Stuart Spechler M.D.

Spechler, S. J., D. A. Katzka and R. C. Fitzgerald (2018). “New Screening Techniques in Barrett’s Esophagus: Great Ideas or Great Practice?” Gastroenterology 154(6): 1594-1601.

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A number of lines of evidence suggest that Barrett’s metaplasia is a risk factor for esophageal adenocarcinoma (EAC). To prevent deaths from this tumor, medical societies in countries around the world have recommended screening for and surveillance of Barrett’s esophagus. However, the majority of Barrett’s is undiagnosed and compliance with this advice and the adherence to standardized protocols is highly variable among physicians and patients. As a result the impact of screening and surveillance on population-based mortality from this cancer is negligible. Owing to the low incidence of this cancer, compared with cancers such as breast or colon, population-based screening with endoscopy for the purpose of ongoing surveillance has not been recommended except in those with multiple risk factors including a high body mass index, male gender, white race, chronic reflux, and family history. To date, it is not proven that endoscopic screening is beneficial and there are downsides that need to be considered, including the fiscal and psychological costs as well as the possibility of adverse events . . . Does it make sense to use a non-endoscopic screening test in a much larger population than currently recommended to identify even more patients for entry into an endoscopic surveillance program of questionable benefit? Adoption of such a new screening strategy has the potential to succeed where the current strategy has failed to decrease overall deaths from esophageal cancer. However, there also is the potential for harm in identifying asymptomatic patients with Barrett’s esophagus. In addition to the high costs and small risks of standard endoscopy, the diagnosis of Barrett’s esophagus can cause psychological stress, have a negative impact on quality of life, result in higher premiums for health and life insurance, and might identify innocuous lesions that lead to potentially hazardous invasive treatments. Efforts should, therefore, be continued to combined biomarkers for Barrett’s with risk stratification. Overall, although these vexing uncertainties must temper enthusiasm for the unqualified endorsement of any screening test for Barrett’s esophagus, the alternative of making no attempt to stem the rapidly rising incidence of a lethal malignancy also is unpalatable. (Excerpts from text, p. 1594, 1599; no abstract available.)

Spechler, S. J. (2018). “Cardiac Metaplasia: Follow, Treat, or Ignore?” Dig Dis Sci. Apr 18. [Epub ahead of print].

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Over the past two decades, evidence has accumulated to challenge the traditional view that cardiac mucosa, which is comprised exclusively of mucus glands, is the normal lining of the most proximal portion of the stomach (the gastric cardia). There is now considerable evidence to suggest that cardiac mucosa develops as a GERD-induced, squamous-to-columnar esophageal metaplasia in some, if not all, cases. Although cardiac mucosa lacks the goblet cells commonly required for a histologic diagnosis of intestinal metaplasia, cardiac mucosa has many molecular features of an intestinal-type mucosa, and appears to be the precursor of intestinal metaplasia with goblet cells. In apparently normal individuals, cardiac mucosa is commonly found in a narrow band, less than 3 mm in extent, on the columnar side of the squamo-columnar junction at the end of the esophagus. A greater extent of cardiac mucosa can be found in GERD patients, and the magnitude of that extent appears to be an index of GERD severity. Presently, the risk of adenocarcinoma imposed by cardiac mucosa is not clear, but appears to be far less than that of intestinal metaplasis with goblet cells. The British Society of Gastroenterology accepts an esophagus lined by cardiac mucosa as a “Barrett’s esophagus”. However, if one defines Barrett’s esophagus as a metaplasia that predisposes to cancer, then only intestinal metaplasia clearly fulfills that criterion at this time. Well-designed, prospective studies are needed to establish the malignant potential of cardiac mucosa.

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.

Spechler, S. J., D. A. Katzka and R. C. Fitzgerald (2018). “New Screening Techniques in Barrett’s Esophagus: Great Ideas or Great Practice?” Gastroenterology Mar 23. [Epub ahead of print].

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Recommendations: We support the current recommendation of GI societies that screening endoscopy for Barrett’s esophagus should be performed only in a well-defined, high-risk population. We do not recommend the use of any alternative test to screen for Barrett’s esophagus at this time. Some of the alternative tests show great promise for Barrett’s screening and will likely find a place in clinical practice in the near future. In addition to refinement and validation of the alternative tests, there should be a complementary focus on using readily available demographic and clinical factors as well as noninvasive tools to further define an acceptable screening population for the next step in screening procedures. The stringency with which these populations can be defined will need to be balanced with the costs and risks of the potential screening tools proposed. (Excerpt from text, p. 6; no abstract available.)

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.)