Rhonda Souza M.D.

Bresalier, R. S. and R. F. Souza (2018). “A Goblet (Cell) Half Full: What Do We Really Know About Barrett’s Esophagus-A Tribute to Emmet Keeffe.” Dig Dis Sci Jun 9. [Epub ahead of print].

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It is our pleasure to introduce this fourth annual special supplement to Digestive Diseases and Sciences (DDS) dedicated to its former Editor-in-Chief, the late, great Emmet B. Keeffe. Through our many interactions with Emmet, either as Associate Editor (RSB) or as President of the Gastroenterology Research Group (RFS), which named Digestive Diseases and Sciences its official journal (a relationship enthusiastically encouraged and promoted by Emmet), we witnessed first-hand Emmet’s tireless efforts to create a journal relevant to both clinicians and scientists. In 2007 Emmet called me (RSB) to ask if I might serve as an Associate Editor for DDS as he had been recently tasked to “reinvent” the journal. His idea was that while other excellent gastroenterology-based journals existed, DDS could fill a niche as a truly translational journal with appeal to a broad audience. I had known Emmet for many years and knew him to be a true Renaissance man, clinician, scientist, and consummate educator and communicator. Needless to say I jumped at the chance to work with him on this exciting project. Under his leadership and that of the current Editor-in-Chief, Jonathan Kaunitz, articles received per year have doubled to over 2000, usage increased greater than 4.5-fold (617,734 in 2017), page count increased 1.5-fold, editorials published increased 15-fold, and impact factor doubled, while time to first decision was reduced from 67 to 23 days. We are honored to Guest Edit this Special Issue devoted to Barrett’s esophagus. We recruited authors who are not only experts in the field, but who also have active research endeavors in the areas of pathology, endoscopy, epidemiology, and molecular biology of Barrett’s esophagus. The emphasis is not only on the state of the art of what we know, but how ideas are evolving to answer the many gaps in our knowledge [hence a goblet (cell) half full]. We are confident that Emmet would be pleased with the quality, scope, and utility of this Special Issue, and we hope that our readers will be as well. (Excerpt from text of this Editor’s Introduction to a special issue of Digestive Diseases and Sciences; no abstract available.)

Wang, J., J. Y. Park, R. Huang, R. F. Souza, S. J. Spechler and E. Cheng (2018). “Obtaining adequate lamina propria for subepithelial fibrosis evaluation in pediatric eosinophilic esophagitis.” Gastrointest Endosc 87(5): 1207-1214.e1203.

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BACKGROUND AND AIMS: Subepithelial fibrosis in eosinophilic esophagitis (EoE) can be detected only in esophageal biopsy specimens with adequate amounts of lamina propria (LP). We investigated how often pediatric esophageal biopsy specimens contain adequate LP, and whether esophageal eosinophilia influences the acquisition rates. METHODS: We evaluated 284 esophageal biopsy specimens from 39 patients with EoE, and 87 biopsy specimens from 32 patients without esophageal eosinophilia or other esophageal abnormalities for the presence of adequate LP and fibrosis. RESULTS: On a per biopsy specimen basis, there was no significant difference in the rate of procuring adequate amounts of LP between patients with EoE and patients without esophageal eosinophilia (43% vs 31%, P = .14). Eighty-five percent of patients with EoE had fibrosis. Fibrosis in patients with EoE was patchy and more likely to be detected in the middle or distal esophagus (odds ratio, 19.93; 95% confidence interval, 4.12-91.52). Among patients with fibrosis, the probability of its detection reached >95% with 7 middle-distal esophageal biopsy specimens. Most children with newly diagnosed EoE already had subepithelial fibrosis despite exhibiting only inflammatory endoscopic features. CONCLUSIONS: Most individual esophageal biopsy specimens in children are inadequate for assessing subepithelial fibrosis, and the rates of procuring adequate LP per biopsy specimen are similar in patients with and without EoE. To reliably detect fibrosis in patients with EoE, at least 7 biopsy specimens should be taken from the middle-distal esophagus. The finding of fibrosis in children with newly diagnosed EoE and only inflammatory endoscopic features suggests that fibrosis can occur early in this disease.

Huo, X., X. Zhang, C. Yu, E. Cheng, Q. Zhang, K. B. Dunbar, T. H. Pham, J. P. Lynch, D. H. Wang, R. S. Bresalier, S. J. Spechler and R. F. Souza (2018). “Aspirin prevents NF-kappaB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett’s oesophagus.” Gut 67(4): 606-615.

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OBJECTIVE: In previous studies using oesophageal squamous cells from patients with Barrett’s oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett’s oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. DESIGN: We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IkappaB-NF-kappaB-PKAc complex activation, p65 NF-kappaB subunit function, and CDX2 expression. RESULTS: In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IkappaB-NF-kappaB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IkappaB and p65 and greater NF-kappaB transcriptional activity than NES-G cells, indicating greater IkappaB-NF-kappaB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IkappaB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. CONCLUSIONS: Differences between NES-B and NES-G cells in NF-kappaB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett’s oesophagus while others do not, and why aspirin might protect against development of Barrett’s oesophagus.

Souza, R. F., J. H. Rubenstein, J. Y. Kao and I. Hirano (2018). “Contributions From Gastroenterology: Acid Peptic Disorders, Barrett’s Esophagus and Eosinophilic Esophagitis.” Gastroenterology 154(5): 1209-1214.

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Over the past three-quarters of a century, manuscripts published in Gastroenterology have had a substantial impact on our clinical recognition, understanding, and management of peptic ulcer disease (PUD), Helicobacter pylori, gastroesophageal reflux disease (GERD), Barrett’s esophagus, and eosinophilic esophagitis (EoE). This article highlights selected, highly cited works with overlapping themes of acid injury, chronic mucosal inflammation, and H pylori infection.

Odiase, E., A. Schwartz, R. F. Souza, S. J. Spechler, J. Martin and V. Konda (2018). “New Eosinophilic Esophagitis Concepts Call for Change in Proton Pump Inhibitor Management Before Diagnostic Endoscopy.” Gastroenterology. Mar 3. [Epub ahead of print].

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Irrespective of the stimulus, acid secretion by the gastric parietal cells ultimately involves H+, K+-ATPase, the enzyme that pumps hydrogen ions (protons) out of the cell and into the gastric lumen in exchange for potassium ions. Proton pump inhibitors (PPIs) bind irreversibly to H+, K+-ATPase, thereby disabling the enzyme and profoundly decreasing gastric acid secretion. It is well-established and widely appreciated that PPIs are remarkably effective agents for treating diseases mediated by gastric acid such as gastroesophageal reflux disease (GERD) and peptic ulcer disease. Far less well-known are the numerous potential anti-inflammatory effects that have been described for PPIs, including their inhibitory influence on inflammatory cells and on proinflammatory cytokine production by endothelial and epithelial cells.These anti-inflammatory PPI effects, which are independent of their effects on gastric acid secretion, might enable PPIs to heal inflammatory disorders of the upper gastrointestinal tract other than GERD and peptic ulceration. Nevertheless, physicians generally have regarded a symptomatic response to PPI therapy as de facto evidence of acid peptic disease. Physicians often prescribe PPIs empirically for patients who have symptoms that might be acid related (eg, heartburn, dyspepsia), withholding diagnostic endoscopy for those whose symptoms persist despite PPI therapy. For patients who experience partial symptom relief, the PPIs are not stopped routinely before endoscopy, and physicians generally are aware that this practice creates ≥2 potential problems: (1) PPIs can mask endoscopic evidence of early gastric cancers, and (2) PPIs can eliminate endoscopic evidence of reflux esophagitis. Although there are well-documented cases of PPIs obliterating endoscopic evidence of early gastric cancer by healing associated ulcerations,4 this phenomenon seems to be very uncommon in Western countries in which the incidence of gastric cancer is low. It is less clear why endoscopists evaluating patients with GERD symptoms so readily accept the strong possibility that PPIs will eliminate evidence of reflux esophagitis at diagnostic endoscopy. The endoscopic demonstration of reflux esophagitis for patients with GERD at baseline (off antireflux therapy) has important therapeutic implications. PPI treatment is required indefinitely for patients with severe reflux esophagitis, whereas PPI treatment might be tapered, stopped, or not needed at all for patients with no reflux esophagitis at baseline. For patients who undergo endoscopy while taking PPIs, no meaningful assessment can be made regarding the baseline presence of reflux esophagitis. (Excerpt from text, p.1; no abstract available.)