Publications by authors named "Frederic Clayton"

31 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, Tex; Department of Pathology, Baylor College of Medicine, Houston, Tex.

Background: End points 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: We sought 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 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life.

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 and 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

Esophageal Eosinophilia Is Common Among Relatives of Eosinophilic Esophagitis Patients.

Clin Gastroenterol Hepatol 2020 Nov 19. Epub 2020 Nov 19.

Department of Gastroenterology, Salt Lake City, Utah. Electronic address:

Background & Aims: Familial clustering of eosinophilic esophagitis (EoE) has been described, and we report on the biopsy-assessed prevalence of esophageal eosinophilia (EE) in first-degree family members. The aim was to determine the prevalence of EE in first-degree adult relatives (FDRs) of EoE patients.

Methods: Index EoE patients diagnosed by EE (>15 eosinophils per high-power field) and proton pump inhibitor nonresponsiveness were identified and family trees were constructed. Adult FDRs were invited to undergo upper endoscopy with esophageal biopsies and to complete reflux, dysphagia, and allergy/atopy questionnaires. Questionnaire information was gathered only for those who responded as per institutional review board purview. Records from other children and adult FDRs with prior EoE diagnoses also were obtained when permission was obtained. Simple and multivariable logistic regression models were used to evaluate the unadjusted and odds ratios of EoE for demographic and clinical variables.

Results: A total of 239 FDRs from 37 index EoE patients were identified. Seventy-one of 239 adult (age, >18 y) FDRs completed endoscopy and questionnaires and 18 of 71 FDRs had EE. An additional 17 FDRs were confirmed to have EE after external medical record retrieval, resulting in a total of 35 of 239 (14.6%) FDRs with EE. Significantly more male FDRs had EE compared with female FDRs (P = .027). Proton pump inhibitors, dysphagia, gastroesophageal reflux disease, asthma, and reflux symptoms predicted EE in FDRs. FDRs who had EE reported hay fever, allergic eye symptoms, and food allergy more frequently than those without EE (P = .03, P = .001, and P = .02, respectively). Specifically, younger age, higher serum eosinophils, being male, and having food allergies all were associated with higher odds of EoE (P = .0211, P = .0031, P = .0362, and P = .0089, respectively).

Conclusions: The prevalence of esophageal eosinophilia is extremely high and male-predominant in first-degree relatives of EoE patients. Symptoms of hay fever, allergic eye symptoms, and food allergy were predictors of EE in FDRs. Dysphagia did not predict esophageal eosinophilia. Family members of EoE patients are at risk for EE, particularly those who have atopic symptoms.
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http://dx.doi.org/10.1016/j.cgh.2020.11.023DOI Listing
November 2020

Primary Esophageal Angiosarcoma.

Ann Thorac Surg 2021 05 20;111(5):e365-e367. Epub 2020 Oct 20.

Department of Surgery, University of Utah, Salt Lake City, Utah.

Primary esophageal angiosarcoma is an extremely rare cancer. Thus, evidence-based guidance on diagnosis and treatment is lacking. The current workup and management is extrapolated from other esophageal and angiosarcoma pathology. We describe a case report that depicts unique diagnostic and therapeutic challenges.
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http://dx.doi.org/10.1016/j.athoracsur.2020.07.087DOI Listing
May 2021

Pulmonary Eosinophilic Granulomatosis with Polyangiitis Has IgG4 Plasma Cells and Immunoregulatory Features.

Am J Pathol 2020 07 3;190(7):1438-1448. Epub 2020 Apr 3.

University of Utah, Salt Lake City, Utah. Electronic address:

The immunologic mechanisms promoting eosinophilic granulomatosis with polyangiitis (EGPA) are unclear. To characterize the mechanisms underlying pulmonary EGPA, we examined and compared EGPA paraffin-embedded lung biopsies with normal lung biopsies, using immunostaining, RNA sequencing, and RT-PCR. The results revealed novel type 2 as well as immuneregulatory features. These features included basophils and increased mast cell contents; increased immunostaining for tumor necrosis factor ligand superfamily member 14; sparse mast cell degranulation; numerous forkhead box protein P3 (FoxP3)+ regulatory T cells and IgG4 plasma cells; and abundant arachidonate 15-lipoxygenase and 25-hydroxyvitamin D-1 α hydroxylase, mitochondrial. Significantly decreased 15-hydroxyprostaglandin dehydrogenase [NAD()], which degrades eicosanoids, was observed in EGPA samples. In addition, there was significantly increased mRNA for chemokine (C-C motif) ligands 18 and 13 and major collagen genes, IgG4-rich immune complexes coating alveolar macrophages, and increased immunostaining for phosphorylated mothers against decapentaplegic homolog 2/SMAD2, suggesting transforming growth factor-β activation. These findings suggest a novel self-promoting mechanism of activation of alveolar macrophages by arachidonate 15-lipoxygenase-derived eicosanoids to express chemokines that recruit a combined type 2/immunoregulatory immune response, which produces these eicosanoids. These results suggest that the pulmonary EGPA immune response resembles the immune response to a tissue-invasive parasite infection.
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http://dx.doi.org/10.1016/j.ajpath.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322366PMC
July 2020

Oral Administration of Technetium-Labeled Heparin in Eosinophilic Esophagitis.

Mayo Clin Proc 2020 03;95(3):449-458

Departments of Dermatology and Medicine, University of Utah, Salt Lake City, Utah. Electronic address:

Objective: To determine if heparin labeled with Technetium (Tc) could be an imaging probe to detect eosinophil-related inflammation in eosinophilic esophagitis and to determine the biodistribution and radiation dosimetry of Tc-heparin oral administration using image-based dosimetry models with esophageal modeling.

Methods: Freshly prepared Tc-heparin was administered orally to 5 research subjects. Radioactivity was measured by whole-body scintigraphy and single-photon emission computed tomography during the 24 hours postadministration. Following imaging, endoscopic examination was performed. The biodistribution of esophageal radioactivity was compared with endoscopic findings, eosinophil counts in biopsy tissues, and immunostaining for eosinophil granule major basic protein-1 (eMBP1). These studies were conducted from July 1, 2013, until April 22, 2017.

Results: Oral administration of Tc-heparin was well tolerated in all 5 subjects. The entire esophagus could be visualized dynamically during oral administration. Bound esophageal radioactivity marked areas of inflammation as judged by endoscopy scores, by eosinophils per high power field and by localization of eMBP1 using immunostaining. Ninety percent of the radioactivity did not bind to the esophagus and passed through the gastrointestinal tract.

Conclusion: The biodistribution of ingested Tc-heparin is almost exclusively localized to the gastrointestinal tract. Radiation exposure was highest in the lower gastrointestinal tract and was comparable with other orally administered diagnostic radiopharmaceuticals. The use of swallowed Tc-heparin may aid in assessing eosinophil-related inflammation in the esophagus.
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http://dx.doi.org/10.1016/j.mayocp.2019.12.029DOI Listing
March 2020

Disseminated toxoplasmosis and haemophagocytic lymphohistiocytosis following chimeric antigen receptor T-cell therapy.

Br J Haematol 2020 04 20;189(1):e4-e6. Epub 2020 Jan 20.

Intermountain Blood and Marrow Transplant and Acute Leukemia Program, Intermountain Healthcare, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1111/bjh.16402DOI Listing
April 2020

Epithelial Inclusions in Gallbladder Specimens Mimic Parasite Infection: Histologic and Molecular Examination of Reported Cystoisospora belli Infection in Gallbladders of Immunocompetent Patients.

Am J Surg Pathol 2018 10;42(10):1346-1352

Department of Pathology.

Recent publications have described epithelial cytoplasmic vacuoles and inclusions incidentally noted within gallbladder epithelium and concluded that they represent coccidian parasite infection, in particular, Cystoisospora belli. We identified 8 gallbladder specimens from our institution in the past 3 years in which this diagnosis was suggested or in which similar epithelial alterations were prominent. Molecular analysis was performed on the 8 gallbladder specimens and on 3 positive control specimens: small bowel biopsies from acquired immunodeficiency syndrome patients with diarrhea. Polymerase chain reaction using primers designed to amplify an internal transcribed spacer (ITS2) in the C. belli ribosomal gene cluster was performed on the DNA samples. All 8 gallbladder specimens were negative for amplification, while a product consistent with C. belli was amplified from all 3 positive controls. Histologically, the gallbladder cytoplasmic inclusions stained diffusely positive for Grocott-Gomori's methenamine silver and Periodic acid-Schiff with diastase. In contrast, sections from a positive control small bowel biopsy demonstrated organisms that were negative for Grocott-Gomori's methenamine silver and showed a distinct capsular and punctate internal staining on Periodic acid-Schiff with diastase in various parasite forms. Together, the lack of molecular evidence of C. belli and the distinct morphologic and special staining patterns in these gallbladders compared with positive control small bowel suggest that these epithelial changes do not represent true C. belli infection. Our results suggest that gallbladders of immunocompetent patients may occasionally show epithelial changes that can morphologically mimic C. belli infection. Pathologists should be aware of this histologic variant to minimize unnecessary treatment, testing, and patient anxiety.
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http://dx.doi.org/10.1097/PAS.0000000000001094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133732PMC
October 2018

Eosinophilic Esophagitis: Pathophysiology and Definition.

Gastrointest Endosc Clin N Am 2018 Jan 7;28(1):1-14. Epub 2017 Oct 7.

Division of Gastroenterology, The University of Utah, 30 North 1900 East SOM 4R118, Salt Lake City, UT 84132, USA. Electronic address:

Eosinophilic esophagitis is an adaptive immune response to patient-specific antigens, mostly foods. Eosinophilic esophagitis is not solely IgE-mediated and is likely characterized by Th2 lymphocytes with an impaired esophageal barrier function. The key cytokines and chemokines are thymic stromal lymphopoeitin, interleukin-13, CCL26/eotaxin-3, and transforming growth factor-β, all involved in eosinophil recruitment and remodeling. Chronic food dysphagia and food impactions, the feared late complications, are related in part to dense subepithelial fibrosis, likely induced by interleukin-13 and transforming growth factor-β.
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http://dx.doi.org/10.1016/j.giec.2017.07.011DOI Listing
January 2018

Rapid onset of hemophagocytic lymphohistiocytosis in a patient with refractory chronic lymphocytic leukemia treated with ibrutinib.

Leuk Lymphoma 2017 05 17;58(5):1258-1261. Epub 2016 Oct 17.

a Division of Hematology and Hematologic Malignancies , Huntsman Cancer Hospital, University of Utah , Salt Lake City , UT , USA.

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http://dx.doi.org/10.1080/10428194.2016.1243679DOI Listing
May 2017

Measurement of Inflammation in Eosinophilic Esophagitis Using an Eosinophil Peroxidase Assay.

Am J Gastroenterol 2016 07 24;111(7):933-9. Epub 2016 May 24.

Department of Internal Medicine, Division of Gastroenterology, University of Utah, Salt Lake City, Utah, USA.

Objectives: We describe a simple, quick method to measure an eosinophil granule protein, eosinophil peroxidase (EPO), as a marker of eosinophil activity, in eosinophilic esophagitis (EoE).

Methods: Esophageal mucosal brushings initially were collected from 36 patients with active EoE (n=13), resolved EoE (n=13), and controls (n=10) before endoscopic biopsy collection; the brushes were frozen at -80 ºC until assayed. EPO on the brush was measured in a colorimetric assay visually and by spectrophotometric absorbance measurements (at 492 nm), and was compared with peak eosinophil counts in esophageal biopsy specimens. The assay was calibrated with known EPO concentrations; as EPO increased in the assay, the color changed from light yellow to dark brown.

Results: Mucosal brush specimens from active EoE yielded orange to dark brown colors with absorbance measurements > 1.1 U; in contrast, control and resolved EoE brush specimens yielded a light to dark yellow color with absorbance measurements < 1.1. We then corroborated the results at the bedside (real time) in 16 additional patients. EPO on the brush was measured directly in < 1 h in the assay visually and by absorbance at 492 nm. Absorbance units strongly correlated with peak eosinophil counts both with the frozen brush (rs=0.79, P<0.0001) and with the bedside (rs=0.86, P<0.00017) approaches.

Conclusions: The results support the use of this rapid method to detect and monitor EoE disease activity. Moreover, because eosinophils infiltrate and degranulate in the esophagus in EoE in a patchy manner, this method may be more accurate than current practice by testing for an eosinophil constituent from both intact and degranulated cells, and by sampling large portions of the esophageal lumen rather than small biopsy specimens that may not be representative of eosinophil involvement.
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http://dx.doi.org/10.1038/ajg.2016.184DOI Listing
July 2016

Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases.

World Allergy Organ J 2016 11;9. Epub 2016 Feb 11.

Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy.

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.
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http://dx.doi.org/10.1186/s40413-016-0094-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751725PMC
February 2016

Association of rituximab with graphene oxide confers direct cytotoxicity for CD20-positive lymphoma cells.

Oncotarget 2016 Mar;7(11):12806-22

Department of Pathology, University of Utah, Salt Lake City, Utah, USA.

Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies among adults for which the chimeric monoclonal anti-CD20 antibody (Ab) rituximab (RTX) is used as first-line therapy. As RTX itself is not directly cytotoxic but relies on host immune effector mechanisms or chemotherapeutic agents to attack target cells, its therapeutic capacity may become limited when host effector mechanisms are compromised. Currently, refractory disease and relapse with NHL are still common, highlighting the need for novel anti-CD20 antibody strategies with superior therapeutic efficacy over current protocols. We hypothesized that making RTX directly cytotoxic might improve the therapeutic efficacy. Graphene oxide (GO) has recently emerged as a highly attractive nanomaterial for biomedical applications; and several studies have reported cytotoxic effect of GO on benign and malignant cells in vitro. Herein, we report that RTX can be stably associated with GO, and that GO-associated RTX (RTX/GO) demonstrates remarkably high avidity for CD20. Binding of GO-associated RTX to CD20-positive lymphoma cells induces CD20 capping and target cell death through an actin dependent mechanism. In vivo, GO-associated RTX, but not free RTX, quickly eliminates high-grade lymphomas in the absence of host effector mechanisms in a xenograft lymphoma mouse model. Our findings represent the first demonstration of using GO-associated antibody as effective cytotoxic therapy for human B cell malignancies in the absence of chemotherapy, and these findings could have important clinical implications.
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http://dx.doi.org/10.18632/oncotarget.7230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914323PMC
March 2016

Benign melanocytic lymph node deposits in the setting of giant congenital melanocytic nevi: the large congenital nodal nevus.

J Cutan Pathol 2015 Nov 18;42(11):832-9. Epub 2015 Sep 18.

Department of Dermatology, University of Utah, Salt Lake City, UT, USA.

Background: Benign melanocytic rests are a frequent finding in superficial lymph nodes removed during sentinel lymph node biopsies for melanoma. Whereas the histopathology of these deposits is well understood, very little is known regarding melanocytic lymph node deposits in the setting of giant congenital melanocytic nevi.

Methods: We analyzed lymph nodes removed from the drainage basin of giant congenital melanocytic nevi in three patients who had developed melanoma within their giant congenital nevi.

Results: Two of three patients showed widespread, capsular and parenchymal melanocytic deposits in multiple nodes (9 of 11 nodes in one patient and 6 of 8 in the other). Melanocytes were small, non-mitotically active and resembled those in the associated giant congenital melanocytic nevus. Melanocytes were arranged singly and in small nests ∼0.05 mm in diameter, with some larger sheets up to 1 mm. Nodal melanocytes stained for Melan A and S100 on immunohistochemical evaluation, but showed negative or minimal HMB-45 reactivity.

Conclusions: Evaluation of lymph nodes in the setting of giant congenital melanocytic nevi is complicated by the presence of often numerous, parenchymal melanocytic nevic deposits. Bland cytology and minimal or absent HMB-45 staining may be helpful in differentiating these nodal melanocytic nevi from metastatic melanoma. We term this phenomena large congenital nodal nevus.
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http://dx.doi.org/10.1111/cup.12580DOI Listing
November 2015

Extracellular Eosinophil Granule Protein Deposition in Ringed Esophagus with Sparse Eosinophils.

Dig Dis Sci 2015 Sep 23;60(9):2646-53. Epub 2015 Apr 23.

Department of Medicine, Health Sciences Center, University of Utah, Salt Lake City, UT, USA,

Background: Eosinophilic esophagitis (EoE) remains difficult to classify because of varying presentations. Not uncommonly, patients present with symptoms of esophageal dysfunction and have esophageal changes on endoscopy resembling EoE but without >15 eosinophils/HPF. Patients with low numbers of eosinophils in esophageal biopsy specimens may have esophageal changes and symptomatic disease brought about by eosinophil granule protein deposition without recognizable intact cells.

Aim: To determine whether extracellular eosinophil granule protein deposition is present in the esophagi of patients with low eosinophil numbers who have clinical symptoms and characteristic endoscopic esophageal changes of EoE including ringed esophagus (RE).

Methods: Esophageal biopsy specimens were studied from eight EoE patients with >15 eosinophils per high power field (HPF) and nine patients with RE (<15 eosinophils/HPF). The specimens were analyzed for eosinophil granule proteins, major basic protein 1 (eMBP1) and eosinophil-derived neurotoxin (EDN), by indirect immunofluorescence.

Results: Both EoE and RE showed positive EDN and eMBP1 extracellular deposition; control esophagus showed minimal or none. Comparing EoE and RE, extracellular EDN and eMBP1 were similar except that EDN in EoE was greater in the distal esophagus.

Conclusions: This study highlights the importance of assessing eosinophil granule protein deposition in esophageal disease with potential eosinophil involvement. Persistent/progressive esophageal changes may be brought about by eosinophil granule proteins despite low numbers of intact cells. The meaning of "resolution" in EoE may need to be redefined based on numbers of esophageal eosinophils, extracellular eosinophil granule protein deposition, and subsequent clinical course of patients.
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http://dx.doi.org/10.1007/s10620-015-3665-1DOI Listing
September 2015

Reply: To PMID 24907494.

Gastroenterology 2015 Feb 24;148(2):454. Epub 2014 Dec 24.

Gastroenterology Division, University of Utah School of Medicine, Salt Lake City, Utah.

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http://dx.doi.org/10.1053/j.gastro.2014.12.026DOI Listing
February 2015

Rapidly Fatal Internal Carotid Artery Mycotic Aneurysm Rupture in a Rheumatoid Patient Taking a TNF-α Inhibitor: Case Report and Literature Review.

J Neurol Surg A Cent Eur Neurosurg 2015 May 21;76(3):249-54. Epub 2014 Jul 21.

Department of Neurosurgery, University of Utah, Salt Lake City, Utah, United States.

Object: Tumor necrosis factor (TNF)-α inhibitors are effective at treating certain inflammatory and autoimmune disorders. They are generally safe; potential adverse events include infections (bacterial, fungal, and viral), congestive heart failure exacerbations, and the potential for demyelinating diseases and possibly certain malignancies. We present the first documented case of fungal internal carotid artery (ICA) mycotic aneurysm in a patient being treated with a TNF-α inhibitor. We also review the literature on infections with TNF-α inhibition and the management of previously reported fungal ICA mycotic aneurysm cases.

Case Description: A 76-year-old woman with rheumatoid arthritis, treated with etanercept and methotrexate, presented with a 2-week history of left temporal headaches. She was treated empirically for giant cell arteritis (GCA) with oral prednisone, which provided no symptom relief. She was subsequently hospitalized for a superficial temporal artery biopsy, which was negative for GCA. She returned 2 weeks later after experiencing a left thromboembolic ischemic stroke. She had an acute neurologic decline, and a head computed tomography scan showed diffuse subarachnoid hemorrhage from a ruptured left fusiform paraclinoid ICA aneurysm. She was taken emergently for a craniotomy for clip-wrapping of the aneurysm, but intraoperative ultrasound revealed poor flow in the left anterior cerebral circulation and a complete infarct of the left-sided anterior circulation. The family withdrew care and the patient died. Postmortem analysis demonstrated fungi consistent with Aspergillus invading the necrotic left ICA.

Conclusions: Although fungal mycotic aneurysms of the ICA are rare, their incidence may increase with the expanded use of immunosuppressive medications. Patients with rheumatoid arthritis who take potent immunosuppression regimens may be prime candidates for mycotic aneurysms because they often have two favoring conditions: atherosclerosis and immunosuppression. These ICA aneurysms carry a high mortality rate, so early diagnosis and aggressive therapy, potentially by endovascular trapping/vessel occlusion coupled with long-term antifungal therapy, is essential.
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http://dx.doi.org/10.1055/s-0034-1372435DOI Listing
May 2015

Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE.

Gastroenterology 2014 Sep 4;147(3):602-9. Epub 2014 Jun 4.

Gastroenterology Division, University of Utah School of Medicine, Salt Lake City, Utah.

Background & Aims: Eosinophilic esophagitis is usually triggered by foods, by unclear mechanisms. We evaluated the roles of IgE and IgG4 in the development of eosinophilic esophagitis.

Methods: We performed a prospective, randomized, double-blind, placebo-controlled trial of adults with eosinophilic esophagitis given an antibody against IgE (omalizumab, n = 16) or placebo (n = 14) every 2-4 weeks for 16 weeks, based on weight and serum level of IgE. Endoscopy was performed, esophageal biopsy specimens were collected, and symptoms were assessed at baseline and at 16 weeks. Maximum numbers of eosinophils/high-power field were determined. Homogenates of esophageal biopsy specimens from 11 subjects with eosinophilic esophagitis and 8 without (controls) were assessed for IgM, IgA, and IgG subclasses. In a retrospective analysis, we performed immunofluorescence analysis of IgG4 in fixed esophageal tissues from 2 patients with eosinophilic esophagitis who underwent esophagectomy and 47 consecutive autopsies (controls). We also performed immunofluorescence analysis of IgG4 in esophageal mucosal biopsy specimens from 24 subjects with eosinophilic esophagitis and 9 without (controls). Finally, sera were collected from 15 subjects with eosinophilic esophagitis and from 41 without (controls), and assayed for total and food-reactive IgG4.

Results: Omalizumab did not alter symptoms of eosinophilic esophagitis or eosinophil counts in biopsy samples compared with placebo. Homogenates of esophageal tissues from patients with eosinophilic esophagitis had a 45-fold increase in IgG4 compared with controls (P < 3 × 10(-5)), but no significant increases in other IgG subclasses, IgM, or IgA. Sparse stromal deposits resembling immune complexes were found in 2 of 5 eosinophilic esophagitis biopsy specimens based on ultrastructural analysis. Esophagectomy samples from 2 patients with eosinophilic esophagitis contained 180 and 300 IgG4 plasma cells/maximal high-power field, mainly in the deep lamina propria; these levels were greater than in tissues from controls. Fibrosis essentially was exclusive to the lamina propria. Granular extracellular IgG4 was detected in biopsy specimens from 21 of 24 patients with eosinophilic esophagitis, but in none of the specimens from 9 controls (P = 6 × 10(-6)). The total serum level of IgG4 increased only slightly in patients with eosinophilic esophagitis, compared with controls. Subjects with eosinophilic esophagitis had increased serum levels of IgG4 that reacted with milk, wheat, egg, and nuts-the 4 foods that most commonly trigger this condition (P ≤ 3 × 10(-4) for each food).

Conclusions: In a prospective trial, omalizumab did not reduce symptoms of eosinophilic esophagitis or tissue eosinophil counts compared with placebo. This finding, along with observed granular deposits of IgG4, abundant IgG4-containing plasma cells, and serum levels of IgG4 reactive to specific foods, indicate that, in adults, eosinophilic esophagitis is IgG4-associated, and not an IgE-induced allergy. ClinicalTrials.gov number: NCT 00123630.
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http://dx.doi.org/10.1053/j.gastro.2014.05.036DOI Listing
September 2014

⁹⁹mTechnetium-labeled heparin: a new approach to detection of eosinophilic esophagitis-associated inflammation.

J Allergy Clin Immunol 2013 Dec 26;132(6):1446-8. Epub 2013 Jul 26.

Department of Chemical Engineering, University of Utah, Salt Lake City, Utah. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2013.06.009DOI Listing
December 2013

Elemental diet induces histologic response in adult eosinophilic esophagitis.

Am J Gastroenterol 2013 May 5;108(5):759-66. Epub 2013 Feb 5.

Department of Gastroenterology, University of Utah Health Sciences Center, Salt Lake City, UT 84132, USA.

Objectives: Elemental diets have not been studied in adults with eosinophilic esophagitis (EoE). The goal of this trial was to assess the efficacy of an elemental diet in adults with EoE.

Methods: A total of 18 adults with EoE were given an elemental diet for 4 weeks, or just 2 weeks if their response was complete. Symptoms and histologic findings, based on biweekly biopsies, were monitored. Six subjects were rebiopsied 2-7 days after resuming a normal diet.

Results: After therapy, esophageal tissue eosinophil content decreased from 54 to 10 per maximal high power field (P=0.0006). There was complete or nearly complete response (≤10 eosinophils) in 72% of subjects. Mast cell content, parabasal layer thickness, and endoscopic furrows and exudates also significantly decreased. Of the 29 qualified subjects, 11 (38%) failed to adhere to the diet. Several subjects had significant weight loss. Symptoms and endoscopic fixed strictures did not improve. After the subjects resumed a normal diet, the eosinophil content increased substantially in 3-7 days.

Conclusions: While symptoms did not improve and dietary compliance was problematic, there was substantial histologic improvement after 4 weeks on the elemental diet. EoE in adults is substantially triggered by foods.
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http://dx.doi.org/10.1038/ajg.2012.468DOI Listing
May 2013

An inherited disorder with splenomegaly, cytopenias, and vision loss.

Am J Med Genet A 2012 Mar 3;158A(3):475-81. Epub 2012 Feb 3.

Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.

We describe a novel inherited disorder consisting of idiopathic massive splenomegaly, cytopenias, anhidrosis, chronic optic nerve edema, and vision loss. This disorder involves three affected patients in a single non-consanguineous Caucasian family, a mother and two daughters, who are half-sisters. All three patients have had splenectomies; histopathology revealed congestion of the red pulp, but otherwise no abnormalities. Electron microscopic studies of splenic tissue showed no evidence for a storage disorder or other ultrastructural abnormality. Two of the three patients had bone marrow examinations that were non-diagnostic. All three patients developed progressive vision loss such that the two oldest patients are now blind, possibly due to a cone-rod dystrophy. Characteristics of vision loss in this family include early chronic optic nerve edema, and progressive vision loss, particularly central and color vision. Despite numerous medical and ophthalmic evaluations, no diagnosis has been discovered.
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http://dx.doi.org/10.1002/ajmg.a.34437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242507PMC
March 2012

Using the modern Silverhawk™ atherectomy catheter to characterize biliary structures that appear malignant: review of initial experience.

HPB (Oxford) 2011 Nov;13(11):823-9

Department of General Surgery, Section of Transplantation, University of Utah School of Medicine, Salt Lake City, USA.

Background: Diagnosis of a biliary stricture often hinges on cytological interpretation. In the absence of accompanying stroma, these results can often be equivocal. In theory, advanced shave biopsy techniques would allow for the preservation of tissue architecture and a more accurate definition of biliary pathology.

Objectives: We sought to determine the initial diagnostic utility of the modern Silverhawk™ atherectomy (SA) catheter in the evaluation of biliary strictures that appear to be malignant.

Methods: A total of 141 patients with biliary pathology were identified during a retrospective review of medical records for the years 2006-2011. The SA catheter was employed 12 times in seven patients for whom a tissue diagnosis was otherwise lacking.

Results: Neoplasia was definitively excluded in seven specimens from four patients. These four individuals were followed for 1-5 years to exclude the development of cholangiocarcinoma (CC). Samples were positive for CC in three patients, one of whom became eligible for neoadjuvant therapy and orthotopic liver transplantation.

Conclusions: The SA catheter appears to be a useful adjunct in diagnosing patients with biliary pathology. The existence of this technique, predicated on tissue architecture, may impact therapy, allow more timely diagnosis, and exclude cases of equivocal cytology. Although the initial results of SA use are promising, more experience is required to effectively determine its clinical accuracy.
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http://dx.doi.org/10.1111/j.1477-2574.2011.00376.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238018PMC
November 2011

Palliative chemoradiation in advanced hepatocellular carcinoma.

J Clin Oncol 2010 May 22;28(15):e231-2. Epub 2010 Mar 22.

Department of Radiation Oncology, Huntsman Cancer Center, University of Utah, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1200/JCO.2009.25.6859DOI Listing
May 2010

Extraosseous Ewing's sarcoma.

J Clin Oncol 2007 Oct;25(30):4845-8

Department of Pathology, University of Utah, School of Medicine, Salt Lake City, UT, USA.

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http://dx.doi.org/10.1200/JCO.2007.13.0930DOI Listing
October 2007

Conditional deletion of beta1 integrins in the intestinal epithelium causes a loss of Hedgehog expression, intestinal hyperplasia, and early postnatal lethality.

J Cell Biol 2006 Nov;175(3):505-14

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.

Conditional deletion of beta1 integrins in the intestinal epithelium, unlike in epidermal and mammary epithelia, of mice does not result in decreased cell adhesion and proliferation, but instead causes a profound increase in epithelial proliferation with dysplasia and polypoid structures. The increased epithelial proliferation inhibited epithelial differentiation that caused severe malnutrition and early postnatal lethality. The striking similarities between beta1 integrin-deleted mice and neonatal mice with defective Hedgehog signaling led to the discovery that Hedgehog expression was markedly reduced in the former mice. beta1 integrins were found to drive the expression of Hedgehogs in intestinal epithelial cells in an HNF-3beta (Foxa2)-dependent fashion. The expression of Tcf-4, a transcription factor known to be required for intestinal epithelial stem cell proliferation, was increased and mislocalized in the intestinal epithelia of the beta1 integrin-deleted mice and in newborn mice treated with the Hedgehog signaling inhibitor cyclopamine. This study shows that beta1 integrins are key regulators of proliferation and homeostasis in the intestine and achieve this not through anchorage-dependent effects but by generating Hh expression and signaling.
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http://dx.doi.org/10.1083/jcb.200602160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064526PMC
November 2006

An unusual pathologic feature associated with dermatomyositis.

Neuromuscul Disord 2006 Jun 11;16(6):391-3. Epub 2006 May 11.

Department of Neurology, University of Utah, Salt Lake City, UT, USA.

We present a case of juvenile dermatomyositis with unusual histopathologic findings. The child presented with a course consistent with dermatomyositis, a diagnosis confirmed by finding reticulotubular aggregates in endothelial cells on electron microscopy. However, histopathology of his muscle biopsy revealed a striking pattern of glycogen accumulation, to an extent similar to that seen in glycogen storage diseases; this degree of accumulation could potentially confound histopathologic diagnosis.
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http://dx.doi.org/10.1016/j.nmd.2006.03.013DOI Listing
June 2006

Lipopolysaccharide upregulates renal shiga toxin receptors in a primate model of hemolytic uremic syndrome.

Am J Nephrol 2005 Nov-Dec;25(6):536-40. Epub 2005 Sep 22.

Department of Pathology, Salt Lake VA Medical Center, University of Utah School of Medicine, 50 N Medical Drive, Salt Lake City, 84132-2101, USA.

Background: Although Shiga toxin (Stx) mediates classical hemolytic uremic syndrome (HUS), it is not fully understood why only some subjects exposed to Stx-expressing Escherichia coli develop HUS. We have previously shown in a baboon model of Stx-mediated HUS that coadministration of lipopolysaccharide (LPS) results in an augmented host response to otherwise subtoxic Stx1 doses. We used this model to test the hypothesis that LPS upregulates renal Stx receptor (Gb(3)) expression.

Methods: Juvenile baboons were treated with either Stx1 (100 ng/kg), LPS (1 mg/kg as two divided doses 24 h apart), or a sham injection of saline, and sacrificed and immediately autopsied at 72 h. Renal cortical tissue Gb(3) content was quantitated by lipid extraction and thin-layer chromatography, and Stx1 and Gb(3)/CD77 immunostaining was assessed by quantitative immunofluorescent microscopy.

Results: Compared to saline-injected controls, LPS administration resulted in a 2.2-fold increase in renal cortical Gb(3) by chromatography (p < 0.01), a 2.5-fold increase in Stx1 staining (p = 0.003) and a 1.7-fold increase in CD77 immunostaining (p = 0.004). Stx treatment did not significantly alter either Stx or CD77 immunostaining.

Conclusion: These observations
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http://dx.doi.org/10.1159/000088523DOI Listing
February 2006

Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats.

Kidney Int 2005 Oct;68(4):1613-7

Department of Bone Marrow Transplantation, University of Hamburg, Hamburg, Germany.

Background: Adult stem cells are promising for the development of novel therapies in regenerative medicine. Acute renal failure (ARF) remains a frequent clinical complication, associated with an unacceptably high mortality rate, in large part due to the ineffectiveness of currently available therapies. The aim of this study was, therefore, to evaluate the therapeutic effectiveness of bone marrow-derived mesenchymal stem cells in a rat model of ischemia/reperfusion (I/R) ARF.

Methods: We used a common I/R model in rats to induce ARF by clamping both renal pedicles for 40 minutes. Mesenchymal stem cells were iron-dextran-labeled for in vivo tracking studies by magnetic resonance imaging (MRI) and kidneys were imaged for mesenchymal stem cells immediately after infusion and at day 3 after ARF. Renal injury was scored on day 3 and cells were additionally tracked by Prussian blue staining.

Results: We show in I/R-induced ARF in rats, modeling the most common form of clinical ARF, that infusion of mesenchymal stem cells enhances recovery of renal function. Mesenchymal stem cells were found to be located in the kidney cortex after injection, as demonstrated by MRI. Mesenchymal stem cells-treated animals had both significantly better renal function on days 2 and 3 and better injury scores at day 3 after ARF. Histologically, mesenchymal stem cells were predominantly located in glomerular capillaries, while tubules showed no iron labeling, indicating absent tubular transdifferentiation.

Conclusion: We conclude that the highly renoprotective capacity of mesenchymal stem cells opens the possibility for a cell-based paradigm shift in the treatment of I/R ARF.
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http://dx.doi.org/10.1111/j.1523-1755.2005.00573.xDOI Listing
October 2005

Novel application of a fibrin cell block method to evaluate melanocytic cell populations.

Pigment Cell Res 2003 Dec;16(6):662-9

Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.

Confirming melanocytic lineage and purity is important for experiments using cultured human melanocytes. The objective of this study was to develop a simple, reliable method to evaluate and archive cultured melanocytic cells. Melanocytes were isolated from adult skin biopsies or from neonatal foreskins using standard culturing methods. Fibrin cell blocks (FCBs) were prepared from cultured cells at passages two and six. Fibrin blocks were paraffin-embedded and sectioned for immunohistochemical (CD68, Melan-A, and HMB-45) and H & E staining. Flow cytometry was performed (Melan-A) at passage six. A mixing experiment with cultured melanocytes and fibroblasts was performed and cell population purity was determined by manual counts of positively staining cells in the FCBs and by flow cytometry. The FCB method of evaluating population purity was validated experimentally and by correlation with flow cytometry results. Preparation of a FCB followed by immunohistochemical staining is an easy and inexpensive way to confirm melanocytic lineage, estimate population purity, and provide a permanent archive of cultured cells.
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http://dx.doi.org/10.1046/j.1600-0749.2003.00095.xDOI Listing
December 2003

Shigatoxin-1 binding and receptor expression in human kidneys do not change with age.

Pediatr Nephrol 2003 Mar 7;18(3):246-53. Epub 2003 Feb 7.

Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah, USA.

Postdiarrheal hemolytic-uremic syndrome (D+HUS) occurs predominantly in young children. The rarity of D+HUS in adults has been ascribed to aging-associated loss of glomerular globotriaosylceramide (Gb3) expression, the major cognate receptor for shigatoxin. This belief, however, is based on relatively little data. The current study was undertaken to examine renal shigatoxin-1 (Stx-1) binding and Gb3 expression by human kidneys from varying aged subjects. Immunofluorescent staining and thin layer chromatography of neutral lipid extracts were performed. Abundant Stx-1 binding to both glomeruli and tubules was observed in frozen renal sections from all subjects of all ages (6 months to 85 years). The pattern of Stx-1 binding was identical between adults and children, with glomerular endothelial cells and cortical tubules being strongly labeled. Stx-1 binding affinity was similar between pediatric and adult kidneys. Antibodies to Gb3 showed a similar pattern and degree of staining regardless of donor age. In addition, Gb3 levels in glomeruli and tubules isolated from fresh kidney tissue were comparable between different aged donors. These data demonstrate that intrinsic renal binding of Stx-1 does not vary with age. It is suggested that factors other than basal renal Gb3 expression account for the age-related incidence of acute renal failure in D+HUS.
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http://dx.doi.org/10.1007/s00467-002-1025-9DOI Listing
March 2003

The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line.

J Biomed Sci 2003 Jan-Feb;10(1):156-66

Institut Méditerranéen de Recherche en Nutrition, UMR-INRA 1111, Faculté des Sciences de St-Jérôme, Marseille, France.

Background: Malabsorption and diarrhea are common, serious problems in AIDS patients, and are in part due to the incompletely understood entity HIV enteropathy. Our prior in vitro work has shown that increased transepithelial permeability and glucose malabsorption, similar to HIV enteropathy, are caused by HIV surface protein gp120, although the mechanism remains unclear.

Results: We studied the effects of HIV surface protein gp120 on the differentiated intestinal cell line HT-29-D4, specifically the effects on microtubules, transepithelial resistance, and sodium glucose cotransport. gp120 induced extensive microtubule depolymerization, an 80% decrease in transepithelial resistance, and a 70% decrease in sodium-dependent glucose transport, changes closely paralleling those of HIV enteropathy. The effects on transepithelial resistance were used to study potential inhibitors. Neutralizing antibodies to GPR15/Bob but not to CXCR4 (the coreceptor allowing infection with these HIV strains) inhibited these effects. Antibodies to galactosylceramide (GalCer) and a synthetic analog of GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelial cells.

Conclusion: We conclude that direct HIV infection and gp120-induced cytopathic effects are distinct phenomena. While in vivo confirmation is needed to prove this, gp120 could be a virotoxin significantly contributing to HIV enteropathy.
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http://dx.doi.org/10.1007/BF02256007DOI Listing
November 2003
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