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Introduction: Mdm2 inhibits p53 transactivation by forming a p53-Mdm2 complex on chromatin. Upon DNA damage-induced complex disruption, such latent p53 can be activated, but in cells overexpressing Mdm2 because of a homozygous single nucleotide polymorphism at position 309 (T --> G) of mdm2, the complex is highly stable and cannot be disrupted by DNA damage, rendering p53 inactive.Methods: To determine whether the p53 response phenotype is influenced differentially in cells with variable mdm2 genotypes, we compared responses to DNA damage and targeted p53-Mdm2 complex disruption by Nutlin-3 in the following wild-type p53 human cancer cell lines: A875 and CCF-STTG-1 (G/G for mdm2 SNP309), SJSA-1 (mdm2 genomic amplification and T/T for mdm2 SNP309), MCF-7 (estrogen-induced Mdm2 overexpression and T/G for mdm2 SNP309), ML-1 and H460 (T/T for mdm2 SNP309), and K562 (p53-null and T/G for mdm2 SNP309). We also examined mdm2 gene-splicing patterns in these lines by cloning and sequencing analyses.Results: While Mdm2-overexpressing G/G cells were resistant to p53 activation by DNA damage, they were sensitive to Nutlin-3. Strikingly, the p53 G1 checkpoint in G/G cells was activated by Nutlin-3 but not by etoposide, whereas in other Mdm2-overexpressing cells, both drugs activated p53 and subsequent G1 arrest or apoptosis. cDNA clones lacking exons 5-9 were generated at a high frequency in cells overexpressing Mdm2.Conclusion: Nutlin-3 and DNA damage distinguish a differential phenotype in human cancer cells with G/G mdm2 SNP309 from other Mdm2 overexpressers. Categorization of the Mdm2 isoforms produced and their influence on p53 activity will help in characterization and treatment development for different cancers. [ABSTRACT FROM AUTHOR]

Background: The mechanistic basis of the variable symptomatology seen in eosinophilic esophagitis (EoE) remains poorly understood., Objective: We examined the correlation of a validated, patient-reported outcome metric with a broad spectrum of esophageal transcripts to uncover potential symptom pathogenesis., Methods: We extracted data from 146 adults with EoE through the Consortium of Eosinophilic Gastrointestinal Disease Researchers. Patients were subgrouped by esophageal dilation history. We compared a validated patient-reported outcome metric, the EoE Activity Index (EEsAI), with a set of transcripts expressed in the esophagus of patients with EoE, the EoE Diagnostic Panel (EDP). We used single-cell RNA sequencing data to identify the cellular source of EEsAI-related EDP genes and further analyzed patients with mild and severe symptoms., Results: The EEsAI correlated with the EDP total score, especially in patients without recent esophageal dilation (r = -0.31; P = .003). We identified 14 EDP genes that correlated with EEsAI scores (r ≥ 0.3; P < .05). Of these, 11 were expressed in nonepithelial cells and three in epithelial cells. During histologic remission, only four of 11 nonepithelial genes (36%) versus all three epithelial genes (100%) had decreased expression to less than 50% of that in active EoE. Fibroblasts expressed five of 11 nonepithelial EEsAI-associated EDP genes (45%). A subset of nonepithelial genes (eight of 11; 73%), but not EoE-representative genes (none of four; 0%; CCL26, CAPN14, DSG1, and SPINK7), was upregulated in patients with EoE with the highest versus lowest symptom burden., Conclusion: The correlation of symptoms and nonepithelial esophageal gene expression substantiates that nonepithelial cells (eg, fibroblasts) likely contribute to symptom severity., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Because young children cannot self-report symptoms, there is a need for parent surrogate reports. Although early work suggested parent-child alignment for eosinophil esophagitis (EoE) patient-reported outcomes (PROs), the longitudinal alignment is unclear., Objective: We sought to assess the agreement and longitudinal stability of PROs between children with EoE and their parents., Methods: A total of 292 parent-child respondents completed 723 questionnaires over 5 years in an observational trial in the Consortium of Eosinophilic Gastrointestinal Disease Researchers. The change in and agreement between parent and child Pediatric Eosinophilic Esophagitis Symptom Score version 2 (PEESSv2.0) and Pediatric Quality of Life Eosinophilic Esophagitis Module (PedsQL-EoE) PROs over time were assessed using Pearson correlation and Bland-Altman analyses. Clinical factors influencing PROs and their agreement were evaluated using linear mixed models., Results: The cohort had a median disease duration equaling 3.7 years and was predominantly male (73.6%) and White (85.3%). Child and parent PEESSv2.0 response groups were identified and were stable over time. There was strong correlation between child and parent reports (PEESSv2.0, 0.83;PedsQL-EoE, 0.74), with minimal pairwise differences for symptoms. Longitudinally, parent-reported PedsQL-EoE scores were stable (P ≥ .32), whereas child-reported PedsQL-EoE scores improved (P = .026). A larger difference in parent and child PedsQL-EoE reports was associated with younger age (P < .001), and differences were driven by psychosocial PRO domains., Conclusions: There is strong longitudinal alignment between child and parent reports using EoE PROs. These data provide evidence that parent report is a stable proxy for objective EoE symptoms in their children., Competing Interests: Disclosure statement CEGIR (U54 AI117804) is part of the Rare Disease Clinical Research Network, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is funded through a collaboration between NIAID, the National Institute of Diabetes and Digestive and Kidney Diseases, and NCATS and funded in part by the Division of Intramural Research, NIAID. CEGIR is also supported by patient advocacy groups including the American Partnership for Eosinophilic Disorders, Campaign Urging Research for Eosinophilic Diseases, and Eosinophilic Family Coalition. As a member of the Rare Disease Clinical Research Network, CEGIR is supported by its Data Management and Coordinating Center (grant no. U2CTR002818). Funding support for the Data Management and Coordinating Center is provided by NCATS and the National Institute of Neurological Disorders and Stroke. G.S.H. is supported by a grant from the National Institutes of Health (NIH) (grant no. K23 DK131341). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Disclosure of potential conflict of interest: M. E. Rothenberg is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nexstone One, Santa Ana Bio, EnZen Therapeutics, Bristol Myers Squibb, AstraZeneca, Pfizer, GlaxoSmithKline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first 9 listed; receives royalties from Teva Pharmaceuticals (reslizumab), Mapi Research Trust (PEESSv2.0), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital. J. M. Spergel is a consultant for ReadySetfood, Regeneron/Sanofi, and ARS Pharma; has grant support from Novartis, Regeneron/Sanofi, Bristol Myers Squibb, Food Allergy Research and Education (FARE), and NIH; receives royalties from UpToDate; and serves on the Data Safety and Monitoring Board for Alladapt and NIAID. M. H. Collins is a consultant for Allakos, Arena/Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, Robarts Clinical Trials, Inc/Alimentiv, Inc, and Shire/Takeda. S. S Aceves is a consultant and an educational speaker for Regeneron/Sanofi; has grant support from the NIH, Campaign Urging Research for Eosinophilic Diseases, Bristol Myers Squibb, and Implicit Biosciences; and is a coinventor of oral viscous budesonide patented by the University of California San Diego and licensed by Takeda. M. Pletneva is a consultant for Allakos. S. K. Gupta is a consultant and/or Data Safety and Monitoring Board member for Adare, Bristol Myers Squibb, QOL, Takeda, Medscape, PVI, ViaSkin, and UpToDate; and receives research support from Allakos, Ellodi, and AstraZeneca. J. B. Wechsler is a consultant for Bristol Myers Squibb, Ellodi, AstraZeneca, Allakos, and Regeneron/Sanofi; and receives research support from Regeneron. N. Gonsalves is a consultant for AstraZeneca, Allakos, Sanofi/Regeneron, AbbVie, Knopp, and Bristol Myers Squibb; is on the speaker bureau for Sanofi/Regeneron; and receives publication royalties from UpToDate. G. W. Falk is a consultant for Allakos, Bristol Myers Squibb/Celgene, Adare/Ellodi, Nexstone, Upstream Bio, and Sanofi/Regeneron; and receives research support from Allakos, Adare/Ellodi, Bristol Myers Squibb/Celgene, and Regeneron/Sanofi. I. Hirano has received research funding from Adare Pharmaceuticals/Ellodi Pharmaceuticals, Allakos, AstraZeneca, Meritage Pharma, Inc, Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, and Shire/Takeda; and is a consultant for Adare Pharmaceuticals/Ellodi Pharmaceuticals, Allakos, Arena Pharmaceuticals, Aslan Pharmaceuticals, AstraZeneca, Calyx/Parexel, Celldex Therapeutics, Inc, Dermavant, EsoCap Biotech, Gossamer Bio, Eli Lilly, Nexstone, Meritage Pharma, Inc, Phathom Pharmaceuticals, Receptos/Celgene/Bristol Myers Squibb, Sanofi/Regeneron Pharmaceuticals, and Shire/Takeda. M. Chehade has received consultant fees from Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, Bristol Myers Squibb, Recludix Pharma, Allakos, Shire/Takeda, and Phathom; and has received research support from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone. C. M. Davis has received grant funding from DBV Technologies, Aimmune Therapeutics, Regeneron Pharmaceuticals, and Allergenis. E. S. Dellon is a consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/Bristol Myers Squibb, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GlaxoSmithKline, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio; has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GlaxoSmithKline, Meritage, Miraca, Nutricia, Celgene/Receptos/Bristol Myers Squibb, Regeneron, Revolo, and Shire/Takeda; and has received an educational grant from Allakos, Aqilion, Holoclara, and Invea. G. T. Furuta is Chief Medical Officer for EnteroTrack; and receives research funding from Arena/Pfizer. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: The Index of Severity for Eosinophilic Esophagitis (I-SEE) is a new expert-defined clinical tool that classifies disease severity of eosinophilic esophagitis (EoE)., Objective: We aimed to determine whether I-SEE is associated with patient characteristics, molecular features of EoE, or both., Methods: We analyzed a prospective cohort of patients with EoE from the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). Associations between I-SEE and clinical and molecular features (assessed by an EoE diagnostic panel [EDP]) were assessed., Results: In 318 patients with chronic EoE (209 adults, 109 children), median total I-SEE score was 7.0, with a higher symptoms and complications score in children than adults (4.0 vs 1.0; P < .001) and higher inflammatory and fibrostenotic features scores in adults than children (3.0 vs 1.0 and 3.0 vs 0, respectively; both P < .001). Total I-SEE score had a bimodal distribution with the inactive to moderate categories and severe category. EDP score correlated with total I-SEE score (r = -0.352, P < .001) and both inflammatory and fibrostenotic features scores (r = -0.665, P < .001; r = -0.446, P < .001, respectively), but not with symptoms and complications scores (r = 0.047, P = .408). Molecular severity increased from inactive to mild and moderate, but not severe, categories. Longitudinal changes of modified I-SEE scores and inflammatory and fibrostenotic features scores reflected histologic and molecular activity., Conclusions: I-SEE score is associated with select clinical features across severity categories and with EoE molecular features for nonsevere categories, warranting further validation., Competing Interests: Disclosure statement Supported by National Institutes of Health (NIH) grant K99/R00 AI158660 (to T.S.) and the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR, U54 AI117804), which is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS), and is cofunded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NCATS, and in part by the Intramural Research Program of NIAID. CEGIR is also supported by patient advocacy groups, including the American Partnership for Eosinophilic Disorders (APFED), Campaign Urging Research for Eosinophilic Disease (CURED), and Eosinophilic Family Coalition (EFC). As a member of the RDCRN, CEGIR is also supported by its Data Management and Coordinating Center (DMCC) (U2CTR002818). Funding support for the DMCC is provided by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). This project was supported in part by NIH P30 DK078392 (Gene Expression Core, Pathology Research Core, and Confocal Imaging Core) of the Digestive Diseases Research Core Center in Cincinnati. Disclosure of potential conflict of interest: E. S. Dellon is consultant for Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/ Bristol Meyers Squibb (BMS), Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. E. S. Dellon has received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda; and has received educational grants from Allakos, Holoclara, and Invea. S. S. Aceves is disease state awareness speaker and consultant for Sanofi/Regeneron, consultant for Ferring Pharma; has research funding from Implicit Biosciences and BMS; and is a coinventor of oral viscous budesonide UCSD patent, Takeda license. M. Chehade served as consultant for Regeneron, Adare/Ellodi, AstraZeneca, Sanofi, BMS, Allakos, Shire/Takeda, Phathom, Recludix Pharma, Nexstone Immunology; and received research funding from Regeneron, Allakos, AstraZeneca, Adare/Ellodi, BMS, Danone, and Shire/Takeda. M. H. Collins is consultant for Allakos, Arena Pharmaceuticals, AstraZeneca, BMS, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene, Regeneron Pharmaceuticals, Robarts Clinical Trials/Alimentiv, Sanofi, and Shire/Takeda. C. M. Davis receives research funding from the NIH/NIAID (U01AI126614, UM2AI130836, U54AI117804), DBV Technologies, Aimmune Therapeutics, Regeneron Pharmaceuticals, Takeda, and Allergenis. G. W. Falk is consultant for Ellodi, Sanofi/Regeneron, BMS/Celgene, Takeda, Ubiquity Bio, and Phathom Pharmaceuticals; and receives research funding from Arena/Pfizer, Ellodi, Sanofi/Regeneron, BMS/Celgene, Takeda, Allakos, Nexteos, and Celldex Therapeutics. G. T. Furuta receives research funding from Pfizer/Arena; is consultant for Sanofi/Regeneron and BMS; and is chief medical officer for EnteroTrack. N. P. Gonsalves is consultant for Allakos, AstraZeneca, BMS, and Sanofi/Regeneron; is speaker for Sanofi/Regeneron; and receives publication royalties from UpToDate. S. K. Gupta is consultant/data safety monitoring board member of Adare, BMS, QOL, Takeda, MedScape, PVI, ViaSkin, and UpToDate; and receives research funding from Allakos, Ellodi, and AstraZeneca. I. Hirano has received research funding from Ellodi/Adare, Allakos, Pfizer/Arena Pharmaceuticals, AstraZeneca, Meritage Pharma, Receptos/Celgene, Sanofi, Regeneron, and Shire/Takeda; and is is consultant for Ellodi/Adare, Allakos, AstraZeneca, BMS/Receptos/Celgene, Calyx/Parexel, EsoCap Biotech, Gossamer Bio, Lilly, Meritage Pharma, Pfizer/Arena Pharmaceuticals, Phathom, Sanofi/Regeneron, and Shire/Takeda. K. A. Peterson is consultant/advisory for AGA, Alladapt, AstraZeneca, Allakos, BMS, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, Takeda, and WebMD; receives research funding from AstraZeneca, Allakos, Regeneron-Sanofi, Revolo, Adare, Ellodi, BMS, and Celldex; is speaker for AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; has grant support (unrestricted) from Allakos; and has equity in Nexeos Bio. M. A. Pletneva is consultant for Allakos and Sanofi/Regeneron. J. M. Spergel is consultant for Novartis, Regeneron, and Sanofi; and receives grant support from Regeneron and Sanofi. J. B. Wechsler is speaker for Sanofi/Regeneron; and consultant for Sanofi/Regeneron, Celldex, Celgene/Receptos/BMS, Allakos, Ellodi, and AstraZeneca. M. E. Rothenberg is consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, BMS, AstraZeneca, Ellodi Pharma, Glaxo Smith Kline, Sanofi/Regeneron, Revolo Biotherapeutics, and Guidepoint; has equity interest in the first 6 listed; receives royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust), and UpToDate; and is an inventor of patents owned by Cincinnati Children’s Hospital Medical Center. T. Shoda is a coinventor of patents owned by Cincinnati Children’s Hospital Medical Center. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Microscopic examination of esophageal biopsies is essential to diagnose eosinophilic esophagitis (EoE). Eosinophil inflammation is the basis for the diagnosis, but additional abnormalities may contribute to persistent symptoms and epithelial barrier dysfunction. Both peak eosinophil count and assessments of additional features should be included in pre-therapy and post-therapy pathology reports. Pathologic abnormalities identified in esophageal biopsies of EoE are reversible in contrast to esophageal strictures., Competing Interests: Disclosures M.H. Collins is a consultant for Allakos, Arena/Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc./Alimentiv, Inc. and Shire, a Takeda company. M. Pletneva is a consultant for Allakos. N.C. Arva, A. Bernieh, O. Lopez-Nunez and G.-Y. Yang do not have conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The relationship between histopathologic and molecular ("MMDx"®) assessments of endomyocardial biopsy (EMB) and serum donor-derived cell-free DNA (ddcfDNA) in acute rejection (AR) assessment following pediatric heart transplantation (HT) is unknown., Methods: EMB sent for MMDx and histopathology from November 2021 to September 2022 were reviewed. MMDx and histopathology results were compared. DdcfDNA obtained ≤1 week prior to EMB were compared with histopathology and MMDx results. The discrimination of ddcfDNA for AR was assessed using receiver-operating curves., Findings: In this study, 177 EMBs were obtained for histopathology and MMDx, 101 had time-matched ddcfDNA values. MMDx and Histopathology displayed moderate agreement for T-cell-mediated rejection (TCMR, Kappa = 0.52, p < .001) and antibody-mediated rejection (ABMR, Kappa = 0.41, p < .001). Discordant results occurred in 24% of cases, most often with ABMR. Compared with no AR, ddcfDNA values were elevated in cases of AR diagnosed by both histopathology and MMDx (p < .01 for all). Additionally, ddcfDNA values were elevated in injury patterns on MMDx, even when AR was not present (p = .01). DdcfDNA displayed excellent discrimination (AUC 0.83) for AR by MMDx and/or histopathology. Using a threshold of ≥0.135%, ddcfDNA had a sensitivity of 90%, specificity of 63%, PPV of 52%, and NPV of 94%., Conclusions: Histopathology and MMDx displayed moderate agreement in diagnosing AR following pediatric HT, with most discrepancies noted in the presence of ABMR. DdcfDNA is elevated with AR, with excellent discrimination and high NPV particularly when utilizing MMDx. A combination of all three tests may be necessary in some cases., (© 2024 Wiley Periodicals LLC.)

Eosinophilic gastrointestinal diseases (EGID), such as eosinophilic gastritis (EoG), eosinophilic enteritis, and eosinophilic colitis (EoC), are chronic inflammatory conditions characterized by persistent gastrointestinal symptoms and elevated levels of activated eosinophils in the gastrointestinal tract. EoG and eosinophilic duodenitis (EoD) are strongly associated with food allergen triggers and T H 2 inflammation, whereas EoC shows minimal transcriptomic overlap with other EGIDs. The level of expression of certain genes associated with T H 2 immune response is associated with certain histopathologic findings of EoG, EoD, and EoC. Current immune therapy for EoG depletes tissue eosinophilia with persistence of other histopathologic features of disease., Competing Interests: Disclosures M. Pletneva is a consultant for Allakos. M.H. Collins is a consultant for Allakos, Arena/Pfizer, AstraZeneca, Calypso Biotech, EsoCap Biotech, GlaxoSmithKline, Receptos/Celgene/BMS, Regeneron Pharmaceuticals, Robarts Clinical Trials Inc./Alimentiv, Inc. and Shire, a Takeda company. N.C. Arva, A. Bernieh, O. Lopez-Nunez, and G-Y. Yang do not have conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context.—: Mast cells are essential components of the immune system and play crucial pathogenetic roles in several digestive diseases, including mastocytic enterocolitis and eosinophilic gastrointestinal disorders. Pathologists have rarely been asked to evaluate the distribution and density of mast cells in gastrointestinal (GI) biopsy specimens. However, such requests are becoming more common because of an increasing awareness of the role of mast cells in functional GI disease and in both esophageal and nonesophageal eosinophilic gastrointestinal disorders., Objective.—: To provide pathologists with tools to incorporate the assessment of mast cells in the evaluation of esophageal, gastric, and intestinal specimens by developing a systematic approach to their evaluation, counting, and reporting., Design.—: This study consisted of a review of the literature followed by multiple consensus sessions to decide where to count mast cells and what a countable mast cell is., Results.—: We reviewed 135 papers addressing the content of mast cells in the digestive tract, selected 21 that detailed how cells were counted (microscope lens, area of high-power fields, locations evaluated, type of cells considered as countable), and summarized their data in a table. Then, drawing from both the acceptable literature and our own extensive experience, we reached a tentative consensus on: (1) the normal numbers in the different segments of the GI tract; (2) the morphology of countable mast cells; and (3) the locations and strategies for counting them., Conclusions.—: The result is a set of suggestions for reporting mast cell counts, their distribution, and their location in a way clinicians can understand and use for management decisions., (© 2024 College of American Pathologists.)

Background: Chronic graft failure (CGF) in pediatric heart transplant (PHT) is multifactorial and may present with findings of fibrosis and microvessel disease (MVD) on endomyocardial biopsy (EMB). There is no optimal CGF surveillance method. We evaluated associations between cardiac magnetic resonance imaging (CMR) and historical/EMB correlates of CGF to assess CMR's utility as a surveillance method., Methods: Retrospective analysis of PHT undergoing comprehensive CMR between September 2015 and January 2022 was performed. EMB within 6 months was graded for fibrosis (scale 0-5) and MVD (number of capillaries with stenotic wall thickening per field of view). Correlation analysis and logistic regression were performed., Results: Forty-seven PHT with median age at CMR of 15.7 years (11.6, 19.3) and time from transplant of 6.4 years (4.1, 11.0) were studied. Cardiac allograft vasculopathy (CAV) was present in 11/44 (22.0%) and historical rejection in 14/41 (34.2%). CAV was associated with higher global T2 (49.0 vs. 47.0 ms; p = 0.038) and peak T2 (57.0 vs. 53.0 ms; p = 0.013) on CMR. Historical rejection was associated with higher global T2 (49.0 vs. 47.0 ms; p = 0.007) and peak T2 (57.0 vs. 53.0 ms; p = 0.03) as well as global extracellular volume (31.0 vs. 26.3%; p = 0.03). Higher fibrosis score on EMB correlated with smaller indexed left ventricular mass (rho = -0.34; p = 0.019) and greater degree of MVD with lower indexed left ventricular end-diastolic volume (rho = -0.35; p = 0.017)., Conclusion: Adverse ventricular remodeling and abnormal myocardial characteristics on CMR are present in PHT with CAV, historical rejection, as well as greater fibrosis and MVD on EMB. CMR has the potential use for screening of CGF., (© 2023 Wiley Periodicals LLC.)

Background: The conventionally understood pathogenesis of agminated Spitz nevi includes a mosaic HRAS mutation followed by copy number gains in 11p. However, we have recently observed agminated presentations of fusion-driven melanocytic neoplasms., Methods: We retrieved cases from our database of benign fusion-induced melanocytic neoplasms with an agminated presentation. Both the primary lesion and the secondary lesion were sequenced. TERT-promoter mutational testing and the melanoma fluorescence in situ hybridization assay were also performed., Results: Three cases were included. Two had a PRKCA fusion (partners ATP2B4 and MPZL1) and one had a ZCCHC8::ROS1 fusion. None of the cases met morphologic or molecular criteria for malignancy. There was no evidence of tumor progression in secondary lesions. The same fusion was identified in the primary and secondary lesions. None of the patients developed evidence of nodal or systemic metastasis., Conclusions: We present accumulating evidence that fusion-driven melanocytic neoplasms can present with an agminated presentation. The differential diagnosis of an agminated presentation versus a locally recurrent or potentially locally metastatic tumor is critical, and accurate diagnosis has significant prognostic and therapeutic consequences for the patient. As with HRAS mutations, fusion-driven melanocytic tumors may have an agminated presentation., (© 2023 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background & Aims: The nature of the involvement of esophageal tissue in eosinophilic esophagitis (EoE) is unclear. We estimated the intrabiopsy site agreements of the EoE Histologic Scoring System (EoEHSS) scores for the grade (degree) and stage (extent) of involvement of the esophageal epithelial and lamina propria and examined if the EoE activity status influenced the intrabiopsy site agreement., Methods: Demographic, clinical, and EoEHSS scores collected as part of the prospective Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages study were analyzed. A weighted Cohen's kappa agreement coefficient (k) was used to calculate the pairwise agreements for proximal:distal, proximal:middle, and middle:distal esophageal biopsy sites, separately for grade and stage scores, for each of the 8 components of EoEHSS. A k > 0.75 was considered uniform involvement. Inactive EoE was defined as fewer than 15 eosinophils per high-powered field., Results: EoEHSS scores from 1263 esophageal biopsy specimens were analyzed. The k for the stage of involvement of the dilated intercellular spaces across all 3 sites in inactive EoE was consistently greater than 0.75 (range, 0.87-0.99). The k for lamina propria fibrosis was greater than 0.75 across some of the biopsy sites but not across all 3. Otherwise, the k for all other features, for both grade and stage, irrespective of the disease activity status, was 0.75 or less (range, 0.00-0.74)., Conclusions: Except for the extent of involvement of dilated intercellular spaces in inactive EoE, the remaining epithelial features and lamina propria are involved unevenly across biopsy sites in EoE, irrespective of the disease activity status. This study enhances our understanding of the effects of EoE on esophageal tissue pathology., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To outline our experimental gonadal tissue cryopreservation (GTC) protocol that does not disrupt the standard of care in medically-indicated gonadectomy for patients with differences of sex development, including highlighting the multidisciplinary collaborative protocol for when neoplasm is discovered in these cases., Methods: Two patients with complete gonadal dysgenesis who were undergoing medically-indicated prophylactic bilateral gonadectomy elected to pursue GTC. Both were found to have germ cell neoplasia in situ on initial pathologic analysis, requiring recall of the gonadal tissue, which had been cryopreserved., Results: Cryopreserved gonadal tissue was successfully thawed and transferred to pathology for complete analysis. No germ cells were identified in either patient nor were found to have malignancy, so further treatment beyond gonadectomy was not indicated. Pathologic information was communicated to each family, including that long-term GTC was no longer possible., Conclusion: Organizational planning and coordination between the clinical care teams, GTC laboratory, and pathology were key to handling these cases with neoplasia. Processes that anticipated the possibility of discovering neoplasia within tissue sent to pathology and the potential need to recall GTC tissue to complete staging included (1) documenting the orientation and anatomical position of tissue processed for GTC, (2) defining parameters in which tissue will be recalled, (3) efficiently thawing and transferring GTC tissue to pathology, and (4) coordinating release of pathology results with verbal communication from the clinician to provide context. GTC is desired by many families and at the time of gonadectomy and is (1) feasible for patients with DSD, and (2) did not inhibit patient care in 2 patients with GCNIS., Competing Interests: DECLARATION OF COMPETING INTEREST Authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We investigated reproducibility and generalizability of the recently developed web-based model to predict lamina propria fibrosis (LPF) in esophageal biopsies with inadequate lamina propria (LP) from patients with eosinophilic esophagitis (EoE) using an independent dataset (N = 183). For grade and stage scores of LPF, the area under the curve for predictive model was 0.77 (0.69-0.84) and 0.75 (0.67-0.82), and its accuracy was 78% and 72%, respectively. These model performance metrics were similar to that of the original model. A significant positive correlation was noted between the models' predictive probability and the grade and stage of LPF assessed by a pathologist (grade: r2 = 0.48, P < 0.001; and stage: r2 = 0.39, P < 0.001). These results support the reproducibility and generalizability of the web-based model to predict the presence of LPF in esophageal biopsies with inadequate LP in EoE. Additional studies are warranted to refine the web-based predictive models to provide predictive probability for sub-scores of LPF severity., Competing Interests: G.H. is a consultant for Allakos, Bristol Myers Squibb, Regeneron, and has received speaker fees from Bristol Myer Squibb. J.B.W. is a consultant for Regeneron/Sanofi, InVea Therapeutics, and AstraZeneca, has received research funding from Allakos and Regeneron/Sanofi, and has received speaker fees from Regeneron/Sanofi. The remaining author reports no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background: Empirical elimination diets are effective for achieving histological remission in eosinophilic oesophagitis, but randomised trials comparing diet therapies are lacking. We aimed to compare a six-food elimination diet (6FED) with a one-food elimination diet (1FED) for the treatment of adults with eosinophilic oesophagitis., Methods: We conducted a multicentre, randomised, open-label trial across ten sites of the Consortium of Eosinophilic Gastrointestinal Disease Researchers in the USA. Adults aged 18-60 years with active, symptomatic eosinophilic oesophagitis were centrally randomly allocated (1:1; block size of four) to 1FED (animal milk) or 6FED (animal milk, wheat, egg, soy, fish and shellfish, and peanut and tree nuts) for 6 weeks. Randomisation was stratified by age, enrolling site, and gender. The primary endpoint was the proportion of patients with histological remission (peak oesophageal count <15 eosinophils per high-power field [eos/hpf]). Key secondary endpoints were the proportions with complete histological remission (peak count ≤1 eos/hpf) and partial remission (peak counts ≤10 and ≤6 eos/hpf) and changes from baseline in peak eosinophil count and scores on the Eosinophilic Esophagitis Histology Scoring System (EoEHSS), Eosinophilic Esophagitis Endoscopic Reference Score (EREFS), Eosinophilic Esophagitis Activity Index (EEsAI), and quality of life (Adult Eosinophilic Esophagitis Quality-of-Life and Patient Reported Outcome Measurement Information System Global Health questionnaires). Individuals without histological response to 1FED could proceed to 6FED, and those without histological response to 6FED could proceed to swallowed topical fluticasone propionate 880 μg twice per day (with unrestricted diet), for 6 weeks. Histological remission after switching therapy was assessed as a secondary endpoint. Efficacy and safety analyses were done in the intention-to-treat (ITT) population. This trial is registered on ClinicalTrials.gov, NCT02778867, and is completed., Findings: Between May 23, 2016, and March 6, 2019, 129 patients (70 [54%] men and 59 [46%] women; mean age 37·0 years [SD 10·3]) were enrolled, randomly assigned to 1FED (n=67) or 6FED (n=62), and included in the ITT population. At 6 weeks, 25 (40%) of 62 patients in the 6FED group had histological remission compared with 23 (34%) of 67 in the 1FED group (difference 6% [95% CI -11 to 23]; p=0·58). We found no significant difference between the groups at stricter thresholds for partial remission (≤10 eos/hpf, difference 7% [-9 to 24], p=0·46; ≤6 eos/hpf, 14% [-0 to 29], p=0·069); the proportion with complete remission was significantly higher in the 6FED group than in the 1FED group (difference 13% [2 to 25]; p=0·031). Peak eosinophil counts decreased in both groups (geometric mean ratio 0·72 [0·43 to 1·20]; p=0·21). For 6FED versus 1FED, mean changes from baseline in EoEHSS (-0·23 vs -0·15; difference -0·08 [-0·21 to 0·05]; p=0·23), EREFS (-1·0 vs -0·6; difference -0·4 [-1·1 to 0·3]; p=0·28), and EEsAI (-8·2 vs -3·0; difference -5·2 [-11·2 to 0·8]; p=0·091) were not significantly different. Changes in quality-of-life scores were small and similar between the groups. No adverse event was observed in more than 5% of patients in either diet group. For patients without histological response to 1FED who proceeded to 6FED, nine (43%) of 21 reached histological remission; for patients without histological response to 6FED who proceeded to fluticasone propionate, nine (82%) of 11 reached histological remission., Interpretation: Histological remission rates and improvements in histological and endoscopic features were similar after 1FED and 6FED in adults with eosinophilic oesophagitis. 6FED had efficacy in just less than half of 1FED non-responders and steroids had efficacy in most 6FED non-responders. Our findings indicate that eliminating animal milk alone is an acceptable initial dietary therapy for eosinophilic oesophagitis., Funding: US National Institutes of Health., Competing Interests: Declaration of interests NG receives royalties from UpToDate; is a consultant for Allakos, Regeneron-Sanofi, AstraZeneca, AbbVie, Takeda, Knopp, Bristol Meyers Squibb, and Nutricia; and has received payment or honoraria for speaker's bureaus for Takeda and Regeneron-Sanofi. ESD has received research support from Ellodi (formerly Adare), Allakos, Arena, AstraZeneca, GlaxoSmithKline, Meritage, Miraca, Nutricia, Celgene (formerly Receptos and a subsidiary of Bristol Myers Squibb), Regeneron, Revolo, and Shire (a subsidiary of Takeda); is a consultant for Abbott, AbbVie, Ellodi, Aimmune, Akesobio, Allakos, Amgen, Arena, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene, Celldex, Eli Lilly, EsoCap, GlaxoSmithKline, Gossamer Bio, Invea, Landos, Lucid Diagnostics, Morphic, Nutricia, Calyx (formerly Parexel), Phathom, Regeneron, Revolo, Alimentiv (formerly Robarts), Salix, Sanofi, Shire, and Target RWE; and has education grants with Allakos, Banner, and Holoclara. DAK has received consulting fees and payments for presentations from Celgene; has served on a data and safety monitoring board at the University of North Carolina; and serves on the governing board of the American Gastroenterological Association. JPA has received research support from Cures Within Reach and Celgene; has received payment or honoraria for lectures from Takeda; and has served on a data and safety monitoring board for Octapharma USA. SSA has received research support from Implicit Biosciences and the Campaign Urging Research for Eosinophilic Disease (CURED) Foundation; has received consulting fees from Bristol Meyers Squibb, Regeneron-Sanofi, and AstraZeneca; has received payment for presentations or events from Regeneron-Sanofi; and receives patent royalties and is co-inventor of oral viscous budesonide, patented by University of California San Diego and licensed by Shire. KEC is employed by and has an equity interest in Alnylam. MC has received consulting fees from Regeneron, Allakos, Ellodi, Shire, AstraZeneca, Sanofi, Bristol Myers Squibb, Phathom; has received research support from Regeneron, Allakos, Shire, AstraZeneca, Ellodi, and Danone; and holds leadership roles in the American Partnership for Eosinophilic Disorders (APFED) and the American Academy of Allergy, Asthma and Immunology (AAAAI). AC has received research support from Aimmune and DBV Technologies; has served on a data and safety monitoring board for Regeneron, Sanofi, AstraZeneca, and DBV Technologies; and holds leadership roles in the AAAAI, European Academy of Allergy and Clinical Immunology, and American College of Allergy, Asthma and Immunology. MHC is a consultant for Allakos, AstraZeneca, Bristol Myers Squibb, Esocap, GlaxoSmithKline, Shire, Regeneron, Celgene, Sanofi, and Ellodi; has received research funding from Shire, Regeneron, Celgene, and AstraZeneca; holds leadership roles in the APFED, CURED Foundation, and The International Gastrointestinal Eosinophil Researchers; and has received travel support from Regeneron and Celgene. GWF is a consultant for Ellodi, Allakos, Celgene, Lucid, Nexstone, Phathom, Regeneron, Bristol Myers Squibb, Upstream Bio, and Shire; has served on a data and safety monitoring board for Revolo; has a leadership role in the International Society for Diseases of the Esophagus; and has equity in Bristol Myers Squibb. SKG has received research support from Allakos, Ellodi, and AstraZeneca; receives royalties from UpToDate; is a consultant for Ellodi, Bristol Myers Squibb, QOL Medical, Takeda, and Viaskin; has received payment from Medscape and PeerView Institute for Medical Education; has served on a data and safety monitoring board for Bristol Myers Squibb; and has a leadership role in the Association of Pediatric Gastroenterology and Nutrition Nurses, American Gastroenterological Association, and Journal of Pediatric Gastroenterology and Nutrition. JL has received research funding AstraZeneca, Allakos, Takeda, Provention Bio, Ellodi, Arena Pharmaceuticals, GI Health Foundation, Ellodi, ALK Abelló, Revolo Biotherapeutics, Bristol Myers Squibb, Regeneron, Phathom Pharmaceuticals; has received consulting fees from Guidepoint, Takeda, Third Bridge, Boston Consulting Group, AbbVie, Sanofi, Huron Consulting Services, Ribon Therapeutics, Tegus, Slingshot, Cowen, and AstraZeneca; has received speaker payments from Regeneron, Sanofi, AGA Carney, AGA Tufts, and Maine Medical Center; has received payment for expert testimony for Devine, Millimet and Branch Professional Education; and has a leadership role with Kwong Kow Chinese School. IH has received consulting fees from Ellodi, AstraZeneca, Arena, Allakos, Calyx (formerly Parexel), Celgene, Celldex, Regeneron, Esocap, Gossamer Bio, Lilly, Phathom, Sanofi, and Shire; has received research funding Meritage, Ellodi, Celgene, Regeneron-Sanofi, and Shire; and participated in a speaker bureau for Regeneron and Sanofi. LJM has received honoraria from Akron's Children's Hospital and is co-inventor on a patent for Cysteamine. VAM has received consulting fees from Shire, Allakos, Regeneron, and Sanofi; and has received research funding and support from Meritage and Shire. KAP has received research support from Allakos, Ellodi, AstraZeneca, Chobani, Regeneron-Sanofi, and Revolo; is a consultant for AGA, AstraZeneca, Allakos, Bristol Meyers Squibb, Ellodi, Invea, Lucid, Nexstone, WebMD, Peerview, Regeneron, Revolo, and Takeda; has received speaker payments from AGA, Regeneron, Peerview, Takeda, Allakos, and WebMD; has served on a data and safety monitoring board for Alladapt; and has a patent and stock options with Nexeos Bio. JMS is a consultant for Regeneron, Sanofi, DBV Technology, Ready Set Food, and Kaleo; has received research support from Regeneron-Sanofi, Food Allergy Research and Education, and Novartis; and has received royalties from UpToDate. GTF is Chief Medical Officer of EnteroTrack; and is a consultant for Shire. MER is a consultant for AstraZeneca, Bristol Myers Squibb, Regeneron-Sanofi, Revolo Biotherapeutics, Celldex, Nexstone One, and Guidepoint; has received research support from AstraZeneca, Regeneron-Sanofi, GlaxoSmithKline, the CURED Foundation, Food Allergy Fund, and a US–Israel Binational Grant (number 2019016); has equity interest in PulmOne Therapeutics, Spoon Guru, ClostraBio, Serpin Pharm, Celldex, Nextstone One, and Allakos; receives royalties from Ception Therapeutics (for reslizumab), Mapi Research Trust (for the Pediatric Eosinophilic Esophagitis Symptom Score version 2) and UpToDate; has received equipment from Phadia; has a leadership role in the International Eosinophil Society; has received payment for expert testimony from Tucker Ellis; and is an inventor on a patent (US patent 9,345,763) owned by Cincinnati Children's Hospital Medical Center. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Chronic graft failure (CGF) is the leading cause of mortality in pediatric heart transplant (PHT) patients and has multifactorial pathogenesis including cardiac allograft vasculopathy (CAV). CGF can present with microvessel disease (MVD) and myocardial fibrosis on endomyocardial biopsies (EMB). We investigated if CGF due to moderate- severe (M-S) CAV has histopathologic MVD and fibrosis prior to or at the time of CAV diagnosis., Method: This retrospective case-control study included PHT with CGF secondary to M-S CAV. Control patients had no CAV or CGF. EMBs from CAV (3 sets: at 1-year post-transplant 1yrCAV, pre-CAV, and at the time of CAV diagnosis) and non-CAV cohorts were reviewed to grade the fibrosis and quantify MVD. Histopathologic changes were correlated and compared between CAV/non-CAV groups., Results: Each group had 8 patients. The median age at transplantation and time since transplant were similar between the two groups (P=.71 and P=.91, respectively). Fibrosis grade was 3.0 for CAV cohort compared to 1.0 for control (P= .003) and MVD score was 2.1 in CAV and 0.5 in non-CAV patients (P=.003). Similar degrees of fibrosis and MVD were present even before any evidence of CAV (1yrCAV fibrosis grade 2.5, pre-CAV fibrosis grade 2; 1yrCAV vs CAV P=.75, pre-CAV vs CAV P=.63; 1yrCAV MVD score 2, pre-CAV MVD score 2; 1yrCAV vs CAV P=1, pre-CAV vs CAV P=.91). The degree of MVD correlated with fibrosis (r=0.63, P<.0001) for all EMBs., Conclusion: Simultaneous myocardial fibrosis and MVD are noted in CGF secondary to M-S CAV, changes that occur before angiographic CAV. EMBs can reveal significant changes in patients with subsequent development of CAV and may be used to modify the follow-up and treatment for these high-risk patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to determine the mucosal microbiota associated with eosinophilic esophagitis (EoE) and eosinophilic gastritis (EoG) in a geographically diverse cohort of patients compared to controls., Methods: We conducted a prospective study of individuals with eosinophilic gastrointestinal disease (EGID) in the Consortium of Eosinophilic Gastrointestinal Disease Researchers, including pediatric and adult tertiary care centers. Eligible individuals had clinical data, mucosal biopsies, and stool collected. Total bacterial load was determined from mucosal biopsy samples by quantitative polymerase chain reaction (PCR). Community composition was determined by small subunit rRNA gene amplicons., Results: One hundred thirty-nine mucosal biopsies were evaluated corresponding to 93 EoE, 17 EoG, and 29 control specimens (18 esophageal) from 10 sites across the United States. Dominant community members across disease activity differed significantly. When comparing EoE and EoG with controls, the dominant taxa in individuals with EGIDs was increased ( Streptococcus in esophagus; Prevotella in stomach). Specific taxa were associated with active disease for both EoE ( Streptococcus , Gemella ) and EoG ( Leptotrichia ), although highly individualized communities likely impacted statistical testing. Alpha diversity metrics were similar across groups, but with high variability among individuals. Stool analyses did not correlate with bacterial communities found in mucosal biopsy samples and was similar in patients and controls., Conclusions: Dominant community members ( Streptococcus for EoE, Prevotella for EoG) were different in the mucosal biopsies but not stool of individuals with EGIDs compared to controls; taxa associated with EGIDs were highly variable across individuals. Further study is needed to determine if therapeutic interventions contribute to the observed community differences., Competing Interests: G.T.F. Chief Medical Officer, EnteroTrack, received research funding from NIH, Arena, and Holoclara. S.S.A. is co-inventor, oral viscous budesonide, Takeda license, UCSD patent. She received consulting fees from Regeneron/Sanofi, AstraZeneca, and Bristol Meyers Squibb. She received funding from NIH/NIAID/NIDDK. M.C. received consultant fees from Regeneron, Allakos, Adare/Ellodi, Shire/Takeda, AstraZeneca, Sanofi, Bristol Myers Squibb, and Phathom. She received research funding from Regeneron, Allakos, Shire/Takeda, AstraZeneca, Adare/Ellodi, and Danone. S.K.G. received consultant fees from Abbott, Adare, Celgene, Gossamer Bio, QOL, Takeda, MedScape, ViaSkin, and UpToDate. He received research support from Allakos, Ellodi, and AstraZeneca. V.A.M. received consultant fees from Takeda, Allakos, and Sanofi. He is on the Adjudication Committee of Alladapt. The remaining authors report no conflicts of interest., (Copyright © 2022 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background & Aims: Substantial heterogeneity in terminology used for eosinophilic gastrointestinal diseases (EGIDs), particularly the catchall term "eosinophilic gastroenteritis," limits clinical and research advances. We aimed to achieve an international consensus for standardized EGID nomenclature., Methods: This consensus process utilized Delphi methodology. An initial naming framework was proposed and refined in iterative fashion, then assessed in a first round of Delphi voting. Results were discussed in 2 consensus meetings, and the framework was updated and reassessed in a second Delphi vote, with a 70% threshold set for agreement., Results: Of 91 experts participating, 85 (93%) completed the first and 82 (90%) completed the second Delphi surveys. Consensus was reached on all but 2 statements. "EGID" was the preferred umbrella term for disorders of gastrointestinal (GI) tract eosinophilic inflammation in the absence of secondary causes (100% agreement). Involved GI tract segments will be named specifically and use an "Eo" abbreviation convention: eosinophilic gastritis (now abbreviated EoG), eosinophilic enteritis (EoN), and eosinophilic colitis (EoC). The term "eosinophilic gastroenteritis" is no longer preferred as the overall name (96% agreement). When &gt;2 GI tract areas are involved, the name should reflect all of the involved areas., Conclusions: This international process resulted in consensus for updated EGID nomenclature for both clinical and research use. EGID will be the umbrella term, rather than "eosinophilic gastroenteritis," and specific naming conventions by location of GI tract involvement are recommended. As more data are developed, this framework can be updated to reflect best practices and the underlying science., (Copyright © 2022. Published by Elsevier Inc.)

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory condition of the esophagus associated with elevated esophageal eosinophils. Second only to gastroesophageal reflux disease, EoE is one of the leading causes of chronic refractory dysphagia in adults and children. EoE is a clinicopathologic disorder and the histological portion of the diagnosis requires enumerating the density of esophageal eosinophils in esophageal biopsies, and evaluating additional features such as basal zone hyperplasia is helpful. However, this task requires time-consuming, somewhat subjective manual analysis, thus reducing the ability to process the complex tissue structure and infer its relationship with the patient's clinical status. Previous artificial intelligence (AI) approaches that aimed to improve histology-based diagnosis focused on recapitulating identification and quantification of the area of maximal eosinophil density, the gold standard manual metric for determining EoE disease activity. However, this metric does not account for the distribution of eosinophils or other histological features, over the whole slide image. Here, we developed an artificial intelligence platform that infers local and spatial biomarkers based on semantic segmentation of intact eosinophils and basal zone distributions. Besides the maximal density of eosinophils [referred to as Peak Eosinophil Count (PEC)] and a maximal basal zone fraction, we identify the value of two additional metrics that reflect the distribution of eosinophils and basal zone fractions. This approach enables a decision support system that predicts EoE activity and potentially classifies the histological severity of EoE patients. We utilized a cohort that includes 1,066 biopsy slides from 400 subjects to validate the system's performance and achieved a histological severity classification accuracy of 86.70%, sensitivity of 84.50%, and specificity of 90.09%. Our approach highlights the importance of systematically analyzing the distribution of biopsy features over the entire slide and paves the way toward a personalized decision support system that will assist not only in counting cells but can also potentially improve diagnosis and provide treatment prediction., Competing Interests: Author MER is a consultant for Pulm One, Spoon Guru, ClostraBio, Serpin Pharm, Allakos, Celldex, Nextstone One, Bristol Myers Squibb, Astra Zeneca, Ellodi Pharma, GlaxoSmith Kline, Regeneron/Sanofi, Revolo Biotherapeutics, and Guidepoint and has an equity interest in the first seven listed, and royalties from reslizumab (Teva Pharmaceuticals), PEESSv2 (Mapi Research Trust) and UpToDate. MER is an inventor of patents owned by Cincinnati Children's Hospital. Author MC: Allakos, Arena, AstraZeneca, Bristol Myers Squibb, Calypso, EsoCap, GlaxoSmithKline, Regeneron Pharmaceuticals, Inc., Sanofi, Shire—consultant; Receptos/Celgene/Bristol Myers Squibb, Regeneron Pharmaceuticals, Inc., Shire a Takeda company—research funding. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Larey, Aknin, Daniel, Osswald, Caldwell, Rochman, Wasserman, Collins, Arva, Yang, Rothenberg and Savir.)

Background & Aims: Cow's milk protein (CMP) is the most common trigger of inflammation in children and adults with eosinophilic esophagitis (EoE). We sought to assess the clinical, endoscopic, and histologic efficacy of dietary elimination of all CMP-containing foods in EoE., Methods: We performed a prospective observational study in children with EoE treated with the 1-food elimination diet (1FED), excluding all CMP. Children and their caretakers were educated by a registered dietitian regarding dietary elimination of all CMP-containing foods, with substitutions to meet nutritional needs for optimal growth and development, and daily meal planning. Upper endoscopy with biopsies was performed after 8 to 12 weeks of treatment. The primary end point was histologic remission, defined as fewer than 15 eosinophils per high-power field. Secondary end points were symptomatic, endoscopic, and quality-of-life (QOL) improvements., Results: Forty-one children (76% male; ages, 9 ± 4 years; 88% white) underwent 1FED education and post-treatment endoscopy with biopsies. Histologic remission occurred in 21 (51%) children, with a decrease in peak eosinophils per high-power field from a median of 50 (interquartile range, 35-70) to a median of 1 (interquartile range, 0-6; P < .0001). Endoscopic abnormalities improved in 24 (59%) patients, while symptoms improved in 25 (61%). Improved symptoms included chest pain, dysphagia, and pocketing/spitting out food. Parents perceived worse QOL, while children perceived improved QOL with the 1FED., Conclusions: One-food elimination of CMP-containing foods from the diet induced histologic remission in more than 50% of children with EoE and led to significant improvement in symptoms and endoscopic abnormalities. The ease of implementation and adherence supports the 1FED as first-line dietary treatment., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Eosinophilic esophagitis (EoE) is an allergic inflammatory condition of the esophagus associated with elevated numbers of eosinophils. Disease diagnosis and monitoring require determining the concentration of eosinophils in esophageal biopsies, a time-consuming, tedious and somewhat subjective task currently performed by pathologists. Here, we developed a machine learning pipeline to identify, quantitate and diagnose EoE patients' at the whole slide image level. We propose a platform that combines multi-label segmentation deep network decision support system with dynamics convolution that is able to process whole biopsy slide. Our network is able to segment both intact and not-intact eosinophils with a mean intersection over union (mIoU) of 0.93. This segmentation enables the local quantification of intact eosinophils with a mean absolute error of 0.611 eosinophils. We examined a cohort of 1066 whole slide images from 400 patients derived from multiple institutions. Using this set, our model achieved a global accuracy of 94.75%, sensitivity of 94.13%, and specificity of 95.25% in reporting EoE disease activity. Our work provides state-of-the-art performances on the largest EoE cohort to date, and successfully addresses two of the main challenges in EoE diagnostics and digital pathology, the need to detect several types of small features simultaneously, and the ability to analyze whole slides efficiently. Our results pave the way for an automated diagnosis of EoE and can be utilized for other conditions with similar challenges.

Although Down syndrome (DS), the most common developmental genetic cause of intellectual disability, displays proliferation and migration deficits in the prenatal frontal cortex (FC), a knowledge gap exists on the effects of trisomy 21 upon postnatal cortical development. Here, we examined cortical neurogenesis and differentiation in the FC supragranular (SG, II/III) and infragranular (IG, V/VI) layers applying antibodies to doublecortin (DCX), non-phosphorylated heavy-molecular neurofilament protein (NHF, SMI-32), calbindin D-28K (Calb), calretinin (Calr), and parvalbumin (Parv), as well as β-amyloid (APP/Aβ and Aβ 1-42 ) and phospho-tau (CP13 and PHF-1) in autopsy tissue from age-matched DS and neurotypical (NTD) subjects ranging from 28-weeks (wk)-gestation to 3 years of age. Thionin, which stains Nissl substance, revealed disorganized cortical cellular lamination including a delayed appearance of pyramidal cells until 44 wk of age in DS compared to 28 wk in NTD. SG and IG DCX-immunoreactive (-ir) cells were only visualized in the youngest cases until 83 wk in NTD and 57 wk DS. Strong SMI-32 immunoreactivity was observed in layers III and V pyramidal cells in the oldest NTD and DS cases with few appearing as early as 28 wk of age in layer V in NTD. Small Calb-ir interneurons were seen in younger NTD and DS cases compared to Calb-ir pyramidal cells in older subjects. Overall, a greater number of Calb-ir cells were detected in NTD, however, the number of Calr-ir cells were comparable between groups. Diffuse APP/Aβ immunoreactivity was found at all ages in both groups. Few young cases from both groups presented non-neuronal granular CP13 immunoreactivity in layer I. Stronger correlations between brain weight, age, thionin, DCX, and SMI-32 counts were found in NTD. These findings suggest that trisomy 21 affects postnatal FC lamination, neuronal migration/neurogenesis and differentiation of projection neurons and interneurons that likely contribute to cognitive impairment in DS., (© 2022. The Author(s).)

Background & Aims: Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) is undetermined., Methods: Subjects with EoC (n = 27) and controls (normal [NL, n = 20], Crohn's disease [CD, n = 14]) were enrolled across sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers. EoC was diagnosed as colonic eosinophilia (ascending ≥100, descending ≥85, sigmoid ≥65 eosinophils/high-power field) with related symptoms. Colon biopsies were subjected to RNA sequencing. Associations between gene expression and histologic features were analyzed with Spearman correlation; operational pathways and cellular constituents were computationally derived., Results: We identified 987 differentially expressed genes (EoC transcriptome) between EoC and NL (>1.5-fold change, P < .05). Colonic eosinophil count correlated with 31% of EoC transcriptome, most notably with CCL11 and CLC (r = 0.78 and 0.77, P < .0001). Among EoC and other EGIDs, there was minimal transcriptomic overlap and minimal evidence of a strong allergic type 2 immune response in EoC compared with other EGIDs. Decreased cell cycle and increased apoptosis in EoC compared with NL were identified by functional enrichment analysis and immunostaining using Ki-67 and cleaved caspase-3. Pericryptal circumferential eosinophil collars were associated with the EoC transcriptome (P < .001). EoC transcriptome-based scores were reversible with disease remission and differentiated EoC from IBD, even after controlling for colonic eosinophil levels (P < .0001)., Conclusions: We established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment., (Copyright © 2022. Published by Elsevier Inc.)

Background & Aims: Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and peak esophageal eosinophils per high-power field (eos/hpf)., Methods: Adults enrolled in a multisite prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers Outcome Measures for Eosinophilic Gastrointestinal Diseases Across Ages observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsy specimens. Patients were stratified based on dilation status as absent, performed 1 year or less before endoscopy, and performed more than 1 year before endoscopy. Assessments included Spearman 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: Among 100 patients (n = 61 males; median age, 37 y), 15 and 40 patients underwent dilation 1 year or less and more than 1 year before index endoscopy, respectively. In nondilated patients, the association between eos/hpf and symptoms was moderate (ρ = 0.49; P < .001); for a 10-eos/hpf increase, the predicted EEsAI increased by 2.69 (P = .002). In patients dilated 1 or less and more than 1 year before index endoscopy, this association was abolished (ρ = -0.38; P = .157 for ≤1 y and ρ = 0.02; P = .883 >1 y); for a 10-eos/hpf increase, the predicted EEsAI changed by -1.64 (P = .183) and 0.78 (P = .494), respectively. Dilation modified the association between symptoms and eos/hpf (P = .005 and P = .187 for interaction terms of eos/hpf and dilation 1 or less years before and more than 1 year before index endoscopy, respectively)., Conclusions: In nondilated EoE adults, eos/hpf correlate modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than 1 year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up evaluation., (Copyright © 2022. Published by Elsevier Inc.)

Marijuana is the most widely used illicit drug in the United States. As marijuana becomes legalized in more states and its use increases among adolescents, pediatricians must be aware of the impact of marijuana on pediatric health. Marijuana smoking as well as cigarette smoking has been associated with numerous lung diseases, including chronic bronchitis and bullous lung diseases. This case report postulates that regular marijuana smoking may be associated with pulmonary Langerhans cell histiocytosis, a severe lung disease that lacks definitive treatment and can cause respiratory failure. Given the potential risk of life-threatening lung diseases, pediatricians must screen adolescents with respiratory symptoms for marijuana use. In addition, this case underscores the need for further research and improved understanding of the relationship between marijuana smoking and lung disease., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Introduction: Approximately half of esophageal biopsies from patients with eosinophilic esophagitis (EoE) contain inadequate lamina propria, making it impossible to determine the lamina propria fibrosis (LPF). This study aimed to develop and validate a web-based tool to predict LPF in esophageal biopsies with inadequate lamina propria., Methods: Prospectively collected demographic and clinical data and scores for 7 relevant EoE histology scoring system epithelial features from patients with EoE participating in the Consortium of Eosinophilic Gastrointestinal Disease Researchers observational study were used to build the models. Using the least absolute shrinkage and selection operator method, variables strongly associated with LPF were identified. Logistic regression was used to develop models to predict grade and stage of LPF. The grade model was validated using an independent data set., Results: Of 284 patients in the discovery data set, median age (quartiles) was 16 (8-31) years, 68.7% were male patients, and 93.4% were White. Age of the patient, basal zone hyperplasia, dyskeratotic epithelial cells, and surface epithelial alteration were associated with presence of LPF. The area under the receiver operating characteristic curve for the grade model was 0.84 (95% confidence interval: 0.80-0.89) and for stage model was 0.79 (95% confidence interval: 0.74-0.84). Our grade model had 82% accuracy in predicting the presence of LPF in an external validation data set., Discussion: We developed parsimonious models (grade and stage) to predict presence of LPF in esophageal biopsies with inadequate lamina propria and validated our grade model. Our predictive models can be easily used in the clinical setting to include LPF in clinical decisions and determine its effect on treatment outcomes., (Copyright © 2021 by The American College of Gastroenterology.)

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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences., Methods: Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro., Results: TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P < .001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P < .001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P < .001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling., Conclusions: Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk., (Copyright © 2022 AGA Institute. All rights reserved.)

DICER1 tumor predisposition syndrome is a rare genetic disorder that predisposes individuals to multiple benign and malignant neoplasms. The phenotype is vast and includes pleuropulmonary blastoma (PPB), thyroid nodules, cystic nephroma, Wilms tumor, ovarian Sertoli-Leydig cell tumor, and medulloepithelioma, among others. Herein, we describe a patient with a DICER1 germline pathogenic variant presenting with two neoplasms that are not commonly encountered in the context of DICER1 syndrome. The first tumor is a multiloculated cystic hepatic lesion with a biphasic pattern, composed of cysts lined by bland biliary type (CK19-positive) epithelium surrounded by a condensation of sarcomatous spindled cell proliferation in a myxoid stroma. This neoplasm resembled PPB or cystic nephroma with malignant transformation. The second tumor is a chest nodule consistent with low-grade hidradenocarcinoma. Although it is difficult to speculate with just a single case, these unusual neoplasms occurring in particular at a young age raises the possibility that they can be inherent to, and thus, be part of the DICER1 tumor predisposition syndrome phenotype.

Patients with biallelic mutations in the nuclear-encoded mitochondrial gene C1QBP/p32 have been described with syndromic features and autosomal recessive cardiomyopathy. We describe the clinical course in two siblings who developed cardiomyopathy and ventricular fibrillation in infancy. We provide genomic analysis and clinical-pathologic correlation. Both siblings had profound cardiac failure with ventricular arrhythmia. One child died suddenly. The second sibling survived resuscitation but required extracorporeal cardiopulmonary support and died shortly afterward. On cardiac autopsy, the left ventricle was hypertrophied in both children. Histological examination revealed prominent cardiomyocyte cytoplasmic clearing, and electron microscopy confirmed abnormal mitochondrial structure within cardiomyocytes. DNA sequencing revealed compound heterozygous variants in C1QBP (p.Thr40Asnfs*45 and p.Phe204Leu) in both children. Family segregation analysis demonstrated each variant was inherited from an unaffected, heterozygous parent. Inherited loss of C1QBP/p32 is associated with recessive cardiomyopathy, ventricular fibrillation, and sudden death in early life. Ultrastructural mitochondrial evaluation in the second child was similar to findings in engineered C1qbp-deficient mice. Rapid trio analysis can define rare biallelic variants in genes that may be implicated in sudden death and facilitate medical management and family planning. (184/200)., (© 2021 Wiley Periodicals LLC.)

Although the prenatal hippocampus displays deficits in cellular proliferation/migration and volume, which are later associated with memory deficits, little is known about the effects of trisomy 21 on postnatal hippocampal cellular development in Down syndrome (DS). We examined postnatal hippocampal neuronal profiles from autopsies of DS and neurotypical (NTD) neonates born at 38-weeks'-gestation up to children 3 years of age using antibodies against non-phosphorylated (SMI-32) and phosphorylated (SMI-34) neurofilament, calbindin D- 28k (Calb), calretinin (Calr), parvalbumin (Parv), doublecortin (DCX) and Ki-67, as well as amyloid precursor protein (APP), amyloid beta (Aβ) and phosphorylated tau (p-tau). Although the distribution of SMI-32-immunoreactive (-ir) hippocampal neurons was similar at all ages in both groups, pyramidal cell apical and basal dendrites were intensely stained in NTD cases. A greater reduction in the number of DCX-ir cells was observed in the hippocampal granule cell layer in DS. Although the distribution of Calb-ir neurons was similar between the youngest and oldest NTD and DS cases, Parv-ir was not detected. Conversely, Calr-ir cells and fibers were observed at all ages in DS, while NTD cases displayed mainly Calr-ir fibers. Hippocampal APP/Aβ-ir diffuse-like plaques were seen in DS and NTD. By contrast, no Aβ 1-42 or p-tau profiles were observed. These findings suggest that deficits in hippocampal neurogenesis and pyramidal cell maturation and increased Calr immunoreactivity during early postnatal life contribute to cognitive impairment in DS.

Background: Pediatric bone marrow assessment by MRI is challenging and primarily experiential and qualitative, with a paucity of clinically useful quantitative imaging techniques., Objective: MRI fat fraction (MRI-FF) is a technique used to quantify the degree of fat in other organ systems. The purpose of this study was to assess whether MRI-FF accurately measures bone marrow composition., Materials and Methods: This two-part study included a validation phase, followed by an application phase. For the validation phase, the MRI-FF of piglet bones (6 long bones, 8 axial bones) was performed at 1.5 tesla (T) and 3.0 T, and correlated to the histological fat fraction (H-FF). We used Bland-Altman plots to compare MRI-FF at 1.5 tesla T and 3.0 T. For the application phase, five children with malignant marrow disease were recruited along with seven age- and gender-matched control subjects. The MRI-FF in the children was correlated to the H-FF. Boxplots were used to compare the MRI-FF of patients and control subjects., Results: For the validation animal study, the MRI-FF of piglet bones at both 1.5 T and 3.0 T demonstrated moderate positive correlation to H-FF (r=0.41 and 0.42, respectively). MRI-FF at 1.5 T and 3.0 T were in good agreement, on average 7.7% apart. For the application phase, we included 5 children (4 with leukemia, 1 rhabdomyosarcoma) with median age 7 years, range (3-10 years). All children had MRI-FF and H-FF below 10%. The MRI-FF in patients (3.8±1.2) was significantly lower than that of control subjects (46.1±12.3%) (P<0.01)., Conclusion: MRI-FF is a valid technique to assess bone marrow fat fraction at both 1.5 T and 3.0 T. The MRI-FF in children with malignant marrow processes is significantly lower than in control subjects with normal marrow.

Background: Pathologic examination of conduction system (CS) is not routinely performed, and histologic changes are mostly reported in forensic practice., Methods: We studied the value of dissecting the CS in a cohort of pediatric patients with unexplained sudden death or severe, inexplicable arrhythmias. Histopathologic changes present in CS components were recorded and correlated with findings noted in other cardiac structures., Results: Twenty-one subjects (11 unexplained sudden deaths and 10 life-threatening arrhythmias) were identified; 18 (86%) had CS pathologic abnormalities. In 13 patients (62%), the CS findings mirrored those found in other cardiac sections (inflammation, allograft vasculopathy, vascular fibromuscular dysplasia, cardiomyopathy-related changes, and tumor/tumor-like conditions). Five cases (24%) had abnormalities restricted to CS (bundle of His [BH] with fibrotic scar and patch material following ventricular septal defect repair, inflammation, BH with fibrosis and calcifications, and intimal fibroplasia of sinoatrial node artery)., Conclusions: Pathologic changes within the CS are present in a high number of pediatric patients presenting with unexplained sudden death or life-threatening arrhythmias. Frequently, the findings mirror those observed in other cardiac structures. However, in a significant number of cases (24%), the changes are restricted to CS and likely explain the patients' symptoms or cause of death, suggesting that systematic dissection of CS unveils valuable information.

Objectives: Barrett esophagus (BE) and intestinal metaplasia of gastroesophageal junction (IMGEJ) are rare in the pediatric population. This multi-institutional retrospective study evaluated the clinicopathologic characteristics and natural history of BE and IMGEJ in children., Methods: Data from 20 BE patients (70% boys, mean age: 14.9 years) and 17 IMGEJ patients (71% boys, mean age: 14 years) were retrospectively obtained from chart review. Endoscopic and pathologic findings from index and follow-up endoscopies were analyzed., Results: Most patients (70% BE and 59% IMGEJ) had underlying conditions which put them at risk for gastroesophageal reflux disease. Increased body mass index (BMI) was observed in patients without underlying conditions (BE: 30.1 ± 9.8; IMGEJ: 23.9 ± 6.3) compared with those with underlying conditions (BE: 19.6 ± 7.8; IMGEJ: 16.4 ± 2.1) (BE, P = 0.02; IMGEJ, P = 0.01). Incomplete intestinal metaplasia (IM) was the predominant histology seen in BE (80%) and IMGEJ patients (75%). Dysplasia and malignancy were not identified in the initial and follow-up biopsies. Concurrent gastric biopsies showed various findings (79% BE and 40% IMGEJ were normal), with 1 IMGEJ patient showing coexisting gastric IM (7%). Follow-up in 12 BE patients (mean follow-up time 51.6 months) showed 100% persistent endoscopic disease and 58% persistent IM histologically. Three of 6 IMGEJ patients (mean follow-up time 24 months) demonstrated endoscopic and histologic features consistent with BE on subsequent procedures. Moreover, a subset of BE (57%) and IMGEJ patients (67%) who underwent endoscopy before initial diagnosis showed nongoblet columnar mucosa above the anatomic gastroesophageal junction., Conclusions: Increased BMI may be a risk factor for BE and IMGEJ in pediatric patients without underlying conditions. Nongoblet columnar metaplasia and IMGEJ might represent incomplete forms of BE. Our data suggest that these patients should be closely monitored.

Objectives: Mast cells (MCs) are increased in eosinophilic esophagitis (EoE). Endoscopic abnormalities, symptoms, and epithelial changes can persist after treatment despite a reduction of esophageal eosinophilia. It is unknown whether this could be due to persistent MC infiltration. We aimed to determine whether patients with histologically inactive (HI) EoE (defined as <15 eosinophils per high-powered field) with persistent symptoms, endoscopic, or epithelial abnormalities after treatment have increased MCs., Methods: Secondary analysis of prospective data from 93 children with EoE undergoing post-treatment endoscopy between 2011 and 2015. Thirty-five non-EoE controls were included. Immunohistochemistry for tryptase, an MC marker, was performed on mid and distal esophageal biopsies. Total and degranulated intraepithelial MCs per high-powered field (MC/hpf) were quantified. Symptoms and endoscopic findings were recorded at time of endoscopy. MC/hpf were compared between HI-EoE and control, and among HI-EoE based on endoscopic and histologic findings, and symptoms. Nine clinical remission (CR) patients were identified, with absence of endoscopic abnormalities and symptoms., Results: MC/hpf were increased in HI-EoE compared with control (17 ± 11 vs 8 ± 6, P < 0.0). Patients with persistent endoscopic abnormalities had increased total (20 ± 12 vs 13 ± 10, P = 0.001) and degranulated (8 ± 6 vs 5 ± 4, P = 0.002) MC/hpf, with no difference in eosinophils. MC/hpf predicted furrowing (odds ratio = 1.06, P = 0.01) and rings (odds ratio = 1.05, P = 0.03) after controlling for treatment type, proton-pump inhibitor, eosinophils, and duration of therapy. Patients with persistent basal zone hyperplasia and dilated intercellular spaces had increased MC/hpf. Eosinophils were weakly correlated with MC/hpf in the mid (r = 0.30, P < 0.001) and distal (r = 0.29, P < 0.001) esophagus. Clinical remission patients had lower MC/hpf compared with patients with persistent symptoms and/or endoscopic abnormalities., Discussion: MC density is increased in patients with endoscopic and epithelial abnormalities, as well as a few symptoms, despite resolution of esophageal eosinophilia after treatment. This association warrants further study to ascertain whether MCs play an eosinophil independent role in EoE.

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 18 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 18 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., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Pediatric renal tumors (PRT) with small round blue or spindle cell morphology can be diagnostically challenging and only a limited number of immunohistochemical markers have been documented to help in the diagnosis: paired box (Pax) 2 and nerve growth factor receptor (NGFR) positivity have been demonstrated in Wilms tumor (WT) and clear cell sarcoma of the kidney (CCSK), respectively. However, the immunohistochemical expression of these markers in other PRT remains unknown. This study investigated Pax8, Pax2, and NGFR immunophenotype in a large series of PRT. Pax8 and Pax2 showed an identical staining pattern, and were expressed in all (100%) WT while most CCSK were negative. All congenital mesoblastic nephromas, metanephric stromal tumors, primitive neuroectodermal tumors, desmoplastic small round blue cell tumors, most rhabdoid tumors, and synovial sarcomas were negative for Pax8. NGFR was expressed in 96% of CCSK (diffuse expression in 91%). Only a minority of WT stained for NGFR: 16% showed expression in the blastemal and 25% in the mesenchymal components. NGFR expression was noted in synovial sarcomas (67%, with diffuse expression seen in only 1 case, 8%), rhabdoid tumors (19%), cellular congenital mesoblastic nephromas (13%) and metanephric stromal tumors (12.5%). Primitive neuroectodermal tumors and desmoplastic small round blue cell tumors were negative for NGFR. In conclusion, Pax8/Pax2 and NGFR are sensitive markers for the diagnosis of WT and CCSK, respectively. However, their specificity is limited by variable reactivity within a subset of other renal neoplasms.

Background & Aims: Over the last decade, clinical experiences and research studies raised concerns regarding use of proton pump inhibitors (PPIs) as part of the diagnostic strategy for eosinophilic esophagitis (EoE). We aimed to clarify the use of PPIs in the evaluation and treatment of children and adults with suspected EoE to develop updated international consensus criteria for EoE diagnosis., Methods: A consensus conference was convened to address the issue of PPI use for esophageal eosinophilia using a process consistent with standards described in the Appraisal of Guidelines for Research and Evaluation II. Pediatric and adult physicians and researchers from gastroenterology, allergy, and pathology subspecialties representing 14 countries used online communications, teleconferences, and a face-to-face meeting to review the literature and clinical experiences., Results: Substantial evidence documented that PPIs reduce esophageal eosinophilia in children, adolescents, and adults, with several mechanisms potentially explaining the treatment effect. Based on these findings, an updated diagnostic algorithm for EoE was developed, with removal of the PPI trial requirement., Conclusions: EoE should be diagnosed when there are symptoms of esophageal dysfunction and at least 15 eosinophils per high-power field (or approximately 60 eosinophils per mm 2 ) on esophageal biopsy and after a comprehensive assessment of non-EoE disorders that could cause or potentially contribute to esophageal eosinophilia. The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (noniEFVPTC) has low risk of adverse outcome in adults, warranting reclassification as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In children, thyroid nodules have higher risk of malignancy and it is unknown if encapsulated FVPTC (EFVPTC) and infiltrative FVPTC (IFVPTC) tumors have different behavior. We analyzed the clinicopathologic features of follicular variant of papillary thyroid carcinoma (FVPTC) subtypes in our pediatric population to determine if noniEFVPTC has an indolent course as reported in adults., Procedure: We retrospectively studied all patients diagnosed with FVPTC at our institution. The clinicopathologic characteristics of the histologic subtypes were compared., Results: Eighteen patients were identified, all treated with total thyroidectomy. No significant differences in age, sex, tumor size, focality, or prior malignancy were detected between subtypes. Extrathyroidal extension had significantly higher incidence in IFVPTC (5/8) compared with EFVPTC (1/10, P = 0.03), translating in significantly more T3 tumors within IFVPTC subtype (5/8), whereas most EFVPTC cases had T1 staging (6/10, T1 vs. T3, P = 0.05). EFVPTC had significantly lower rate of lymph node involvement (N1 in 2/8) compared with IFVPTC (N1 in 8/8, P = 0.003). Only one patient diagnosed with IFVPTC developed extranodal recurrence. When noniEFVPTC and iEFVPTC were separately compared, the noninvasive form showed no propensity for invasive growth (T3 staging: 0/4 vs. 2/6), lymph node metastasis (N1: 0/3 vs. 2/5) or extranodal recurrence., Conclusion: In children, noniEFVPTC/NIFTP has indolent behavior, warranting consideration of less aggressive management, similar to adults., (© 2018 Wiley Periodicals, Inc.)

Aims: Malignant ectomesenchymoma is a rare pediatric neoplasm with dual mesenchymal and neuroectodermal elements. Mesenchymal component is usually rhabdomyosarcoma, particularly embryonal subtype, whereas neuroectodermal derivatives are frequently a neuroblastic tumor. Ectomesenchymoma manifests in various sites given the wide migration of neural crest cells during development, though the pelvis/perineum is most often involved. Moreover, no unique unifying molecular abnormality has been determined., Methods: We conducted a retrospective study to analyze the spectrum of ectomesenchymal tumors encountered in our pediatric population. Six patients were identified and data pertaining to patients' demographic, tumor size and site, histologic components with immunophenotypic profile, molecular alterations, treatment, and outcome were collected., Results: Mesenchymal elements, represented by rhabdomyosarcoma in all instances, were the dominant component in the majority of cases (5/6). Embryonal and alveolar morphology had similar distribution (3/6) and all patients with alveolar subtype harbored the characteristic translocations of this entity. The neuroectodermal component was most often a neuroblastic-like neoplasm (4/6); however, 2/6 cases demonstrated primitive neuroectodermal tumor-like morphology. No unifying alterations were found on molecular studies., Conclusions: Our analysis extends the histologic and molecular spectrum of these tumors and highlights their heterogeneity. The percentage of cases with alveolar rhabdomyosarcoma or primitive neuroectodermal-like tumor components suggests that these types of elements might be underreported. This study is also the first to demonstrate FOXO1 gene rearrangements in malignant ectomesenchymoma with alveolar rhabdomyosarcoma subtype.

Thrombotic complications are a significant source of morbidity and mortality following hematopoietic stem cell transplants. Among them, transplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized syndrome that can affect various organ systems. Its etiology is related to endothelial injury accompanied by complement activation. As many of the signs and symptoms of the disease are also encountered in other complications following hematopoietic stem cell transplant, it can often be difficult to establish the diagnosis based on clinical data alone. Histopathologic examination of various tissues may be performed in difficult cases. However, the microscopic features of TA-TMA also overlap with those seen in other posttransplant complications, suggesting a need for additional tests to help in diagnosis. Here we describe a patient who presented with hemolytic anemia, thrombocytopenia, renal and neurological impairment, who also developed significant bloody diarrhea. Flexible sigmoidoscopy with biopsies was performed to determine the exact etiology of his gastrointestinal bleed. A diagnosis of intestinal TA-TMA was established with the use of immunohistochemical stains for complement components C5b-9 and C4d. This is the first report that highlights the utility of complement staining on histologic sections from digestive samples to render a definitive diagnosis of intestinal TA-TMA.

EGID is a known post-transplant complication. Its etiology has been related to antirejection medication, but other factors may also play a role as only few transplant recipients develop EGID despite standardized treatment. This study aimed to determine whether EGID is associated with rejection events and with a specific phenotype of the rejection-positive graft biopsies in children with solid organ transplant. All patients with liver, heart, and kidney transplant followed at our institution were included in the study. Digestive tract eosinophilia was more common in heart and liver recipients and was a rare event after renal transplantation. Subjects with EGID had higher incidence of rejection and elevated peripheral blood AEC. The first rejection event and high AEC values preceded EGID diagnosis in the majority of patients. Histologically, the initial rejection-positive graft biopsy revealed accentuated eosinophilia in EGID patients compared with non-EGID cohort, which correlated with higher blood eosinophil counts at the time of first rejection episode. Prominent graft tissue and peripheral blood eosinophilia prior to EGID diagnosis suggests a predisposition for eosinophil activation in patients with post-transplant digestive eosinophilic disorder. These parameters can be used as markers for subsequent development of EGID., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in melanoma cells cultured with melanocyte conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating radical oxygen species, to investigate potential anti-oxidant effect of MDM on Nodal expression and signaling in melanoma, melanoma cells were treated with either N-acetyl-l-cysteine (NAC), a component of the anti-oxidant glutathione or synthetic melanin, which in addition to providing pigmentation can also exert free radical scavenging activity. Melanoma cells treated with NAC or synthetic melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated melanoma cells. Thus, the potential role for Nodal in melanoma development in LCMN is less evident than in adult dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro-melanoma effects of Nodal via anti-oxidant effects of MDM.

Epstein-Barr virus (EBV) has oncogenic potential and has been implicated in the etiology of a wide range of malignancies. Certain EBV-driven neoplasms, such as smooth muscle tumors (SMTs), manifest typically in immunocompromised patients. In children, these neoplasms have been encountered in the setting of primary immune disorders, specifically severe combined and common variable immunodeficiency syndromes. Human immunodeficiency virus infection and posttransplant immunosuppression, in particular liver and kidney transplantation, likewise increase the risk in the pediatric population. The location of these neoplasms appears related to the type of immunodeficiency: in acquired immunodeficiency syndrome they are frequently located intracranially or intraspinally, whereas after transplant they usually involve the liver or lung. We report 2 distinct cases of EBV-related SMT, unique through their coassociated immunosuppressive state or location: the 1st occurred in a patient with immunodeficiency secondary to NEMO gene mutation following hematopoietic stem cell transplantation; the 2nd developed in the orbit after heart transplant.

Aim: In children the percentage of "Atypia of undetermined significance/follicular lesion of undetermined significance" ("AUS/FLUS") cases is greater and the risk of malignancy is higher than expected. Our study aimed to determine if cytologically atypical nodules can be better characterized using imaging techniques for appropriate management of pediatric patients., Methods: Thyroid fine needle aspiration (FNA) specimens were reclassified using the Bethesda System for Reporting Thyroid Cytopathology (BSRTC). Cytologic-histologic correlation was performed to determine if the cytopathologic groups had different associations with the surgical outcome. The "AUS/FLUS" lesions were then subdivided based on radiologic features and the outcome was analyzed for each subgroup., Results: Histologically benign follicular nodules showed uniform distribution between the "benign" vs. "AUS/FLUS" (p=0.09) or between the "AUS/FLUS" vs. "follicular neoplasm" ("FN") cytologic groups (p=0.27). The follicular neoplasms were also evenly distributed between the "FN" vs. "AUS/FLUS" categories (p=0.31). "Benign", "AUS/FLUS", and "FN" designations showed comparable associations with papillary thyroid carcinoma classical variant (PTC-cv). Reclassification of atypical lesions based on ultrasound findings yielded two subcategories with different risk of malignancy: one similar to the "benign" group (11% malignancy rate) and one comparable with the "FN" category (28% risk of malignant neoplasm)., Conclusion: "AUS/FLUS" designation does not add significant value in categorization of pediatric thyroid nodules. These lesions can be reclassified based on radiologic features to provide accurate information for follow-up.

Background: The current literature suggests that approximately 5% to 10% of melanonychia striata cases in adults are the result of subungual melanoma., Objective: We sought to evaluate the clinical and histopathologic features and to determine the outcomes and causes of melanonychia striata in a cohort of children., Methods: We assessed 30 childhood cases of melanonychia striata for features typically associated with melanoma such as Hutchinson sign, width of the pigmented band, evolution, color, and nail dystrophy. We assessed the histopathology of lesional biopsy specimens, including melanocyte counts and suprabasal movement of melanocytes. Clinical follow-up information was reviewed when available., Results: Histopathologic diagnoses included subungual lentigo in 20 cases, subungual nevus in 5 cases, and atypical melanocytic hyperplasia in 5 cases. Although a number of cases exhibited worrisome clinical or histopathologic features, none showed evidence of aggressive behavior or warranted a diagnosis of melanoma., Limitations: The sample size and follow-up times are limited., Conclusions: Melanonychia striata is typically associated with benign stable melanocytic proliferations in childhood. The overwhelming majority of cases can be managed conservatively. Biopsy is required in select cases., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Biliary atresia is an inflammatory cholangiopathy of still undetermined etiology. Correlations between histologic findings and clinical outcome in this disease have largely been based on evaluation of liver parenchyma. This study aimed to characterize the pattern of inflammation within the biliary remnant and identify associations between the type and degree of inflammation and clinical outcome as reflected by the transplant-free interval. The inflammation within the fibrous plates and livers of 41 patients with biliary atresia was characterized using immunohistochemical markers and the cell populations were digitally quantified. The type and quantity of cells within the infiltrate were then correlated with length of time from Kasai portoenterostomy until transplant. Histologic and immunohistochemical features of the biliary remnant allowed stratification of patients into "inflammatory plate" and "fibrotic plate" groups. Overall there was no significant difference in transplant-free interval between the two cohorts; however, there was a trend towards a longer time to transplant among patients in the "fibrotic plate" group. In addition, the composition of the inflammatory infiltrate in the fibrous plate was distinctly different from that present in the liver and only the characteristics of the inflammation in the fibrous plate, in particular the number of Foxp3+ T regulatory lymphocytes correlated with clinical outcome. The results of this study support the view of the extra-hepatic biliary tree as the primary site of injury in BA with the changes seen in the liver as secondary manifestations of outflow obstruction. The association between specific inflammatory cell subtypes within the fibrous plate and the length of transplant-free interval also supports the role of the immune system in the initial process of bile duct damage in biliary atresia., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6.