BACKGROUND AND AIMS:Recurrent esophageal strictures reduce the quality of life for patients and represent a significant burden for health care providers. A novel drug-coated balloon (DCB) dilator has been developed to decrease stricture recurrence. We report the first U.S.-based prospective study of the DCB evaluating pharmacokinetic parameters and clinical outcomes after treatment of recurrent esophageal strictures. This study was a substudy conducted before initiating a randomized controlled trial but using the same entry criteria. METHODS:25 patients with recurrent esophageal strictures were enrolled at 10 U.S. CENTERS:All patients' index treatment included endoscopy with stricture assessment with a functional lumen imaging probe (FLIP), symptom assessment using the Ogilvie Score and Dysphagia Handicap Index (DHI), followed by dilation with the drug-coated balloon. Follow-up was conducted at 1, 3, 6, and 12 months posttreatment with symptom assessments, endoscopy, and functional lumen imaging probe performed at 6 months. Stricture recurrence was defined as a diameter <13 mm on FLIP or any clinically driven reintervention. RESULTS:Strictures were primarily peptic (88%) with a median of 6 lifetime dilations prior to entry. Freedom from stricture recurrence was 40% (10/25) in the 12 months post-DCB versus an expected 0% based on past history. Symptoms were improved (by DHI and Ogilvie Score) at 12 months. Systemic exposure to paclitaxel was limited, with only 7 subjects showing measurable levels of drug (0.1-0.2 ng/mL) in their blood after treatment. No adverse events were related to the DCB. CONCLUSIONS:Treatment of esophageal strictures with DCB demonstrated decreased recurrence of significant stricture compared to historical needs, improved dysphagia symptoms compared to baseline, and limited systemic exposure to paclitaxel. Prospective randomized studies are needed to confirm these results.

The poor response of pancreatic ductal adenocarcinoma (PDAC) to treatment, including immunotherapy, is attributed to its tumor microenvironment (TME). An ongoing challenge is the desmoplastic and immunosuppressed TME that evades immune surveillance. Here, we investigate transient modulation of the TME to overcome immunosuppression using a light-activated process, termed photodynamic priming (PDP). As a first step, this study captures the temporal dynamics of variations in immune infiltrates and subsequent immune responses in the TME, spleen, and blood of the KPC mouse model of PDAC post-PDP. In response to PDP, there were transient increases in tumor infiltrating lymphocytes (TIL) in tumors. The TIL population post-PDP includes an enrichment of CD8+ T cells, accompanied by temporal increases in PD-1, CTLA-4, and TIM-3 immune checkpoints on both CD8+ T and CD4+ T cells. Significant increases in CD11C+MHC-11+ dendritic cells and proliferating lymphocytes are observed in the spleen within several hours post-tumor PDP, suggesting initiation of adaptive immune responses. These observations are followed by an expansion of CD44+CD62-CD8+ effector memory T cells in the blood over several days as evidence of a systemic immune response. Post-PDP TME alterations also included the reduced formation of blood (CD31+) and lymphatic (Lyve-1+) vessels as well as decreases in PD-L1 and collagen content. Collectively, these data suggest that PDP helps to mitigate immunosuppressive mechanisms and promote enhanced tumor permeability. The temporal dynamics of the processes elucidated here pave the way to develop strategies in future work for combined PDP-immunotherapy utilizing the immune checkpoint expression dynamics for precision therapy.

Bile acids are a major component of gastro-esophageal refluxate, thought to contribute to the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). As the microbiome shifts with EAC progression and bile acids influence bacterial composition, we examined these connections in a multi-center, cross-sectional study. We analyzed biospecimens from patients undergoing endoscopy using LC-MS to quantify bile acids in gastric aspirates, 16S rRNA sequencing for tissue microbiome profiling, and RNA sequencing on BE or cardia tissue. Among 153 patients (52 controls, 101 BE: 50 no dysplasia, 10 indefinite, 17 low-grade dysplasia, 17 high-grade dysplasia, and 7 EAC), we observed increased Streptococcus in BE tissue; dysplasia and EAC were associated with more Lactobacillus and decreased Actinomyces and other genera. Refluxate bile acids were mainly conjugated, indicating minimal bacterial metabolism, while BE patients had elevated secondary bile acid levels. Streptococcus correlated with upregulation of IL6, FGF2, and HGF, and decreased Actinomyces showed the most associations with gene expression, including the oxidative phosphorylation pathway. We identified two distinct BE gene expression clusters independent of histology, bile acid, or microbiome composition. These findings suggest bile acids shape the BE microbiome and associate with gene expression changes potentially relevant to EAC development.

Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1-1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high-grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high-risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high-level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.

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: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. METHODS: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. RESULTS: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. DISCUSSION: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.

INTRODUCTION:Endoscopic eradication therapy (EET) is standard of care for T1a esophageal adenocarcinoma (EAC). However, data on outcomes in high-risk T1a EAC are limited. We assessed and compared outcomes after EET of low-risk and high-risk T1a EAC, including intraluminal EAC recurrence, extraesophageal metastases, and overall survival. METHODS:Patients who underwent EET for T1a EAC at 3 referral Barrett's esophagus endotherapy units between 1996 and 2022 were included. Patients with submucosal invasion, positive deep margins, or metastases at initial diagnosis were excluded. High-risk T1a EAC was defined as T1a EAC with poor differentiation and/or lymphovascular invasion, with low-risk disease being defined without these features. All pathology was systematically assessed by expert gastrointestinal pathologists. Baseline and follow-up endoscopy and pathology data were abstracted. Time-to-event analyses were performed to compare outcomes between groups. RESULTS:One hundred eighty-eight patients with T1a EAC were included (high risk, n = 45; low risk, n = 143) with a median age of 70 years, and 84% were men. Groups were comparable for age, sex, Barrett's esophagus length, lesion size, and EET technique. Rates of delayed extraesophageal metastases (11.1% vs 1.4%) were significantly higher in the high-risk group ( P = 0.02). There was no significant difference in the rates of intraluminal EAC recurrence ( P = 0.79) and overall survival ( P = 0.73) between the 2 groups. DISCUSSION:Patients with high-risk T1a EAC undergoing successful EET had a substantially higher rate of extraesophageal metastases compared with those with low-risk T1a EAC on long-term follow-up. These data should be factored into discussions with patients while selecting treatment approaches. Additional prospective data in this area are critical.

INTRODUCTION: Esophageal adenocarcinoma (EAC) is the second-most lethal cancer in the United States, with Barrett esophagus (BE) being the strongest risk factor. Assessing the future risk of neoplastic progression in patients with BE is difficult; however, high-grade dysplasia (HGD) and early EAC are treatable by endoscopic eradication therapy (EET), with survival rates of 90%. Thus, it would be beneficial to develop a molecular assay to identify high-risk patients, who merit more frequent endoscopic surveillance or EET, as well as low-risk patients, who can avoid EET and undergo less frequent surveillance. METHODS: Deidentified endoscopic biopsies were acquired from 240 patients with BE at 6 centers and confirmed as future progressors or nonprogressors. Tissues were analyzed by a set of methylation-specific biomarker assays. Test performance was assessed in an independent validation set using 4 stratification levels: low risks, low-moderate risks, high-moderate risks, and high risks. RESULTS: Relative to patients in the low-risk group, high-risk patients were 15.2 times more likely to progress within 5 years to HGD or EAC. For patients in the high-risk category, the average risk of progressing to HGD or EAC within 5 years was 21.5%, 4-fold the BE population prevalence within 5 years, whereas low-risk patients had a progression risk of only 1.85%. DISCUSSION: This clinical assay, Esopredict, stratifies future neoplastic progression risk to identify higher-risk patients with BE who can benefit from EET or more frequent surveillance and lower-risk patients who can benefit from reduced surveillance.

INTRODUCTION:Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS:We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS:The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway ( P = 0.01), amplifications of oncogenes ( P = 0.01), and deletions of tumor suppressor genes ( P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION:Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett’s esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

Background and aims:Benign esophageal strictures can result in dysphagia and decreased quality of life. A novel drug-coated balloon (DCB) for dilation was developed to dilate strictures while concurrently delivering paclitaxel to reduce recurrence. Initial preclinical histologic and pharmacokinetic (PK) data in addition to first-in-human pilot data are presented. Methods:Thirty-nine healthy swine were treated by using 3 different paclitaxel dosing regimens or a bare balloon. Paclitaxel PK elimination profile in plasma and tissue as well as local tissue responses were evaluated. Nine adult human subjects were treated and followed up for up to 2 years with dysphagia scores, safety, and imaging. Results:In the animal studies, histologic and PK analysis revealed paclitaxel present in treated tissues through 28 days' postprocedure, whereas plasma levels were minimal (1 ng/mL at 155 mg total drug dose). No local or systemic drug toxicity was found. Nine human subjects with an average initial stricture diameter of 6.4 mm and an average Ogilvie Dysphagia Score of 2.2 were treated. No major treatment-related adverse events occurred. The retreatment rate through 2 years was 11%. Five subjects completed 2-year follow-up, with an average 2-year Ogilvie Dysphagia Score of 0. Stricture diameter improved to 19.4 ± .9 mm at 1 year (n = 5). Conclusions:The animal studies show that DCB treatment of esophageal mucosa appears safe with paclitaxel still present in tissue after 1 month but at minimal plasma levels. Initial results in humans indicate DCB can be safely applied with clinically relevant increases in esophageal lumen at 1 year with symptomatic improvement. (Clinical trial registration number: NCT03885310.).

Background and Aims: Endoscopic eradication therapy (EET) is guideline endorsed for management of early-stage (T1) esophageal adenocarcinoma (EAC). Patients with baseline high-grade dysplasia (HGD) and EAC are at highest risk of recurrence after successful EET, but limited data exist on long-term (>5 year) recurrence outcomes. Our aim was to assess the incidence and predictors of long-term recurrence in a multicenter cohort of patients with T1 EAC treated with EET. Methods: Patients with T1 EAC achieving successful endoscopic cancer eradication with a minimum of 5 years' clinical follow-up were included. The primary outcome was neoplastic recurrence, defined as dysplasia or EAC, and it was characterized as early (<2 years), intermediate (2-5 years), or late (>5 years). Predictors of recurrence were assessed by time to event analysis. Results: A total of 84 T1 EAC patients (75 T1a, 9 T1b) with a median 9.1 years (range, 5.1-18.3 years) of follow-up were included. The overall incidence of neoplastic recurrence was 2.0 per 100 person-years of follow-up. Seven recurrences (3 dysplasia, 4 EAC) occurred after 5 years of EAC remission. Overall, 88% of recurrences were treated successfully endoscopically. EAC recurrence-related mortality occurred in 3 patients at a median of 5.2 years from EAC remission. Complete eradication of intestinal metaplasia was independently associated with reduced recurrence (hazard ratio, .13). Conclusions: Following successful EET of T1 EAC, neoplastic recurrence occurred after 5 years in 8.3% of cases. Careful long-term surveillance should be continued in this patient population. Complete eradication of intestinal metaplasia should be the therapeutic end point for EET.