Cancer Risk in Barrett's Esophagus: A Clinical Review.

Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence and is associated with a poor prognosis. Barrett's esophagus (BE) is a known precursor of esophageal adenocarcinoma. This review aims to explore Barrett's esophagus, esophageal adenocarcinoma, and the progression from the former to the latter. An overview of the definition, diagnosis, epidemiology, and risk factors for both entities are presented, with special attention being given to the areas of debate in the literature. The progression from Barrett's esophagus to esophageal adenocarcinoma is reviewed and the relevant molecular pathways are discussed. The definition of Barrett's esophagus remains debated and without international consensus. This, alongside other factors, has made establishing the true prevalence of Barrett's esophagus challenging. The degree of dysplasia can be a histological challenge, but is necessary to guide clinical management. The progression of BE to EAC is likely driven by inflammatory pathways, pepsin exposure, upregulation of growth factor pathways, and mitochondrial changes. Surveillance is maintained through serial endoscopic evaluation, with shorter intervals recommended for high-risk features.

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

EDUCATIONAL OBJECTIVE: At the conclusion of this presentation, participants should better understand the carcinogenic potential of pepsin and proton pump expression in Barrett's esophagus. OBJECTIVE: 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. STUDY DESIGN: In vitro translational. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. LEVEL OF EVIDENCE: NA Laryngoscope, 133:59-69, 2023.

Association of e-Cigarette Exposure with Pediatric Otitis Media Recurrence.

OBJECTIVE: Otitis media (OM) is a common inflammatory disease spectrum in children and a leading cause of pediatric physician visits, antibiotic prescriptions and surgery. Tobacco exposure is associated with increased risk of OM recurrence, chronicity and surgeries. Tobacco products have changed dramatically in recent years with the advent of electronic cigarettes (e-cigarettes). While users frequently perceive vape as less harmful than traditional cigarettes, burgeoning evidence supports its contribution to respiratory pathologies. The consequences of secondhand exposure, particularly among children, are understudied. The aim of this study was to examine the association of e-cigarette emissions (EE) with OM recurrence and surgeries in the US. METHODS: Questionnaire data regarding ear infections and tobacco exposure was gathered for all pediatric respondents of the National Health and Nutrition Examination Survey (NHANES) 2017 to 2018. Weighted analyzes and logistic regression models were used to assess associations. RESULTS: Data was available for 2022 participants (aged 6-17); all were included for analyzes. Tobacco exposure was observed in 42%; 9% were exposed to EE. EE contributed to risk of ≥3 ear infections (OR = 1.61, 95% CI 1.01-2.58, P = .047). After adjustment for significant covariates (race and asthma), the association fell below significance (P = .081). No other significant associations were observed between ear infections, or tympanostomy tube insertion and exposure variables (EE, gestational or other household exposure). CONCLUSIONS: Exposure to EE may confer greater risk of pediatric OM than previously identified factors such as household smoke, or gestational exposure. Further investigation of EE and its health implications in children is warranted. LEVEL OF EVIDENCE: IV.

RNA Sequencing and Pathways Analyses of Middle Ear Epithelia From Patients With Otitis Media.

OBJECTIVES: Otitis media (OM) is the most common pediatric diagnosis in the United States. However, our understanding of the molecular pathogenesis of OM remains relatively poor. Investigation of molecular pathways involved in OM may improve the understanding of this disease process and elucidate novel therapeutic targets. In this study, RNA sequencing (RNA-Seq) was used to discern cellular changes associated with OME compared to healthy middle ear epithelium (MEE). STUDY DESIGN: Ex vivo case-control translational. METHODS: Middle ear epithelia was collected from five pediatric patients diagnosed with OME undergoing tympanostomy tube placement and five otherwise healthy pediatric patients undergoing cochlear implantation. Specimens underwent RNA-Seq and pathways analyses. RESULTS: A total of 1,292 genes exhibited differential expression in MEE from OME patients compared to controls including genes involved in inflammation, immune response to bacterial OM pathogens, mucociliary clearance, regulation of proliferation and transformation, and auditory cell differentiation. Top networks identified in OME were organismal injury and abnormalities, cell morphology, and auditory disease. Top Ingenuity canonical pathways identified were axonal guidance signaling, which contains genes associated with auditory development and disease and nicotine degradation II and III pathways. Associated upstream regulators included ß-estradiol, dexamethasone, and G-protein-coupled estrogen receptor-1 (GPER1), which are associated with otoprotection or inflammation during insult. CONCLUSIONS: RNA-Seq demonstrates differential gene expression in MEE from patients with OME compared to healthy controls with important implications for infection susceptibility, hearing loss, and a role for tobacco exposure in the development and/or severity of OME in pediatric patients. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:2590-2597, 2021.