Risk Factor For Esophageal Adenocarcinoma Research Articles

Regulation of pro-apoptotic and anti-apoptotic factors in obesity-related esophageal adenocarcinoma

BackgroundObesity is a risk factor for esophageal adenocarcinoma (EAC). It was reported that obesity -associated inflammation correlates with insulin resistance and increased risk of EAC. The objective of the study is to investigate the role of obesity associated inflammatory mediators in the development of EAC.MethodsWe included 23 obese and nonobese patients with EAC or with or without Barrett’s esophagus (BE) after IRB approval. We collected 23 normal, 10 BE, and 19 EAC tissue samples from endoscopy or esophagectomy. The samples were analyzed for the expression levels of pro-apoptotic and anti-apoptotic factors, PKC-δ, cIAP2, FLIP, IGF-1, Akt, NF-kB and Ki67 by immunofluorescence and RT-PCR. We compared the expression levels between normal, BE, and EAC tissue using Students’ t-test between two groups.ResultsOur results showed decreased gene and protein expression of pro-apoptotic factors (bad, bak and bax) and increased expression of anti-apoptotic factors (bcl-2, Bcl-xL) in BE and EAC compared to normal tissues. There was increased gene and protein expression of PKC-δ, cIAP2, FLIP, NF-kB, IGF-1, Akt, and Ki67 in BE and EAC samples compared to normal esophagus. Further, an increased folds changes in mRNA expression of proapoptotic factors, antiapoptotic factors, PKC-δ, IGF-1, Akt, and Ki-67 was associated with obesity.ConclusionPatients with EAC had increased expression of cIAP2 and FLIP, and PKC-δ which is associated with inhibition of apoptosis and possible progression of esophageal adenocarcinoma.

Shifts in Serum Bile Acid Profiles Associated With Barrett's Esophagus and Stages of Progression to Esophageal Adenocarcinoma.

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. 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. 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. 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.

Predicting the potential deterioration of Barrett's esophagus based on gut microbiota: a Mendelian randomization analysis.

Esophageal adenocarcinoma (EAC) is one of the most malignant tumors in the digestive system. To make thing worse, the scarcity of treatment options is disheartening. However, if detected early, there is a possibility of reversing the condition. Unfortunately, there is still a lack of relevant early screening methods. Considering that Barrett's esophagus (BE), a precursor lesion of EAC, has been confirmed as the only known precursor of EAC. Analyzing which BE cases will progress to EAC and understanding the processes and mechanisms involved is of great significance for early screening of such patients. Considering the significant alterations in the gut microbiota of patients with BE and its potential role in the progression to EAC, this study aims to analyze the relationship between BE, EAC, and GM to identify potential diagnostic biomarkers and therapeutic targets. This study utilized comprehensive statistical data on gut microbiota from a large-scale genome-wide association meta-analysis conducted by the MiBioGen consortium (n = 18,340). Subsequently, we selected a set of single nucleotide polymorphisms (SNPs) that fell below the genome-wide significance threshold (1 × 10-5) as instrumental variables. To investigate the causal relationship between gut microbiota and BE and EAC, we employed various MR analysis methods, including Inverse Variance Weighting (IVW), MR-Egger regression, weighted median (WM), and weighted mean. Additionally, we assessed the level of pleiotropy, heterogeneity, and stability of genetic variations through MR-Egger intercept test, MR-PRESSO, Cochran's Q test, and "leave-one-out" sensitivity analysis. Furthermore, we conducted reverse MR analysis to identify the causal relationships between gut microbiota and BE and EAC. The results from the Inverse Variance-Weighted (IVW) analysis indicate that Alistipes (P = 4.86 × 10-2), Lactobacillus (P = 2.11 × 10-2), Prevotella 7 (P = 4.28 × 10-2), and RuminococcaceaeUCG004 (P = 4.34 × 10-2) are risk factors for Barrett's esophagus (BE), while Flavonifractor (P = 8.81 × 10-3) and RuminococcaceaeUCG004 (P = 4.99 × 10-2) are risk factors for esophageal adenocarcinoma (EAC). On the other hand, certain gut microbiota genera appear to have a protective effect against both BE and EAC. These include Eubacterium (nodatum group) (P = 4.51 × 10-2), Holdemania (P = 1.22 × 10-2), and Lactococcus (P = 3.39 × 10-2) in the BE cohort, as well as Eubacterium (hallii group) (P = 4.07 × 10-2) and Actinomyces (P = 3.62 × 10-3) in the EAC cohort. According to the results of reverse MR analysis, no significant causal effects of BE and EAC on gut microbiota were observed. Furthermore, no significant heterogeneity or pleiotropy was detected in the instrumental variables. We have established a causal relationship between the gut microbiota and BE and EAC. This study holds profound significance for screening BE patients who may be at risk of deterioration, as it can provide them with timely medical interventions to reverse the condition.

Abstract 3268: A novel signaling axis of APE1-redox-sensitive SOX9 activation underlying reflux-condition-associated chemoresistance in esophageal adenocarcinoma

Abstract Chronic gastroesophageal reflux disease (GERD), characterized by the reflux of acidic bile salts (ABS) into the esophagus, stands as the primary risk factor for esophageal adenocarcinoma (EAC). EAC, known for its aggressive nature and limited response to therapy, exhibits a disheartening 5-year survival rate of less than 20%. Overcoming drug resistance remains a pressing challenge in achieving optimal therapeutic outcomes for EAC patients. Previous studies from our team have unveiled that exposure to ABS leads to the overexpression of Apurinic/apyrimidinic endonuclease (APE1), which orchestrates various oncogenic pathways in EAC cells. In this study, we delve into the influence of ABS in driving APE1-redox-mediated activation of the SOX9 pathway, thus contributing to the chemoresistance observed in EAC. To identify the enrichment of the SOX9 pathway and the heightened downstream target genes in EAC, we analyzed RNA sequencing data and public databases. Cell models, patient tissue arrays, pL2-IL1β transgenic mice, and de-identified xenografts derived from EAC patients (PDXs) were employed to investigate the signaling axis of APE1-redox-SOX9 in oxaliplatin resistance of EAC. Our analysis of public databases unveiled a significant enrichment of the SOX9 pathway in EAC patients. RNA sequencing data from EAC cells exposed to ABS, with or without APE1-knockdown, suggested APE1's involvement in the GERD-activated SOX9 signaling pathway. Immunohistochemistry staining of human patient tissue arrays, along with immunofluorescent staining of L2-IL1ß transgenic mice, confirmed the co-overexpression of APE1, SOX9, and ALDH1A1 in EAC. Furthermore, APE1 silencing led to the downregulation of SOX9 and exhibited synergistic effects with oxaliplatin in chemo-resistant EAC cells. Mechanistically, we uncovered that APE1's redox function is crucial for AKT-GSK3ß-mediated SOX9 stability. Treatment with the APE1-redox-specific inhibitor, APX2009, sensitized patient-derived xenograft (PDX) tumors to oxaliplatin by repressing SOX9-regulated chemoresistance genes. This study sheds light on a novel signaling axis involving APE1-redox-AKT-GSK3ß-SOX9 in Barrett’s carcinogenesis. The pharmacological inhibition of APE1-redox function presents itself as a promising therapeutic approach to target the previously intractable SOX9 signals, potentially overcoming chemoresistance in EAC. Citation Format: Heng Lu, Lei Chen, Farah Ballout, Dunfa Peng, Zheng Chen, Jianwen Que, Steven Chen, Oliver Gene McDonald, Alexander Zaika, Wael El-Rifai. A novel signaling axis of APE1-redox-sensitive SOX9 activation underlying reflux-condition-associated chemoresistance in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3268.

Abstract 3269: APE1/NF-κB/PRDX2 activated by reflux conditions mediates chemoresistance in esophageal adenocarcinoma by suppressing ferroptosis

Abstract Background: Esophageal adenocarcinoma (EAC) stands out as one of the most lethal malignancies, characterized by a discouragingly low 5-year survival rate of less than 20%. Accumulating lines of evidence indicate that ferroptosis, a novel type of cell death, can regulate drug resistance. Peroxiredoxin 2 (PRDX2), an antioxidant enzyme, plays an antioxidant protective role in the cells under stress by regulating redox homeostasis. We aimed to elucidate the role of PRDX2 in regulating reactive oxygen species (ROS), ferroptosis, and chemoresistance in EAC. Methods: In this investigation, we analyzed RNA sequencing data and public databases to uncover the aberrant overexpression and potential chemoresistance function of PRDX2 in EAC. We employed transient acidic bile salts exposure (ABS) and repeated ABS exposure (rABS) to mimic gastroesophageal reflux disease, the main risk factor for EAC, in in vitro cell models. EAC cells and 3D organotypic culture (OTC) served as platforms to delve into the anti-ferroptosis function and regulatory mechanisms of PRDX2. The findings were validated using patient-derived xenografts (PDX) and human EAC tissue microarrays (TMA). Results: Elevated PRDX2 level was observed in both EAC patients and cell lines exhibiting poor responsiveness to chemotherapy. Intrinsic overexpression of PRDX2 emerged as a crucial factor in the recovery from ABS-exposure-induced lipid peroxidation. Silencing PRDX2 heightened the sensitivity of EAC cells to Oxaliplatin by inhibiting ferroptosis in a GPX4-dependent manner. Mechanistically, we found ABS activate the APE1/redox/NF-kB signal axis, leading to the upregulation of PRDX2 transcription. The co-overexpression of APE1 and PRDX2 was identified through both immunofluorescent staining in cells/OTC and immunohistochemistry staining in TMA. Moreover, the APE1-redox-specific inhibitor, APX2009, significantly sensitized EAC cells to Oxaliplatin by repressing PRDX2 and inducing ferroptosis. Remarkably, the combination therapy of Oxaliplatin and APX2009 achieved a synergistic effect in EAC-PDX tumors. Conclusion: The study unveils a novel signaling axis, APE1/NF-kB/PRDX2, linking disease-associated ROS unbalance and ferroptosis-related chemoresistance. Targeting PRDX2 signaling by APE1-redox-specific inhibition provides a potential novel strategy for combined chemotherapies in refractory EAC. Citation Format: Lei Chen, Heng Lu, Farah Ballout, Dunfa Peng, Zheng Chen, Jianwen Que, Steven Chen, Oliver McDonald, Alexander Zaika, Wael El-Rifai. APE1/NF-κB/PRDX2 activated by reflux conditions mediates chemoresistance in esophageal adenocarcinoma by suppressing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3269.

Efficacy of Nissen Sleeve Gastrectomy on Mid-term Barrett's Esophagus Regression.

Sleeve gastrectomy is the most commonly performed bariatric operation globally. The main complication is GERD. In the medium term, it can increase the incidence of Barrett's esophagus (BE), which is a risk factor for esophageal adenocarcinoma. Following conventional sleeve gastrectomy, BE is noted in up to 16% of patients postoperatively. Recently, Nissen sleeve gastrectomy (NSG) has been shown to reduce the frequency of postoperative GERD compared to conventional sleeve gastrectomy. This study aims to evaluate the impact of NSG on the incidence and remission of BE in the long term. This bicentric retrospective study included 692 patients who received NSG from September 2013 to July 2021. All patients underwent preoperative upper GI endoscopy and were then scheduled to receive upper GI endoscopy between 1 and 2years and then between 3 and 5years postoperatively. BE was systematically confirmed by biopsies. Seventy-four patients had endoscopic suspicion of BE, which was confirmed on 54/692 patients by histology. The BE lesions consisted of 18.5% intestinal metaplasia and 75.9% fundal metaplasia. Among these 54 patients, 38 underwent endoscopic investigation within 2years postoperatively. The biopsies showed healed BE in 25/38 patients (64.1%). At 5years, two patients had proven BE. Concerning the incidence of BE post NSG: 234 performed the follow-up endoscopy within 2years. The incidence of de novo BE is nil. The NSG is associated with healing of known BE in approximately two-thirds of patients at 2-year follow-up. This is consistent with the GERD improvement that has been shown with NSG.

Esophageal Cancer with Early Onset in a Patient with Cri du Chat Syndrome.

In Cri du Chat (CdC), cancer as comorbidity is extremely rare. In databases from Denmark, Spain, Australia, New Zealand, and Japan, no cancer was reported; in Italy and Germany, four cancers were identified out of 321 CdCs. In a 29-year-old CdC patient, clinical investigations following hematemesis led to the diagnosis of esophageal adenocarcinoma (EAC). A high pain threshold was also observed. Conventional and molecular cytogenetic defined the size of the deletion, and exome analysis on the trio completed the molecular work. Cytogenetic analysis showed a de novo chromosomal alteration: 46,XY,ishdel(5)(p14.3)(D5S28-) and arr[GRCh37] 5p15.33p14.3(1498180_19955760)x1. A quantitative sensory test demonstrated a high heat threshold. A 18f-fluorodeoxyglucose PET/TC scan of the brain failed to detect reduction of metabolism in the somatosensory area or insular cortex. Exome analysis in the trio (patient and parents) failed to identify variants to be interpreted as a likely risk factor for EAC. We conclude that the presence of well-known risk factors (maleness, obesity, gastroesophageal reflux, and Barrett's metaplasia) in a patient with very limited capability of expressing discomfort or referring clinical symptoms have been the main risk factors for developing EAC. At present, based on the available data, there is no evidence of any increased risk of developing cancer in CdC patients.

Reflux conditions induce E-cadherin cleavage and EMT via APE1 redox function in oesophageal adenocarcinoma

ObjectiveChronic gastro-oesophageal reflux disease, where acidic bile salts (ABS) reflux into the oesophagus, is the leading risk factor for oesophageal adenocarcinoma (EAC). We investigated the role of ABS in promoting...

Incidence and Impact of Preoperative Hiatal Hernia in Patients with Esophageal Carcinoma Undergoing Curative Surgical Resection.

Hiatal hernia (HH) and gastroesophageal reflux disease (GERD) are risk factors for esophageal adenocarcinoma. High positive margin rates and poor survival were described among HH patients undergoing esophagectomy. We sought to describe incidence and impact of HH on outcomes following esophagectomy. Patients who underwent esophagectomy 2012-2019 for esophago-junctional carcinoma were included. CT studies were blindly reviewed by two radiologists. A third radiologist reviewed cases of disagreement. Hernias ≥ 3 cm were included in the HH group. Overall, 66 patients (33%) had HH ≥ 3 cm. The no hernia group included 12 patients (6%) with < 3 cm HH and 106 (53%) without HH. Preoperative variables were comparable among groups. Location of anastomosis was similar among cohorts and predominantly cervical (n = 97, 82.2% vs 61, 92.4%, p = 0.113). Postoperatively, HH patients had higher incidence of atrial dysrhythmia (n = 11, 16.7% vs n = 6, 5.1% p = 0.015). Rates of R0 resections were similar (n = 62, 93.9%, vs n = 113, 95.8%, p = 0.724). HH patients had higher rates of signet ring cell histology (n = 14, 21.2% vs n = 9, 7.6% p = 0.025); this was confirmed on subgroup analysis including only adenocarcinoma patients (n = 14, 28.6% vs n = 8, 12.3%, p = 0.042). On Cox regression analysis, HH was not associated with disease-free or overall survival (HR 1.308, p = 0.274 and HR .905, p = 0.722). Patients with preoperative HH had higher rates of postoperative atrial dysrhythmias and signet ring cell features on pathology. In a population with predominant cervical anastomosis, positive margin rates were low and survival comparable among cohorts.

Smoking induces WEE1 expression to promote docetaxel resistance in esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) patients have poor clinical outcomes, with an overall 5-year survival rate of 20%. Smoking is a significant risk factor for EAC. The role of WEE1, a nuclear kinase that negatively regulates the cell cycle in normal conditions, in EAC tumorigenesis and drug resistance is not fully understood. Immunohistochemistry staining shows significant WEE1 overexpression in human EAC tissues. Nicotine, nicotine-derived nitrosamine ketone, or 2% cigarette smoke extract treatment induces WEE1 protein expression in EAC, detected by western blot and immunofluorescence staining. qRT-PCR and reporter assay indicates that smoking induces WEE1 expression through miR-195-5p downregulation in EAC. ATP-Glo cell viability and clonogenic assay confirmed that WEE1 inhibition sensitizes EAC cells to docetaxel treatment invitro. A TE-10 smoking machine with EAC patient-derived xenograft mouse model demonstrated that smoking induces WEE1 protein expression and resistance to docetaxel invivo. MK-1775 and docetaxel combined treatment improves EAC patient-derived xenograft mouse survival invivo. Our findings demonstrate, for the first time, that smoking-induced WEE1 overexpression through miRNA dysregulation in EAC plays an essential role in EAC drug resistance. WEE1 inhibition is a promising therapeutic method to overcome drug resistance and target treatment refractory cancer cells.

Missed opportunities for screening for Barrett's esophagus in the primary care setting of a large health system.

The rate of esophageal adenocarcinoma (EAC) is rising. This is partly due to the lack of identification of Barrett's esophagus (BE), the main risk factor for EAC. Identifying neoplastic BE can allow for endoscopic therapy to prevent EAC. Our aim was to determine how many eligible patients for screening are being screened for BE in the primary care setting of a large health system. A digital search algorithm was constructed using the established gastroenterology guidelines and Kunzmann model for screening for BE. The algorithm was then applied to the electronic medical record of all patients seen in the primary care setting of the health system. A manual review of charts of the identified patients was performed to confirm the high-risk status and determine if screening occurred. Of 936,371 primary care charts analyzed by the algorithm, 3535 patients (0.4%) were determined to be high-risk for BE. Of the 3535 patients, only 1077 (30%) were screened for BE in clinical practice with endoscopy. The algorithm identified 2,458 (70%) additional high-risk patients. Of the patients screened in clinical practice, 105 (10%) were found to have BE (10% with neoplasia). Numerous screening opportunities for Barrett's esophagus are missed in the primary care setting of a large health system. Collaboration between gastroenterology and primary care services is needed to improve the screening rate.

Dutch individuals’ views of screening for oesophageal cancer: a focus group study

ObjectiveScreening for early oesophageal adenocarcinoma (OAC), including its precursor Barrett’s oesophagus (BO), can potentially reduce OAC-related morbidity and mortality. This study explores Dutch at-risk individuals’ views of screening an at-risk...

Letter to Editor "Barret’s Esophagus Screening: An Inevitable Urge For Gastroenterologists"

The presence of benign esophageal diseases including gastroesophageal reflux disease, barrets esophagus,hiatal hernia and achalasia have been arousing the curiosity of young clinicians , scientists and researchers for decades and years to follow.1 Dyspepsia is one of the most common symptoms experienced by the patients and witnessed by the doctors during routine clinical consultations. This does accompany regurgitation of food, bad taste in mouth early morning, chest pain and sometimes alarm symptoms including hematemesis, malena, unintentional weight loss and dysphagia.That is the point where one has to rethink and diagnosis treatment strategies and review patients accordingly.2&#x0D; Barrett’s oesophagus is defined as ‘an oesophagus in which any portion of the normal squamous lining has been replaced by metaplastic columnar epithelium. Barrets esophagus is a benign condition with a potential to transform to oesophageal carcinoma.3 There is a long history gastroesopheal reflux disease symptoms. In our country there is a trend of self medicating oneself before coming to any physician in the general practice who also treats the patients for years before referral to gastroenterologist who can think out of the box and do invasive investigations like endoscopy, CT chest and non invasive one like barium swallow. Most of the people ponder over when is right moment for screening the patients for Barrets esophagus and Esophageal Cancer Screening. A lot depends on the biopsy report and its findings in terms of having low grade, indefinite for dysplasia and high grade dysplasia.4&#x0D; Low grade dysplasia in terms of surveillance carries less significance in which the guidelines suggest the time interval can be enhanced to 2-3 years in case of permanent regression with proton pump inhibitors given for 8 weeks The high grade dysplasia is an alarm finding for any gastroenterologist requirement more aggressive screening and management as there is a 30-40% risk of oesophageal carcinoma.5 This will need discussion by multidisciplinary teams including gastroenterologists, oncologists and pathologists as well.5&#x0D; There is usage of proton pump inhibitors for years by the patients that is itself a risk factor for complications such as atrophic gastritis, pernicious anaemia, osteoporosis and even cancer.6 The resistance of symptoms to standard and even high doses of proton pump inhibitors is an indication for endoscopy as well. The role of PPI in asymptomatic patients is not substantiated by enough evidence in the literature However, in clinical practice, most patients are advised long term PPI based on the premise that chronic acid exposure may contribute towards Barrett’s Esophagus.6 So the bottom line is that there should be no hesitation in expediting the referral of such patients for urgent gastroenterology consultation who may do subsequent endoscopy after thorough examination of the patients.&#x0D; American Gastroenterological Association has strong recommendations for screening for Barrett oesophagus in patients older than 50 years with symptomatic GERD and at least one additional risk factor for oesophageal adenocarcinoma.7 Almost similar guidelines have been formulated by other reputed societies as well including British Society Of Gastroenterology. There is a phobia of endoscopies in general public and they are reluctant to do them. But once the indication is clear then the patient should be counselled thorough as in case of oesophageal cancer for which a Barrets Oesophagus is a risk factor, early diagnosis is the key as surgery is curative. Indeed it is and should be irresistible urge for gastroenterologists to screen such patients.7

Abstract P059: A case of stage I esophageal adenocarcinoma diagnosed using a multi-cancer early detection test

Abstract Introduction: There is no guideline-recommended screening test for esophageal cancer, a cancer that occurs in approximately 1 in 125 men and 1 in 417 women in the US. Risk factors for esophageal adenocarcinoma include gastroesophageal reflux disease, Barrett’s esophagus, obesity, and smoking. A multi-cancer early detection (MCED) test that analyzes methylation patterns of cell-free DNA in the blood using sequencing assays and machine-learning classifiers is available as a complement to existing single-cancer screening tests. The MCED test reports either (1) ‘cancer signal detected’ with 1 or 2 cancer signal origin (CSO) prediction(s) or (2) ‘cancer signal not detected’. A case of esophageal adenocarcinoma is presented here to demonstrate early detection using the MCED test and to review the diagnostic journey following a cancer signal detected (positive) test result. Case Description/Methods: An asymptomatic 63-year-old White male (BMI: 27 kg/m2) with history of peptic ulcer disease was screened using the MCED test. He reported moderate alcohol use (6/week) and no tobacco use. His last colonoscopy was 5 years prior to using the test. Nine days after a blood sample was collected for analysis by the MCED test, a positive test result (CSO prediction=Stomach/Esophagus) was reported and communicated to the patient (Day 1). Computed tomography (CT) of the chest, abdomen, and pelvis with contrast showed no significant findings (Day 13). A submucosal bulge just below the gastroesophageal junction (GEJ) was noted on upper endoscopy. The lesion, and area above the GEJ were extensively biopsied (Day 15). Pathologic evaluation confirmed diagnosis of Clinical Stage I esophageal adenocarcinoma with superficial focally invasive adenocarcinoma arising in a background of intestinal metaplasia with high grade dysplasia (Day 29). The patient underwent total gastrectomy without complications (Day 104). He will undergo appropriate follow-up 6 months post-op. Discussion: The MCED test detected a cancer signal and predicted a gastrointestinal CSO for an asymptomatic individual with Clinical Stage I esophageal cancer. Diagnostic resolution was achieved within 1 month and treatment was provided with curative intent. Given that there is no guideline-recommended screening test available for esophageal cancer, the use of this MCED test detected cancer early, directed diagnostic workup, and potentially improved outcomes for this asymptomatic patient. Citation Format: David DeAtkine Jr. A case of stage I esophageal adenocarcinoma diagnosed using a multi-cancer early detection test. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P059.

S431 Associations of Dietary Fiber and Fat Intake with Barrett’s Esophagus and Stages of Progression to Esophageal Adenocarcinoma

Introduction: The incidence of esophageal adenocarcinoma (EAC) has increased dramatically over the past half century. Changes in dietary patterns over this time may partially account for this trend. Prior studies have found inverse associations between fiber intake and both Barrett’s esophagus (BE) and EAC, and studies of fat intake have reported increased risk or no association. However, it is unknown whether fiber or fat intake contribute to neoplastic progression in BE patients. Methods: We performed a multi-center case-control study of patients with and without BE. We collected demographic, anthropometric, and clinical data and categorized BE by worst degree of histology ever. Subjects completed the NCI DHQII, a validated food frequency questionnaire assessing dietary intake over the preceding 12 months. We used multivariable logistic regression analyses to assess associations of energy adjusted fat and fiber intake with BE and with advanced neoplasia (high grade dysplasia or EAC vs. no dysplasia/indefinite/low grade dysplasia). Four models were developed: 1) fat and fiber intake; 2) Model 1 and EAC risk factors (age, sex, BMI, smoking history, family history); 3) Model 2 and aspirin and statin use; 4) reduced parsimonious model (final model: age, sex, family history). Results: We enrolled 162 subjects; 108 subjects (37 non-BE, 71 BE; 21 with advanced neoplasia) completed the questionnaire and were analyzed. Compared to controls, BE patients were older and more likely (p< 0.01) to be male, aspirin users, statin users, and ever smokers. BE patients had significantly higher energy-adjusted fiber intake but no difference in fat intake compared to controls. (Figure A-B) Adjusted for fat intake, increased fiber intake was associated with reduced odds of BE (per g/1000 kcal, OR 0.81, 95%CI 0.70-0.93), with similar associations in all the models (Table). There was no association between fat intake and BE. There was no significant association between fat or fiber intake and stages of progression to EAC (Figure C-D), and neither fat nor fiber intake was associated with advanced neoplasia in multivariable analyses. (Table) Conclusion: Fiber intake was inversely associated with BE but not with stages of progression to EAC. There was no association between fat intake and BE or dysplasia or EAC, but this may reflect our small sample size. Future larger studies are warranted to elucidate the mechanisms by which fiber may protect against the development of BE.Figure 1.: Comparisons of energy-adjusted intake of A) fat and B) fiber between BE and non-BE subjects. Comparisons of energy-adjusted intake of C) fat and D) fiber across stages of progression to EAC. Table 1. - Multivariable logistic regression models for associations between energy-adjusted fat (% kcal) and fiber (g/1000 kcal) intake with BE (vs. no BE) and with advanced neoplasia (HGD/EAC vs. ND/IND/LGD). (ORs per unit increase) Model 1 Model 2 Model 3 Model 4 BE Fat 1.01 (0.95- 1.08 1.03 (0.95- 1.08) 1.03 (0.94- 1.11) 1.03 (0.95- 1.11) Fiber 0.81 (0.70- 0.93) 0.82 90.67- 0.99) 0.82 (0.67-1.00) 0.80 (0.66- 0.97) Advanced neoplasia Fat 1.00 (0.93- 1.08 1.00 (0.92- 1.09) 1.02 (0.93- 1.12) 1.01 (0.98- 1.09) Fiber 0.94 (0.75- 1.18) 0.85 (0.65- 1.1) 0.87 (0.65- 1.16) 0.96 (0.75- 1.24)

608. INCIDENCE AND IMPACT OF PREOPERATIVE HIATAL HERNIA IN PATIENTS WITH ESOPHAGEAL CARCINOMA UNDERGOING CURATIVE SURGICAL RESECTION

Abstract Hiatal hernia (HH) and gastroesophageal reflux disease (GERD) are risk factors for esophageal adenocarcinoma. High positive margin rates and poor survival were previously described among HH patients undergoing esophagectomy. We sought to describe incidence and impact of HH on outcomes following esophagectomy in a population of patients undergoing predominantly cervical anastomosis. Patients who underwent esophagectomy 2012-2019 for esophago-junctional carcinoma were included. CT studies were blindly reviewed by two radiologists. A third radiologist reviewed cases of disagreement. Hernias &amp;gt;3 cm were included in the HH group. Overall, 66 patients (33%) had HH &amp;gt;3 cm. The control group included 12 patients (6%) with &amp;lt;3 cm HH and 106 (53%) without HH. Patients with HH had higher Charlson Comorbidity Index (CCI) (p=0.017). Location of anastomosis was similar among cohorts (cervical anastomosis 82.2% vs 92.4%, p=0.113). HH patients had higher incidence of atrial dysrhythmia (16.7% vs 5.1% p=0.015). Rates of R0 resections were similar (95.8% vs 93.9%, p=0.724). Subgroup analysis on adenocarcinoma patients confirmed higher rates of signet ring cell features among HH patients (28.6% vs 12.3%, p=0.034). HH was not associated with poor disease free survival (p=0.274). Patients with preoperative HH had higher CCI, higher rates of postoperative atrial dysrhythmias and signet ring cell features on pathology. In a population with predominant cervical anastomosis, positive margin rates were low and survival comparable among cohorts.

Barrett&amp;apos;s Esophagus

Barrett’s esophagus (BE) is caused by metaplasia of squamous epithelium into columnar epithelium, mainly in the lower esophagus. Updates have been made in the etiology, diagnosis and treatment of BE since its first report as an ulcerative lesion in the lower esophagus. Columnar metaplasia of the lower esophagus has been reported as a result of gastroesophageal reflux, rather than genetic factors. When specialized intestinal metaplasia (SIM) is confirmed on biopsy, it is diagnosed as BE; otherwise, it is described as columnar line esophagus (CLE). Recent recommendations state that the following two conditions must be satisfied to diagnose BE: CLE with a length ≥1 cm proximal to the gastroesophageal junction, or SIM, with goblet cells confirmed on biopsy. BE is a key risk factor for esophageal adenocarcinoma. Early detection and treatment of BE, dysplasia, and early esophageal adenocarcinoma arising from BE has become a critical issue in the USA and Europe. The prevalence of BE in Korea is likely to increase because of the increasing prevalence of gastroesophageal reflux diseases. However, there are few reports on the diagnosis and treatment of BE in Korea. In this narrative review, important historical discoveries related to BE, the anatomical structures and endoscopic findings around the gastroesophageal junction required for diagnosing CLE and BE, and a brief review of the guidelines for the diagnosis and treatment of BE are summarized.

Pilot Study Showing Feasibility of Phosphoproteomic Profiling of Pathway-Level Molecular Alterations in Barrett's Esophagus.

(1) Background: Barrett’s esophagus is a major risk factor for esophageal adenocarcinoma. In this pilot study, we employed precision mass spectrometry to map global (phospho)protein perturbations in Barrett’s esophagus lesions and adjacent normal tissue to glean insights into disease progression. (2) Methods: Biopsies were collected from two small but independent cohorts. Comparative analyses were performed between Barrett’s esophagus samples and adjacent matched (normal) tissues from patients with known pathology, while specimens from healthy patients served as additional controls. (3) Results: We identified and quantified 6810 proteins and 6395 phosphosites in the discovery cohort, revealing hundreds of statistically significant differences in protein abundances and phosphorylation states. We identified a robust proteomic signature that accurately classified the disease status of samples from the independent patient cohorts. Pathway-level analysis of the phosphoproteomic profiles revealed the dysregulation of specific cellular processes, including DNA repair, in Barrett’s esophagus relative to paired controls. Comparative analysis with previously published transcriptomic profiles provided independent evidence in support of these preliminary findings. (4) Conclusions: This pilot study establishes the feasibility of using unbiased quantitative phosphoproteomics to identify molecular perturbations associated with disease progression in Barrett’s esophagus to define potentially clinically actionable targets warranting further assessment.

Pepsinogen/Proton Pump Co-Expression in Barrett's Esophageal Cells Induces Cancer-Associated Changes.

At the conclusion of this presentation, participants should better understand the carcinogenic potential of pepsin and proton pump expression in Barrett's esophagus. Barrett's esophagus (BE) is a well-known risk factor for esophageal adenocarcinoma (EAC). Gastric H+ /K+ ATPase proton pump and pepsin expression has been demonstrated in some cases of BE; however, the contribution of local pepsin and proton pump expression to carcinogenesis is unknown. In this study, RNA sequencing was used to examine global transcriptomic changes in a BE cell line ectopically expressing pepsinogen and/or gastric H+ /K+ ATPase proton pumps. In vitro translational. BAR-T, a human BE cell line devoid of expression of pepsinogen or proton pumps, was transduced by lentivirus-encoding pepsinogen (PGA5) and/or gastric proton pump subunits (ATP4A, ATP4B). Changes relative to the parental line were assessed by RNA sequencing. Top canonical pathways associated with protein-coding genes differentially expressed in pepsinogen and/or proton pump expressing BAR-T cells included those involved in the tumor microenvironment and epithelial-mesenchymal transition. Top upstream regulators of coding transcripts included TGFB1 and ERBB2, which are associated with the pathogenesis and prognosis of BE and EAC. Top upstream regulators of noncoding transcripts included p300-CBP, I-BET-151, and CD93, which have previously described associations with EAC or carcinogenesis. The top associated disease of both coding and noncoding transcripts was cancer. These data support the carcinogenic potential of pepsin and proton pump expression in BE and reveal molecular pathways affected by their expression. Further study is warranted to investigate the role of these pathways in carcinogenesis associated with BE. NA Laryngoscope, 133:59-69, 2023.

Advanced imaging and artificial intelligence for Barrett's esophagus: What we should and soon will do.

Barrett’s esophagus (BE) is a well-established risk factor for esophageal adenocarcinoma. It is recommended that patients have regular endoscopic surveillance, with the ultimate goal of detecting early-stage neoplastic lesions before they can progress to invasive carcinoma. Detection of both dysplasia or early adenocarcinoma permits curative endoscopic treatments, and with this aim, thorough endoscopic assessment is crucial and improves outcomes. The burden of missed neoplasia in BE is still far from being negligible, likely due to inappropriate endoscopic surveillance. Over the last two decades, advanced imaging techniques, moving from traditional dye-spray chromoendoscopy to more practical virtual chromoendoscopy technologies, have been introduced with the aim to enhance neoplasia detection in BE. As witnessed in other fields, artificial intelligence (AI) has revolutionized the field of diagnostic endoscopy and is set to cover a pivotal role in BE as well. The aim of this commentary is to comprehensively summarize present evidence, recent research advances, and future perspectives regarding advanced imaging technology and AI in BE; the combination of computer-aided diagnosis to a widespread adoption of advanced imaging technologies is eagerly awaited. It will also provide a useful step-by-step approach for performing high-quality endoscopy in BE, in order to increase the diagnostic yield of endoscopy in clinical practice.