Esophageal Adenocarcinoma Cases Research Articles

Prevalence of Gastroesophageal Reflux Disease in Congenital Diaphragmatic Hernia Survivors From Infancy to Adulthood

BackgroundGastroesophageal reflux disease (GERD) is a common comorbidity associated with congenital diaphragmatic hernia (CDH), with reported cases of Barrett's esophagus (BE) and esophageal adenocarcinoma before the age of 25. The prevalence and natural course of GERD in CDH survivors remain uncertain due to variations in diagnostic methods. We aimed to analyse the GERD prevalence from infancy through young adulthood. MethodsWe retrospectively analyzed pH-impedance measurements and endoscopic findings in 96 CDH survivors evaluated as routine care using well established clinical protocols.GERD was defined as an abnormal acid exposure time for pH-MII measurements and as presence of reflux esophagitis or BE at upper endoscopy. Clinical data including symptoms at time of follow-up and use of antireflux medication were collected. ResultsGERD prevalence remained consistently low (≤10%) across all age groups, yet many patients experienced GER symptoms. Histological abnormalities were observed in 80% of adolescents and young adults, including microscopic esophagitis in 50%. BE was diagnosed in 7% before the age of 18, all had GER symptoms. CDH severity, anatomy at the time of CDH correction, alcohol usage, and smoking did not emerge as significant risk factors for GERD. ConclusionsGiven the low GERD prevalence in CDH survivors, a symptom-driven approach to diagnosis and follow-up is warranted. We advise long-term follow-up for all adult patients due to the early onset of BE and the limited evidence available. The longitudinal course and impact of GERD on other long-term CDH-related comorbidities should be explored in larger cohorts. Level of EvidenceNot applicable

Disentangling oncogenic amplicons in esophageal adenocarcinoma

Esophageal adenocarcinoma is a prominent example of cancer characterized by frequent amplifications in oncogenes. However, the mechanisms leading to amplicons that involve breakage-fusion-bridge cycles and extrachromosomal DNA are poorly understood. Here, we use 710 esophageal adenocarcinoma cases with matched samples and patient-derived organoids to disentangle complex amplicons and their associated mechanisms. Short-read sequencing identifies ERBB2, MYC, MDM2, and HMGA2 as the most frequent oncogenes amplified in extrachromosomal DNAs. We resolve complex extrachromosomal DNA and breakage-fusion-bridge cycles amplicons by integrating of de-novo assemblies and DNA methylation in nine long-read sequenced cases. Complex amplicons shared between precancerous biopsy and late-stage tumor, an enrichment of putative enhancer elements and mobile element insertions are potential drivers of complex amplicons’ origin. We find that patient-derived organoids recapitulate extrachromosomal DNA observed in the primary tumors and single-cell DNA sequencing capture extrachromosomal DNA-driven clonal dynamics across passages. Prospectively, long-read and single-cell DNA sequencing technologies can lead to better prediction of clonal evolution in esophageal adenocarcinoma.

Clinico-pathological study of esophageal mucoepidermoid carcinoma: a 10-year survival from a single center

BackgroundMucoepidermoid Carcinoma of the Esophagus (MECE) is a relatively rare tumor type, with most of the current data derived from case reports or small sample studies. This retrospective study reports on the 10-year survival data and detailed clinicopathological characteristics of 48 patients with esophageal MEC.MethodsData were collected from 48 patients who underwent curative surgery for esophageal MEC at the Fourth Hospital of Hebei Medical University between January 1, 2004, and December 31, 2020. These were compared with contemporaneous cases of Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC). Using the Kaplan-Meier method and multivariate Cox regression analysis, we investigated the clinicopathological factors affecting the survival of patients with MEC.ResultsThe incidence of MECE was predominantly higher in males, with a male-to-female ratio of approximately 7:1. The mid-thoracic segment emerged as the most common site of occurrence. A mere 6.3% of cases were correctly diagnosed preoperatively. The lymph node metastasis rate stood at 35.4%. The overall 1-year, 3-year, 5-year, and 10-year survival rates for all patients were 85.4%, 52.1%, 37.0%, and 31.0%, respectively. Post 1:1 propensity score matching, no significant statistical difference was observed in the Overall Survival (OS) between MEC patients and those with Esophageal Squamous Cell Carcinoma (ESCC) and Esophageal Adenocarcinoma (EAC) (P = 0.119, P = 0.669). Univariate analysis indicated that T staging and N staging were the primary factors influencing the prognosis of esophageal MEC.ConclusionsMECE occurs more frequently in males than females, with the mid-thoracic segment being the most common site of occurrence. The rate of accurate preoperative endoscopic diagnosis is low. The characteristic of having a short lesion length yet exhibiting significant extramural invasion may be a crucial clinicopathological feature of MECE. The OS of patients with MEC does not appear to significantly differ from those with esophageal squamous carcinoma and adenocarcinoma.

Development of an Artificial Intelligence Diagnostic System Using Linked Color Imaging for Barrett's Esophagus.

Background: Barrett's esophagus and esophageal adenocarcinoma cases are increasing as gastroesophageal reflux disease increases. Using artificial intelligence (AI) and linked color imaging (LCI), our aim was to establish a method of diagnosis for short-segment Barrett's esophagus (SSBE). Methods: We retrospectively selected 624 consecutive patients in total at our hospital, treated between May 2017 and March 2020, who experienced an esophagogastroduodenoscopy with white light imaging (WLI) and LCI. Images were randomly chosen as data for learning from WLI: 542 (SSBE+/- 348/194) of 696 (SSBE+/- 444/252); and LCI: 643 (SSBE+/- 446/197) of 805 (SSBE+/- 543/262). Using a Vision Transformer (Vit-B/16-384) to diagnose SSBE, we established two AI systems for WLI and LCI. Finally, 126 WLI (SSBE+/- 77/49) and 137 LCI (SSBE+/- 81/56) images were used for verification purposes. The accuracy of six endoscopists in making diagnoses was compared to that of AI. Results: Study participants were 68.2 ± 12.3 years, M/F 330/294, SSBE+/- 409/215. The accuracy/sensitivity/specificity (%) of AI were 84.1/89.6/75.5 for WLI and 90.5/90.1/91.1/for LCI, and those of experts and trainees were 88.6/88.7/88.4, 85.7/87.0/83.7 for WLI and 93.4/92.6/94.6, 84.7/88.1/79.8 for LCI, respectively. Conclusions: Using AI to diagnose SSBE was similar in accuracy to using a specialist. Our finding may aid the diagnosis of SSBE in the clinic.

Risk of Esophageal Adenocarcinoma After Helicobacter pylori Eradication Treatment in a Population-Based Multinational Cohort Study

Helicobacter pylori infection is associated with a decreased risk of esophageal adenocarcinoma, and the decreasing prevalence of such infection might contribute to the increasing incidence of this tumor. We examined the hypothesis that eradication treatment of H pylori increases the risk of esophageal adenocarcinoma. This population-based multinational cohort, entitled "Nordic Helicobacter Pylori Eradication Project (NordHePEP)," included all adults (≥18 years) receiving H pylori eradication treatment from 1995-2018 in any of the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) with follow-up throughout 2019. Data came from national registers. We calculated standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) by dividing the cancer incidence in the exposed cohort by that of the entire Nordic background populations of the corresponding age, sex, calendar period, and country. Analyses were stratified by factors associated with esophageal adenocarcinoma (ie, education, comorbidity, gastroesophageal reflux, and certain medications). Among 661,987 participants who contributed 5,495,552 person-years after eradication treatment (median follow-up, 7.8 years; range, 1-24 years), 550 cases of esophageal adenocarcinoma developed. The overall SIR of esophageal adenocarcinoma was not increased (SIR= 0.89; 95% CI, 0.82-0.97). The SIR did not increase over time after eradication treatment, but rather decreased and was 0.73 (95% CI, 0.61-0.86) at 11-24 years after treatment. There were no major differences in the stratified analyses. The overall SIR of esophageal squamous cell carcinoma, calculated for comparison, showed no association (SIR= 0.99; 95% CI, 0.89-1.11). This absence on an increased risk of esophageal adenocarcinoma after eradication treatment of H pylori suggests eradication is safe from a cancer perspective.

Abstract 2670: Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer

Abstract We have applied a single cell cloning technology to patient-matched endoscopic biopsies of Barrett's esophagus and co-existing lesions of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC). In vitro differentiation and xenografting of these clones yields epithelia with histology corresponding to the origin of these clones, and the EAC clones yield aggressive tumors in vivo. In addition, genomic analyses of these clones reveals their phylogenetic relationships based on common and accumulating mutations. In efforts to identify drugs that would target the Barrett's stem cells for preemptive therapeutics, we performed parallel screens of small molecule libraries against Barrett's stem cells and patient-matched normal esophageal stem cells. Synthetic lethal strategies ultimately yielded drug combinations that showed low nanomolar efficacy against Barrett's stem cells that spared normal esophageal stem cells even at micromolar concentrations. The synthesis of new compositions of matter corresponding to these leads has identified powerful analogs that not only selectively eliminate stem cells of Barrett's esophagus but show similar efficacy in vitro against stem cells of LGD, HGD, and EAC. In vitro, these drug combinations show broad efficacy against Barrett's and EAC, with nanomolar elimination of 20 of 23 Barrett's cases and 6 of 7 EAC cases. In tumors derived from xenografting EAC clones, these new drug combinations show robust activity marked by tumor shrinkage and a profound loss of tumor cell clonogenicity. We foresee the potential of these synthetic lethal drug combination both as topical delivery for premetastatic lesions in the distal esophagus and perhaps as systemic applications for advanced EAC cases. Citation Format: Wa Xian, Jennifer Lin, Mona Oraei, Frank McKeon, Shan Wang, Jaffer Ajani, Christopher Crum, William Bachovchin, Melina Khorrami, Amber Su, Melika Khorrami, Shumei Song, Jeremy Siegelman, Matt Vincent, Khek Yu Ho, Yusuke Yamamoto. Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2670.

Antibiotic Exposure is Associated With a Risk of Esophageal Adenocarcinoma

Antibiotic exposure leads to changes in the gut microbiota. Our objective was to evaluate the association between antibiotic exposure and esophageal adenocarcinoma (EAC) risk. We performed a nested case-control study using data from the Veterans Health Administration from 2004 through 2020. The case group consisted of patients who received an incident diagnosis of EAC. For each case, up to 20 matched controls were selected using incidence density sampling. Our primary exposure of interest was any oral or intravenous antibiotic use. Our secondary exposures included cumulative number of days of exposure and classification of antibiotics by various subgroups. Conditional logistic regression was used to estimate the crude and adjusted odds ratios (aORs) for the risk of EAC associated with antibiotic exposure. The case-control analysis included 8226 EAC cases and 140,670 matched controls. Exposure to any antibiotic was associated with an aOR for EAC of 1.74 (95% confidence interval [CI], 1.65-1.83) vs no antibiotic exposure. Compared with no antibiotic exposure, the aOR for EAC was 1.63 (95% CI, 1.52-1.74; P < .001) for cumulative exposure to any antibiotic for 1 to 15 days; 1.77 (95% CI, 1.65-1.89; P < 0 .001) for 16 to 47 days; and 1.87 (95% CI, 1.75-2.01; P < .001) for ≥48 days, respectively (P for trend < .001). Exposure to any antibiotic is associated with an increased risk of EAC, and this risk increases as the cumulative days of exposure increase. This novel finding is hypothesis-generating for potential mechanisms that may play a role in the development or progression of EAC.

Interleukin-4 Levels Predict Survival Independent of Pathologic Stage in a Mixed Esophageal Cancer Cohort

INTRODUCTION: Esophageal cancer (EC) is known to originate in the setting of chronic inflammation. While previous studies have sought to understand the role of inflammatory signaling in EC, little is known regarding the effect of these immunologic changes on patient outcomes. Several studies have linked serum cytokine levels with prognostic measures; however, these studies consist primarily of patients with esophageal squamous cell carcinoma (ESCC) with few esophageal adenocarcinoma (EAC) cases. The objective was to evaluate the relationship between serum cytokine levels and survival in patients with EC and to validate these findings at the RNA level. METHODS: 37 serum cytokines were profiled at time of resection using multiplex ELISA in 47 patients (42 EAC, 5 ESCC). Cytokine levels were binarized in relation to the median and assessed using Log-rank tests and Cox Regression models. Findings were validated at the RNA-level using TCGA Esophageal Carcinoma cohort (77 EAC, 81 ESCC). RESULTS: Univariate analysis revealed serum Interleukin-4 (IL-4) was associated with survival (p = 0.042) (Figure). Multivariable analysis showed that high serum IL-4, pathologic stage, and body mass index were strong and independent predictors of survival (p < 0.001, p < 0.001 and p = 0.039). Univariate analysis of IL4 RNA levels revealed that IL4 was associated with survival (p = 0.012). Multivariable analysis showed that high IL4 expression, and post-surgical stage were strong and independent predictors of patient survival (p = 0.01, p < 0.001 respectively).FigureCONCLUSION: These results show that IL4 levels associate with survival in EC. Notably, this relationship is independent of clinical/pathologic staging, indicating its potential as a novel prognostic biomarker in EC.

490. CORRELATION BETWEEN HISTOLOGICAL AND MOLECULAR ALTERATIONS WITH POOR SURVIVAL IN ESOPHAGEAL ADENOCARCINOMA

Abstract The incidence of esophageal adenocarcinoma (EAC) has constantly risen in western countries over the past decades, often diagnosed at advanced stage and with a five-year survival around 20%1. In a previous study on EAC cases submitted to surgery (without neoadjuvant treatment) an algorithm (EACGSE classification)2 based on morphologic distinctions provided a significant prognostic impact. We aimed to evaluate the molecular basis underlying these differences, to improve patient management. The EAC cohort classified according to EACGSE2 was included in the study. Genomic DNA was available from formalin fixed paraffin embedded surgical specimens for 207 cases. The cases were sequenced for 26 cancer-related genes (panel #226722257; IDT) with high coverage on NextSeq500 (Illumina). Data analysis was performed using a dedicated pipeline3. 245 cases were analyzed for SMAD4 immunostaining (IHC). Loss of SMAD4 immunostaining was reported as % of negative tumor cells (at least 35% of neoplastic cells). TP53 was the most frequently altered gene (134/207 cases with at least one mutation). The presence of TP53 missense variants was associated to a poor cancer-specific survival (CSS) in the high-risk cases (glandular poorly differentiated, mucinous invasive, diffuse anaplastic, mixed) according to EACGSE2 (P=0.0005). A significant correlation was observed for TP53 truncative variants and loss of SMAD4 staining (P=0.008). Actually, SMAD4 loss was observed in 85/245 (35%) of all EAC cases analyzed via immunostaining. SMAD4 loss correlated with poor CCS (P=0.007) and disease-free survival (P=0.002) in EACGSE high-risk cases. TP53 missense mutations correlated to poor outcomes (CSS) in high-risk cases, TP53 truncative mutations were associated to SMAD4 loss. SMAD4 loss itself resulted a frequent event in EAC and correlated with lower CCS and disease-free survival in high-risk cases. Therefore, we were able to correlate EAC histological classification, clinical outcomes and molecular phenotypes. Validation in independent samples is warranted to corroborate these findings.

456. THE PROGNOSTIC IMPACT OF TUMOR BUDDING IN ESOPHAGEAL ADENOCARCINOMA

Abstract In a previous study on esophageal adenocarcinoma (EAC) cases submitted to surgery (without neoadjuvant treatment), an algorithm (EACGSE classification) 1 based on morphologic distinctions provided significant prognostic impact. Tumor budding is a specific type of invasive growth pattern and was found to be an important prognostic parameter in gastrointestinal cancers. 2–3 We aimed to evaluate the prevalence of budding in glandular adenocarcinomas and its impact on survival. The EAC cohort classified according to EACGSE 1 was included in the study: among the different histotypes, 215 cases, classified as well (WD) and poorly (PD) differentiated glandular adenocarcinomas, were considered. Tumor budding was defined as single cells or clusters of up to four cells at the invasive margin. Budding was grouped according to ITBCC 2 into Bd1 (0-4 buds), Bd2 (5-9 buds), and Bd3 (10 or more buds). Furthermore, the most prognostically relevant cut off for bud number in EAC was defined by ROC analysis. Cancer specific survival analyses were performed using the Kaplan–Meier method and Cox regression analyses. Tumor budding was assessed in one hotspot (a field measuring 0.785 mm2) at the invasive front and ROC analysis identified 8 buds per field cut off as the most informative in relation to survival. By using this cut off, frequency of budding was higher in glandular PD (84/124,68%) cases than in WD ones (7/91,8%, p &amp;lt; 0.001). Budding was a strong negative predictor of survival both in univariate (p &amp;lt; 0.001) and multivariate analyses (p &amp;lt; 0.001) (Fig. 1). Using the 3 categories proposed by ITBCC, 2 budding was significantly related to survival in univariate analysis (p = 0.006) but lost significance in multivariate analysis. Tumor budding showed a prognostically negative impact in glandular EACs. The 8 buds per field cut off appears to provide the best prognostic discriminant. Tumor budding assessment should be added to the identification of other prognostic factors already described in the same series (stage, histotype and vascular invasion). 1

640. ESOPHAGECTOMY FOR ESOPHAGEAL AND GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA IN RYGB PATIENTS. A LITERATURE REVIEW ON OPERATIVE TECHNIQUES, SAFETY AND ONCOLOGIC OUTCOME

Abstract Roux-en-Y gastric bypass (RYGB) surgery changes the anatomy of the gastrointestinal tract, and thus renders the surgical management of esophageal and gastroesophageal junction adenocarcinoma cases technically confusing. No consensus exists regarding the the optimal surgical technique in terms of safety and oncologic outcomes in these cases. The aim of this study is to compile and analyze the available operative/technical data in the literature on surgical management of esophageal and gastroesophageal junction adenocarcinoma in RYGB patients. A literature review was performed in Cochrane Database, Embase, Medline, PubMed, and Scopus electronic databases to find all cases of esophagectomy for esophageal and gastroesophageal junction adenocarcinoma in RYGB patients. Keywords used were esophageal adenocarcinoma, esophagogastric junction adenocarcinoma, gastric bypass, bariatric surgery, esophagectomy, Ivor Lewis esophagectomy, transhiatal esophagectomy, and thoracoabdominal esophagectomy. All abstracts retrieved were screened, and for each one deemed relevant, the full text was obtained. Finally, 11 articles containing 17 cases were studied and analyzed. Extracted data included: Esophagectomy type, incision type, gastric pouch management, conduit used, Roux limb management, and most importantly complications and oncologic outcome. Esophagectomy was Ivor Lewis, transhiatal, and thoracoabdominal in 58.82%, 23.53% and 17.65% respectively. Esophagectomy was open in 46.67%, and minimally invasive in 53.33%. Gastric pouch was reconnected to the excluded stomach in 14.29%, while it was resected in 85.71%. Gastric, colonic and jejunal conduits were used in 87.5%, 6.25% and 6.25% respectively. In 63.64%, the Roux limb (RL) was connected to the abdominal wall and a feeding jejunostomy was placed. In the remaining 36.36%, the RL was either totally resected, or its proximal end was anastomosed to the distal end of the biliopancreatic limb. No complications were reported. No differences in oncologic outcome or safety were observed between open versus minimally invasive esophagectomy. Minimally invasive esophagectomy is safe and technically feasible with appropriate oncologic outcomes for esophageal and gastroesophageal junction adenocarcinoma patients with previous gastric bypass. Therefore open esophagectomy is not necessary. Post RYGB Esophageal and gastroesophageal junction adenocarcinoma might be underreported, and the number of cases will undoubtedly continue to increase in the coming years.

1260TiP The efficacy of the addition of TRAstuzumab and Pertuzumab to neoadjuvant chemoradiation: A randomized multi-center study in resectable HER2 overexpressing adenocarcinoma of the esophagus or gastroesophageal junction (TRAP-2)

Despite promising results following implementation of neoadjuvant chemoradiation (nCRT) prior to surgery in resectable esophageal adenocarcinoma (EAC) (van Hagen et al., NEJM, 2012) and the introduction of adjuvant nivolumab in case of incomplete response (Kelly et al., NEJM, 2021), prognosis remains dismal. Many patients eventually develop metastatic disease, and there is an unmet need to improve current therapies. In 15% to 43% of EAC cases, overexpression and/or gene amplification of the human epidermal growth factor receptor 2 (HER2) is observed.

Characterization of Desmoglein 3 (DSG3) as a Sensitive and Specific Marker for Esophageal Squamous Cell Carcinoma.

Although P40 and P63 are both sensitive and specific for routine esophageal squamous cell carcinoma (SCC) diagnosis, we recently showed that P40 and P63 immunoreactivities were significantly lower in well-differentiated SCC than those in higher grade tumors. Therefore, a novel esophageal SCC marker, ideally performing better in well-differentiated SCC, is still needed. We characterized desmoglein 3 (DSG3) immunohistochemistry in esophageal SCC, esophageal adenocarcinoma, small-cell lung carcinoma, and large B-cell lymphoma, alongside P40 and CK5/6. The World Health Organization classification was used to grade tumors as well-differentiated (WD), moderately differentiated (MD), or poorly differentiated (PD). There were 20 WD, 26 MD, and 17 PD components among 39 esophageal SCC cases. All esophageal SCC components showed significant DSG3 immunoreactivity (mean, 80%; range, 30%–100%), and the proportions of DSG3 immunoreactive cells were higher in the WD and MD components than in the PD components. No esophageal adenocarcinoma cases showed more than 10% DSG3 immunoreactivity with only weak cytoplasmic staining. With a 5% immunoreactivity cutoff, DSG3 positivity was 100% in all 63 SCC components, 18% in adenocarcinoma cases, and 0% in small-cell lung carcinoma or large B-cell lymphoma cases. The overall DSG3 specificity was 94%. To the best of our knowledge, this is the first study to characterize DSG3 as a sensitive and specific marker for esophageal SCC.

Novel epigenetic network biomarkers for early detection of esophageal cancer

BackgroundEarly detection of esophageal cancer is critical to improve survival. Whilst studies have identified biomarkers, their interpretation and validity is often confounded by cell-type heterogeneity.ResultsHere we applied systems-epigenomic and cell-type deconvolution algorithms to a discovery set encompassing RNA-Seq and DNA methylation data from esophageal adenocarcinoma (EAC) patients and matched normal-adjacent tissue, in order to identify robust biomarkers, free from the confounding effect posed by cell-type heterogeneity. We identify 12 gene-modules that are epigenetically deregulated in EAC, and are able to validate all 12 modules in 4 independent EAC cohorts. We demonstrate that the epigenetic deregulation is present in the epithelial compartment of EAC-tissue. Using single-cell RNA-Seq data we show that one of these modules, a proto-cadherin module centered around CTNND2, is inactivated in Barrett’s Esophagus, a precursor lesion to EAC. By measuring DNA methylation in saliva from EAC cases and controls, we identify a chemokine module centered around CCL20, whose methylation patterns in saliva correlate with EAC status.ConclusionsGiven our observations that a CCL20 chemokine network is overactivated in EAC tissue and saliva from EAC patients, and that in independent studies CCL20 has been found to be overactivated in EAC tissue infected with the bacterium F. nucleatum, a bacterium that normally inhabits the oral cavity, our results highlight the possibility of using DNAm measurements in saliva as a proxy for changes occurring in the esophageal epithelium. Both the CTNND2/CCL20 modules represent novel promising network biomarkers for EAC that merit further investigation.

Esophageal abnormalities and the risk for gastroesophageal cancers—a histopathology-register-based study in Sweden

BackgroundThe poor survival of patients with gastroesophageal cancers may improve if additional esophageal precursor lesions to Barrett’s esophagus and squamous dysplasia are identified. We estimated the risk for gastroesophageal cancers among patients with various histopathological abnormalities in the esophagus, including Barrett’s esophagus, subdivided by histopathological types.MethodsHistopathology data from esophageal biopsies obtained 1979–2014 were linked with several national population-based registers in Sweden. Patients were followed from 2 years after the first biopsy date until cancer, death, emigration, esophagectomy/gastrectomy or end of follow-up, 31st of December 2016, whichever came first. We estimated standardized incidence ratios (SIRs) as measures of relative risk with the Swedish general population as reference.ResultsIn total 367 esophageal adenocarcinoma (EAC) cases were ascertained during 831,394 person-years of follow-up. The incidence rate (IR) for EAC was 0.1 per 1000 person-years for normal morphology, 0.2–0.5 for inflammatory changes, and 0.8–2.9 for metaplasia. The IR was 1.0 per 1000 person-years (95% confidence interval 0.7–1.3) among patients with non-dysplastic intestinal metaplasia, 0.9 (0.8–1.1) in non-dysplastic gastric/glandular metaplasia and 2.9 (2.0–4.2) among columnar metaplasia patients with low-grade dysplasia. The SIRs were 11.7 (95% confidence interval 8.6–15.5), 12.0 (10.0–14.2) and 30.2 (20.5–42.8), respectively. The SIRs for gastric cardia adenocarcinoma (GCA) were moderately elevated.ConclusionsFor the first time, we demonstrate that patients with esophageal inflammatory and other metaplastic abnormalities than Barrett’s esophagus have an increased risk of EAC and GCA compared to the general population. Moreover, patients with different histopathologic subtypes of Barrett’s esophagus have a comparable risk for EAC.

Expression of DNA Mismatch Repair Proteins, PD1 and PDL1 in Barrett's Neoplasia.

Cancers with a microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) status respond to immune checkpoint inhibition (ICI). Regardless of the tumor type, MSI-H/dMMR status is a reliable biomarker for ICI responsiveness. This study aimed at determining the MSI-H status in precursor lesions to esophageal adenocarcinoma (EAC) such as Barrett's esophagus (BE) and BE with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We performed immunohistochemical staining (IHC) for PMS2, MSH6, PD1, and PD-L1. All cases of BE (50), LGD (48), and HGD (50) had intact PMS2 and MSH6 nuclear expression; were negative for PD1; and had a PD-L1 combined positive score (CPS) score <1. One EAC case (2%) was negative for PMS2 nuclear expression. One HGD case (2%) and two EAC cases (4%) were PD1 positive (CPS score <1 applied to PD1). One EAC case (2%) had a CPS score >1, and one EAC case (2%) was MSI-H. MSI-H tumors usually show PD-L1 expression, although the MSI-H EAC in this study had a PD-L1 CPS score of <1. Further studies investigating EAC and its precursor lesions for PD1, PD-L1, and dMMR status may be informative regarding the immunogenicity of the evolution of EAC.

Limitations of Heartburn and Other Societies’ Criteria in Barrett’s Screening for Detecting De Novo Esophageal Adenocarcinoma

Despite extensive Barrett's esophagus (BE) screening efforts, most patients with esophageal adenocarcinoma (EAC) present de novo. It is unclear how much of this problem is the result of insensitivity or poor applications of current screening guidelines. We aimed to evaluate the sensitivity of guidelines by determining the proportion of prevalent EAC cases that meet the American College of Gastroenterology (ACG) or the British Society of Gastroenterology (BSG) guidelines for BE screening and determine whether changes to criteria would enhance detection. A retrospective single-center cohort from the United States (n= 663) and a prospective multicenter cohort from the United Kingdom (n= 645) were collected and analyzed independently. Screening eligibility was determined as patients with chronic reflux and at least 2 or more risk factors as defined by the guidelines. We calculated the proportion of screening-eligible patients and then compared BE/EAC risk factors between screening-eligible and screening-ineligible patients using the chi-squared or Student t test as appropriate. In the Mayo clinic cohort there were 54.9% EAC cases and in the UK cohort there were 38.9% EAC cases that were not identified by ACG or BSG screening criteria, respectively. Among patients who did not meet the screening criteria, lack of heartburn was observed in 86.5% in the Mayo clinic cohort and in 61.4% in the UK cohort. Other risk factors that were lacking included obesity (defined as a body mass index of ≥30 kg/m2) and family history of EAC. Eliminating chronic reflux from the ACG/BSG criteria improved eligibility for screening from 45.1% to 81.3% (P < .001) in the Mayo Clinic cohort and from 61.1% (n= 394) to 81.5% (n= 526; P < .001) in the UK cohort. However, reflux may be difficult to ascertain from the history, and by including proton pump inhibitor use status in addition to the BSG criteria, screening eligibility improved by 10.0% in the UK cohort (n= 459; P < .001). ACG/BSG BE screening guidelines have limited our ability to detect prevalent EAC. An optimized approach to identifying the individuals most suitable for EAC screening needs to be implemented, particularly one that does not rely on chronic reflux symptoms.

Trends and projections in the incidence of oesophageal cancer in the Netherlands: An age-period-cohort analysis from 1989 to 2041.

In Western populations, the incidence of oesophageal squamous cell carcinoma (OSCC) has been declining, whereas the incidence of oesophageal adenocarcinoma (OAC) has been increasing. Our study examines temporal trends in the incidence of oesophageal cancer in the Netherlands between 1989 and 2016, in addition to predicting future trends through 2041. Data from the Netherlands Cancer Registry and Statistics Netherlands were collected to obtain incidence trends of OSCC and OAC for the period 1989 to 2016. Age‐period‐cohort (APC) modelling was used to estimate the contribution of age, calendar period and birth cohort on the observed incidence trends. To predict the future numbers of new cases of both OSCC and OAC from 2017 to 2041, log‐linear APC models were fitted to the trends of 1989 to 2016. The age‐standardised incidence rates of OSCC have decreased slightly for men and increased slightly for women. In contrast, a marked increase in the incidence of OAC was observed, ranging from 2.8 per 100 000 persons in 1989 to 10.1 in 2016. This increase in OAC incidence was more prominent in men, and it will result in an increased risk of OAC for successive generations. Future projections indicate that the incidence of OAC will further increase to 13.1 per 100 000 persons in 2037 to 2041, meaning that there will be 13 259 cases of OAC in 2037 to 2041, as compared to 9386 diagnoses in 2017 to 2021. The changing epidemiologic trends in oesophageal cancer in the Netherlands should be reflected in the development of prevention, early detection and treatment strategies.

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

Post-endoscopy Esophageal Neoplasia in Barrett’s Esophagus: Consensus Statements From an International Expert Panel

S445 Study of Compliance, Practice Patterns, and Barriers Regarding Established National Screening Programs for Barrett’s Esophagus Among Gastroenterology (GI) and Primary Care Providers (PCP): SCREEN-BE

Introduction: Professional society guidelines recommend upper endoscopy to screen for Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) in at-risk individuals. However, the majority of EAC cases do not have a prior BE diagnosis suggesting a failure of current screening practices. Methods: We conducted a web-based survey of GIs and PCPs at 4 academic medical centers and 2 affiliated county hospitals. Questions were adapted from validated cancer screening-related surveys that were pretested and pilot tested. Survey domains included provider and practice characteristics, screening practices, knowledge of guidelines, attitudes, and perceived barriers to implementing BE screening. Results: We obtained a GI and PCP response rate of 74.5% (120/161) and 49.2% (195/396), respectively. Most respondents were physicians (91%), with a wide distribution of numbers of years in practice, and the majority (76% GI, 92% PCP) reported seeing 2+ patients with reflux per week. GI providers were more consistently able to identify BE risk factors that would prompt screening than PCPs. Whereas half (54.17%) of GI providers order an upper endoscopy for BE screening per month, only 17.7% of PCPs reported ordering endoscopy and 25.6% reported referring patients to GI. When presented with clinical vignettes, GI providers were more likely to recommended guideline-concordant screening than PCPs [mean concordance score 6.8 (SD 1.6) vs 5.5 (SD 2.1) (Figure 1). Although over 70% of both GI providers and PCPs believe BE screening is effective for early cancer detection, few believed it reduced mortality and PCPs expressed concerns regarding cost-effectiveness. The majority of both providers agreed more data evaluating screening benefits and harms are needed, including data from randomized controlled trials (Table 1). Whereas GIs reported minimal barriers to performing BE screening, PCPs identified several barriers at the provider level (e.g., limited knowledge of guidelines) and system level (e.g. clinic time constraints and concerns about insurance coverage). Conclusion: GI providers and PCPs believe BE screening can improve EAC early detection; however there is a desire for increased data evaluating benefits and harms of BE screening. PCPs also report several barriers to BE screening. These data provide insights for the implementation of BE screening strategies in the era of BE risk-stratification models and novel, minimally invasive non-endoscopic tools. Funded by the ACG Clinical Research Award 2020.Figure 1.: GI and PCP application of guidelines to 9 clinical vignettes. Bars represent responses concordant with screening guidelines. GI responses were concordant if they recommended upper endoscopy for screening (or appropriately did not recommend endoscopy) and PCP responses were concordant if they referred to GI to discuss screening or recommended upper endoscopy (or appropriately did not recommend endoscopy).Table 1.: Gastroenterology and Primary Care Provider Attitudes and Barriers related to BE screening