Dysplastic Barrett's Esophagus Research Articles

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.

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.

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 four quadrant biopsies of the original Barrett's length. To inform post-CRIM surveillance protocols, we aimed to identify the anatomic location, appearance and histology of Barrett's recurrences. We performed an analysis of 216 patients who achieved CRIM following endoscopic eradication therapy (EET) for dysplastic Barrett's esophagus (BE) at a Barrett's referral unit between 2008 and 2021. The anatomic location, the recurrence histology and endoscopic appearance of dysplastic recurrences were evaluated. After a median (p25-p-75) 5.5 years (2.9-7.2) of follow up post-CRIM, 57 patients (26.4%) developed NDBE recurrence and 18 patients (8.3%) developed dysplastic recurrence. From a total of 8,158 routine surveillance biopsies of normal appearing tubular esophageal neosquamous epithelium, the yield for recurrent NDBE or dysplasia was 0%. 100% of dysplastic tubular esophageal recurrences were visible and in Barrett's islands, whilst 77.8% of GEJ dysplastic recurrences were non-visible. Four distinct endoscopic features suspicious for recurrent advanced dysplasia or neoplasia were identified: (1) Buried or sub-squamous Barrett's, (2) Irregular mucosal pattern, (3) Loss of vascular pattern, (4) Nodularity or depression. The yield of routine surveillance biopsies of normal appearing tubular esophageal neosquamous epithelium was zero. Barrett's islands with indistinct mucosal or loss of vascular pattern, nodularity or depression and/or signs of buried Barrett's should raise clinician suspicion for advanced dysplasia or neoplasia recurrence. We suggest a new surveillance biopsy protocol with a focus on meticulous inspection, followed by targeted biopsies of visible lesions and random four quadrant biopsies of the GEJ.

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.

State-of-the-art management of dysplastic Barrett's esophagus.

Endoscopic eradication therapy (EET) has become a standard of care for treatment of dysplastic Barrett's esophagus (BE) and early Barrett's neoplasia. EET mainly consists of removal of any visible lesions via endoscopic resection and eradication of all remaining Barrett's mucosa using endoscopic ablation. Endoscopic mucosal resection and endoscopic submucosal dissection are the two available resection techniques. After complete resection of all visible lesions, it is crucial to perform endoscopic ablation to ensure complete eradication of the remaining Barrett's segment. Endoscopic ablation can be done either with thermal techniques, including radiofrequency ablation and argon plasma coagulation, or cryotherapy techniques. The primary end point of EET is achieving complete remission of intestinal metaplasia (CRIM) to decrease the risk of dysplastic recurrence after successful EET. After CRIM is achieved, a standardized endoscopic surveillance protocol needs to be implemented for early detection of BE recurrence.

Predictors of recurrence of dysplasia or cancer in patients with dysplastic Barrett's esophagus following complete eradication of dysplasia: a single-center retrospective cohort study.

Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) for Barrett's esophagus (BE)-related high-grade dysplasia (HGD) and early esophageal adenocarcinoma (EAC) are considered effective treatments for eradication of BE. Little is known about the impact of achieving complete eradication of intestinal metaplasia (CE-IM) following the complete eradication of neoplasia (CE-N), specifically if CE-IM reduces the risk of recurrent dysplasia. Retrospective cohort study of consecutive patients with BE and HGD or intramucosal cancer (IMC)-treated endoscopically at a tertiary referral center between 2001 and 2019. Association between CE-IM and recurrent dysplasia after CE-N was evaluated. A total of 433 patients treated with EMR and/or RFA were included. Of these, 381 (88%) achieved CE-N, of which 345 (80%) had adequate follow-up for inclusion in the analysis. A total of 266 (77%) patients achieved CE-IM; with a median follow-up since initial treatment for HGD/IMC of 45.9months (IQR 25.9, 93.1); 20 patients (5.8%) had recurrent dysplasia after achieving CE-N. Kaplan Meier survival curves revealed that time free of recurrence in those who achieved CE-IM was significantly higher (p = 0.002). In the multivariable analysis, CE-IM was associated with a significant lower hazard of recurrence (HR 0.2, 95% CI 0.1, 0.6), whereas the number of endoscopic treatments to achieve CE-N was associated with a significant higher hazard of recurrence (HR 1.1, 95% CI 1.0, 1.2). Achieving CE-IM following CE-N reduces the risk of recurrent dysplasia and should be considered a treatment target among patients with BE undergoing endoscopic therapies for HGD or EAC.

Endoscopic management of Barrett's dysplasia and early neoplasia: efficacy, safety and long-term outcomes in a UK tertiary centre.

Endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) are effective treatments for dysplastic Barrett's esophagus (BE). This study evaluates efficacy, durability and safety in a single high-volume UK tertiary centre with 15-years' experience. Prospective data were collected from Nottingham University Hospitals 2004-2019 for endotherapy of dysplastic BE or intramucosal adenocarcinoma. Procedural outcome measures include complete resection, complications and surgery rates. Efficacy outcomes include complete remission of dysplasia (CR-D) and intestinal metaplasia (CR-IM), recurrence, treatment failure rates, durability of RFA, median follow up and tumor-associated mortality. A total of 319 lesions were resected; 671 RFAs were performed on 239 patients. Median age was 67 (±9.5) years, male:female ratio was 5:1 and median BE length was C3 [interquartile range (IQR): 6] M6 (IQR: 5). The most common lesion was Paris IIa (64%) with a median size of 10 mm (3-70). Final histology was adenocarcinoma in 50%. Complete resection rates were 96%. The multiband mucosectomy technique (91%) was most commonly used. The median number of RFA sessions was 3 (IQR: 2). The rates of CR-D and CR-IM were 90.4%% and 89.8% achieved after a median of 20.1 (IQR: 14) months. The most common complications: EMR was bleeding 2.2% and RFA was stricture (5.4%) requiring a median of 2 (range 1-7) dilatations. Median follow up post CR-IM/CR-D was 38 months (14-60). Metachronous lesions developed in 4.7% after CR-D and tumor-related mortality was 0.8%. Dysplasia and intestinal metaplasia-free survival at 5 years was 95 and 90%, respectively. BE endotherapy is minimally invasive, effective, safe and deliverable in a day-case setting.

Loss of SMAD4 Is Sufficient to Promote Tumorigenesis in a Model of Dysplastic Barrett's Esophagus.

Background & AimsEsophageal adenocarcinoma (EAC) develops from its precursor Barrett’s esophagus through intermediate stages of low- and high-grade dysplasia. However, knowledge of genetic drivers and molecular mechanisms implicated in disease progression is limited. Herein, we investigated the effect of Mothers against decapentaplegic homolog 4 (SMAD4) loss on transforming growth factor β (TGF-β) signaling functionality and in vivo tumorigenicity in high-grade dysplastic Barrett’s cells.MethodsAn in vivo xenograft model was used to test tumorigenicity of SMAD4 knockdown or knockout in CP-B high-grade dysplastic Barrett’s cells. RT2 polymerase chain reaction arrays were used to analyze TGF-β signaling functionality, and low-coverage whole-genome sequencing was performed to detect copy number alterations upon SMAD4 loss.ResultsWe found that SMAD4 knockout significantly alters the TGF-β pathway target gene expression profile. SMAD4 knockout positively regulates potential oncogenes such as CRYAB, ACTA2, and CDC6, whereas the CDKN2A/B tumor-suppressor locus was regulated negatively. We verified that SMAD4 in combination with CDC6-CDKN2A/B or CRYAB genetic alterations in patient tumors have significant predictive value for poor prognosis. Importantly, we investigated the effect of SMAD4 inactivation in Barrett’s tumorigenesis. We found that genetic knockdown or knockout of SMAD4 was sufficient to promote tumorigenesis in dysplastic Barrett’s esophagus cells in vivo. Progression to invasive EAC was accompanied by distinctive and consistent copy number alterations in SMAD4 knockdown or knockout xenografts.ConclusionsAltogether, up-regulation of oncogenes, down-regulation of tumor-suppressor genes, and chromosomal instability within the tumors after SMAD4 loss implicates SMAD4 as a protector of genome integrity in EAC development and progression. Foremost, SMAD4 loss promotes tumorigenesis from dysplastic Barrett’s toward EAC.

Esophageal cancer after sleeve gastrectomy: a population-based comparative cohort study.

Sleeve gastrectomy (SG) is the most common bariatric surgery; however, this approach may induce gastroesophageal reflux disease (GERD). Both obesity and GERD are independent risk factors for esophageal cancer, however the impact of SG on risk of esophageal cancer remains unknown. To evaluate the risk of esophageal cancer after reflux-prone bariatric surgery. Population-level, provincial administrative healthcare database, Quebec, Canada. We identified a population-based cohort of all patients with obesity who underwent reflux-prone surgery (SG and duodenal switch [DS]) or reflux-protective Roux-en-Y gastric bypass (RYGB) during 01/2006-12/2012 in Quebec, Canada. For every surgical patient, 2-3 nonsurgical controls with obesity matched for age, sex, and geography were also identified. Crude incidence rate ratios (IRRs) for esophageal cancer were calculated using person-time analysis. Hazard ratios (HRs) were obtained using multivariate cox regression. A total of 4121 patients had reflux-prone procedures and 852 underwent RYGB. At a mean follow-up of 7.6 years, 8 cases of esophageal cancer were identified after bariatric surgery. Compared with RYGB, IRR for esophageal cancer in reflux-prone group was 1.45 (95%CI: .19-65.5) and HR = .83 (95%CI: .10-7.27). The crude incidence rate of esophageal cancer in the reflux-prone group was higher than that of nonsurgical controls (n = 12,159; IRR = 3.46, 95%CI: 1.00-12.5), but after adjustment the difference disappeared (HR = 2.47, 95%CI: .82-7.45). Long-term incidence of esophageal cancer after reflux-prone bariatric surgery is not greater than RYGB. While crude incidence of esophageal cancer after reflux-prone surgery is higher than in nonsurgical patients with obesity, such difference disappears after accounting for confounders. Given the low incidence of esophageal cancer and slow progression of dysplastic Barrett esophagus, studies with longer follow-up are needed.