Lamina Propria Fibrosis Research Articles

Myointimal hyperplasia of the mesenteric veins mimicking inflammatory bowel disease in a 13‐year‐old patient

AbstractIdiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is a rare entity reported in adults, frequently mimicking inflammatory bowel disease (IBD). We report the first case of intestinal ischemia secondary to IMHMV presenting as IBD in a pediatric patient with Down syndrome. Chronic intestinal ischemia is rare in children, and this case emphasizes the need to consider this in the differential, when histopathology is suggestive. Clinical findings and colonoscopy in these patients may mimic IBD. The mucosal biopsies do not show classic features of IBD. Instead, there can be variable extent of mucosal changes such as dilated small capillaries in the lamina propria, edema, and early fibrosis. These changes may in fact represent early chronic ischemia. These findings should alert for vascular imaging and a full‐thickness biopsy to assess submucosal and subserosal larger vessels since medium‐ and large‐caliber veins in the colonic wall and mesentery are affected in IMHMV.

The effects of radiofrequency electromagnetic radiation emitted by mobile phones on rat parotid gland histology - an experimental study.

The advancement of telecommunication technology and devices promptly transformed mobile phones into indispensable objects in our day-to-day lives, but their biological effects remain unclear. Therefore, this study aimed to investigate the potential histopathological changes induced by mobile phone radiation in the parotid gland and the nearby tissues. Thirty female Rattus Norvegicus rats were divided into three groups: group 1 (exposed for 30 days), group 2 (exposed for 60 days), and control group (non-exposed). Each subject was exposed to mobile phone radiation in the form of a phone call for two hours every day for their subsequent exposure time. The exposure was always directed towards the same side of the face throughout the whole exposure period. At the end of the exposure period, a comprehensive examination was conducted, including inspection of the orofacial structures, tissue sections of the parotid glands, overlying skin, oral mucosa, and cervical lymph nodes, as well as obtaining smears from the oral cavity. To highlight the presence of micronuclei within the exfoliated squamous cells of the oral epithelium, Feulgen stain was performed. The results showed a significant activation of the fibroblasts in the parotid gland septa, in both exposed experimental groups, compared to the control group. We also detected significant cervical lymph node reactive changes, hyperkeratosis of the oral epithelium, and activated fibroblasts in the dermis and oral mucosa lamina propria in both experimental groups. Dermal fibrosis and lamina propria fibrosis were significantly increased in the second experimental group, compared to the control group. Moreover, vascular congestion in the parotid gland, dermal, and lamina propria fibrosis were significantly increased in the second study group compared to the first one. These findings suggest that exposure to mobile phone radiation may lead to pathological changes in the parotid gland and nearby tissues of experimental rats.

Transnasal Endoscopy Acquires Esophageal Biopsies Adequate for Comprehensive Pathology Evaluation in Patients With Eosinophilic Esophagitis.

Transnasal endoscopy (TNE) does not require general anesthesia, an attractive characteristic for monitoring eosinophilic esophagitis (EoE). We evaluated the adequacy of TNE-obtained esophageal biopsies using the EoE Histology Scoring System (EoEHSS). The Cincinnati Center for Eosinophilic Disorders database was searched for esophageal biopsies obtained by the same endoscopist, using either TNE or conventional endoscopy (CE). Whole-slide biopsy images were evaluated. The Mann-Whitney test was used for median (interquartile range) values and Fisher exact test for categorical variables. P ≤ .05 was considered significant. Median age (P = .82) or height (P = .83) did not differ between TNE (n = 17) and CE (n = 17) groups. Although median largest piece size (mm2) differed between the groups (TNE: 0.59 (0.45, 0.86), CE: 2.24 (1.09, 2.82), P < .001), all 8 EoEHSS features were evaluated in each group; only 1 feature (lamina propria fibrosis) was missing in both groups (TNE: 19/34, CE: 11/34, P = .09). The median peak eosinophil count/high-power field differed (TNE: 3 (0, 29), CE: 16 (1, 66), P = .03), but overall grade (TNE: 0.17 (0.10, 0.29), CE: 0.22 (0.14, 0.46), P = .12), stage (TNE: 0.14 (0.10, 0.24), CE: 0.20 (0.10, 0.43), P = .15), and non-eosinophil-related individual EoEHSS scores did not differ. TNE- and CE-obtained esophageal biopsies are similarly sufficient for evaluation of key pathological features in EoE.

Characterization of lamina propria remodeling in pediatric eosinophilic esophagitis using second harmonic generation microscopy

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition characterized by an intense infiltration of eosinophils into the esophageal epithelium. When not adequately controlled, eosinophilic inflammation can lead to changes in components of the extracellular matrix (ECM) of the lamina propria. Particularly, alterations to the collagen fiber matrix can lead to lamina propria fibrosis (LPF), which plays an important role in the fibrostenotic complications of EoE. Current approaches to assess LPF in EoE are prone to inter-observer inconsistencies and provide limited insight into the structural remodeling of the ECM. An objective approach to quantify LPF can eliminate inter-observer inconsistencies and provide novel insights into the fibrotic transformation of the lamina propria in EoE. Second harmonic generation (SHG) microscopy is a powerful modality for objectively quantifying disease associated alterations in ECM collagen structure that is finding increasing use for clinical research. We used SHG with morphometric analysis (SHG-MA) to characterize lamina propria collagen fibers and ECM porosity in esophageal biopsies collected from children with active EoE (n = 11), inactive EoE (n = 11), and non-EoE (n = 11). The collagen fiber width quantified by SHG-MA correlated positively with peak eosinophil count (r = 0.65, p < 0.005) and histopathologist scoring of LPF (r = 0.52, p < 0.005) in the esophageal biopsies. Patients with active EoE had a significant enlargement of ECM pores compared to inactive EoE and non-EoE (p < 0.005), with the mean pore area correlating positively with EoE activity (r = 0.76, p < 0.005) and LPF severity (r = 0.65, p < 0.005). These results indicate that SHG-MA can be utilized to objectively characterize and provide novel insights into lamina propria ECM structural remodeling in children with EoE, which could aid in monitoring disease progression.

Machine learning–based identification and characterization of mast cells in eosinophilic esophagitis

BackgroundEosinophilic esophagitis (EoE) is diagnosed and monitored using esophageal eosinophil levels; however, EoE also exhibits a marked, understudied esophageal mastocytosis. ObjectiveUsing machine learning, we localized and characterized esophageal mast cells to decipher their potential role in disease pathology. MethodsEsophageal biopsy samples (EoE, control) were stained for mast cells by anti-tryptase and imaged using immunofluorescence; high-resolution whole tissue images were digitally assembled. Machine learning software was trained to identify, enumerate, and characterize mast cells, designated Mast Cell-Artificial Intelligence (MC-AI). ResultsMC-AI enumerated cell counts with high accuracy. During active EoE, epithelial mast cells increased and lamina propria (LP) mast cells decreased. In controls and EoE remission patients, papillae had the highest mast cell density and negatively correlated with epithelial mast cell density. Mast cell density in the epithelium and papillae correlated with the degree of epithelial eosinophilic inflammation, basal zone hyperplasia, and LP fibrosis. MC-AI detected greater mast cell degranulation in the epithelium, papillae, and LP in EoE patients compared with control individuals. Mast cells were localized further from the basement membrane in active EoE than EoE remission and control individuals but were closer than eosinophils to the basement membrane in active EoE. ConclusionUsing MC-AI, we identified a distinct population of homeostatic esophageal papillae mast cells; during active EoE, this population decreases, undergoes degranulation, negatively correlates with epithelial mast cell levels, and significantly correlates with distinct histologic features. Overall, MC-AI provides a means to understand the potential involvement of mast cells in EoE and other disorders.

Vitamin D Levels as a Potential Modifier of Eosinophilic Esophagitis Severity in Adults.

Vitamin D deficiency is associated with atopic and immune-mediated diseases but has not been extensively assessed in eosinophilic esophagitis (EoE). We aimed to assess if vitamin D levels in newly diagnosed EoE patients were lower than in non-EoE controls and examine levels in relation to EoE clinical features. This secondary analysis of a prospective cohort study used data and biosamples from adults who underwent outpatient esophagogastroduodenoscopy. Before each procedure, blood was obtained and stored at -80oC. Serum 25-hydroxy-vitamin D3 (25(OH)D3) was measured by ELISA. Levels for cases and controls were compared at baseline. Within cases, 25(OH)D3 levels were compared for clinical, endoscopic, and histologic measures. We analyzed 40 EoE and 40 non-EoE controls. Mean serum 25(OH)D3 level was slightly lower in EoE patients than controls (30.9 ± 15.3 ng/mL vs. 35.9 ± 15.4; p = 0.15). After controlling for age, sex, and race, adjusted levels were 10.8 ng/mL lower in EoE patients (95% CI: -19.0, -2.5), but 25(OH)D3 deficiency (< 20ng/mL) was similar in cases and controls (20% vs. 15%; p = 0.56). Levels of 25(OH)D3 were not associated with differences in clinical or endoscopic features of EoE, and EREFS and eosinophil counts did not significantly correlate with 25(OH)D3 levels (R of -0.28 [p = 0.08] and - 0.01 [p = 0.93], respectively). 25(OH)D3 levels were lower in EoE cases with lamina propria fibrosis (23.2 ± 9.6 vs. 45.0 ± 17.7; p = 0.03). After adjusting for age, sex, and race, 25(OH)D3 levels were lower in EoE cases than controls, but deficiency was not common. 25(OH)D3 levels were generally similar across most EoE disease features.

The Use of a Dehydrated Cellularized Collagen Matrix to Replace Fibrotic Vocal Fold Mucosa.

Fibrosis of the vocal fold lamina propria reduces vocal cord vibration resulting in a chronically hoarse voice. We describe a novel approach using umbilical cord-derived mesenchymal stem cells in a dehydrated collagen matrix (cellogen) to reconstruct the delicate balance of extracellular matrix within the vocal fold lamina propria whilst limiting the host inflammatory response to the implant. Human umbilical cord-derived mesenchymal stem-cells were embedded in bovine type I collagen hydrogel and dehydrated using the RAFT™ 3D culture system. The extracellular matrix, cellular viability and composition, paracrine profile, and genomic profile were assessed and the scaffold engrafted onto the hind muscle of NUDE mice. The cells retained stem-cell markers following fabrication and secreted collagen III, fibronectin, and glycosaminoglycans within the scaffold. Electron microscopy showed the scaffold consisted of single strands of protein with interspersed bundles of a similar size to native vocal fold lamina propria. The use of the dehydration step improved cell viability and upregulated the expression of genes important in wound healing and matrix organization compared with unmodified collagen hydrogel carriers. The cells were shown to secrete exosomes and cytokines and, following engraftment within an immunocompromised mouse model, appeared to modulate the host inflammatory response compared with controls. This article provides a scalable cell-protein scaffold that with further modifications could provide a replacement for lost or damaged vocal fold mucosa. Further investigations are required to assess the mechanical properties of the scaffold and inhibit the differentiation of the umbilical cord-derived stem-cells following implantation. Laryngoscope, 134:882-893, 2024.

Benefits of accurate and guided endoureterotomy versus ureteral balloon dilatation in the management of ureteral strictures-comparative animal study.

Endoscopic treatment of ureteral strictures provides a minimally invasive approach with a shorter hospital stay and less postoperative pain. There are different therapeutic options, the dilatation balloon and endoureterotomy with holmium yttrium-aluminum-garnet (Ho:YAG) laser are the most used. To assess histological changes after endoureterotomy in the ureteral stricture treatment comparing Ho:YAG laser endoureterotomy versus balloon dilatation endoureterotomy. The subjects used were a total of 48 female pigs. The initial assessment consisted of an endoscopic, nephrosonographic, and contrast fluoroscopic evaluation of the urinary tract. Subsequently, a model of ureteral stricture was performed. Three weeks later, the ureteral stricture was diagnosed and treated. Then animals were randomly assigned to two groups (group A, Balloon dilatation endoureterotomy and group B, Holmium laser retrograde endoureterotomy) in which a double-pigtail ureteral stent was placed for 3 weeks. Follow-up assessments were performed at 3-6 weeks. The final follow-up was completed at 5 months and included the pathological study. In terms of therapeutic effectiveness, the overall success was 81.2%. The success rate was 91.7% in group B and 70.8%in group A without statistical significance. No evidence of vesicoureteral reflux nor urinary tract anomalies were observed. Histological assessment showed statistical significance in overall score, lamina propria fibrosis and serosal alterations in group A with higher histological changes. The overall histopathological score after ureteral stricture treatment in an animal model showed better remodeling of incised ureteral wall healing after Ho:YAG laser endoureterotomy. Laser endoureterotomy tends to have higher success rate compared to balloon dilatation.

262. DUPILUMAB REDUCED EOSINOPHIL COUNTS AND IMPROVED HISTOLOGY GRADE/STAGE SCORES IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS: LIBERTY EOE TREET RESULTS

Abstract Background In the 3-part, phase 3 LIBERTY EoE TREET study (NCT03633617) dupilumab 300 mg weekly (qw) demonstrated significant improvements in symptoms and eosinophil counts, and clinically meaningful improvement in endoscopic features vs placebo, in adults and adolescents with EoE. The objective of this analysis was to further assess the effect of dupilumab vs placebo on histologic aspects of disease in Parts A and B of LIBERTY EoE TREET. Methods Patients aged ≥12 years were randomized 1:1 to dupilumab 300 mg qw or placebo. Endpoints (at Week 24) were the proportion of patients achieving ≤1, ≤6, and &amp;lt; 15 eosinophils per high-power field (eos/hpf), change from baseline in peak eosinophil count and Histologic Scoring System (HSS) scores, specifically the severity (grade) and extent (stage) of abnormality of the 8 components (basal zone hyperplasia [BZH], eosinophil inflammation [EI], eosinophil abscess [EA], eosinophil surface layering [ESL], dilated intercellular spaces [DIS], surface epithelial alteration [SEA], dyskeratotic epithelial cells [DEC], and lamina propria fibrosis [LPF]). P-values are nominal unless otherwise specified. Results Dupilumab significantly increased the proportion of patients achieving ≤1, ≤6, and &amp;lt; 15 eos/hpf in Part A (P &amp;lt; 0.0001, P &amp;lt; 0.05, and P &amp;lt; 0.0001, respectively) and Part B (all P &amp;lt; 0.0001) vs placebo. Percent change in peak eosinophil count from baseline and HSS grade/stage scores were significantly improved with dupilumab vs placebo for Parts A and B (all P &amp;lt; 0.0001) (Table). Significant improvements were observed for the histologic components BZH, EI, EA, ESL, SEA grade/stage scores (P &amp;lt; 0.0001) in both Parts, DIS grade score in Part A (P &amp;lt; 0.05), and DEC grade/stage scores in Part B (P &amp;lt; 0.05); other components showed numeric improvements. Dupilumab was generally well tolerated. Conclusions Dupilumab 300 mg qw significantly decreased eosinophil counts and improved the severity and extent of histologic aspects of the disease as measured by HSS versus placebo in adults and adolescents with EoE up to 24 weeks, documenting a more global improvement in addition to eosinophil counts. Overall safety was consistent with the known dupilumab safety profile.

Eosinophilic Esophagitis Histologic Scoring System: Correlation with Histologic, Endoscopic, and Symptomatic Disease and Clinical Use.

The eosinophilic esophagitis histologic scoring system (EoEHSS) was developed to enhance the diagnostic standard of peak eosinophil count (PEC) in evaluating disease activity in EoE. (1) Correlate the EoEHSS and PEC to measures of symptomatic and endoscopic disease activity, (2) Correlate EoEHSS grade and stage subcomponents to clinical, radiology, and endoscopic markers of fibrotic disease, (3) Evaluate EoEHSS remission in asymptomatic patients with PEC < 15 eosinophils per high powered field (eos/hpf). Secondary analysis of prospective cohort data of 22 patients with EoE that underwent dietary therapy and endoscopy at 3 time points. Active disease was defined by EoEHSS grade or stage > 0.125, symptomatic disease by EoE symptom activity index > 20, endoscopic disease by endoscopic reference score > 2, and histologic disease by PEC ≥ 15 eos/hpf. EoEHSS remission was defined by esophageal inflammation (EI) grade of 0-1, EI stage of 0, total grade ≤ 3, and total stage ≤ 3. EoEHSS grade and stage did not correlate with symptomatic disease but did with endoscopic and histologic disease. PEC showed similar correlation pattern. Abnormal grade and stage had strong sensitivity (87-100%) but poor specificity (11-36%) to detect symptomatic, endoscopic, and histologic disease activity. Lamina propria fibrosis was evaluated in 36% of biopsies and did not correlate with minimum esophageal diameter. Out of 14 patients who were in complete symptomatic, endoscopic, and histologic remission, 8 met criteria for EoEHSS remission. The positive and negative correlations of EoEHSS to specific measures of symptomatic, histologic, and endoscopic activity suggest that it provides complementary information in EoE.

Reproducibility and Generalizability of the Web-Based Tool to Predict Lamina Propria Fibrosis in Eosinophilic Esophagitis.

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.

Effect of Proton Pump Inhibitor Treatment in "PPI Non-responsive" Patients with Eosinophilic Esophagitis.

Some eosinophilic esophagitis (EoE) patients can have a decline in eosinophil count after proton pump inhibitor (PPI) treatment without achieving histologic response, but little is known about this group. We aimed to determine the effect of PPIs on reducing esophageal eosinophilia in patients deemed non-responsive to PPI therapy. We analyzed prospectively collected cohort data from newly diagnosed adults with EoE who were histologic non-responders (≥15 eos/hpf) to PPI-only therapy. Symptoms, endoscopic histologic features were assessed before and after PPI. Pre- and post-PPI treatment esophageal biopsies were read by pathologists to determine peak eosinophil counts and other histologic findings. Of 125 patients, peak eosinophil counts were 102.1 ± 69.8 and 102.9 ± 101.1 (p=0.93) before and after PPI treatment, respectively, but lamina propria fibrosis decreased from 97% to 41% (p<0.001). Heartburn frequency also decreased (19% to 11%; p=0.006), though endoscopic findings did not change. There were 75 patients (60%) who had some decrease in eosinophil counts, with 30 patients (24%) having ≥50% decrease in counts. When comparing the ≥50% and <50% decrease groups, differences in endoscopic features were identified, but the ≥50% group had improvement in eosinophil degranulation, microabscesses, spongiosis, and basal cell hyperplasia. Peak eosinophil counts did not decrease overall after PPI treatment, but symptoms of heartburn improved. Approximately a quarter had ≥50% decrease in eosinophil counts, with associated decreases in other histologic findings. Further research may consider what role PPIs have in this subset of non-responders or in combination therapies.

Esophageal Epithelium and Lamina Propria Are Unevenly Involved in Eosinophilic Esophagitis

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. 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. 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). 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.

Challenges in Inter-rater Agreement on Lamina Propria Fibrosis in Esophageal Biopsies.

Mucosal biopsies in eosinophilic esophagitis (EoE) can exhibit lamina propria (LP) fibrosis, which may portend stenotic complications; however, the histologic diagnosis of LP fibrosis is subjective. We sought to assess and improve the consistency of LP fibrosis diagnosis among our pathologist group. At a large pediatric hospital, 25 esophageal biopsy slides from 19 patients (16 with EoE) exhibiting a wide spectrum of LP area, artifacts, and fibrosis severity were scanned into whole-slide images. Staff pediatric pathologists (n = 8) separate from the authors classified each biopsy by LP adequacy and fibrosis severity 1 month before and after completion of an educational tutorial. Consensus was defined as >70% agreement. At baseline, 16/25 (64%) cases reached consensus for no fibrosis (n = 3), fibrosis (n = 7), or inadequate LP (n = 6); agreement was fair (α = 0.34). Post-tutorial, 13/25 (52%) cases reached consensus for no fibrosis (n = 2), fibrosis (n = 7), or inadequate LP (n = 4); agreement was again fair (α = 0.33). There was moderate agreement in grading of fibrosis severity (α = 0.54). We document only fair-to-moderate agreement in the diagnosis of esophageal LP fibrosis and adequacy in a large pediatric pathologist group despite targeted education, highlighting a challenge in incorporating this feature into EoE research and clinical decision-making.

Клинико-морфологическая диагностика эозинофильного эзофагита

Eosinophilic esophagitis (EoE) is an immune-mediated disease that presents with dysphagia and esophageal bolus obstruction and is characterized by predominant intraepithelial eosinophilic infiltration at histology. The aim of our literature review was to delineate clinical and morphological EoE features in terms of differential diagnosis with other esophageal diseases, i.e., gastroesophageal reflux disease (GERD), inflammatory bowel diseases (IBDs), autoimmune diseases, and rare esophageal disorders. Clinical features of dysphagia and esophageal bolus obstruction and endoscopic criteria (according to EREFS) are typical of EoE. Nevertheless, eosinophilia of the esophageal mucosa is not a specific marker of mucosal injury and is not sufficient for EoE diagnosis. Therefore, eosinophilic esophagitis histological scoring system (EoEHSS) was developed. It involves assessment of intraepithelial eosinophilic infiltration, basal zone hyperplasia, eosinophilic abscesses, eosinophil surface layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis. Complex clinical, endoscopic, and histological evaluation allows accurate diagnosis of EoE and other causal factors of esophageal eosinophilia. Keywords: eosinophilic esophagitis, esophageal eosinophilia, gastroesophageal reflux disease, celiac disease, inflammatory bowel diseases, achalasia, atopy

Oral Immunotherapy and Risk of Eosinophilic Esophagitis in Children: 15 Years' Experience.

Oral immunotherapy (OIT) is an effective treatment for children with persistent food allergy, and has concerns about its safety, including eosinophilic esophagitis (EoE). The aim of this study was to evaluate the prevalence of EoE in a large cohort of children who underwent OIT in our center, and to determine if there were any clinical, endoscopic, or histologic differences depending on the food employed for the OIT. A retrospective study was performed over a 15-year period (2005-2020). Children who underwent cow's milk (CM), egg, and/or peanut OIT and developed EoE were included. Six hundred and seven OIT were carried out (277 CM-OIT, 322 egg-OIT, and 8 peanut-OIT). Seventeen patients (2.8%) had a confirmed histologic diagnosis of EoE with a higher prevalence for patients who underwent CM-OIT (3.9%) than egg-OIT (2.2%). Symptoms suggestive of EoE and a confirmed diagnosis occurred at median times of 25 and 36 months, respectively, after the build-up phase of the OIT was completed. Choking, abdominal pain, and dysphagia were the most frequent symptoms and lamina propria fibrosis was observed in 41.2% of patients. No significant differences in clinical symptoms, endoscopic, or histologic findings between patients under CM or egg-OIT were found. One-third of patients reported mild symptoms suggestive of EoE before the OIT. EoE appears to be a rare but important adverse event that can occur even years after OIT. Validated questionnaires to screen EoE before the OIT and in the follow-up of these patients may be the main tool for an early diagnosis.

233. ENDOSCOPIC REFERENCE SCORE AND HISTOLOGICAL SCORING SYSTEM ARE COMPLEMENTARY ASSESSMENTS FOR CHARACTERIZING FIBROSTENOTIC OR INFLAMMATORY PHENOTYPES IN EOSINOPHILIC ESOPHAGITIS PATIENTS

Abstract The Histologic Scoring System (HSS) assesses severity/extent of histologic features (eosinophil density [ED]/basal zone hyperplasia [BZH]/eosinophil abscesses [EA]/eosinophil surface layering [SL]/surface epithelial alteration [SEA]/dyskeratotic epithelial cells [DEC]/dilated intercellular spaces [DIS]/lamina propria fibrosis [LPF]) in eosinophilic esophagitis (EoE). The Endoscopic Reference Score (EREFS) assesses endoscopic feature severity (edema/exudates/furrows/rings/strictures). We correlated HSS components with inflammatory/remodeling EREFS components in placebo-treated EoE patients from 2 trials—phase 2 proof-of-concept (POC; NCT02379052), phase 3 TREET part A (Phase3-PartA; NCT03633617). POC was a 12-week trial in adults, and Phase3-PartA was a 24-week trial in adults and adolescents. Proximal/mid/distal esophagus biopsies were collected at baseline/end of treatment (EOT) and scored by HSS for grade (severity)/stage (extent)/components (higher scores = greater severity). Endoscopies were scored by EREFS (higher scores = greater severity) and inflammatory (edema+exudates+furrows) and remodeling (rings+stricture) subscores calculated. Pearson correlation and single co-variate regression model analyses were performed between baseline HSS grade/stage, total/individual components scores and EREFS total/components scores and subscores, and for the change in scores from baseline at EOT (ΔEOT). Moderate-to-strong correlations (r &amp;gt; 0.3) were observed between total EREFS and HSS grade/stage for baseline/ΔEOT in POC and baseline in Phase3-PartA (Table). Moderate correlations were observed between BZH and EREFS remodeling subscore and rings for ΔEOT in Phase3-PartA; DIS grade and EREFS remodeling subscore and strictures for baseline and ΔEOT in POC but not Phase3-PartA; and EREFS inflammation and remodeling subscores and components for SEA and SL at baseline and ΔEOT in POC. Moderate-to-strong correlations were observed between EREFS inflammation subscore and DIS stage and between edema and DIS grade/stage at baseline in both studies. Similar results were observed using regression analyses. Specific components of HSS and EREFS, reflecting inflammatory and remodeling processes, are closely correlated, when examined by Pearson correlations or regression analyses, and can aid identification of fibrostenotic or inflammatory phenotypes in EoE. Correlations of DIS with endoscopic inflammatory and remodeling features reflect the role of barrier dysfunction in maintaining chronic inflammation that ultimately leads to remodeling.

MP05-17 INFLAMMATORY CYTOKINES PROMOTE FIBROSIS IN OBSTRUCTED URETERS

You have accessJournal of UrologyCME1 May 2022MP05-17 INFLAMMATORY CYTOKINES PROMOTE FIBROSIS IN OBSTRUCTED URETERS Alina Reicherz, Felipe Eltit, Khaled Almutairi, Roman Herout, Michael Cox, Ben Chew, and Dirk Lange Alina ReicherzAlina Reicherz More articles by this author , Felipe EltitFelipe Eltit More articles by this author , Khaled AlmutairiKhaled Almutairi More articles by this author , Roman HeroutRoman Herout More articles by this author , Michael CoxMichael Cox More articles by this author , Ben ChewBen Chew More articles by this author , and Dirk LangeDirk Lange More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002522.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: To better understand the impact of ureteral obstruction on ureteral tissue, triggered inflammatory response and fibrotic changes. METHODS: Twenty-four murine ureters were obstructed unilaterally for 7 days. 11 mice were euthanized after clamp removal; 13 mice were recovered after clamp removal for 8 days. Unobstructed ureters from 9 mice served as controls. Peristalsis was determined by magnified observation, and hydronephrosis was evaluated by ultrasound. Ureters were harvested, and ureteral tissue was evaluated histologically. 44 cytokines, chemokines and 5 matrix-metalloproteases were quantified using Multiplex panels (Eve Technologies). RESULTS: We observed grade 4 hydronephrosis in all obstructed mice. Similarly, peristalsis was reduced significantly and did not recover fully during the 8 days recovery after clamp removal. Histologically, obstructed ureters showed urothelial changes, fibrosis of lamina propria and adventitia, and thickened muscular layers. Collagen fibres infiltrate the muscular layer of all obstructed ureters but are not observed in non-obstructed ureters. Inflammatory changes in the connective tissue of obstructed ureters are characterized by hyperaemia and leukocytes. Through unsupervised hierarchical clustering, we demonstrate a different cytokine pattern between the groups in which all samples cluster. The highest similarities are observed between the control group and the group of contralateral ureters (ipsilateral side obstructed for 7 days). The group of ureters obstructed for 7 days, and their contralateral ureters are the most different. Consistently, matrix-metalloproteases (MMP-2, MMP-3 and MMP-8) increased significantly after obstruction. Cytokines from T-cell recruitment (IL-16, TARC, MDC) were increased in the obstructed ureter. In addition, the unobstructed, contralateral ureters showed significantly increased levels of cytokines of T-helper cells (Th1: IFN-γ, IL-2, IL-12p40, TNFα; Th2: IL-9, IL-10, IL-13). CONCLUSIONS: Ureteral obstruction triggered a pro-inflammatory response and subsequent fibrosis. These changes seem to impair long-term ureteral functionality. Strikingly, the increase of pro-inflammatory cytokines in the contralateral ureters indicates a systemic effect of unilateral ureteral obstruction. Source of Funding: Alina Reicherz (RE 4611/2-1) is funded by the German Research Foundation (DFG) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e74 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alina Reicherz More articles by this author Felipe Eltit More articles by this author Khaled Almutairi More articles by this author Roman Herout More articles by this author Michael Cox More articles by this author Ben Chew More articles by this author Dirk Lange More articles by this author Expand All Advertisement PDF DownloadLoading ...

The Impact of Early Life Exposure to Glyphosate

Eosinophilic esophagitis (EoE) is a chronic immune mediated disease that affects populations of all ages. It is characterized by eosinophilic inflammation of the esophageal mucosa, decreased epithelial integrity, and lamina propria fibrosis. Clinically, the symptoms of EoE can range from mild (dysphagia, abdominal pain, vomiting), to severe (food impaction, inability to thrive), to complete loss of esophageal function in extreme cases. This disease, first described in 1993, is rising in incidence and prevalence. Unfortunately, the reason for disease emergence is unknown and environmental triggers have been postulated as a potential source. The role of environmental toxins, specifically herbicides, has never been examined in the pathophysiology of atopic disease. Glyphosate, the active ingredient in Roundup, is the most used herbicide in the United States, and is frequently used as a desiccant prior to harvest. Residual amounts can be detected in harvested crops and downstream food products, potentially leading to a diet of chronic exposure. Herein we sought to determine the effects of early life glyphosate treatment and the consequences of exposure on the development of eosinophilic esophagitis and the maintenance of epithelial integrity.We exposed mice to physiologic levels of glyphosate in utero and throughout their life cycle to simulate glyphosate consumption in the typical American diet. We then induced EoE in mice using our established protocol and evaluated epithelial integrity and inflammation. Interestingly, we found that chronic glyphosate treatment alone induced a 2‐fold increase in esophageal eosinophils over baseline, similar to mice undergoing EoE. Secondarily, we exposed primary human esophageal and intestinal organoids to short term glyphosate treatment. We observed no changes in the esophageal organoids. However, we found increased gene expression of mucin 2 (MUC2) in organoids derived from terminal ileum and proximal colon.Taken together these results suggest that there is increased inflammation in the glyphosate treated mice and this may be due, in part, to a response generated in the small intestine by glyphosate exposure.

Development and Validation of Web-Based Tool to Predict Lamina Propria Fibrosis in Eosinophilic Esophagitis.

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. 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. 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. 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.