Development Of Esophageal Adenocarcinoma Research Articles

GRAIL1 stabilizes misfolded mutant p53 through a ubiquitin ligase-independent, chaperone regulatory function.

Frequent (>70%) TP53 mutations often promote its protein stabilization, driving esophageal adenocarcinoma (EAC) development linked to poor survival and therapy resistance. We previously reported that during Barrett's (BE) progression to EAC, an isoform switch occurs in the E3 ubiquitin ligase RNF128 (aka GRAIL - gene related to anergy in lymphocytes), enriching isoform 1 (hereby GRAIL1) and, stabilizing the mutant p53 protein. Consequently, GRAIL1 knockdown degrades mutant p53. But how GRAIL1 stabilizes the mutant p53 protein remains unclear. In search for a mechanism, here we performed biochemical and cell biology studies to identify that GRAIL has a binding domain (315-PMCKCDILKA-325) for Hsp40/DNAJ. This interaction can influence DNAJ chaperone activity to modulate misfolded mutant p53 stability. As predicted, either the overexpression of a GRAIL fragment (Frag-J) encompassing the DNAJ binding domain, or a cell permeable peptide (Pep-J) encoding the above 10 amino acids, can bind and inhibit DNAJ-Hsp70 co-chaperone activity thus degrading misfolded mutant p53. Consequently, either Frag-J or Pep-J can reduce the survival of mutant p53 containing dysplastic BE and EAC cells and inhibit growth of patient-derived dysplastic BE organoids (PDOs) in 3D cultures. The misfolded mutant p53 targeting and growth inhibitory effects of Pep-J is comparable to simvastatin, a cholesterol lowering drug, that can degrade misfolded mutant p53 also via inhibiting DNAJA1, although by a distinct mechanism. Implications: We identified a novel ubiquitin ligase independent, chaperone regulating domain in GRAIL and further synthesized a first-in-class novel misfolded mutant p53 degrading peptide having future translational potential.

Abstract 555: Role of TRIM31 in the pathogenesis of esophageal adenocarcinoma

Abstract Background: Esophageal adenocarcinoma (EAC) is one the deadliest cancers in United States (US) and the only major cancer in the US with increasing incidence. Gastroesophageal reflux disease (GERD) can cause Barrett’s esophagus (BE), a columnar metaplasia of the esophagus strongly associated with the development of EAC. GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal esophageal cells and found high expression of tripartite motif-containing protein 31 (TRIM31) in BE and EAC compared to normal esophagus (NE) by transcriptomic profiling of RNA extracted from human esophageal tissues. E3 ubiquitin ligase TRIM 31 is a new member of TRIM family and it has been reported to have oncogenic potentials in some cancers. However, its role in EAC pathogenesis is yet to be understood. Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot analysis. The Het-1A cell line, after exposure to acidic pH and bile acids, was assessed for variable TRIM31 expression. Cell morphology and viability analyses of NE and EAC cell lines after exposure to acidic pH and bile acids either alone or in combinations were observed by microscopy and WST-1 assay respectively. Results: Transcriptomic analysis showed that BE and EAC are similar in their differential gene expression with upregulation of the TRIM31 compared to that in NE. Concordant with their columnar phenotype, BE and EAC groups displayed a multitude of differentially expressed genes relative to NE samples; however, less differentially expressed genes were found comparing BE and EAC groups. Western blot demonstrated frequent overexpression of TRIM31 in EAC cell lines with very low expression of TRIM31 in NE epithelial cell line. When NE epithelial cell line Het-1A was exposed to acidic pH as well as bile acids in acidic pH, we saw a change in cell morphology that may correlate with the metaplasia of these cells to more resilient forms, as seen in human BE and EAC. Interestingly, bile acids in acidic pH increased TRIM31 expression in NE cell line Het-1A. Bile acids had a greater effect on decreasing cell viability at high concentrations and that effect is enhanced when bile acids were added in acidic pH. WST-1 cell viability assay revealed that EAC cells were more resistant to bile acids as well as bile acids in acidic pH induced decreased in cell viability compared to that in NE cell line Het-1A. The sustained cell viability of EAC cell lines under these harsh conditions correlates with the upregulation of TRIM31. Conclusions: Thus, TRIM31 may be an important oncogenic factor in GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC. Citation Format: Md Sazzad Hassan, Jesse Mast, Annie Ritter, Saisantosh Ponna, Niranjan Awasthi, Urs von Holzen. Role of TRIM31 in the pathogenesis of 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 555.

Abstract 6184: A novel approach to Barrett's esophagus risk stratification: Whole-slide image analysis for aneuploidy detection

Abstract Background Barrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC) and there is a need for biomarkers in BE for risk stratification for cancer progression. Aneuploidy has been suggested as a factor in the development, initiation or progression of EAC in patients with BE, and it has been found predictive for EAC progression (Hadjinicolaou, et al. 2020, Sikkema, et al. 2009). However, current assays for detecting aneuploidy require valuable tissue, hence validation studies are limited. We hypothesise that routine histology images can be used to detect ploidy status. We aim to develop a sensitive, accurate, and easy-to-use deep learning tool for this purpose. Methods We used a weakly supervised deep learning-based approach called clustering-constrained-attention multiple-instance learning (CLAM) (Lu et al., 2021) to detect aneuploidy on hematoxylin and eosin-stained whole slide images of endoscopical biopsies from BE, for which the ploidy status had been determined by flow cytometry. To benchmark the model’s performance, we also trained a traditional fully supervised algorithm, ResNet50 (He et al., 2016), with the same dataset. The models were trained on 388 slides (51 aneuploid) from the Seattle Barrett’s Esophagus Annotated Resource (BEAR) and then applied to an independent test cohort of BEAR patients, consisting of 279 slides (36 aneuploid). Results The multi-attention-branch CLAM model achieved AUC of 0.82 and 76.4% balanced accuracy for aneuploidy on the internal test subset (10% of the cohort). On the independent test dataset, the model achieved AUC of 0.85 and 79.3% balanced accuracy, while performance of the fully supervised model was AUC of 0.65 and 33.1 balanced accuracy. In a challenging subset for image-based diagnosis, including 253 samples (29 aneuploid) without dysplasia or atypical mitosis (a major feature of aneuploidy samples) the model achieved a 67.6% accuracy and an AUC of 0.83. Both the flow results (p=2.84e-7) and the model's predictions (p=2.18e-3) revealed a correlation between progression to EAC and ploidy status. Conclusion We developed a deep learning model for predicting aneuploidy in BE biopsies. The weakly-supervised approach can perform much better compared to the traditional fully-supervised model. Aneuploidy is correlated with cancer progression and stands as a promising candidate for the prediction of cancer progression in BE patients. Although atypical mitosis is the primary histological indicator of aneuploidy, our model can still make aneuploid predictions in the absence of atypical mitosis, as it doesn't rely solely on a single parameter. Our model is efficient, capable of processing hundreds of samples resource-effectively, and thus an ideal adjunct to standard histologic evaluation. This classifier may facilitate molecular-based improvements in identifying individuals at high risk of progression. Citation Format: Caner Ercan, Xiaoxi Pan, Thomas G. Paulson, Matthew D. Stachler, Carlo C. Maley, Yinyin Yuan. A novel approach to Barrett's esophagus risk stratification: Whole-slide image analysis for aneuploidy detection [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 6184.

Abstract 2177: Postbiotic metabolites secreted by L. acidophilus reduce DNA damage in an experimental model of Barrett’s tumorigenesis

Abstract The origins of esophageal adenocarcinoma (EAC) are commonly attributed to the progression from gastroesophageal reflux disease (GERD) to Barrett’s Esophagus (BE) and finally to esophageal adenocarcinoma. During GERD, various types of bile induce oxidative stress and generate reactive oxygen species (ROS), resulting in DNA damage and inflammation in cells. Although there has been much research documenting the shift in the esophageal microbiome from gram-positive to gram-negative bacteria during this progression, there has also been an observed increase in the presence of Lactobacillus, a gram-positive commensal bacterium with probiotic qualities, in the esophagus during the progression from GERD to BE and eventually to EAC. Our previous research has demonstrated the ability of Lactobacillus spp. to not only colonize the esophagus under in vitro conditions of GERD, but also their anti-inflammatory and anti-genotoxic properties on esophageal cells exposed to bile. To assess the extent of reflux-induced DNA damage and oxidative stress during the progression of BE, we exposed two BE cell lines, CP-B and BAR-T, and the EAC cell line FLO-1 to ox bile or deoxycholic acid. Both bile types demonstrated significant increases in phosphorylated H2AX, as a marker for pronounced DNA damage repair. Next, we supplemented both live L. acidophilus and its postbiotic metabolites to cells exposed to ox bile and deoxycholic acid. We show a significant reduction in DNA damage as measured by pH2AX with both the live treatment and the treatment with postbiotic metabolites when compared to untreated, bile-exposed cells at various stages of BE and EAC. Ongoing experiments include assessing anti-genotoxic effects of postbiotic metabolites through DNA repair protein RAD51, reductions in oxidative stress though ROS marker 8-oxo-guanine, and anti-inflammatory effects through NFkB-associated inflammation. BE and EAC cell viability and proliferation upon bile exposure and postbiotic metabolite administration will also be assessed. This study aims to determine the supplementation with Lactobacillus postbiotic metabolites in the prevention and intervention of esophageal adenocarcinoma development. Citation Format: Divya Joshi, Claudia Andl. Postbiotic metabolites secreted by L. acidophilus reduce DNA damage in an experimental model of Barrett’s tumorigenesis [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 2177.

MiRNA profiling of esophageal adenocarcinoma using transcriptome analysis.

Esophageal adenocarcinoma (EAC) occurs following a series of histological changes through epithelial-mesenchymal transition (EMT). A variable expression of normal and aberrant genes in the tissue can contribute to the development of EAC through the activation or inhibition of critical molecular signaling pathways. Gene expression is regulated by various regulatory factors, including transcription factors and microRNAs (miRs). The exact profile of miRs associated with the pathogenesis of EAC is largely unknown, though some candidate miRNAs have been reported in the literature. To identify the unique miR profile associated with EAC, we compared normal esophageal tissue to EAC tissue using bulk RNA sequencing. RNA sequence data was verified using qPCR of 18 selected genes. Fourteen were confirmed as being upregulated, which include CDH11, PCOLCE, SULF1, GJA4, LUM, CDH6, GNA12, F2RL2, CTSZ, TYROBP, and KDELR3 as well as the downregulation of UGT1A1. We then conducted Ingenuity Pathway Analysis (IPA) to analyze for novel miR-gene relationships through Causal Network Analysis and Upstream Regulator Analysis. We identified 46 miRs that were aberrantly expressed in EAC compared to control tissues. In EAC tissues, seven miRs were associated with activated networks, while 39 miRs were associated with inhibited networks. The miR-gene relationships identified provide novel insights into potentially oncogenic molecular pathways and genes associated with carcinogenesis in esophageal tissue. Our results revealed a distinct miR profile associated with dysregulated genes. The miRs and genes identified in this study may be used in the future as biomarkers and serve as potential therapeutic targets in EAC.

On-chip Raman spectroscopy of live single cells for the staging of oesophageal adenocarcinoma progression.

The absence of early diagnosis contributes to oesophageal cancer being the sixth most common cause of global cancer-associated deaths, with a 5-year survival rate of < 20%. Barrett's oesophagus is the main pre-cancerous condition to adenocarcinoma development, characterised by the morphological transition of oesophageal squamous epithelium to metaplastic columnar epithelium. Early tracking and treatment of oesophageal adenocarcinoma could dramatically improve with diagnosis and monitoring of patients with Barrett's Oesophagus. Current diagnostic methods involve invasive techniques such as endoscopies and, with only a few identified biomarkers of disease progression, the detection of oesophageal adenocarcinoma is costly and challenging. In this work, single-cell Raman spectroscopy was combined with microfluidic techniques to characterise the development of oesophageal adenocarcinoma through the progression of healthy epithelial, Barrett's oesophagus and oesophageal adenocarcinoma cell lines. Principal component analysis and linear discriminant analysis were used to classify the different stages of cancer progression. with the ability to differentiate between healthy and cancerous cells with an accuracy of 97%. Whilst the approach could also separate the dysplastic stages from healthy or cancer with high accuracy-the intra-class separation was approximately 68%. Overall, these results highlight the potential for rapid and reliable diagnostic/prognostic screening of Barrett's Oesophagus patients.

TRIM31: A Protein With an Oncogenic Role in Esophageal Adenocarcinoma

Background: Esophageal adenocarcinoma (EAC) is a major cancer in the United States with increasing incidence. It is an aggressive cancer involving columnar-type cells different from the normal esophageal (NE) squamous cells. This metaplasia often involves an intermediary morphology called Barrett’s esophagus (BE), which occurs from repeated acid exposure of the esophagus from gastroesophageal reflux disease (GERD). GERD leading to BE is a common pre-occurrence in EAC patients, but the mechanism remains obscure. To explore the mechanism and its components, we compared gene expression in BE and EAC cells with normal cells and discovered the overexpression of TRIM31 in the pathogenic cells. Although previous studies have shown oncogenic potential of TRIM31 in some cancers, its role in EAC is yet to be understood.&#x0D; Methods: RNA sequencing and transcriptomic profiling were performed on human NE, BE, and EAC epithelial tissue samples. TRIM31 expression in NE cell line (Het-1A) and EAC cell lines (OE19, Flo-1, OE33, SK-GT-2, and OACM5.1C) were identified by Western blot. The Het-1A cell line, after exposure to acidic pH and bile acid, was assessed for variable TRIM31 expression. Cell viability analysis of NE and EAC cell lines after exposure to acidic pH and bile acids was observed by WST-1 assay.&#x0D; Results: RNA sequencing, transcriptomic profiling, and western blot revealed overexpression of TRIM31 in BE and EAC epithelium. Exposure of Het-1A cells to bile acids in acidic pH changed the cell morphology with enhanced expression of TRIM31. WST-1 revealed that EAC cells were more resistant to acidic pH and bile acid exposure.&#x0D; Conclusions and potential impact: Our data suggests that increased TRIM31 expression correlates with esophageal epithelium resistance when exposed to bile acids and acidic pH. Consequently, TRIM31 may be a key player in the metaplasia of GERD-induced EAC development and may be an innovative therapeutic target and marker for EAC.

Incidence rates of Barrett’s esophagus and esophageal adenocarcinoma: a systematic review and meta-analysis

Background and AimsBarrett’s esophagus (BE) surveillance is commonly performed to detect early dysplasia and esophageal adenocarcinoma (EAC). However, high-quality incidence rates for the development of dysplasia and EAC in patients with BE are limited. This study aims to perform a systematic review and meta-analysis to provide an updated incidence rates for the development of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC in a population of patients with BE undergoing endoscopic surveillance. MethodsWe performed a systematic search of EMBASE and Medline from inception to September 2022 to identify studies reporting the incidence rates of LGD, EAC, or HGD/EAC as an outcome in patients with non-dysplastic BE (NDBE), LGD, or HGD. Respective pooled incidence rates were estimated using a meta-analysis. ResultsTwenty-five studies were included in this meta-analysis comprising 2,587 patients with a combined follow-up of 218,351 person-years. For patients with NDBE, pooled incidence rates for progression to LGD, HGD, EAC, and HGD/EAC were 4.29, 0.52, 0.21, and 0.57 per 100 person-years, respectively. For patients with LGD, pooled incidence rates were 3.18 (HGD), 1.16 (EAC), and 5.05 (HGD/EAC) per 100 person-years. For those with HGD, the pooled incidence rate for EAC was 14.16 per 100 person-years. ConclusionsProgression to EAC and HGD/EAC remained low for patients with NDBE. Patients with confirmed LGD (≥2 pathologists) may be more likely to develop EAC, prompting a need to assess current BE surveillance strategies in this group.

Molecular Biology and Clinical Management of Esophageal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a highly lethal malignancy. Due to its rising incidence, EAC has become a severe health challenge in Western countries. Current treatment strategies are mainly chosen based on disease stage and clinical features, whereas the biological background is hardly considered. In this study, we performed a comprehensive review of existing studies and discussed how etiology, genetics and epigenetic characteristics, together with the tumor microenvironment, contribute to the malignant behavior and dismal prognosis of EAC. During the development of EAC, several intestinal-type proteins and signaling cascades are induced. The anti-inflammatory and immunosuppressive microenvironment is associated with poor survival. The accumulation of somatic mutations at the early phase and chromosomal structural rearrangements at relatively later time points contribute to the dynamic and heterogeneous genetic landscape of EAC. EAC is also characterized by frequent DNA methylation and dysregulation of microRNAs. We summarize the findings of dysregulations of specific cytokines, chemokines and immune cells in the tumor microenvironment and conclude that DNA methylation and microRNAs vary with each different phase of BE, LGD, HGD, early EAC and invasive EAC. Furthermore, we discuss the suitability of the currently employed therapies in the clinic and possible new therapies in the future. The development of targeted and immune therapies has been hampered by the heterogeneous genetic characteristics of EAC. In view of this, the up-to-date knowledge revealed by this work is absolutely important for future EAC studies and the discovery of new therapeutics.

427. CAN WE OPTIMIZE THE RECOMMENDATIONS FOR FOLLOW-UP OF BARRETT’S ESOPHAGUS THROUGH CRITICAL ANALYSIS OF RISK FACTORS IN A SPECIFIC POPULATION?

Abstract Introduction Barrett’s esophagus (BE) affects approximately 3 million people in Brazil with its incidence has been increasing in recent years. In this pathology, the genetically unstable metaplastic epithelium leads to risks of progression to dysplasia and esophageal adenocarcinoma (EAC). In a scenario where most EACs arise in the presence of BE, it is necessary to study the epidemiological risk factors associated with this evolution to implement optimized surveillance recommendations. Objective Evaluate the epidemiological risk factors involved in the development of dysplasia and adenocarcinoma from BE in a specific population and propose an appropriate suggestion on how to carry out the follow-up according to these factors. Methodology A retrospective cross-sectional study was conducted in a tertiary center with patients with BE followed in this center. Patients with BE who presented adenocarcinoma and/or dysplasia were compared to those who did not, considering the variables gender, age, smoking, BMI, ethnicity, and extent of Barrett’s. Logistic regression was performed to measure the odds ratio (OR) between risk factors for the outcome of adenocarcinoma and the outcome of dysplasia. Finally, the presence of proven epidemiological risk factors in this population was correlated with the time of development of EAC from BE. Results There was a statistically significant difference between smoking, race, gender, extent of Barrett’s, and age among patients that presented adenocarcinoma and not. Smokers and ex-smokers had a 4.309 times higher risk of developing adenocarcinoma, and the extent of Barrett’s increased this risk by 1.193 times per centimeter. Among the group that presented dysplasia compared to the group that did not, smoking, the extent of Barrett’s, and age were statistically significant, with the extent of Barrett’s increasing the risk of developing dysplasia by 1.128 times per centimeter and age increased the risk of this outcome by 1.023 per year. Patients without risk factors did not develop EAC in less than 12 months, even if they had dysplasia before. Conclusion The study confirmed a higher risk of developing dysplasia and adenocarcinoma in specific epidemiological groups, which can redirect follow-up in patients with BE in a more cost-effective manner.

IL-1β transgenic mouse model of inflammation driven esophageal and oral squamous cell carcinoma

Chronic inflammation is integral to the development of esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although the latter has not been associated with reflux esophagitis. The L2-IL-1β transgenic mice, expressing human interleukin (IL)-1β in the oral, esophageal and forestomach squamous epithelia feature chronic inflammation and a stepwise development of Barrett’s esophagus-like metaplasia, dysplasia and adenocarcinoma at the squamo-columnar junction. However, the functional consequences of IL-1β-mediated chronic inflammation in the oral and esophageal squamous epithelia remain elusive. We report for the first time that in addition to the previously described Barrett’s esophagus-like metaplasia, the L2-IL-1β mice also develop squamous epithelial dysplasia with progression to squamous cell carcinoma (SCC) in the esophagus and the tongue. L2-IL-1β showed age-dependent progression of squamous dysplasia to SCC with approximately 40% (n = 49) and 23.5% (n = 17) incidence rates for esophageal and tongue invasive SCC respectively, by 12–15 months of age. Interestingly, SCC development and progression in L2-IL-1β was similar in both Germ Free (GF) and Specific Pathogen Free (SPF) conditions. Immunohistochemistry revealed a T cell predominant inflammatory profile with enhanced expression of Ki67, Sox2 and the DNA double-strand break marker, γ-H2AX, in the dysplastic squamous epithelia of L2-IL-1β mice. Pro-inflammatory cytokines, immunomodulatory players, chemoattractants for inflammatory cells (T cells, neutrophils, eosinophils, and macrophages) and oxidative damage marker, iNOS, were significantly increased in the esophageal and tongue tissues of L2-IL-1β mice. Our recent findings have expanded the translational utility of the IL-1β mouse model to aid in further characterization of the key pathways of inflammation driven BE and EAC as well as ESCC and Oral SCC.

Decreased Risk of Esophageal Adenocarcinoma After Gastric Bypass Surgery in a Cohort Study From 3 Nordic Countries.

The objective of this study was to test the hypothesis that bariatric surgery decreases the risk of esophageal and cardia adenocarcinoma. Obesity is strongly associated with esophageal adenocarcinoma and moderately with cardia adenocarcinoma, but whether weight loss prevents these tumors is unknown. This population-based cohort study included patients with an obesity diagnosis in Sweden, Finland, or Denmark. Participants were divided into a bariatric surgery group and a nonoperated group. The incidence of esophageal and cardia adenocarcinoma (ECA) was first compared with the corresponding background population by calculating standardized incidence ratios (SIR) with 95% CIs. Second, the bariatric surgery group and the nonoperated group were compared using multivariable Cox regression, providing hazard ratios (HR) with 95% CI, adjusted for sex, age, comorbidity, calendar year, and country. Among 748,932 participants with an obesity diagnosis, 91,731 underwent bariatric surgery, predominantly gastric bypass (n=70,176; 76.5%). The SIRs of ECA decreased over time after gastric bypass, from SIR=2.2 (95% CI, 0.9-4.3) after 2 to 5 years to SIR=0.6 (95% CI, <0.1-3.6) after 10 to 40 years. Gastric bypass patients were also at a decreased risk of ECA compared with nonoperated patients with obesity [adjusted HR=0.6, 95% CI, 0.4-1.0 (0.98)], with decreasing point estimates over time. Gastric bypass was followed by a strongly decreased adjusted risk of esophageal adenocarcinoma (HR=0.3, 95% CI, 0.1-0.8) but not of cardia adenocarcinoma (HR=0.9, 95% CI, 0.5-1.6), when analyzed separately. There were no consistent associations between other bariatric procedures (mainly gastroplasty, gastric banding, sleeve gastrectomy, and biliopancreatic diversion) and ECA. Gastric bypass surgery may counteract the development of esophageal adenocarcinoma in morbidly obese individuals.

Resident Esophageal Microbiota Dysbiosis Correlates with Cancer Risk in Barrett's Esophagus Patients and Is Linked to Low Adherence to WCRF/AICR Lifestyle Recommendations.

Esophageal adenocarcinoma (EAC) is the consequence of longstanding gastroesophageal reflux, which leads to inflammation and could cause Barrett's esophagus (BE), the main risk factor for EAC development. The 5 year survival rate of EAC is poor since the diagnosis occurs at the late stage of the disease. To improve patient management, a better comprehension of the mechanism undergoing the evolution through to adenocarcinoma is needed. Within this scenario, the resident microbiome investigation was studied. This study aimed to explore the esophageal microbial profile in patients affected by non-dysplastic BE, low- and high-grade dysplastic BE, and EAC to identify parameters characterizing cancer progression and to develop a score suitable for clinical practice to stratify cancer risk. The microbiota was investigated through the 16S rRNA gene sequencing of esophageal biopsies. The microbial composition was evaluated at each different taxonomic level along the disease progression. To further investigate bacteria potentially associated with cancer development, non-dysplastic and dysplastic/cancer patients were compared. The presence of the six significant microbial features with multivariate analysis was used to develop a multiparametric score (Resident Esophageal Microbial Dysbiosis Test) to predict the risk of progression toward EAC. Finally, the diagnostic ability of the test and its discrimination threshold for its ability to identify dysplastic/cancer patients were demonstrated. Since EAC has been related to obesity, the relationship between these microbial parameters and patients' diet/lifestyle habits was also investigated. Developing microbiome-based risk prediction models for esophageal adenocarcinoma onset could open new research avenues, demonstrating that the resident microbiome may be a valid cancer risk biomarker.

Impact of Residing in Below Median Household Income Districts on Outcomes in Patients with Advanced Barrett's Esophagus.

Barrett's esophagus (BE) is a premalignant condition to esophageal adenocarcinoma (EAC). Low socioeconomic (SES) status adversely impacts care and outcomes in patients with EAC, but this has not been evaluated in BE. As the treatment of BE is similarly intensive, we aimed to evaluate the effect of SES on achieving complete eradication of intestinal metaplasia (CE-IM), dysplasia (CE-D) and development of invasive EAC. Our study was a retrospective cohort study. Consecutive patients between January 1, 2010, to December 31, 2018, referred for BE-associated high-grade dysplasia or intramucosal adenocarcinoma were included. Pre, intra and post-procedural data were collected. Household income data was collected from the 2016 census based on postal code region. Patients were divided into income groups relative to the 2016 median household income in Ontario. Multivariate regression was performed for outcomes of interest. Four hundred and fifty-nine patients were included. Rate of CE-IM was similar between income groups. Fifty-five per cent (n = 144/264) versus 65% (n = 48/264) in the below and above-income groups achieved CE-D, respectively, P = 0.02. Eighteen per cent (n = 48/264) versus 11% (n = 22/195) were found to have invasive EAC during their treatment course in below and above-income groups, respectively, P = 0.04. Residing in a below-median-income district was associated with developing invasive EAC (Odds Ratio, [OR] 1.84, 95% confidence interval [CI] 1.01 to 3.35) and failure to achieve CE-D (OR 0.64, 95% CI 0.42 to 0.97). Residing in low-income districts is associated with worse outcomes in patients with advanced BE. Further research is needed to guide future initiatives to address the potential impact of SES barriers in the optimal care of BE.

Increased Risk of Colorectal Cancer in Patients With Celiac Disease: A Population-Based Study.

The association between celiac disease (CD) and the development of small bowel lymphoproliferative disorders and esophageal adenocarcinoma has been established in the literature. However, there is only a little evidence demonstrating an increased risk of colorectal cancer (CRC) in patients with CD. Hence, we conducted a cross-sectional population-based study to evaluate the risk of developing CRCin patients who have had a diagnosis of CD. We used a commercial database (Explorys Inc, Cleveland, OH), which includeselectronic health records from 26 major integrated US healthcare systems. Patients aged 18-65 years were included. Patients with inflammatory bowel disease (IBD) were excluded. Multivariate analysis using backward stepwise logistic regression was performed to calculate the risk of developing CRCin potential confounders. A two-sided P-value <0.05 was considered statistically significant. 79,843,332 individuals were screened in the database and 47,400,960 were selected in the final analysis after accounting for inclusion and exclusion criteria. Using a stepwise multivariate regression analysis, the odds of having CRC amongpatientswith CD was 10.18 (95% CI 9.72-10.65) (P-value <0.001). The odds also remained high amongmales 1.49 (95% CI 1.36-1.63), African Americans 1.51 (95% CI 1.35-1.68), patients who have type 2 diabetes mellitus (T2DM) 2.71 (95% CI 2.66-2.76), are smokers 2.49 (95% CI 2.44-2.54), are obese 2.21 (95% CI 2.17-2.25), and are alcoholic 1.72 (95% CI 1.66-1.78). Our study demonstrates that patients with CD are frequently found to have CRCeven when adjusting for common risk factors. This adds to the literature and helps spread awareness to clinicians that the effects of CD are not only limited to the small bowel as the disease tends to involve other parts of the gastrointestinal tract also, especially the colon. The threshold to screen patients with CD should be considered to be lowered.

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.

Endoscopic therapy for Barrett’s esophagus: a narrative review of potential complications and their management

: Barrett’s esophagus (BE) is a well-known risk factor for the development of esophageal adenocarcinoma (EAC). This histologic transformation occurs in a stepwise fashion with progression from intestinal metaplasia (IM) to low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal adenocarcinoma (IMCA), and ultimately invasive EAC. Standardized guidelines have been developed for screening, surveillance and treatment of dysplastic/neoplastic BE. Endoscopic eradication therapy (EET) is recommended over esophagectomy for dysplasia and early (mucosal) neoplasia based on its efficacy and favorable risk profile. EET consists of endoscopic resection of any nodular lesions followed by endoscopic ablation of Barrett’s mucosa. Endoscopic resection can be performed by endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). There are several effective modalities available for endoscopic ablation including radiofrequency ablation (RFA), cryoablation, argon plasma coagulation (APC), and/or hybrid-APC. Often times, multimodal endoscopic therapy is utilized with a combination of endoscopic resection and ablation techniques. While generally well tolerated, complications from these therapeutic procedures do occur, including sedation-related events, post-procedure chest pain, luminal perforation, bleeding and esophageal stricture. Complications may occur intraprocedure, immediately post-procedure, or delayed post-procedure. Treatment depends upon the severity of the complication, hemodynamic stability of the patient, and timing of presentation. This review highlights the potential complications associated with BE endotherapy and the management thereof.

Barrett's Esophagus: An Updated Review.

Barrett's esophagus (BE) is a change in the distal esophageal mucosal lining, whereby metaplastic columnar epithelium replaces squamous epithelium of the esophagus. This change represents a pre-malignant mucosal transformation which has a known association with the development of esophageal adenocarcinoma. Gastroesophageal reflux disease is a risk factor for BE, other risk factors include patients who are Caucasian, age &gt; 50 years, central obesity, tobacco use, history of peptic stricture and erosive gastritis. Screening for BE remains selective based on risk factors, a screening program in the general population is not routinely recommended. Diagnosis of BE is established with a combination of endoscopic recognition, targeted biopsies, and histologic confirmation of columnar metaplasia. We aim to provide a comprehensive review of the epidemiology, pathogenesis, screening and advanced techniques of detecting and eradicating Barrett's esophagus.

Protein adduction causes non-mutational inhibition of p53 tumor suppressor

p53 is a key tumor suppressor that is frequently mutated in human tumors. In this study, we investigated how p53 is regulated in precancerous lesions prior to mutations in the p53 gene. Analyzing esophageal cells in conditions of genotoxic stress that promotes development of esophageal adenocarcinoma, we find that p53 protein is adducted with reactive isolevuglandins (isoLGs), products of lipid peroxidation. Modification of p53 protein with isoLGs diminishes its acetylation and binding to the promoters of p53 target genes causing modulation of p53-dependent transcription. It also leads to accumulation of adducted p53 protein in intracellular amyloid-like aggregates that can be inhibited by isoLG scavenger 2-HOBA invitro and invivo. Taken together, our studies reveal a posttranslational modification of p53 protein that causes molecular aggregation of p53 protein and its non-mutational inactivation in conditions of DNA damage that may play an important role in human tumorigenesis.

The landscape of m6A regulators in esophageal cancer: molecular characteristics, immuno-oncology features, and clinical relevance.

Squamous cell carcinoma (SCC) and adenocarcinoma (AC) are the two main pathological types of esophageal cancer (EC), which differ in molecular features, genetic variation, and treatment sensitivity. However, as a key process in tumorigenesis and development, the role of N6-methyladenosine (m6A) regulators in esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) is not fully understood. This study systematically compared the role of m6A regulators of ESCC and EAC in terms of molecular characteristics, immuno-oncology characteristics, and clinical relevance, and validated our findings in a long-term follow-up patient cohort. There were many differences in m6A regulators between ESCC and EAC in terms of expression patterns, genetic variation, association with tumor pathways, immune signatures, and immunotherapy sensitivity. Furthermore, VIRMA was identified as a factor with opposite functional and prognostic effects in ESCC and EAC. ESCC patients with high VIRMA expression and EAC patients with low VIRMA expression had a better prognosis. Single-center data showed that low expression of FTO may be associated with superior immunotherapy efficacy in ESCC patients. The results herein provide novel ideas for understanding the tumor characteristics, occurrence, and development of ESCC and EAC, and suggest new targets for the treatment and intervention of EC.