further intervention is required. This may facilitate a period during which oral nutrition can be improved. However, SES for BOS is associated with a significant rate of migration, and patients continue to require frequent interventions after stent insertion. We suggest that SES insertion in this setting should be reserved for selected cases where intensive early dilation has failed to achieve progression in diameter with improvement in symptoms and nutrition as part of a standardised approach to improve management of BOS.

Predictive factors of radiofrequency ablation failure in the treatment of dysplastic Barrett's esophagus

IntroductionRadiofrequency ablation (RFA) has become the recommended endoscopic treatment for flat dysplastic Barrett's esophagus. However, the outcomes of this treatment are variable across European countries. Our aim was to report the results of a French high-volume center, and to investigate factors associated with treatment failure. MethodsWe conducted a single-center retrospective study from a prospectively collected database from 2011 to 2020, including all consecutive patients treated with RFA for flat dysplastic Barrett's esophagus. The primary endpoint was the failure rate of esophageal radiofrequency treatment, defined as either persistence of intestinal metaplasia at the end of treatment, or neoplastic progression during RFA. Results96 patients treated with a median of four RFA sessions for a mean C5M6 Barrett's esophagus were included in the analysis. Complete eradication of intestinal metaplasia and dysplasia were achieved in 59% and 79% of patients, respectively, resulting in a treatment failure rate of 41%. Ten patients experienced neoplastic progression during treatment. We recorded 14% of post-RFA esophageal strictures, all successfully treated by endoscopic dilatation. Univariate analysis identified the length of Barrett's esophagus and the absence of hiatal hernia as predictive factors for treatment failure, however not confirmed in multivariate analysis. ConclusionIn our experience, RFA of flat dysplastic Barrett's esophagus had a 41% treatment failure rate. The length of the Barrett's segment might be associated with treatment failure. Although our results confirm a role for RFA in the management of dysplastic Barrett's esophagus, the treatment failure rate was higher than expected. This suggest that endoscopists, even in high-volume centers, should receive specific training in RFA.

Management of Dysplastic Barrett's Esophagus and Early Esophageal Adenocarcinoma.

While patients with Barrett's esophagus without dysplasia may benefit from endoscopic surveillance, those with low-grade dysplasia may be managed with either endoscopic surveillance or endoscopic eradication. Patients with Barrett's esophagus with high-grade dysplasia and/or intramucosal adenocarcinoma will generally require endoscopic eradication therapy. The management of Barrett's esophagus with dysplasia and early esophageal adenocarcinoma is predominantly endoscopic, with multiple effective methods available for the resection of raised neoplasia and ablation of flat neoplasia. High-dose proton-pump inhibitor therapy is advised during the treatment of Barrett's esophagus with dysplasia and early esophageal adenocarcinoma. After the endoscopic eradication of Barrett's esophagus and associated neoplasia, surveillance is required for the diagnosis and retreatment of recurrence or progression.

Validation of Novel Molecular Imaging Targets Identified by Functional Genomic mRNA Profiling to Detect Dysplasia in Barrett's Esophagus.

Simple SummaryBarrett’s esophagus (BE) is the precursor of esophageal adenocarcinoma (EAC). Dysplastic BE (DBE), including low-grade dysplasia (LGD) and high-grade dysplasia (HGD), shows a higher progression risk to EAC compared to non-dysplastic BE (NDBE). If LGD or HGD is detected, more intensive endoscopic surveillance or endoscopic treatment is recommended. This results in a significantly improved prognosis compared to EACs treated by surgery and/or chemoradiotherapy. However, the miss rates for detecting DBE by endoscopy remain high. Fluorescence molecular endoscopy (FME) can fill this gap by targeting the tumor-specific expression of proteins. This study aimed to identify target proteins suitable for FME. We identified SPARC, SULF1, PKCι, and DDR1 as promising imaging targets for FME to differentiate DBE from NDBE tissue. We are also the first to develop near-infrared fluorescent tracers, SULF1-800CW and SPARC-800CW, for the endoscopic imaging of DBE tissue. Barrett’s esophagus (BE) is the precursor of esophageal adenocarcinoma (EAC). Dysplastic BE (DBE) has a higher progression risk to EAC compared to non-dysplastic BE (NDBE). However, the miss rates for the endoscopic detection of DBE remain high. Fluorescence molecular endoscopy (FME) can detect DBE and mucosal EAC by highlighting the tumor-specific expression of proteins. This study aimed to identify target proteins suitable for FME. Publicly available RNA expression profiles of EAC and NDBE were corrected by functional genomic mRNA (FGmRNA) profiling. Following a class comparison between FGmRNA profiles of EAC and NDBE, predicted, significantly upregulated genes in EAC were prioritized by a literature search. Protein expression of prioritized genes was validated by immunohistochemistry (IHC) on DBE and NDBE tissues. Near-infrared fluorescent tracers targeting the proteins were developed and evaluated ex vivo on fresh human specimens. In total, 1976 overexpressed genes were identified in EAC (n = 64) compared to NDBE (n = 66) at RNA level. Prioritization and IHC validation revealed SPARC, SULF1, PKCι, and DDR1 (all p < 0.0001) as the most attractive imaging protein targets for DBE detection. Newly developed tracers SULF1-800CW and SPARC-800CW both showed higher fluorescence intensity in DBE tissue compared to paired non-dysplastic tissue. This study identified SPARC, SULF1, PKCι, and DDR1 as promising targets for FME to differentiate DBE from NDBE tissue, for which SULF1-800CW and SPARC-800CW were successfully ex vivo evaluated. Clinical studies should further validate these findings.

A new artificial intelligence system successfully detectsand localises early neoplasia in Barrett's esophagus by using convolutional neural networks.

Background and aimsSeattle protocol biopsies for Barrett's Esophagus (BE) surveillance are labour intensive with low compliance. Dysplasia detection rates vary, leading to missed lesions. This can potentially be offset with computer aided detection. We have developed convolutional neural networks (CNNs) to identify areas of dysplasia and where to target biopsy.Methods119 Videos were collected in high‐definition white light and optical chromoendoscopy with i‐scan (Pentax Hoya, Japan) imaging in patients with dysplastic and non‐dysplastic BE (NDBE). We trained an indirectly supervised CNN to classify images as dysplastic/non‐dysplastic using whole video annotations to minimise selection bias and maximise accuracy. The CNN was trained using 148,936 video frames (31 dysplastic patients, 31 NDBE, two normal esophagus), validated on 25,161 images from 11 patient videos and tested on 264 iscan‐1 images from 28 dysplastic and 16 NDBE patients which included expert delineations. To localise targeted biopsies/delineations, a second directly supervised CNN was generated based on expert delineations of 94 dysplastic images from 30 patients. This was tested on 86 i‐scan one images from 28 dysplastic patients.FindingsThe indirectly supervised CNN achieved a per image sensitivity in the test set of 91%, specificity 79%, area under receiver operator curve of 93% to detect dysplasia. Per‐lesion sensitivity was 100%. Mean assessment speed was 48 frames per second (fps). 97% of targeted biopsy predictions matched expert and histological assessment at 56 fps. The artificial intelligence system performed better than six endoscopists.InterpretationOur CNNs classify and localise dysplastic Barrett's Esophagus potentially supporting endoscopists during surveillance.

Agrin Loss in Barrett's Esophagus-Related Neoplasia and Its Utility as a Diagnostic and Predictive Biomarker.

There is an unmet need for identifying novel biomarkers in Barrett's esophagus that could stratify patients with regards to neoplastic progression. We investigate the expression patterns of extracellular matrix (ECM) molecules in Barrett's esophagus and Barrett's esophagus-related neoplasia, and assess their value as biomarkers for the diagnosis of Barrett's esophagus-related neoplasia and to predict neoplastic progression. Gene-expression analyses of ECM matrisome gene sets were performed using publicly available data on human Barrett's esophagus, Barrett's esophagus-related dysplasia, esophageal adenocarcinoma (ADCA) and normal esophagus. Immunohistochemical expression of basement membrane (BM) marker agrin (AGRN) and p53 was analyzed in biopsies of Barrett's esophagus-related neoplasia from 321 patients in three independent cohorts. Differential gene-expression analysis revealed significant enrichment of ECM matrisome gene sets in dysplastic Barrett's esophagus and ADCA compared with controls. Loss of BM AGRN expression was observed in both Barrett's esophagus-related dysplasia and ADCA. The mean AGRN loss in Barrett's esophagus glands was significantly higher in Barrett's esophagus-related dysplasia and ADCA compared with non-dysplastic Barrett's esophagus (NDBE; P < 0.001; specificity = 82.2% and sensitivity = 96.4%). Loss of AGRN was significantly higher in NDBE samples from progressors compared with non-progressors (P < 0.001) and identified patients who progressed to advanced neoplasia with a specificity of 80.2% and sensitivity of 54.8%. Moreover, the combination of AGRN loss and abnormal p53 staining identified progression to Barrett's esophagus-related advanced neoplasia with a specificity and sensitivity of 86.5% and 58.7%. We highlight ECM changes during Barrett's esophagus progression to neoplasia. BM AGRN loss is a novel diagnostic biomarker that can identify patients with NDBE at increased risk of developing advanced neoplasia.

Endoscopic eradication therapy for Barrett’s esophagus–related neoplasia: a final 10-year report from the UK National HALO Radiofrequency Ablation Registry

Long-term durability data for effectiveness of radiofrequency ablation (RFA) to prevent esophageal adenocarcinoma in patients with dysplastic Barrett's esophagus (BE) are lacking. We prospectively collected data from 2535 patients with BE (mean length, 5.2 cm; range, 1-20) and neoplasia (20% low-grade dysplasia, 54% high-grade dysplasia, 26% intramucosal carcinoma) who underwent RFA therapy across 28 UK hospitals. We assessed rates of invasive cancer and performed detailed analyses of 1175 patients to assess clearance rates of dysplasia (CR-D) and intestinal metaplasia (CR-IM) within 2 years of starting RFA therapy. We assessed relapses and rates of return to CR-D (CR-D2) and CR-IM (CR-IM2) after further therapy. CR-D and CR-IM were confirmed by an absence of dysplasia and intestinal metaplasia on biopsy samples taken at 2 consecutive endoscopies. Ten years after starting treatment, the Kaplan-Meier (KM) cancer rate was 4.1% with a crude incidence rate of .52 per 100 patient-years. CR-D and CR-IM after 2 years of therapy were 88% and 62.6%, respectively. KM relapse rates were 5.9% from CR-D and 18.7% from CR-IM at 8 years, with most occurring in the first 2 years. Both were successfully retreated with rates of CR-D2 of 63.4% and CR-IM2 of 70.0% 2 years after retreatment. EMR before RFA increased the likelihood of rescue EMR from 17.2% to 41.7% but did not affect the rate of CR-D, whereas rescue EMR after RFA commenced reduced CR-D from 91.4% to 79.7% (χ2P< .001). RFA treatment is effective and durable to prevent esophageal adenocarcinoma. Most treatment relapses occur early and can be successfully retreated.