Publications by authors named "Gary W Falk"

181 Publications

Development of a Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS).

J Allergy Clin Immunol 2021 Jul 6. Epub 2021 Jul 6.

Inform Diagnostics, Irving, TX, USA; Department of Pathology, Baylor College of Medicine, Houston, TX, USA.

Background: Endpoints used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments.

Objective: To develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE.

Methods: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists.

Results: The COS consists of four outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life (QoL). A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a two-round Delphi process and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, EoE Histology Scoring System, EoE Endoscopic Reference Score, and patient-reported measures of dysphagia and QoL.

Conclusions: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE, which will facilitate meaningful treatment comparisons and improve the quality of data synthesis.
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http://dx.doi.org/10.1016/j.jaci.2021.07.001DOI Listing
July 2021

Reply.

Clin Gastroenterol Hepatol 2021 Jun 29. Epub 2021 Jun 29.

Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

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http://dx.doi.org/10.1016/j.cgh.2021.06.033DOI Listing
June 2021

Long-Term Treatment of Eosinophilic Esophagitis with Budesonide Oral Suspension.

Clin Gastroenterol Hepatol 2021 Jun 25. Epub 2021 Jun 25.

Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background And Aims: We evaluated treatment withdrawal, long-term outcomes and safety of budesonide oral suspension (BOS) 2.0 mg b.i.d. in patients with eosinophilic esophagitis who completed a 12-week induction study.

Methods: Induction full responders (≤6 eosinophils per high-power field [eos/hpf] and ≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] score) to BOS 2.0 mg b.i.d. (ORBIT1/SHP621-301/NCT02605837) were randomized to continue BOS (BOS-BOS) or withdraw to placebo (BOS-PBO) for 36 weeks (ORBIT2/SHP621-302/NCT02736409). Induction partial- and non-responders, and patients who received induction placebo, received BOS for 36 weeks. The primary endpoint was the proportion of BOS-BOS and BOS-PBO patients who relapsed (≥15 eos/hpf and ≥4 days of dysphagia [DSQ] over 2 weeks) by week 36. The key secondary endpoint was the proportion of induction partial- and non-responders who fully responded after 52 weeks' total BOS therapy. Secondary endpoints included: proportion of induction full responders with histologic responses (≤1, ≤6, <15 eos/hpf) at week 12 of the extension study, and safety outcomes.

Results: The randomized withdrawal period enrolled 48 patients (BOS-BOS, n=25; BOS-PBO, n=23); 106 induction partial- and non-responders and 65 induction placebo patients received BOS. More BOS-PBO than BOS-BOS patients relapsed over 36 weeks (43.5% vs 24.0%; P=.131) and had histologic responses at week 12 of therapy (P<.001). Overall, 13.2% of induction partial- and non-responders fully responded at week 36. BOS was well-tolerated; therapy duration was not associated with new safety concerns.

Conclusion: For induction full responders, continuing BOS numerically improved maintenance of efficacy versus withdrawal. Longer therapy duration did not raise safety concerns. ClinicalTrials.gov:NCT02736409.
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http://dx.doi.org/10.1016/j.cgh.2021.06.020DOI Listing
June 2021

Determination of Biopsy Yield That Optimally Detects Eosinophilic Gastritis and/or Duodenitis in a Randomized Trial of Lirentelimab.

Clin Gastroenterol Hepatol 2021 Jun 2. Epub 2021 Jun 2.

Baylor College of Medicine, Houston, Texas.

Background & Aims: Eosinophilic gastritis (EG) and eosinophilic duodenitis (EoD), characterized by chronic gastrointestinal (GI) symptoms and increased numbers or activation of eosinophils and mast cells in the GI tract, are likely underdiagnosed. We aimed to determine rates of EG and EoD and number of biopsies required to optimize detection using screening data from a randomized trial of lirentelimab (AK002), an antibody against siglec-8 that depletes eosinophils and inhibits mast cells. We also characterized endoscopic features and symptoms of EG and EoD.

Methods: Subjects with moderate-to-severe GI symptoms, assessed daily through a validated patient-reported outcome questionnaire, underwent endoscopy with a systematic gastric and duodenal biopsy protocol and histopathologic evaluation. EG diagnosis required presence of ≥30 eosinophils/high-power field (eos/hpf) in ≥5 hpfs and EoD required ≥30 eos/hpf in ≥3 hpfs. We analyzed diagnostic yields for EG and EoD and histologic, endoscopic, and clinical findings.

Results: Of 88 subjects meeting symptom criteria, 72 were found to have EG and/or EoD (EG/EoD), including patients with no prior diagnosis of EG/EoD. We found that GI eosinophilia was patchy and that examination of multiple biopsies was required for diagnosis-an average of only 2.6 per 8 gastric biopsies and 2.2 per 4 duodenal biopsies per subject met thresholds for EG/EoD. Evaluation of multiple nonoverlapping hpfs in each of 8 gastric and 4 duodenal biopsies was required to capture 100% of EG/EoD cases. Neither endoscopic findings nor symptom severity correlated with eosinophil counts.

Conclusions: In an analysis of patients with moderate-to-severe GI symptoms participating in a clinical trial of lirentelimab for EG/EoD, we found eosinophilia to be patchy in gastric and duodenal biopsies. Counting eosinophils in at least 8 gastric and 4 duodenal biopsies is required to identify patients with EG/EoD, so they can receive appropriate treatment. (ClinicalTrials.gov, Number: NCT03496571).
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http://dx.doi.org/10.1016/j.cgh.2021.05.053DOI Listing
June 2021

Long-Lasting Dissociation of Esophageal Eosinophilia and Symptoms Following Dilation in Adults with Eosinophilic Esophagitis.

Clin Gastroenterol Hepatol 2021 May 29. Epub 2021 May 29.

Digestive Health Institute, Children's Hospital Colorado, Gastrointestinal Eosinophilic Diseases Program, Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Aurora, Colorado, USA.

Background And Aims: Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and esophageal eosinophil count (eos/hpf).

Methods: Adults enrolled in a multisite, prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers OMEGA observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsies. Patients were stratified based on dilation status as absent, performed ≤1 and >1 year before endoscopy. Assessments included Spearman's correlations of the relationship between symptoms and eos/hpf and linear regression with EEsAI as the outcome, eos/hpf as predictor, and interaction for dilation and eos/hpf.

Results: Amongst 100 patients (n=61 male, median age 37 years), 15 and 40 patients underwent dilation ≤1 year and >1 year before index endoscopy, respectively. In non-dilated patients, association between eos/hpf and symptoms was moderate (Rho=0.49, p-value<0.001); for 10 eos/hpf increase, the predicted EEsAI increased by 2.69 (p-value=0.002). In patients dilated ≤1 and >1 year before index endoscopy, this association was abolished (Rho=-0.38, p-value=0.157 for ≤1 year and Rho=0.02, p-value=0.883 >1 year); for 10 eos/hpf increase, the predicted EEsAI changed by -1.64 (p-value=0.183) and 0.78 (p-value=0.494), respectively). Dilation modifies association between symptoms and eos/hpf (p-value=0.005 and p-value=0.187 for interaction terms of eos/hpf and dilation ≤1 year and >1 year before index endoscopy, respectively).

Conclusion: In non-dilated EoE adults, eos/hpf correlates modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than one year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up.
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http://dx.doi.org/10.1016/j.cgh.2021.05.049DOI Listing
May 2021

Novel Therapeutic Approaches to Eosinophilic Esophagitis.

Gastroenterol Hepatol (N Y) 2020 Jun;16(6):294-301

Dr Beveridge is a gastroenterology and hepatology fellow and Dr Falk is a professor of medicine in the Division of Gastroenterology and Hepatology at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania.

Eosinophilic esophagitis is a chronic inflammatory condition that requires treatment to improve symptoms and prevent complications of esophageal remodeling, such as strictures and narrow-caliber esophagus. First-line treatments include proton pump inhibitors, topical corticosteroids, elimination or elemental diets, and esophageal dilation. Topical corticosteroids have typically required repurposing inhaled asthma medications by swallowing an aerosolized medication or mixing a nebulizer solution into a slurry. New topical corticosteroid formulations undergoing investigation include a premade budesonide oral suspension and disintegrating budesonide and fluticasone propionate tablets. The approach to an elimination diet is also changing, with an emphasis on patient preference when considering a traditional 6-food elimination diet compared with a step-up approach. This approach involves eliminating only 2 or 4 foods initially and expanding if necessary. While this method can be initially less effective for some patients, it generally involves fewer endoscopies and minimizes diet restriction. Beyond conventional therapies, a number of novel biologic agents are also under investigation. These include weekly subcutaneous injections or monthly intravenous infusions of RPC4046, dupilumab, antolimab, and benralizumab. The increasing number of approaches under development as well as anticipated submissions to the US Food and Drug Administration offer the potential of multiple specific therapies becoming available in the near future.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132706PMC
June 2020

The Volume-Outcome Effect Calls for Centralization of Care in Esophageal Adenocarcinoma: Results From a Large National Cancer Registry.

Am J Gastroenterol 2021 04;116(4):811-815

1Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado; 2Adult and Child Center for Health Outcomes Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 3Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 4Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 5Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA; 6Department of Population and Data Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA; 7Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA; 8Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Rochester, Minnesota, USA.

Introduction: Using the National Cancer Database, we assessed the relationship between facility overall esophageal adenocarcinoma (EAC) case volume and survival.

Methods: We categorized facilities into volume quintiles based on annual EAC patient volume and performed a multivariable Cox proportional hazards regression between facility patient volume and survival.

Results: In a cohort of 116,675 patients, facilities with higher vs lower (≥25 vs 1-4 cases) annual EAC patient volume demonstrated improved survival (adjusted hazard ratio: 0.80. 95% confidence interval: 0.70-0.91).

Discussion: This robust volume-outcome effect calls for centralization of care for EAC patients at high annual case volume facilities.
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http://dx.doi.org/10.14309/ajg.0000000000001046DOI Listing
April 2021

Budesonide Oral Suspension Improves Outcomes in Patients With Eosinophilic Esophagitis: Results from a Phase 3 Trial.

Clin Gastroenterol Hepatol 2021 Apr 19. Epub 2021 Apr 19.

Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background & Aims: Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease for which there is currently no pharmacologic therapy approved by the US Food and Drug Administration.

Methods: In this double-blind, placebo-controlled, phase 3 trial, patients 11-55 years of age with EoE and dysphagia were randomized 2:1 to receive budesonide oral suspension (BOS) 2.0 mg twice daily or placebo for 12 weeks at academic or community care practices. Co-primary endpoints were the proportion of stringent histologic responders (≤6 eosinophils/high-power field) or dysphagia symptom responders (≥30% reduction in Dysphagia Symptom Questionnaire [DSQ] score) over 12 weeks. Changes in DSQ score (key secondary endpoint) and EoE Endoscopic Reference Score (EREFS) (secondary endpoint) from baseline to week 12, and safety parameters were examined.

Results: Overall, 318 patients (BOS, n = 213; placebo, n = 105) were randomized and received ≥1 dose of study treatment. More BOS-treated than placebo-treated patients achieved a stringent histologic response (53.1% vs 1.0%; Δ52% [95% confidence interval (CI), 43.3%-59.1%]; P < .001) or symptom response (52.6% vs 39.1%; Δ13% [95% CI, 1.6%-24.3%]; P = .024) over 12 weeks. BOS-treated patients also had greater improvements in least-squares mean DSQ scores and EREFS over 12 weeks than placebo-treated patients: DSQ, -13.0 (SEM 1.2) vs -9.1 (SEM 1.5) (Δ-3.9 [95% CI, -7.1 to -0.8]; P = .015); EREFS, -4.0 (SEM 0.3) vs -2.2 (SEM 0.4) (Δ-1.8 [95% CI, -2.6 to -1.1]; P < .001). BOS was well tolerated; most adverse events were mild or moderate in severity.

Conclusions: In patients with EoE, BOS 2.0 mg twice daily was superior to placebo in improving histologic, symptomatic, and endoscopic outcomes over 12 weeks. BOS 2.0 mg twice daily was well tolerated. ClinicalTrials.gov number: NCT02605837.
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http://dx.doi.org/10.1016/j.cgh.2021.04.022DOI Listing
April 2021

Development of quality indicators for the diagnosis and management of achalasia.

Neurogastroenterol Motil 2021 Mar 15:e14118. Epub 2021 Mar 15.

Division of Gastroenterology, Duke University School of Medicine, Durham, North Carolina, USA.

Background: The management of achalasia has improved due to diagnostic and therapeutic innovations. However, variability in care delivery remains and no established measures defining quality of care for this population exist. We aimed to use formal methodology to establish quality indicators for achalasia patients.

Methods: Quality indicator concepts were identified from the literature, consensus guidelines and clinical experts. Using RAND/University of California, Los Angeles (UCLA) Appropriateness Method, experts in achalasia independently ranked proposed concepts in a two-round modified Delphi process based on 1) importance, 2) scientific acceptability, 3) usability, and 4) feasibility. Highly valid measures required strict agreement (≧ 80% of panelists) in the range of 7-9 for across all four categories.

Key Results: There were 17 experts who rated 26 proposed quality indicator topics. In round one, 2 (8%) quality measures were rated valid. In round two, 19 measures were modified based on panel suggestions, and experts rated 10 (53%) of these measures as valid, resulting in a total of 12 quality indicators. Two measures pertained to patient education and five to diagnosis, including discussing treatment options with risk and benefits and using the most recent version of the Chicago Classification to define achalasia phenotypes, respectively. Other indicators pertained to treatment options, such as the use of botulinum toxin for those not considered surgical candidates and management of reflux following achalasia treatment.

Conclusions & Inferences: Using a robust methodology, achalasia quality indicators were identified, which can form the basis for establishing quality gaps and generating fully specified quality measures.
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http://dx.doi.org/10.1111/nmo.14118DOI Listing
March 2021

Age of diagnosis in familial Barrett's associated neoplasia.

Fam Cancer 2021 Mar 11. Epub 2021 Mar 11.

Case Western Reserve University School of Medicine, Cleveland, OH, USA.

The identification of hereditary cancer genes for esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), may prove critical for the development of novel prevention and treatment strategies. Specifically, efforts for detecting BE and EAC susceptibility genes have focused on families with three or more affected members, since these individuals have an earlier age onset compared to non-familial individuals. Given that the use of BE may overestimate the likelihood of disease heritability, we evaluated the age of diagnosis in kindreds with a restricted definition including only confirmed high-grade dysplasia (HGD) or EAC. The Familial Barrett's Esophagus Consortium database was used to identify individuals with HGD and EAC. These individuals were subsequently split into three kindred groups: non-familial-a single affected family member, duplex-two affected family members, and multiplex-three or more affected family members. Age of cancer diagnosis and other risk factors were compared between individuals in these groups. The study included 441 non-familial, 46 duplex, and 13 multiplex individuals. There was a statistically significant difference for age of diagnosis for individuals in the multiplex families compared to the non-familial and duplex families (56.0 versus 64.3, 63.5; p = 0.049). There was no significant difference between demographic factors and other cancer risk factors between family types. The results of this study support a genetic basis for familial Barrett's associated neoplasia and evaluation of the genetic susceptibility to this disease should continue to focus on families with multiple (three or more) affected members.
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http://dx.doi.org/10.1007/s10689-021-00239-zDOI Listing
March 2021

Characterization of Prevalent, Post-Endoscopy, and Incident Esophageal Cancer in the United States: A Large Retrospective Cohort Study.

Clin Gastroenterol Hepatol 2021 Feb 5. Epub 2021 Feb 5.

Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Electronic address:

Background & Aims: Efforts to assess and improve the effectiveness of Barrett's esophagus (BE) screening and surveillance are ongoing in the United States. Currently, there are limited population-based data in the United States to guide these efforts.

Methods: We performed a retrospective cohort study using data from large commercial and Medicare Advantage health plans in the United States from 2004 - 2019. We identified individuals with BE and analyzed the proportion who developed EAC. EACs were classified as prevalent EAC (diagnosed within 30 days of index endoscopy), post-endoscopy esophageal adenocarcinoma (PEEC, diagnosed 30 - 365 days after index endoscopy), and incident EAC (diagnosed 365 days or more after index endoscopy). Using this cohort, we performed a nested case-control study to identify factors associated with prevalent EAC at BE diagnosis and study healthcare utilization prior to BE diagnosis.

Results: We identified 50,817 individuals with incident BE. Of the 366 who developed EAC, 67.2%, 13.7%, and 19.1% were diagnosed with prevalent EAC, PEEC, and incident EAC respectively. Factors positively associated with prevalent EAC versus BE without prevalent EAC included male sex, dysphagia, weight loss, and Charlson-Deyo comorbidity score. In those with prevalent EAC, most patients with dysphagia or weight loss had their symptoms first recorded within three months of EAC diagnosis. Healthcare utilization rates were similar between those with and without prevalent EAC.

Conclusions: Two-thirds of EACs among individuals with BE are diagnosed at the time of BE diagnosis. Additionally, PEEC accounts for 14% of these EACs. These results may guide future research studies that investigate novel BE diagnostic strategies that reduce the morbidity and mortality of EAC.
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http://dx.doi.org/10.1016/j.cgh.2021.02.005DOI Listing
February 2021

Best Practices in Surveillance for Barrett's Esophagus.

Gastrointest Endosc Clin N Am 2021 Jan 21;31(1):59-75. Epub 2020 Oct 21.

Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania, Perelman School of Medicine, Perelman Center for Advanced Medicine, 7th Floor South Pavilion, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA. Electronic address:

Barrett's esophagus is the precursor lesion for esophageal adenocarcinoma. The goals of endoscopic surveillance are to detect dysplasia and early esophageal adenocarcinoma in order to improve patient outcomes. Despite the ongoing debate regarding the efficacy of surveillance, all current gastrointestinal societies recommend surveillance at this time. Optimal surveillance technique includes adequate inspection time, evaluation using high-definition white light and chromoendoscopy, appropriate documentation of the metaplastic segment using the Prague C & M criteria as well as the Paris classification should lesions be found, utilization of the Seattle biopsy protocol, and endoscopic resection of visible lesions.
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http://dx.doi.org/10.1016/j.giec.2020.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684982PMC
January 2021

Type II achalasia is associated with a comparably favorable outcome following per oral endoscopic myotomy.

Dis Esophagus 2021 Jun;34(6)

Division of Gastroenterology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Per oral endoscopic myotomy (POEM) is a safe and effective treatment for esophageal motility disorder in treatment-naïve patients as well as salvage therapy. Though type II achalasia, compared to other subtypes, is reported to have a more favorable outcome with pneumatic dilation (PD) or Heller myotomy (HM), it is unclear whether achalasia subtype predicts symptom response to POEM. We aimed to evaluate whether type II achalasia is associated with a comparably favorable outcome following POEM. We performed a retrospective review of patients with esophageal motility disorder who were referred for POEM from April 2014 to June 2017. The main outcome was clinical success based on Eckardt score ≤3 and its association with subtype and safety. A total of 63 patients (mean age 51 years [SD 15]; 63% male) underwent a total of 68 POEMs with median of 263 days follow-up. Of these, 45 (71.3%) patients were type II achalasia. In all, 29 (46%) patients were treatment-naïve and 34 (54%) patients had previous endoscopic or surgical therapy including botulinum toxin injection in 16 (25%), PD in 10 (16%), both botulinum toxin injection and PD in 8 (13%) and HM in 3 (5%). Technical success was 100% and clinical success was achieved in 51 (81%) patients. The rate of clinical success was higher in patients with type II achalasia compared to the other subtypes (88.9% vs. 61.1% [P = 0.028]) and type II achalasia patients required fewer redo POEM (2.2% vs. 22.2% [P = 0.021]). Multivariate logistic regression analysis demonstrated the positive prediction of clinical success for type II achalasia following POEM (P = 0.046). As observed with PD and HM, type II achalasia was associated with a favorable clinical outcome following POEM.
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http://dx.doi.org/10.1093/dote/doaa107DOI Listing
June 2021

An Analysis of the GIQuIC Nationwide Quality Registry Reveals Unnecessary Surveillance Endoscopies in Patients With Normal and Irregular Z-Lines.

Am J Gastroenterol 2020 11;115(11):1869-1878

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Introduction: Population-based estimates of adherence to Barrett's esophagus (BE) guidelines are not available. Using a national registry, we assessed surveillance intervals for patients with normal and irregular Z-lines based on the presence or absence of intestinal metaplasia (IM) and among patients with suspected or confirmed BE.

Methods: We analyzed data from the GI Quality Improvement Consortium Registry. Endoscopy data, including procedure indication, demographics, endoscopy and histology findings, and recommendations for further endoscopy, were assessed from January 2013 through December 2019. Patients with an indication of BE screening or surveillance or an endoscopic finding of BE were included. Biopsy and surveillance practices were assessed based on the length of columnar epithelium (0 cm, <1 cm, 1-3 cm, and >3 cm) and diagnosis based on histology findings.

Results: A total of 1,907,801 endoscopies were assessed; 135,704 endoscopies (7.1%) performed in 114,894 patients met the inclusion criteria (men 61.4%, Whites 91%, and mean age of 61.7 years [SD 12.5]). Among patients with normal Z-lines, surveillance endoscopy was recommended for 81% of patients with IM and 20% of individuals without IM. Among patients with irregular Z-lines, surveillance endoscopy was recommended for 81% with IM and 24% without IM. Approximately 30% of patients with confirmed nondysplastic BE (lengths 1-3 and >3 cm) had recommended surveillance intervals of <3 years.

Discussion: An analysis of data from a nationwide quality registry demonstrated that patients without BE are receiving recommendations for surveillance endoscopies and many patients with nondysplastic BE are reexamined too soon.
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http://dx.doi.org/10.14309/ajg.0000000000000960DOI Listing
November 2020

Clinical significance of recurrent gastroesophageal junction intestinal metaplasia after endoscopic eradication of Barrett's esophagus.

Gastrointest Endosc 2021 06 2;93(6):1250-1257.e3. Epub 2020 Nov 2.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA. Electronic address:

Background And Aims: After endoscopic eradication of Barrett's esophagus (BE), recurrence of intestinal metaplasia at the gastroesophageal junction (GEJIM) is common. The clinical significance of this finding is unclear. We assessed whether recurrent GEJIM is associated with increased risk of subsequent dysplasia and whether endoscopic treatment lowers this risk.

Methods: A retrospective, multicenter, cohort study was performed of treated BE patients who achieved complete eradication of intestinal metaplasia (IM). Postablation follow-up was performed at standard intervals. Recurrent GEJIM was defined as nondysplastic IM on gastroesophageal junction biopsy specimens without endoscopic evidence of BE. Patients were categorized as "never-GEJIM," "GEJIM-observed," or "GEJIM-treated." Endoscopic treatment for recurrent GEJIM was at the endoscopists' discretion. The primary outcome was dysplasia recurrence. Analyses were performed using log-rank tests and Cox proportional hazards modeling.

Results: Six hundred thirty-three patients were analyzed; median follow-up was 47 months (interquartile range, 24-69). Most patients (81%) had high-grade dysplasia or intramucosal adenocarcinoma before treatment. Dysplasia recurrence was 2.2% per year. GEJIM-observed patients had the lowest rate of recurrence (.6%/y) followed by GEJIM-treated (2.2%/y) and never-GEJIM (2.6%/y) (log-rank P = .07). In multivariate analyses, compared with never-GEJIM, the risk of dysplasia recurrence was significantly lower in GEJIM-observed patients (adjusted hazard ratio, .19; 95% confidence interval, .05-.81) and not different in GEJIM-treated patients (adjusted hazard ratio, .81; 95% confidence interval, .39-1.67). Older age and longer initial BE length were independently associated with recurrence.

Conclusions: Recurrent GEJIM after endoscopic eradication of BE was not associated with an increased risk of subsequent dysplasia. Future studies are warranted to determine if observation is appropriate for this finding.
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http://dx.doi.org/10.1016/j.gie.2020.10.027DOI Listing
June 2021

Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis.

N Engl J Med 2020 10;383(17):1624-1634

From the University of North Carolina, Chapel Hill (E.S.D.); the University of Utah, Salt Lake City (K.A.P.); Mayo Clinic Rochester, Rochester, MN (J.A.M., A.C.B.); the University of Pennsylvania Perelman School of Medicine, Philadelphia (G.W.F.); Northwestern University, Chicago (N.G., I.H.); the Icahn School of Medicine at Mount Sinai, New York (M.C.); Baylor College of Medicine, Houston (R.M.G.); Tufts University, Boston (J.L.); the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (P.K., A.D.K.); Ventura Clinical Trials, Ventura (S.H.), and Allakos, Redwood City (C.S., A.T.C., B.S., A.P.K., H.S.R.) - both in California; Vanderbilt University, Nashville (M.V.); the Division of Allergy and Immunology, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati (S.R.D., M.E.R.); and Pharma Data Associates, Piscataway, NJ (C.W.).

Background: Eosinophilic gastritis and duodenitis are characterized by gastrointestinal mucosal eosinophilia, chronic symptoms, impaired quality of life, and a lack of adequate treatments. Mast-cell activity may contribute to the pathogenesis of the conditions. AK002 (lirentelimab) is an anti-Siglec-8 antibody that depletes eosinophils and inhibits mast cells and that has shown potential in animal models as a treatment for eosinophilic gastritis and duodenitis.

Methods: In this phase 2 trial, we randomly assigned adults who had symptomatic eosinophilic gastritis, eosinophilic duodenitis, or both conditions in a 1:1:1 ratio to receive four monthly infusions of low-dose AK002, high-dose AK002, or placebo. The primary end point was the change in gastrointestinal eosinophil count from baseline to 2 weeks after the final dose; to maximize statistical power, we evaluated this end point in the placebo group as compared with the combined AK002 group. Secondary end points were treatment response (>30% reduction in total symptom score and >75% reduction in gastrointestinal eosinophil count) and the change in total symptom score.

Results: Of the 65 patients who underwent randomization, 43 were assigned to receive AK002 and 22 were assigned to receive placebo. The mean percentage change in gastrointestinal eosinophil count was -86% in the combined AK002 group, as compared with 9% in the placebo group (least-squares mean difference, -98 percentage points; 95% confidence interval [CI], -121 to -76; P<0.001). Treatment response occurred in 63% of the patients who received AK002 and in 5% of the patients who received placebo (difference, 58 percentage points; 95% CI, 36 to 74; P<0.001). The mean change in total symptom score was -48% with AK002 and -22% with placebo (least-squares mean difference, -26 percentage points; 95% CI, -44 to -9; P = 0.004). Adverse events associated with AK002 were similar to those with placebo, with the exception of higher percentages of patients having mild-to-moderate infusion-related reactions with AK002 (60% in the combined AK002 group and 23% in the placebo group).

Conclusions: In patients with eosinophilic gastritis or duodenitis, AK002 reduced gastrointestinal eosinophils and symptoms. Infusion-related reactions were more common with AK002 than with placebo. (Funded by Allakos; ENIGMA ClinicalTrials.gov number, NCT03496571.).
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http://dx.doi.org/10.1056/NEJMoa2012047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600443PMC
October 2020

Good news for the treatment of narrow-caliber esophagus in eosinophilic esophagitis.

Gastrointest Endosc 2020 07;92(1):54-55

Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

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http://dx.doi.org/10.1016/j.gie.2020.03.3850DOI Listing
July 2020

High Patient Disease Burden in a Cross-sectional, Multicenter Contact Registry Study of Eosinophilic Gastrointestinal Diseases.

J Pediatr Gastroenterol Nutr 2020 10;71(4):524-529

Department of Pediatrics, Cincinnati Children's Hospital Medical Center.

Objectives: Clinical features of eosinophilic esophagitis (EoE) have been well-described in the literature, however, characterization of features experienced by patients with other eosinophilic gastrointestinal diseases (EGIDs) is lacking. Using data collected from a patient contact registry, we sought to characterize and contrast patient-reported gastrointestinal and extragastrointestinal symptoms and comorbidities in non-EoE EGIDs, including eosinophilic gastritis, gastroenteritis and colitis, relative to EoE.

Methods: We conducted a cross-sectional study of contact registry data collected from 2015 to 2018. Statistical comparisons were made using chi-square (categorical measures) and the Mann-Whitney U test (continuous measures). Multivariable analyses were used to evaluate associations between treatment and feelings of isolation.

Results: Of the 715 reporting an EGID diagnosis (n = 525 EoE; n = 190 non-EoE EGID), a higher proportion of those with a non-EoE EGID reported more frequent specific and nonspecific gastrointestinal symptoms, including nausea, abdominal pain, diarrhea, constipation, and bloating (P < 0.01 for all). Participants with a non-EoE EGID were more likely to report higher frequency of fatigue, isolation, and deep muscle or joint pain (P < 0.01 for all). Specific food elimination and elemental formula treatments were associated with increased odds of more frequent (at least weekly) feelings of isolation for participants with EoE (adjusted odds rtaio [aOR]: 2.4; 95% confidence interval [CI]: 1.5--4.1 for specific food elimination and adjusted OR: 1.9; 95% CI: 1.2--3.3 for elemental formula).

Conclusions: Significant differences exist in the symptoms and comorbidities experienced between those with EoE versus non-EoE EGIDs. Additional investigation is needed to elucidate the factors that may contribute to the high disease burden of these poorly understood conditions.
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http://dx.doi.org/10.1097/MPG.0000000000002817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574400PMC
October 2020

Virtual Dysphagia Evaluation: Practical Guidelines for Dysphagia Management in the Context of the COVID-19 Pandemic.

Otolaryngol Head Neck Surg 2020 09 26;163(3):455-458. Epub 2020 May 26.

Department of Otorhinolaryngology-Head and Neck Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

With encouraging signs of pandemic containment nationwide, the promise of return to a full range of clinical practice is on the horizon. Clinicians are starting to prepare for a transition from limited evaluation of emergent and urgent complaints to resumption of elective surgical procedures and routine office visits within the next few weeks to months. Otolaryngology as a specialty faces unique challenges when it comes to the COVID-19 pandemic due to the fact that a comprehensive head and neck examination requires aerosol-generating endoscopic procedures. Since the COVID-19 pandemic is far from being over and the future may hold other highly communicable infectious threats that may require similar precautions, standard approaches to the clinical evaluation of common otolaryngology complaints will have to be modified. In this communication, we present practical recommendations for dysphagia evaluation with modifications to allow a safe and comprehensive assessment.
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http://dx.doi.org/10.1177/0194599820931791DOI Listing
September 2020

Editorial: fluticasone propionate orally disintegrating tablets-interesting concept but is it going anywhere? Authors' reply.

Aliment Pharmacol Ther 2020 05;51(10):990-991

Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

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http://dx.doi.org/10.1111/apt.15713DOI Listing
May 2020

Notch Signaling Mediates Differentiation in Barrett's Esophagus and Promotes Progression to Adenocarcinoma.

Gastroenterology 2020 08 20;159(2):575-590. Epub 2020 Apr 20.

Department of Medicine, Columbia University Irving Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York.

Background & Aims: Studies are needed to determine the mechanism by which Barrett's esophagus (BE) progresses to esophageal adenocarcinoma (EAC). Notch signaling maintains stem cells in the gastrointestinal tract and is dysregulated during carcinogenesis. We explored the relationship between Notch signaling and goblet cell maturation, a feature of BE, during EAC pathogenesis.

Methods: We measured goblet cell density and levels of Notch messenger RNAs in BE tissues from 164 patients, with and without dysplasia or EAC, enrolled in a multicenter study. We analyzed the effects of conditional expression of an activated form of NOTCH2 (pL2.Lgr5.N2IC), conditional deletion of NOTCH2 (pL2.Lgr5.N2fl/fl), or loss of nuclear factor κB (NF-κB) (pL2.Lgr5.p65fl/fl), in Lgr5 (progenitor) cells in L2-IL1B mice (which overexpress interleukin 1 beta in esophagus and squamous forestomach and are used as a model of BE). We collected esophageal and stomach tissues and performed histology, immunohistochemistry, flow cytometry, transcriptome, and real-time polymerase chain reaction analyses. Cardia and forestomach tissues from mice were cultured as organoids and incubated with inhibitors of Notch or NF-kB.

Results: Progression of BE to EAC was associated with a significant reduction in goblet cell density comparing nondysplastic regions of tissues from patients; there was an inverse correlation between goblet cell density and levels of NOTCH3 and JAG2 messenger RNA. In mice, expression of the activated intracellular form of NOTCH2 in Lgr5 cells reduced goblet-like cell maturation, increased crypt fission, and accelerated the development of tumors in the squamocolumnar junction. Mice with deletion of NOTCH2 from Lgr5 cells had increased maturation of goblet-like cells, reduced crypt fission, and developed fewer tumors. Esophageal tissues from in pL2.Lgr5.N2IC mice had increased levels of RelA (which encodes the p65 unit of NF-κB) compared to tissues from L2-IL1B mice, and we found evidence of increased NF-κB activity in Lgr5 cells. Esophageal tissues from pL2.Lgr5.p65fl/fl mice had lower inflammation and metaplasia scores than pL2.Lgr5.N2IC mice. In organoids derived from pL2-IL1B mice, the NF-κB inhibitor JSH-23 reduced cell survival and proliferation.

Conclusions: Notch signaling contributes to activation of NF-κB and regulates differentiation of gastric cardia progenitor cells in a mouse model of BE. In human esophageal tissues, progression of BE to EAC was associated with reduced goblet cell density and increased levels of Notch expression. Strategies to block this pathway might be developed to prevent EAC in patients with BE.
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http://dx.doi.org/10.1053/j.gastro.2020.04.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484392PMC
August 2020

Generation and Characterization of Patient-Derived Head and Neck, Oral, and Esophageal Cancer Organoids.

Curr Protoc Stem Cell Biol 2020 06;53(1):e109

Division of Digestive and Liver Diseases, Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York.

Esophageal cancers comprise adenocarcinoma and squamous cell carcinoma, two distinct histologic subtypes. Both are difficult to treat and among the deadliest human malignancies. We describe protocols to initiate, grow, passage, and characterize patient-derived organoids (PDO) of esophageal cancers, as well as squamous cell carcinomas of oral/head-and-neck and anal origin. Formed rapidly (<14 days) from a single-cell suspension embedded in basement membrane matrix, esophageal cancer PDO recapitulate the histology of the original tumors. Additionally, we provide guidelines for morphological analyses and drug testing coupled with functional assessment of cell response to conventional chemotherapeutics and other pharmacological agents in concert with emerging automated imaging platforms. Predicting drug sensitivity and potential therapy resistance mechanisms in a moderate-to-high throughput manner, esophageal cancer PDO are highly translatable in personalized medicine for customized esophageal cancer treatments. © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Generation of esophageal cancer PDO Basic Protocol 2: Propagation and cryopreservation of esophageal cancer PDO Basic Protocol 3: Imaged-based monitoring of organoid size and growth kinetics Basic Protocol 4: Harvesting esophageal cancer PDO for histological analyses Basic Protocol 5: PDO content analysis by flow cytometry Basic Protocol 6: Evaluation of drug response with determination of the half-inhibitory concentration (IC ) Support Protocol: Production of RN in HEK293T cell conditioned medium.
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http://dx.doi.org/10.1002/cpsc.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350550PMC
June 2020

Esophageal type 2 cytokine expression heterogeneity in eosinophilic esophagitis in a multisite cohort.

J Allergy Clin Immunol 2020 06 19;145(6):1629-1640.e4. Epub 2020 Mar 19.

Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

Background: There is strong evidence for a role of type 2 cytokines in the pathogenesis of eosinophilic esophagitis (EoE); however, heterogeneity in type 2 gene expression has not been examined.

Objective: We examined type 2 immunity-associated gene expression in esophageal biopsy specimens, aiming to determine the degree of cytokine heterogeneity and its potential clinical significance.

Methods: Patients (n = 312) were recruited from 10 sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. In addition to histologic and endoscopic assessment, esophageal biopsy specimens were examined for expression of 96 genes within the EoE diagnostic panel.

Results: Five subgroups of patients with active EoE were identified by unsupervised clustering based on expression of IL4, IL5, IL13, C-C motif chemokine ligand 26 (CCL26), thymic stromal lymphopoietin (TSLP), Charcot-Leyden crystal (CLC), C-C motif chemokine receptor 3 (CCR3), and CPA3. These groups differed in age (P < .02) and EoE diagnostic panel score (P < 1.08E-30) but not in eosinophil levels. The group V patients had the highest expression of IL5, TSLP, and CCL26 and genes associated with tissue remodeling, such as COL8A1, actin γ-2 (ACTG2), and tetraspanin 12 (TSPAN12). IL5 and IL13 were highly expressed in group IV; however, groups IV and V differed in age (34 vs 14 years [P < .05]). Groups II and III, which exhibited intermediate expression of IL5 and CPA3, were differentiated by high TSLP and IL13 in group III.

Conclusion: We observed heterogeneous type 2 gene expression among patients with active EoE. Type 2 gene overexpression was not directly proportional to disease features; this was especially true for tissue remodeling events. These findings highlight a clinical opportunity for leveraging molecular endotypes to implement personalized medicine in EoE.
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http://dx.doi.org/10.1016/j.jaci.2020.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309223PMC
June 2020

Randomised clinical trial: the safety and tolerability of fluticasone propionate orally disintegrating tablets versus placebo for eosinophilic oesophagitis.

Aliment Pharmacol Ther 2020 04 9;51(8):750-759. Epub 2020 Mar 9.

Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: APT-1011, a fluticasone propionate orally disintegrating tablet formulation, is under investigation for the treatment of eosinophilic oesophagitis (EoE).

Aims: To evaluate the safety and tolerability of APT-1011 administered to patients with EoE and to assess the effect on clinical symptoms of EoE, endoscopic appearance and oesophageal eosinophilia.

Methods: A randomised, double-blind, placebo-controlled, multicentre, phase 1b/2a study was conducted at seven medical centres in the US to evaluate the safety and tolerability of APT-1011 over 8 weeks in adults and adolescents with EoE. Participants were randomised to placebo (n = 8), 1.5 mg APT-1011 BID (n = 8) or 3.0 mg APT-1011 QD (n = 8). Safety and tolerability were assessed as the primary outcome; histologic and endoscopic measures were assessed as exploratory outcomes.

Results: There were no deaths, serious treatment-emergent adverse events (TEAEs), severe TEAEs or discontinuations from the study related to a TEAE. In one participant randomised to 1.5 mg APT-1011 BID, a reduction in cortisol was observed, but without evidence of adrenal insufficiency. Compared with placebo, treatment with APT-1011 resulted in greater reductions in oesophageal eosinophil counts, EoE Endoscopic Reference Score, patient global assessment and symptom-based EoE activity index from baseline to end of treatment (Week 8).

Conclusions: APT-1011 was safe and well tolerated in adolescents and adults with EoE. Exploratory efficacy outcomes demonstrated improvement in histologic and endoscopic findings as well evidence of symptom improvement. The results of this study support the continued development of APT-1011 for the treatment of EoE (NCT-01386112).
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http://dx.doi.org/10.1111/apt.15670DOI Listing
April 2020

Modeling Epithelial Homeostasis and Reactive Epithelial Changes in Human and Murine Three-Dimensional Esophageal Organoids.

Curr Protoc Stem Cell Biol 2020 03;52(1):e106

Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

The homeostatic proliferation-differentiation gradient in the esophageal epithelium is perturbed under inflammatory disease conditions such as gastroesophageal reflux disease and eosinophilic esophagitis. Herein we describe the protocols for rapid generation (<14 days) and characterization of single-cell-derived, three-dimensional (3D) esophageal organoids from human subjects and mice with normal esophageal mucosa or inflammatory disease conditions. While 3D organoids recapitulate normal epithelial renewal, proliferation, and differentiation, non-cell autonomous reactive epithelial changes under inflammatory conditions are evaluated in the absence of the inflammatory milieu. Reactive epithelial changes are reconstituted upon exposure to exogenous recombinant cytokines. These changes are modulated pharmacologically or genetically ex vivo. Molecular, structural, and functional changes are characterized by morphology, flow cytometry, biochemistry, and gene expression analyses. Esophageal 3D organoids can be translated for the development of personalized medicine in assessment of individual cytokine sensitivity and molecularly targeted therapeutics in esophagitis patients © 2020 by John Wiley & Sons, Inc. Basic Protocol 1: Generation of esophageal organoids from biopsy or murine esophageal epithelial sheets Basic Protocol 2: Propagation and cryopreservation of esophageal organoids Basic Protocol 3: Harvesting of esophageal organoids for RNA isolation, immunohistochemistry, and evaluation of 3D architecture Basic Protocol 4: Modeling of reactive epithelium in esophageal organoids.
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http://dx.doi.org/10.1002/cpsc.106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288850PMC
March 2020

Is the age of diagnosis of esophageal adenocarcinoma getting younger? Analysis at a tertiary care center.

Dis Esophagus 2020 Sep;33(9)

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

There are emerging data that patients <50 years are diagnosed with esophageal adenocarcinoma (EAC) more frequently, suggesting that the age threshold for screening should be revisited. This study aimed to determine the age distribution, outcomes, and clinical features of EAC over time. The pathology database at the Hospital of the University of Pennsylvania was reviewed from 1991 to 2018. The electronic health records and pathology were reviewed for age of diagnosis, pathology grade, race, and gender for a cohort of 630 patients with biopsy proven EAC. For the patients diagnosed from 2009 to 2018, the Penn Abramson Cancer Center Registry was reviewed for survival and TNM stage. Of the 630 patients, 10.3% (65 patients) were <50 years old [median 43 years, range 16-49]. There was no increase in the number of patients <50 years diagnosed with EAC (R = 0.133, P = 0.05). Characteristics of those <50 years versus >50 years showed no difference in tumor grade. Among the 179 eligible patients in the cancer registry, there was no significant difference in clinical or pathological stage for patients <50 years (P value = 0.18). There was no association between diagnosis age and survival (P = 0.24). A substantial subset of patients with EAC is diagnosed at <50 years. There was no increasing trend of EAC in younger cohorts from 1991 to 2018. We could not identify more advanced stage tumors in the younger cohort. There was no significant association between diagnosis age and survival.
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http://dx.doi.org/10.1093/dote/doz112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471774PMC
September 2020

Outcomes of patients with submucosal (T1b) esophageal adenocarcinoma: a multicenter cohort study.

Gastrointest Endosc 2020 07 15;92(1):31-39.e1. Epub 2020 Jan 15.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Background And Aims: The treatment of submucosal (T1b) esophageal adenocarcinoma (EAC) remains in evolution, with some evidence supporting endoscopic management of low-risk lesions. Using a multicenter cohort, we evaluated outcomes of patients with T1b EAC and predictors of survival.

Methods: Patients diagnosed between 2001 and 2016 with T1b EAC were identified from 3 academic medical centers in the United States. Demographic, clinical, and outcome data were collected. Outcomes studied were overall and cancer-free survival. Cox proportional hazards models were constructed to assess independent predictors of survival.

Results: One hundred forty-one patients were included, of whom 68 (48%) underwent esophagectomy and 73 (52%) were treated endoscopically. Most patients (85.8%) had high-risk histologic features. Thirty-day operative mortality was 2.9%. Median follow-up in the esophagectomy and endoscopic cohorts was 49.4 and 43.4 months, respectively. Patients treated endoscopically were older with higher comorbidity scores, with 46 (63%) achieving histologic remission. Nineteen patients (26.0%) also received chemoradiation. Five-year overall survival rates in the surgical and endoscopic cohorts were 89% and 59%, respectively, whereas 5-year cancer-free survival rates were 92% and 69%. Presence of high-risk histologic features was associated with reduced overall survival.

Conclusions: In this large multicenter study of patients with T1b EAC, esophagectomy was associated with improved overall but not cancer-free survival. High-risk histologic features were associated with poorer survival.
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http://dx.doi.org/10.1016/j.gie.2020.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321863PMC
July 2020

Association Between Endoscopic and Histologic Findings in a Multicenter Retrospective Cohort of Patients with Non-esophageal Eosinophilic Gastrointestinal Disorders.

Dig Dis Sci 2020 07 26;65(7):2024-2035. Epub 2019 Nov 26.

Center for Esophageal Diseases and Swallowing and Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, CB #7080, Chapel Hill, NC, 27599, USA.

Background: Little is known about the endoscopic and histologic findings of non-esophageal eosinophilic gastrointestinal diseases (EGID).

Aim: To characterize the presenting endoscopic and histologic findings in patients with eosinophilic gastritis (EG), eosinophilic gastroenteritis (EGE), and eosinophilic colitis (EC) at diagnosis and 6 months after initiating the treatment.

Methods: We conducted a retrospective cohort study at 6 US centers associated with the Consortium of Eosinophilic Gastrointestinal Researchers. Data abstracted included demographics, endoscopic findings, tissue eosinophil counts, and associated histologic findings at diagnosis and, when available, after initial treatment.

Results: Of 373 subjects (317 children and 56 adults), 142 had EG, 123 EGE, and 108 EC. Normal endoscopic appearance was the most common finding across all EGIDs (62% of subjects). Baseline tissue eosinophil counts were quantified in 105 (74%) EG, 36 (29%) EGE, and 80 (74%) EC subjects. The mean peak gastric eosinophil count across all sites was 87 eos/hpf for EG and 78 eos/hpf for EGE. The mean peak colonic eosinophil count for EC subjects was 76 eos/hpf (range 10-500). Of the 29% of subjects with post-treatment follow-up, most had an improvement in clinical, endoscopic, and histologic findings regardless of treatment utilized. Reductions in tissue eosinophilia correlated with improvements in clinical symptoms as well as endoscopic and histologic findings.

Conclusions: In this large cohort, normal appearance was the most common endoscopic finding, emphasizing the importance of biopsy, regardless of endoscopic appearance. Decreased tissue eosinophilia was associated with improvement in symptoms, endoscopic, and histologic findings, showing that disease activity is reversible.
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http://dx.doi.org/10.1007/s10620-019-05961-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315780PMC
July 2020

Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: Multi-site study.

J Allergy Clin Immunol 2020 01 16;145(1):255-269. Epub 2019 Nov 16.

Division of Allergy and Immunology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Background: Eosinophilic gastritis (EG) is a clinicopathologic disorder with marked gastric eosinophilia and clinical symptoms. There is an unmet need among patients with EG for more precise diagnostic tools.

Objective: We aimed to develop tissue- and blood-based diagnostic platforms for EG.

Methods: Patients with EG and control subjects without EG were enrolled across 9 Consortium of Eosinophilic Gastrointestinal Disease Researchers-associated sites. An EG Diagnostic Panel (EGDP; gastric transcript subset) and EG blood biomarker panel (protein multiplex array) were analyzed. EGDP scores were derived from the expression of 18 highly dysregulated genes, and blood EG scores were derived from dysregulated cytokine/chemokine levels.

Results: Gastric biopsy specimens and blood samples from 185 subjects (patients with EG, n = 74; control subjects without EG, n = 111) were analyzed. The EGDP (1) identified patients with active EG (P < .0001, area under the curve ≥ 0.95), (2) effectively monitored disease activity in longitudinal samples (P = .0078), (3) highly correlated in same-patient samples (antrum vs body, r = 0.85, P < .0001), and (4) inversely correlated with gastric peak eosinophil levels (r = -0.83, P < .0001), periglandular circumferential collars (r = -0.73, P < .0001), and endoscopic nodularity (r = -0.45, P < .0001). For blood-based platforms, eotaxin-3, thymus and activation-regulated chemokine, IL-5, and thymic stromal lymphopoietin levels were significantly increased. Blood EG scores (1) distinguished patients with EG from control subjects without EG (P < .0001, area under the curve ≥ 0.91), (2) correlated with gastric eosinophil levels (plasma: r = 0.72, P = .0002; serum: r = 0.54, P = .0015), and (3) inversely correlated with EGDP scores (plasma: r = -0.64, P = .0015; serum: r = -0.46, P = .0084). Plasma eotaxin-3 levels strongly associated with gastric CCL26 expression (r = 0.81, P < .0001).

Conclusion: We developed tissue- and blood-based platforms for assessment of EG and uncovered robust associations between specific gastric molecular profiles and histologic and endoscopic features, providing insight and clinical readiness tools for this emerging rare disease.
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http://dx.doi.org/10.1016/j.jaci.2019.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949389PMC
January 2020

Targeting the COX1/2-Driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development.

EBioMedicine 2019 Nov 7;49:145-156. Epub 2019 Nov 7.

The Hormel Institute, University of Minnesota, 801 16th Ave NE, Austin, MN 55912, United States. Electronic address:

Background: Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes.

Methods: Patient biopsy samples were evaluated for COX1/2, and thromboxane A2 synthase (TBXAS) expression. Circulating prostaglandins biosynthesis was determined using enzyme immunoassay kits. Anchorage-independent cell growth assay, crystal violet staining assay, and xenograft experiments were conducted to assess BE and EAC cell growth. A surgical mouse model of reflux (i.e., esophagoduodenostomy) was established and samples were analyzed using an enzyme immunoassay kit, immunohistochemistry, immunoblotting, or RT-PCR. Esophageal biopsy samples (pre- and post-intervention) were obtained from a randomized clinical trial in which participants were administered esomeprazole (40 mg) twice daily in combination with an acetylsalicylic acid (ASA) placebo or 81 or 325 mg ASA for 28 days. Esophageal biopsy specimens before and after the intervention period were analyzed.

Findings: COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels. ASA suppressed BE and EAC growth by targeting the TXA2 pathway. Additionally, biopsies from 49 patients (with similar baseline characteristics) showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation.

Interpretation: This study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection.

Funding: Hormel Foundation, Exact Sciences, Pentax Medical, Intromedic and National Cancer.
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http://dx.doi.org/10.1016/j.ebiom.2019.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113183PMC
November 2019
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