Normal Esophageal Biopsies Research Articles

Modeling Epithelial Homeostasis and Perturbation in Three-Dimensional Human Esophageal Organoids.

Background: Esophageal organoids from a variety of pathologies including cancer are grown in Advanced Dulbecco's Modified Eagle Medium-Nutrient Mixture F12 (hereafter ADF). However, the currently available ADF-based formulations are suboptimal for normal human esophageal organoids, limiting the ability to compare normal esophageal organoids with those representing a given disease state. Methods: We have utilized immortalized normal human esophageal epithelial cell (keratinocyte) lines EPC1 and EPC2 and endoscopic normal esophageal biopsies to generate three-dimensional (3D) organoids. To optimize the ADF-based medium, we evaluated the requirement of exogenous epidermal growth factor (EGF) and inhibition of transforming growth factor-(TGF)-β receptor-mediated signaling, both key regulators of the proliferation of human esophageal keratinocytes. We have modeled human esophageal epithelial pathology by stimulating esophageal 3D organoids with interleukin (IL)-13, an inflammatory cytokine, or UAB30, a novel pharmacological activator of retinoic acid signaling. Results: The formation of normal human esophageal 3D organoids was limited by excessive EGF and intrinsic TGFβ-receptor-mediated signaling. Optimized HOME0 improved normal human esophageal organoid formation. In the HOME0-grown organoids, IL-13 and UAB30 induced epithelial changes reminiscent of basal cell hyperplasia, a common histopathologic feature in broad esophageal disease conditions including eosinophilic esophagitis. Conclusions: HOME0 allows modeling of the homeostatic differentiation gradient and perturbation of the human esophageal epithelium while permitting a comparison of organoids from mice and other organs grown in ADF-based media.

Mast Cell Esophagitis: A Novel Entity in Patients with Unexplained Esophageal Symptoms.

It is not known whether esophageal mast cells may be a cause of unexplained esophageal symptoms. We aimed to determine the prevalence of esophageal mastocytosis in patients without other underlying causes of symptoms and assess the relationship between symptoms and mast cells. In this retrospective study, we identified adults with esophageal symptoms, a normal endoscopy, normal esophageal biopsies, and no definitive diagnosis during clinical evaluation. We quantified mast cell density (mast cells/mm2) in archived esophageal biopsies using tryptase immunohistochemistry, and compared mast cell levels by clinical features and physiologic testing. In the 87 patients identified (mean age 37, 72% female, 63% white, 92% non-Hispanic), common symptoms were dysphagia (76%), heartburn (71%), and chest pain (25%). Overall, the mean esophageal epithelial mast cell count was 83.0 ± 51.8 mast cells/mm2; 60% of patients had ≥ 60 mast/mm2, and 17% had ≥ 120 masts/mm2. There were no differences in mast cell counts by type of esophageal testing. Mast cell levels did not differ significantly by type of symptoms, atopic status, medications, smoking status, or alcohol use. There were also no major differences in clinical characteristics by mast cell quartiles or thresholds. In conclusion, esophageal mast cell infiltration was common in patients with symptoms unexplained by prior testing, and levels were higher than previously published values for patients with no underlying esophageal condition. Mast cell esophagitis could be a novel cause of unexplained esophageal symptoms in a subset of patients, though it reamins to be determined if such patients benefit from mast cell-targeted treatment.

Esophageal Microbiome in Healthy Children and Esophageal Eosinophilia.

There is limited knowledge about the role of esophageal microbiome in pediatric esophageal eosinophilia (EE). We aimed to characterize the esophageal microbiome in pediatric patients with and without EE. In the present prospective study, esophageal mucosal biopsies were obtained from 41 children. Of these, 22 had normal esophageal mucosal biopsies ("healthy"), 6 children had reflux esophagitis (RE), 4 had proton pump inhibitor (PPi)-responsive esophageal eosinophilia (PPi-REE), and 9 had eosinophilic esophagitis (EoE). The microbiome composition was analyzed using 16S rRNA gene sequencing. The age median (range) in years for the healthy, RE, PPi-REE, and EoE group were 10 (1.5-18), 6 (2-15), 6.5 (5-15), and 9 (1.5-17), respectively. The bacterial phylum Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria were the most predominant. The Epsilonproteobacteria, Betaproteobacteria, Flavobacteria, Fusobacteria, and Sphingobacteria class were underrepresented across groups. The Vibrionales was predominant in healthy and EoE group but lower in RE and PPi-REE groups. The genus Streptococcus, Rahnella, and Leptotrichia explained 29.65% of the variation in the data with an additional 10.86% variation in the data was explained by Microbacterium, Prevotella, and Vibrio genus. The healthy group had a higher diversity and richness index compared to other groups, but this was not statistically different. The pediatric esophagus has an abundant and diverse microbiome, both in the healthy and diseased states. The healthy group had a higher, but not significantly different, diversity and richness index compared to other groups.

Single-cell RNA sequencing of mast cells in eosinophilic esophagitis reveals heterogeneity, local proliferation, and activation that persists in remission

Mast cells (MCs) are pleiotropic cells that accumulate in the esophagus of patients with eosinophilic esophagitis (EoE) and are thought to contribute to disease pathogenesis, yet their properties and functions in this organ are largely unknown. This study aimed to perform a comprehensive molecular and spatial characterization of esophageal MCs in EoE. Esophageal biopsies obtained from patients with active EoE, patients with EoE in histologic remission, and individuals with histologically normal esophageal biopsies and no history of esophageal disease (ie, control individuals) were subject to single-cell RNA sequencing, flow cytometry, and immunofluorescence analyses. This study probed 39,562 single esophageal cells by single-cell RNA sequencing; approximately 5% of these cells were MCs. Dynamic MC expansion was identified across disease states. During homeostasis, TPSAB1highAREGhigh resident MCs were mainly detected in the lamina propria and exhibited a quiescent phenotype. In patients with active EoE, resident MCs assumed an activated phenotype, and 2 additional proinflammatory MC populations emerged in the intraepithelial compartment, each linked to a proliferating MKI67high cluster. One proinflammatory activated MC population, marked as KIThighIL1RL1highFCER1Alow, was not detected in disease remission (termed "transient MC"), whereas the other population, marked as CMA1highCTSGhigh, was detected in disease remission where it maintained an activated state (termed "persistent MC"). MCs were prominent producers of esophageal IL-13 mRNA and protein, a key therapeutic target in EoE. Esophageal MCs comprise heterogeneous populations with transcriptional signatures associated with distinct spatial compartmentalization and EoE disease status. In active EoE, they assume a proinflammatory state and locally proliferate, and they remain activated and poised to reinitiate inflammation even during disease remission.

Lymphocytic Esophagitis: Assessing Risk Factors and Clinical Outcomes.

Lymphocytic esophagitis is a rare esophageal condition. Our knowledge of potential risk factors and treatment outcomes of lymphocytic esophagitis is limited. To investigate potential risk factors associated with the development of lymphocytic esophagitis and compare clinical characteristics and treatment outcomes of patients diagnosed with lymphocytic esophagitis to patients diagnosed with eosinophilic esophagitis. This is a multicenter retrospective study. Lymphocytic esophagitis patients were identified based on pathology results between 1997 and 2019. Control groups consisted of patients with normal esophageal biopsies and patients diagnosed with eosinophilic esophagitis. Thirteen potential risk factors for lymphocytic esophagitis were analyzed using univariate and multivariate models including IBD, achalasia, hyperlipidemia, hypothyroidism, celiac sprue, CVID, H. pylori, thymoma, aspirin, opioids, ACE-I, metformin, and statin use. Comparative statistics were performed. Ninety-four adult patients with lymphocytic esophagitis, 344 with eosinophilic esophagitis, and 5202 control patients with normal esophageal biopsies were analyzed. Age older than 60 [adjusted odd ratio (AOR) 1.03, 95% CI 1.02-1.05, p = 0.001], aspirin use (2.7, 95% CI 1.4-4.9, p = 0.001), statin use (2.2, 95% CI 1.2-4.2, p = 0.01), or a diagnosis of achalasia (2.4, 95% 1.08-5.67, p = 0.03) were associated with lymphocytic esophagitis. Compared to eosinophilic esophagitis, lymphocytic esophagitis patients were more likely to respond to medical treatment (95% CI 2.54-12.8, p = 0.0001). Our data suggests that lymphocytic esophagitis is more likely to be found in older female patients and is significantly associated with achalasia, statin, and aspirin use. Compared to eosinophilic esophagitis, lymphocytic esophagitis is more likely to respond to treatment with medical therapy.

Methylation panel is a diagnostic biomarker for Barrett’s oesophagus in endoscopic biopsies and non-endoscopic cytology specimens

ObjectiveBarrett’s oesophagus is a premalignant condition that occurs in the context of gastro-oesophageal reflux. However, most Barrett’s cases are undiagnosed because of reliance on endoscopy. We have developed a non-endoscopic...

Reflux Hypersensitivity: A New Functional Esophageal Disorder

Reflux hypersensitivity, recently introduced by Rome IV as a new functional esophageal disorder, is currently considered as the presence of typical heartburn symptoms in patients with normal upper endoscopy and esophageal biopsies, normal esophageal pH test and with evidence of a close correlation between patients’ heartburn and reflux events. Reflux hypersensitivity is very common and together with functional heartburn accounts for more than 90% of the heartburn patients who failed treatment with proton pump inhibitor twice daily. In addition, reflux hypersensitivity affects primarily young to middle aged women, commonly overlaps with another functional gastrointestinal disorders, and is often associated with some type of psychological comorbidity. Diagnosis is made by using endoscopy with esophageal biopsies, pH-impedance, and high-resolution esophageal manometry. Reflux hypersensitivity is primarily treated with esophageal neuromodulators, such as tricyclic anti-depressants and selective serotonin reuptake inhibitors among others. Surgical anti-reflux management may also play an important role in the treatment of reflux hypersensitivity.

Strong NFκB Expression is Associated With High-grade Dysplasia in Barrett's Esophagus.

Nuclear factor kappa B (NFκB) is a transcription factor that regulates the activation of genes involved in proinflammatory response and growth. In this study, we utilized immunohistochemical stains for 2 of the NFκB molecules (RELA and NFκB-1) to evaluate the expression of NFκB in Barrett's esophagus (BE). Forty-three cases of BE [17 cases with no dysplasia, 16 cases with low-grade dysplasia (LGD), and 10 cases with high-grade dysplasia (HGD)], 10 normal esophageal biopsies, and 9 cases of esophageal adenocarcinoma were evaluated. Expression of NFκB-1 and RELA did not occur in normal esophageal squamous mucosa. BE without dysplasia showed weak expression of RELA and NFκB-1 in 35% and 65% of cases, respectively. BE with LGD showed weak expression of RELA and NFκB-1 in 50% and 75% of cases, respectively. Strong expression of RELA and NFκB-1 did not occur in BE without dysplasia or with LGD. BE with HGD showed strong expression of RELA and NFκB-1 in 80% and 90% of cases, respectively. All cases of adenocarcinoma showed strong expression of both RELA and NFκB-1. There was a progressive increase in staining intensity of RELA and NFκB-1 along the metaplasia-dysplasia-adenocarcinoma pathway. Strong expression of NFκB is associated with HGD and adenocarcinoma (P<0.0001). We showed that strong expression of NFκB-1 and RELA correlates highly with BE with HGD and adenocarcinoma.

PTU-154 HMGB1 As a Prognostic Biomarker in The Progression of Barrett’s Oesophagus

Introduction Barrett’s oesophagus (BO) is metaplasia from normal squamous to mucin secreting columnar epithelium. BO is a precursor of neoplastic progression to dysplasia and adenocarcinoma, with no associated progression biomarker available. High Mobility Group Box-1 (HMGB1) is a ubiquitous nuclear protein that regulates gene expression. When phosphorylated, it translocates to the cytoplasm and extracellular space to stimulate pro-inflammatory responses and influence epithelial cell behaviour. Our aim was to assess expression of HMGB1 in BO and neoplastic progression. Methods Epithelial nuclear and cytoplasmic subcellular expression of HMGB1 was assessed immunohistochemically in endoscopically retrieved paraffin embedded biopsies sourced from the Grampian Biorepository (n = 155 total). Ethical approval was granted by the Grampian biorepository scientific committee. A gastrointestinal pathologist (GIM) confirmed histological diagnosis. 18, 25, 78 and 13 biopsies were assessed, from 11 patients with normal oesophageal mucosa, 14 patients with normal gastric mucosa, 20 patients with non-dysplastic BO and 9 patients with dysplastic BO, respectively. Also included were 12 biopsies (7 patients) and 9 biopsies (6 patients) from non-dysplastic BO associated with progression to dysplasia and adenocarcinoma, respectively. Intensity of HMGB1 staining was double scored as none, weak, moderate or strong immunopositivity. Analysis used Fisher’s exact test of 2X2 contingency tables. Results HMGB1 was expressed in the nuclei in all groups. Normal oesophageal biopsies expressed no or weak cytoplasmic HMGB1. Non-dysplastic (p Conclusion There was evidence of dynamic subcellular localisation of HMGB1 expression in association with BO and dysplasia. Cytoplasmic HMGB1 expression may be a novel biomarker to aid diagnosis and predict progression of BO. The functional significance of this warrants further investigation. Disclosure of Interest None Declared

Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis.

Seasonal variation has been reported in diagnosis of eosinophilic oesophagitis (EoE), but results are not consistent across studies and there are no national-level data in the USA. To determine if there is seasonal variation in diagnosis of oesophageal eosinophilia and EoE in the USA, while accounting for factors such as climate zone and geographic variation. This was a cross-sectional study using a USA national pathology database. Patients with oesophageal eosinophilia (≥15 eosinophils per high-power field) comprised the primary case definition and were compared to those with normal oesophageal biopsies. We calculated the crude and adjusted odds of oesophageal eosinophilia by season, as well as by day of the year. Sensitivity analyses were performed using more restrictive case definitions of EoE, and after stratification by climate zone. Exactly, 14524 cases with oesophageal eosinophilia and 90459 normal controls were analysed. The adjusted odds of oesophageal eosinophilia were higher in the late spring and summer months, with the highest odds in July (aOR: 1.13; 95% CI: 1.03-1.24). These findings persisted with increasing levels of oesophageal eosinophilia, as well as across EoE case definitions. Seasonal variation was strongest in temperate and cold climates, and peak diagnosis varied by climate zone. There is a mild but consistent seasonal variation in the diagnosis of oesophageal eosinophilia and EoE, with cases more frequently diagnosed during summer months. These findings take into account climate and geographic differences, suggesting that aeroallergens may contribute to disease development or flare.

Pediatric patients with chronic cough and recurrent croup: The case for a multidisciplinary approach

ObjectiveTo evaluate the results of our multidisciplinary approach to recurrent croup and chronic cough. MethodsRetrospective chart review of all patients with recurrent croup and chronic cough managed at a tertiary care children's hospital by our Comprehensive Airway, Respiratory, and Esophageal (CARE) Team. Charts were reviewed for all patients who carried a diagnosis of recurrent croup or chronic cough. Patients were excluded if they did not receive a full workup, including micro-direct laryngoscopy, flexible and/or rigid bronchoscopy, bronchioalveolar lavage (BAL), and upper endoscopy with biopsies. We reviewed the records for the presence of gastrointestinal complaints, abdominal pain and failure to thrive (FTT) and compared the children with documented esophagitis to the remaining children. ResultsForty patients met inclusion criteria. 53% had airway abnormalities; the most common was tracheomalacia, followed by enlarged adenoids. 38% had esophagitis (group 1) while 62% had normal esophageal biopsies (group 2). Among the children in group 1, 27% met criteria for eosinophilic esophagitis (>15 eosinophils per high powered field). There was no significant difference between groups 1 and 2 based on the presence of gastrointestinal complaints, abdominal pain and/or FTT (p>0.05). There was no significant difference between the groups based on the location or presence of an airway abnormality (p>0.05). ConclusionsChildren with recurrent croup and chronic cough may benefit from a multidisciplinary approach to management. Our CARE Team approach led to a specific diagnosis in almost 95% of patients.

Esophageal Eosinophilia is Increased in Rural Areas With Low Population Density: Results From a National Pathology Database

Eosinophilic esophagitis (EoE) is an increasingly prevalent chronic disease arising from an allergy/immune-mediated process. Generally, the risk of atopic disease differs in rural and urban environments. The relationship between population density and EoE is unknown. Our aim was to assess the relationship between EoE and population density. We conducted a cross-sectional, case-control study of patients with esophageal biopsies in a US national pathology database between January 2009 and June 2012 to assess the relationship between population density and EoE. Using geographic information systems, the population density (individuals per square mile) was determined for each patient zip code. The odds of esophageal eosinophilia and EoE were estimated for each quintile of population density and adjusted for potential confounders. Sensitivity analyses were conducted with varying case definitions and to evaluate the potential for bias from endoscopy volume and patient factors. Of 292,621 unique patients in the source population, 89,754 had normal esophageal biopsies and 14,381 had esophageal eosinophilia with ≥15 eosinophils per high-power field. The odds of having esophageal eosinophilia increased with decreasing population density (P for trend <0.001). Compared with those in the highest quintile of population density, odds of having esophageal eosinophilia were significantly higher among those in the lowest quintile of population density (adjusted odds ratio (aOR) 1.27, 95% confidence interval (CI): 1.18, 1.36). A similar dose-response trend was observed across case definitions with increased odds of EoE in the lowest population density quintile (aOR 1.59, 95% CI: 1.45-1.76). Estimates were robust to sensitivity analyses. Population density is strongly and inversely associated with esophageal eosinophilia and EoE. This association is robust to varying case definitions and adjustment factors. Environmental exposures that are more prominent in rural areas may be relevant to the pathogenesis of EoE.

Esophageal Eosinophilia and Eosinophilic Esophagitis Are Increased in Rural Areas with Low Population Density: Results from a National Pathology Database

Purpose: Eosinophilic esophagitis (EoE) is an increasingly prevalent chronic disease and is thought to arise from an allergy/immune-mediated process. The relationship between population density, EoE, and esophageal eosinophilia is unknown. Our aim was to estimate the association between EoE and esophageal eosinophilia with population density. Methods: We conducted a cross-sectional study of patients with esophageal biopsies in a U.S. national pathology database between January, 2009 and June, 2012. Using Geographic Information Systems (GIS), the population density (number of individuals per square mile) was determined for each patient zip code. The odds of esophageal eosinophilia and EoE were estimated for each quintile of population density after controlling for age, sex, race and distance traveled for endoscopy. Sensitivity analyses were performed with varying case definitions of EoE. Results: Of 292,621 unique patients in the source population, 91,929 had normal esophageal biopsies and 14,739 had esophageal eosinophilia with ≥15 eosinophils per high-power field (eos/hpf). Those with esophageal eosinophilia were generally younger (45 vs. 54 years), more likely to be male (64% vs 35%) and had more dysphagia (54% vs. 26%) than those with normal biopsies (p<0.05 for all). After multivariate analysis, the odds of esophageal eosinophilia decreased with increasing population density (p for trend < 0.001) (Figure). Compared to those in the lowest quintile of population density, odds of esophageal eosinophilia were significantly reduced amongst those in the highest quintile of population density (OR 0.79; 0.73-0.85). A similar dose-response trend was observed across case definitions of EoE (Figure).FigureConclusion: Population density is strongly and inversely associated with both esophageal eosinophilia and EoE, with these conditions being more common in rural areas. This association persists in sensitivity analyses. Environmental exposures in rural areas may be key in the pathogenesis of EoE. Disclosure - Jensen - nothing to disclose Hoffman - nothing to disclose Shaheen - nothing to disclose Genta - employee of Miraca Research Institute and Miraca Life Sciences where the database used in this study is maintained.

Prevalence of Esophageal Eosinophilia Varies by Climate Zone in the United States

The epidemiology of eosinophilic esophagitis (EoE) is rapidly evolving, and differences in climate could impact the prevalence of EoE. We aimed to examine the association between esophageal eosinophilia and climate zones in the United States. This was a cross-sectional study of esophageal biopsies from 2008 to 2010 in a large US pathology database. Cases were patients with esophageal eosinophilia; controls had normal esophageal biopsies. A Köppen-Geiger (K-G) climate class was assigned to each patient, and the association between case-control status and the main K-G climate type (tropical, arid, temperate, or cold) was assessed. A total of 233,649 patients were included, 71,948 (30.8%) with normal esophageal biopsies and 9,995 (4.3%) with esophageal eosinophilia. Using the temperate zone as the referent and after multivariable analysis, the odds of esophageal eosinophilia were highest in the cold climate zone (odds ratio (OR)=1.39, 95% confidence interval (CI): 1.34-1.47), compared with the tropical zone (OR=0.87; 95% CI: 0.71-10.8) and the arid zone (OR=1.27; 95% CI: 1.19-1.36). Increased likelihood of EoE was also associated with increasing odds of being in the cold climate zone. Compared with patients with normal esophageal biopsies, patients with dysphagia, a clinical suspicion of EoE, no reflux or Barrett's esophagus, esophageal eosinophilia, and eosinophilic microabscesses had the highest adjusted odds of being in a cold climate zone (OR 2.02; 1.78-2.28). Esophageal eosinophilia differs significantly between K-G climate zones, with the highest prevalence in the cold and arid zones. Geographical and climate patterns may help identify candidate antigens characteristic to high-prevalence areas to be targeted for future investigation.

Lymphocytic oesophagitis: clinicopathological aspects of an emerging condition

ObjectiveLymphocytic oesophagitis (LyE) has been reported in small series, but no consistent clinical correlations have emerged. The authors sought to determine the prevalence of LyE in a large population and...

Inverse association of esophageal eosinophilia with Helicobacter pylori: Results from a national pathology database

Purpose: Eosinophilic esophagitis (EoE) is an increasingly prevalent chronic disease which is thought to be an allergy/immune mediated process. Helicobacter pylori has been inversely associated with allergic diseases, but the relationship between H. pylori, EoE and esophageal eosinophilia is unknown. Our aim was to determine the association between esophageal eosinophilia and H. pylori. Methods: We performed a cross-sectional study of patients with esophageal biopsies in a United States national pathology database between 2008 and 2010. Patients with and without H. pylori on gastric biopsy were compared and odds of esophageal eosinophilia were determined. Results: Of 233,662 unique patients in the source population, 165,017 had both esophageal and gastric biopsies. Of these, 56,301 (34.1%) had normal esophageal biopsies, 5,767 (3.5%) had esophageal eosinophilia, and 11,170 (4.8%) had H. pylori. Overall, the presence of esophageal eosinophilia was inversely associated with H. pylori infection (OR: 0.77, 95% CI: 0.69-0.87). There was a dose-response trend noted as well, with lower odds of H. pylori as levels of esophageal eosinophilia increased (Figure). Specifically, compared to patients with normal esophageal biopsies, odds of H. pylori were progressively reduced among patients with ≥15 eosinophils per high-power field (eos/hpf) (OR 0.79; 95% CI 0.70-0.88), ≥45 eos/hpf (OR 0.75; 0.61-0.93), ≥75 eos/hpf (OR 0.72; 0.62-0.83), and ≥90 eos/hpf (OR 0.52; 0.31-0.87) (p for trend <0.001). A similar dose-response trend was observed for increasingly restrictive clinicopathologic definitions of EoE (requiring dysphagia symptoms or eosinophilic microabscesses on pathology) and decreasing prevalence of H pylori (Figure). Additionally, severity of histologic manifestation of H. pylori was inversely associated with esophageal eosinophilia. All trends held after multivariate analysis. Conclusion: There is a strong inverse association between H. pylori infection and esophageal eosinophilia in this large nationwide patient population. This association persists on several sensitivity analyses, and may have important implications for understanding the pathogenesis and evolving epidemiology of EoE. Disclosure: Robert M. Genta - employed by Caris Life Sciences, Irving, Texas; shareholder in the company. Richard H. Lash - employed by Caris Life Sciences, Irving, Texas; shareholder in the company. There are no other potential conflicts of interest for any of other the authors pertaining to this study.

Expression of non‐mast cell histidine decarboxylase in tumor‐associated microvessels in human esophageal squamous cell carcinomas

Histamine is produced by mast cells and many other types of cells. The role of histamine released from mast cells in promoting tumor angiogenesis has been intensively studied; however, the role of non-mast cell histamine in regulating tumor angiogenesis has been largely ignored. In this study, tissue specimen sections from 43 patients with esophageal squamous cell carcinoma (ESCC) and normal esophageal biopsies from 17 heath individuals obtained from a high incidence area of north China were used to assess changes in microvessel density (MVD) and non-mast cell L-histidine decarboxylase (HDC) (the only rate-limiting enzyme that catalyzes the formation of histamine from L-histidine) expression in the tumor microenvironment by immunohistochemistry (IHC). In addition, the cellular characterization of non-mast cell HDC-positive cells in microvessels was examined by double IHC combined with HDC/CD34 and HDC/PCNA antibodies. These IHC analyses revealed a significantly increased HDC-positive MVD in ESCC as compared with normal controls, which accounted for approximately 61% of CD34-labeled general MVD in ESCC. Furthermore, IHC in serial sections and double IHC showed that most of these HDC-positive cells were CD34-positive endothelial cells in microvessels with an increased proliferative capacity. Thus, our results suggest that non-mast cell histamine expressed in endothelial cells of microvessels could be an additional cellular source and might play a role in regulating angiogenesis in ESCC.

Selenomethionine Treatment Does Not Alter Gene Expression in Normal Squamous Esophageal Mucosa in a High-Risk Chinese Population

Selenium is a promising cancer chemoprevention agent. A recent randomized controlled chemoprevention trial found that selenomethionine (SeMet) supplementation for 10 months favorably effected a change in esophageal dysplasia grade among participants who started the trial with mild dysplasia. To further explore the role of SeMet in this trial, we compared gene expression profiles by treatment group using Affymetrix HU 133A chips in before/after supplementation paired normal esophageal biopsies from a subset of 29 trial participants, 16 who received SeMet, and 13 who received placebo. Using P < 0.001 as a cutoff, 11 differentially expressed genes were found in the SeMet supplementation group but these genes did not include either known selenoprotein genes or genes previously shown to be modulated by selenium treatment. Because the number of differentially expressed genes (n = 11) was less than expected by chance (n = 18), we concluded that SeMet supplementation had no measurable effect on gene expression in the normal squamous esophagus of these subjects with dysplasia.

THE ROLE OF NON‐ACID REFLUX IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS: A STUDY USING MULTI‐CHANNEL INTRALUMINAL IMPEDANCE (PH‐MII)

Background: Eosinophilic esophagitis (EE) is a clinicopathological disease that typically affects the proximal and distal esophagus. Clinical evidence suggests a role for food or aero-allergens, but the impact of non-acid reflux in patients with EE is uncertain. Aim: To determine whether non-acid reflux is increased in patients with EE. Methods: This is a retrospective study in which pH-MII tracings of children with well-defined clinicopathological features of EE were compared to children with GERD and patients with no evidence of pathologic reflux (controls). GERD patients had reflux symptoms in addition to abnormal pH recordings with a reflux index >6%. Children with EE had a normal pH probe and demonstrated esophageal eosinophilia (>20 eos/HPF) that did not respond to 8 weeks of proton pump inhibition. Patients referred for evaluation of respiratory symptoms with normal esophageal biopsies, a normal pH probe, and no symptoms of GERD were used as controls. Reflux profiles were compared using ANOVA. Results: Consecutive pH-MII tracings from 10 patients with EE, 10 patients with GERD and 9 controls were reviewed. Results are shown (mean ± std) in the table below. No statistically significant differences were found between EE patients compared to controls. Patients with GERD had significantly more acid and pH-only reflux compared to EE and controls.TABLEConclusions: Non-acid reflux does not seem to play a role in the pathogenesis of EE. Antigenic stimulation may occur during initial topical passage of foodstuffs/aeroallergens or as a result of systemic exposure rather than during reflux.

Upregulation of tissue kallikrein, kinin B1 receptor, and kinin B2 receptor in mast and giant cells infiltrating oesophageal squamous cell carcinoma

Background: The mitogenic kinin peptides formed by the serine protease, tissue kallikrein (TK1), stimulate the proliferation of tumour cells and, by increasing vascular permeability, enhance metastasis. Oesophageal mucosal epithelial cells...