Stuart Spechler M.D.

Souza, R. F. and S. J. Spechler (2017). “Oesophagus: A new candidate for the progenitor cell of barrett metaplasia.” Nat Rev Gastroenterol Hepatol: 2017 Nov [Epub ahead of print].

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In Barrett oesophagus, the distal oesophagus is lined by an abnormal columnar epithelium that has both gastric and intestinal features and is predisposed to malignant transformation1. Barrett oesophagus develops through metaplasia, the process in which one adult tissue type replaces another in response to injury, and its pathogenesis typically begins with oesophageal injury from GERD1. With ongoing GERD, damaged stratified squamous epithelium is replaced by metaplastic, single-layer, columnar epithelium which, presumably, is more resistant to GERD injury. This process must involve GERD-induced molecular reprogramming of key developmental transcription factors (transcommitment) in the progenitor cells giving rise to the metaplastic epithelium2.

Spechler, S. J. (2017). “The durability of antireflux surgery.” Jama 318(10): 913-915.

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Patients who have mild, nonerosive gastroesophageal reflux disease (GERD) have many valid treatment options, but patients with severe erosive GERD (those with endoscopy showing large esophageal mucosal breaks extending between mucosal folds) have only 2: take proton pump inhibitors (PPIs) indefinitely or have antireflux surgery with fundoplication.1 No medication other than PPIs (and potassium-competitive acid blockers, which are not available in the United States) reliably heals reflux esophagitis; once healed, that esophagitis will return quickly and severely in most cases if PPIs are stopped.2

Spechler, S. J., J. L. Merchant, T. C. Wang, P. Chandrasoma, J. G. Fox, R. M. Genta, J. R. Goldenring, Y. Hayakawa, E. J. Kuipers, P. K. Lund, F. McKeon, J. C. Mills, R. D. Odze, R. M. Peek, Jr., T. Pham, J. Que, A. K. Rustgi, N. J. Shaheen, R. A. Shivdasani, R. F. Souza, P. Storz, A. Todisco, D. H. Wang and N. A. Wright (2017). “A summary of the 2016 james w. Freston conference of the american gastroenterological association: Intestinal metaplasia in the esophagus and stomach: Origins, differences, similarities and significance.” Gastroenterology 153(1): e6-e13.

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Robert Genta reviewed the histologic features of intestinal metaplasia, and Jason Mills provided a historical overview, noting that Rudolph Virchow coined the term “metaplasia” at the VIIIth International Medical Congress in Copenhagen in 1884. In 1900, the pathologist George Adami presciently contended that there are “mother” (stem) cells that regenerate normal tissue and, “under abnormal conditions, the fully differentiated functioning cells of certain tissues are capable of proliferation and giving rise to cells of like nature, but this is only after a preliminary reversion to a simpler, more embryonic type.” Adami proposed that this process of dedifferentiation leading to increased proliferation might result in “glandular cancer.”2 During the 1930s, developmental biologists largely abandoned Adami’s concepts, instead embracing Conrad Waddington’s notion that stem cell differentiation was unidirectional. However, recent evidence vindicates Adami, showing that differentiated cells can indeed contribute to metaplasia.

Nguyen, A. D., S. J. Spechler, M. N. Shuler, R. F. Souza and K. B. Dunbar (2017). “Unique clinical features of los angeles grade d esophagitis suggest that factors other than gastroesophageal reflux contribute to its pathogenesis.” J Clin Gastroenterol: 2017 Jun [Epub ahead of print].

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BACKGROUND: The Los Angeles (LA) grade of reflux esophagitis (A to D) is assumed to reflect severity of the underlying gastroesophageal reflux disease (GERD). Thus, LA-D esophagitis patients might be expected to have the most conditions predisposing to GERD (eg, obesity, hiatal hernia), and the highest frequency of GERD symptoms. GOALS: The main goal of this study is to compare clinical features of patients with the most severe (LA-D) and mildest (LA-A) grades of esophagitis. STUDY: For this comparative study, we searched our endoscopy database for patients diagnosed with LA-D or LA-A esophagitis, reviewed their endoscopic images, and reviewed medical records of the first 100 we confirmed to have LA-D or LA-A esophagitis. RESULTS: Compared with LA-A patients, LA-D patients were older (mean age, 65+/-13.4 vs. 56+/-13.4 y; P<0.001), had lower body mass index (25.9+/-5.6 vs. 29.4+/-5.3; P<0.001), were more frequently hospitalized (70% vs. 3%; P<0.001), and in the intensive care unit (15% vs. 0%; P<0.001), and had significantly more serious cardiopulmonary disorders and gastrointestinal bleeding. Conversely, a GERD history was more common in LA-A than LA-D patients (67% vs. 45%; P=0.002). Hiatal hernia was more frequent in LA-A patients than LA-D patients, but not significantly (48% vs. 36%; P=0.09). CONCLUSIONS: LA-D esophagitis primarily affects hospitalized, older, nonobese patients who often have serious comorbidities, and no history of GERD or hiatal hernia. In contrast, LA-A patients are generally younger, obese outpatients who often have a history of GERD and hiatal hernia without serious comorbidities. These profound differences between LA-A and LA-D patients suggest that factors other than typical GERD contribute to LA-D esophagitis pathogenesis.

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 (2017). “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: Apr [Epub ahead of print].

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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.