Histological Scoring System Research Articles

African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population

Introduction and objectivesPNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. MethodsWe included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. ResultsA total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. ConclusionAmong NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.

Artificial Intelligence Improves Pathologist Agreement for Fibrosis Scores in Nonalcoholic Steatohepatitis Patients

Artificial Intelligence Improves Pathologist Agreement for Fibrosis Scores in Nonalcoholic Steatohepatitis Patients

Reliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score.

The NASH Clinical Research Network histologic scoring system, the gold-standard NASH histology assessment for clinical trials, has demonstrated intrarater and interrater variability. An expert panel in a previous systematic Research and Development/University of California Los Angeles (RAND/UCLA) study determined that existing histologic scoring systems do not fully capture NASH disease activity and fibrosis, and standardized definitions of histologic features are needed. We evaluated the reliability of existing and alternate histologic measures and their correlations with a disease activity visual analog scale to propose optimal components for an expanded NAFLD activity score (NAS). Four liver pathologists who were involved in the prior RAND/UCLA study underwent standardized training and multiple discussions with the goal of improving agreement. They were blinded to clinical information and scored histologic measures twice, ≥2 weeks apart, for 40 liver biopsies representing the full spectrum of NAFLD. Index intraclass correlation coefficient (ICC) estimates demonstrated intrarater (0.80-0.85) and interrater (0.60-0.72) reliability. Hepatocyte ballooning items had similar interrater ICCs (0.68-0.79), including those extending scores from 0-2 to 0-4. Steatosis measures (interrater ICCs, 0.72-0.80) correlated poorly with disease activity. Correlations with disease activity were largest for hepatocyte ballooning and Mallory-Denk bodies (MDBs), with both used to develop the expanded NAS (intrarater ICC, 0.90; interrater ICC, 0.80). Fibrosis measures had ICCs of 0.70-0.87. After extensive preparation among a group of experienced pathologists, we demonstrated improved reliability of multiple existing histologic NAFLD indices and fibrosis staging systems. Hepatocyte ballooning and MDBs most strongly correlated with disease activity and were used for the expanded NAS. Further validation including evaluation of responsiveness is required.

Reliability of the nonalcoholic steatohepatitis clinical research network and steatosis activity fibrosis histological scoring systems

We aimed to determine whether lobular inflammation and ballooning grades in the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) scoring system can be directly translated into the same for the Steatosis Activity Fibrosis scoring system (SAF) and to look at intra-observer and inter-observer agreement for each individual histological component and for diagnosis of non-alcoholic steatohepatitis (NASH) using the two scoring systems. Four pathologists from two Asian centers scored 20 digitalized slides, twice using the NASH CRN, twice using the SAF. Intra-observer and inter-observer agreement was analyzed using Fleiss' kappa, weighted kappa, or Cohen kappa, where appropriate. The intra-observer discrepancy rate when using the NASH CRN compared with the SAF was higher than when using the individual scoring system for lobular inflammation (15% comparing both scoring systems vs 10% and 1.8% for the NASH CRN and the SAF, respectively) and hepatocyte ballooning (33.8% vs 12.5% and 5%, respectively), but not for diagnosis of NASH (6.3% vs 6.3% and 0%, respectively). Intra-observer and inter-observer agreement was substantial to almost perfect, except for inter-observer agreement for lobular inflammation and diagnosis of NASH, which was only fair to moderate in most instances. These findings do not support the direct inter-translation between the NASH CRN and the SAF. However, the diagnosis of NASH during examinations using the NASH CRN may be comparable with diagnosis of NASH using the SAF, vice versa. The inter-observer agreement for lobular inflammation and NASH diagnosis needs to be improved.

Impact of the biopsy forceps size on histological analysis and performances of the histological scoring systems

To improve the reliability of the quantitative scorings of the synovial biopsies, we evaluate whether diameter of arthroscopic forceps influences histological quality of synovial tissue and/or histological scores and we compare the intra- and inter-observer performances of the main histological scoring systems. Synovial biopsies were retrieved in the same part of the joint using 1, 2 and 4 mm diameters grasping forceps. After standard staining and immunohistochemistry with anti-CD68 antibody, slides were scored blindly by 2 independent experienced operators for tissue quality and with Krenn score, de Bois-Tak score and CD68 semi-quantitative score. Four samples did not pass quality control. No difference other than a higher number of vessels in the 4 mm versus 2 mm forceps (p = 0.01) was found among the 3 groups. CD68 score was significantly higher in the 2 versus 4 mm forceps (p = 0.009). So we concluded that only vessels quantification and CD68 semi-quantitative score seemed affected by the forceps size. The intra-reader agreement was variable across observers and features: 0.78 (0.66–0.87) for the Krenn scoring system, 0.89 (0.78–0.97) for the de Bois-Tak score and 0.93 (0.81–1.00) for the CD68 score. Interobserver reliabilities of Krenn score, de Bois-Tak score and CD68 scores were satisfactory: 0.95 (0.92–0.99) for Krenn, 0.98 (0.96–0.99) for de Bois-Tak and 0.80 (0.71–0.89) for CD68.

Estrogen as primary factor in vaginal healing in rats.

Although the effect of estrogens on wound healing is already known, its complex mechanism is not fully understood in literature. The aim of this study is to investigate the effect of estrogen on vaginal healing after surgical intervention performed in the age group with low estrogen level and in an adult group with high estrogen level. Seven young and seven adult female Wistar Albino rats were procured. For control group, one animal was chosen each from the young (Group I) and adult groups (Group II), and their vaginal tissue was removed. An incision was made to the posterior vaginal wall under anesthesia and sutured with 5-0 polyglactin in all the rats. On the seventh postoperative day, the posterior vaginal wall was excised. A semi-quantitative method was used to evaluate the histological processes and structures during wound healing. Although there were no evident differences in the evaluation of histological scoring system, the presence and distribution of new vascularization and fibroblasts showed that vaginal mucosal healing was more intense in adult rats. The effect of estrogens on vaginal mucosal healing has been discussed in several experimental studies and literature information has been presented; it has been concluded that it would be beneficial to consider the positive effect of vaginoplasty procedures.

Histological Scores in Patients with Inflammatory Bowel Diseases: The State of the Art.

The histological assessment has been advocated as a detailed and accurate measure of disease activity in inflammatory bowel diseases (IBD). In ulcerative colitis (UC), histological activity has been demonstrated to be associated with higher rates of relapse, prolonged corticosteroid use and long-term complications, even when endoscopic remission is achieved. Therefore, histological healing may represent a potential treatment target. Several histological scores have been developed and are available today. The Robarts histopathology index (RHI) and the Nancy index (NI) are the only two recommended by the European Crohn’s and Colitis Organization (ECCO) for use in patients with UC. Conversely, in Crohn’s disease (CD), the discontinuous nature of lesions has limited standardized histological assessment. Most of the available histological scoring systems in CD are complex and not validated. The aim of this review is to comprehensively summarize the latest evidence regarding histological scoring systems in IBD. We guide the reader through understanding the importance of an accurate microscopic evaluation using validated scoring systems, highlighting the strengths and pitfalls of each score. The priorities of future research needs are also addressed.

Repair of experimentally induced femoral chondral defect in a rabbit model using Lyophilized growth promoting factor extracted from horse blood platelets (L-GFequina)

Lyophilized equine platelet derived growth factors (LGF) is a novel advanced platelet rich protein growth factor. It has been successfully applied in various fields of regenerative medicine to treat a variety of inflammatory and degenerative musculoskeletal conditions. Our study aimed to evaluate the efficacy of intraarticularly injected LGF for the remedy of articular cartilage injury, commonly characterized by progressive pain and loss of joint function in osteoarthritic rabbits. Full-thickness cylindrical cartilage defects were generated in both femoral condylar articular surfaces in twenty rabbits. The left joint of all animals was injected with the adjuvant as a self-control negative, while the right joint was injected by LGF. Four- and eight-weeks post-surgery, the femoral condyles were harvested, and assessed grossly, microscopically and immunohistochemically. Cytokines (TNF-α, IL-1β, PDGF and TGF-β1) contents of the chondral defects were quantified by ELISA as well as the gene expression of Col I and Col II via RT-qPCR. The LGF treated defects showed significant higher ICRS (International cartilage repair society) healing scores of cartilaginous regeneration with a significant higher histological healing score on using O'Driscoll histological scoring system. Additionally, LGF significantly lowered the levels of the pro-inflammatory cytokines TNF-α and IL-1β. It also significantly increased the anabolic and angiogenic growth factors (PDGF and TGF-β1), and significantly elevated the expression of chondrogenic-related marker genes; Col I and Col II. The current study reveals that LGF improves chondral healing and thus it can be a superior nominee as an adjunctive therapy to positively influence regeneration of chondral defects in osteoarthritic patients.

DOP58 An artificial intelligence–driven scoring system to measure histological disease activity in Ulcerative Colitis

Abstract Background Histological remission is increasingly regarded as an important and deep therapeutic target for ulcerative colitis (UC). Assessment and scoring of histological images is a tedious procedure, that can be imprecise and prone to inter- and intra-observer variability. Therefore, a need exists for an automated method that is accurate, reproducible and reliable. This study aimed to investigate whether an artificial intelligence (AI) system developed using image processing and machine learning algorithms could measure histological disease activity based on the Nancy index. Methods A total of 200 histological images of patients with UC from a database at University Hospital, Vandoeuvre-lès-Nancy, France were used for this study. The novel AI system was used to fully characterise histological images and automatically measure Nancy index. The in-house AI algorithm was developed using state-of-the-art image processing and machine learning algorithms based on deep learning and feature extraction. The cell regions of each image, followed by Nancy index, were manually annotated and measured independently by 3 histopathologists. Manual and AI-automated measurements of Nancy index score were done and assessed using the intraclass correlation coefficient (ICC). Results The 200-image dataset was divided into 2 groups (80% was used for training and 20% for testing). ICC statistical analyses were performed to evaluate AI tool and used as a reference to calculate the accuracy (Table 1). The average ICC amongst the histopathologists was 89.33 and average ICC between histopathologists and AI tool was 87.20. Despite the small number of image data, the AI tool was found to be highly correlated with histopathologists. Conclusion The high correlation of performance of the AI method suggested promising potential for IBD clinical applications. A standardised and validated histological AI-driven scoring system can potentially be used in daily IBD practice to eliminate the subjectivity of the pathologists and assess the disease severity for treatment decision.

Application of the Eosinophilic Esophagitis Histology Scoring System Grade Scores in Patients at British Columbia Children’s Hospital

Introduction Histologic diagnosis of eosinophilic esophagitis (EoE) involves peak eosinophil counts (PEC) being greater than 15 per high power field. The EoE Histology Scoring System (EoEHSS) was developed to comprehensively evaluate biopsies to better predict symptom and endoscopy response; we aimed to validate the EoEHSS in our provincial registry, where EoEHSS had not been employed. Methods We reviewed 186 esophageal biopsies from 16 patients at diagnosis and follow-up. Statistical analyses were conducted to quantify how grade scores correlate with active EoE status and PEC counts, and each feature’s ability to predict active disease. Results Nearly all EoEHSS variables were associated with active EoE and high PEC, with basal zone hyperplasia, eosinophil abscesses, and surface epithelial alteration being most predictive in identifying active EoE. Conclusions We validated and demonstrated each EoEHSS variable’s strength in tracking traditional PEC counts, resulting in its adoption as a standard reporting element for our research registry.

ECCO Position on Harmonisation of Crohn's Disease Mucosal Histopathology.

In inflammatory bowel disease [IBD], mucosal healing is a major therapeutic target and a reliable predictor of clinical course. However, endoscopic mucosal healing is not synonymous with histological healing, and the additional benefits of including histological remission as a target are unclear. In Crohn´s disease [CD], there are few studies highlighting the value of histological remission as a therapeutic target. Histological activity can persist in CD patients who are in endoscopic remission, and the absence of histological activity may be associated with lower relapse rates. Therefore, standardisation of procedures to evaluate CD histological activity is desirable. Topics that would benefit from standardisation and harmonisation include biopsy procedures, biopsy processing techniques, the content of histological scores, and the definitions of histological remission, histological response, and histological activity. In line with these needs, the European Crohn's and Colitis Organisation [ECCO] assembled a consensus group with the objective of developing position statements on CD histology based on published evidence and expert consensus. There was agreement that definitions of histological remission should include absence of erosion, ulceration, and mucosal neutrophils; that the absence of neutrophilic inflammation is an appropriate histological target in CD; that CD histological scores, such as the Global Histological Disease Activity Score, lack formal validation; and that histological scoring systems for ulcerative colitis, including the Geboes Score, Robarts Histopathology Index, and Nancy Histological Index, can be used for scoring intestinal biopsies in CD patients.

Evaluating the Prognostic Implication of the Collins Histology Scoring System in a Pediatric Eastern Ontario Population With Eosinophilic Esophagitis.

Collins et al developed a histology scoring system (EoE HSS) to assess multiple pathologic features. The aim of this study is to identify if the EoE HSS can better detect endoscopic and symptom improvement vs the Peak Eosinophilic Count (PEC). A retrospective chart review was performed for patients during 2014-2016. All patients ≤18years old with a diagnosis of EoE and whose records included initial and follow-up upper gastrointestinal endoscopies were included. Severity and extent of endoscopic features were scored using 8 parameters, from normal to maximum change for each location of the esophageal biopsy. Forty patients with EoE were included in the study, of which 35 (87.5%) patients demonstrated symptom and 25 (62.5%) endoscopic improvement at the time of follow-up. In the proximal esophagus, the EoE HSS outperformed the change in eosinophil count of the Children's Hospital of Eastern Ontario (CHEO) practice in predicting endoscopic improvement by 16.8% when examining the change in grade and 17.1% when examining the change in stage scores. At our institution, adoption of the EoE HSS in assessing biopsies of EoE patients might be warranted, compared to the traditional practice. However, a bigger sample size may give a more robust difference in all locations.

A Semi-quantitative Scoring System for Green Histopathological Evaluation of Large Animal Models of Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) is a life-threatening, high mortality pulmonary condition characterized by acute lung injury (ALI) resulting in diffuse alveolar damage. Despite progress regarding the understanding of ARDS pathophysiology, there are presently no effective pharmacotherapies. Due to the complexity and multiorgan involvement typically associated with ARDS, animal models remain the most commonly used research tool for investigating potential new therapies. Experimental models of ALI/ARDS use different methods of injury to acutely induce lung damage in both small and large animals. These models have historically played an important role in the development of new clinical interventions, such as fluid therapy and the use of supportive mechanical ventilation (MV). However, failures in recent clinical trials have highlighted the potential inadequacy of small animal models due to major anatomical and physiological differences, as well as technical challenges associated with the use of clinical co-interventions [e.g., MV and extracorporeal membrane oxygenation (ECMO)]. Thus, there is a need for larger animal models of ALI/ARDS, to allow the incorporation of clinically relevant measurements and co-interventions, hopefully leading to improved rates of clinical translation. However, one of the main challenges in using large animal models of preclinical research is that fewer species-specific experimental tools and metrics are available for evaluating the extent of lung injury, as compared to rodent models. One of the most relevant indicators of ALI in all animal models is evidence of histological tissue damage, and while histological scoring systems exist for small animal models, these cannot frequently be readily applied to large animal models. Histological injury in these models differs due to the type and severity of the injury being modeled. Additionally, the incorporation of other clinical support devices such as MV and ECMO in large animal models can lead to further lung damage and appearance of features absent in the small animal models. Therefore, semi-quantitative histological scoring systems designed to evaluate tissue-level injury in large animal models of ALI/ARDS are needed. Here we describe a semi-quantitative scoring system to evaluate histological injury using a previously established porcine model of ALI via intratracheal and intravascular lipopolysaccharide (LPS) administration. Additionally, and owing to the higher number of samples generated from large animal models, we worked to implement a more sustainable and greener histopathological workflow throughout the entire process.

The Effect of Single vs Serial Platelet-Rich Plasma Injection in Osteochondral Lesions Treated with Microfracture: An in Vivo Rabbit Model

Category:Ankle; Basic Sciences/BiologicsIntroduction/Purpose:Platelet-rich plasma (PRP) has gained increasing interest as a potential therapeutic augment for decreasing inflammation and enhancing healing after cartilage injury. However, it remains unknown whether osteochondral repair outcomes benefit from multiple PRP injections. We performed this animal study to investigate the effects of serial PRP injections on cartilage repair tissue, subchondral bone remodeling, and joint inflammation.Methods:Forty-eight adult New Zealand White rabbits were randomly assigned to receive either one (1P), two (2P), or three (3P) PRP injections. Cylindrical full-thickness cartilage defects with subsequent microdrilling were created on the central medial femoral condyle of both knees. PRP injections were provided on the day of surgery and every 2 weeks thereafter until the assigned number of injections was achieved for each group. Rabbits in each group were euthanized at 3, 6, or 12 weeks postoperatively. Cartilage repair tissue was assessed using the International Cartilage Repair Society (ICRS) macroscopic and modified ICRS histological scoring systems. Subchondral bone remodeling was evaluated by micro-computer tomography (µCT) analysis. Joint inflammatory cytokines including IL-1, IL-1ra, IL-6, IL-8, TNFα, and TGFβ were assessed by quantitative polymerase chain reaction.Results:Macroscopic assessment at 3 and 6 weeks demonstrated improved mean ICRS macroscopic scores in the PRP groups compared with the control group, although this difference was not significant. The mean ICRS macroscopic score at 12 weeks in Group 3P was significantly lower than the control, but there was no significant difference compared with Group 1P and Group 2P (Control: 6.1+-3.3, Group 1P: 3.4+-2.7, Group 2P: 4.2+-2.9, Group 3P: 0.7+-1.5). The mean modified ICRS histological score was significantly higher at each time point for the PRP groups compared with the control group, but there was no significant difference in the scores among PRP groups. There were no significant differences in outcomes for the characteristics evaluated by µCT nor inflammatory cytokine levels among each group at each time point.Conclusion:Serial PRP injections, as compared to a single PRP injection, do not have a significant impact on cartilage repair tissue nor inflammatory cytokine levels at 12 weeks after surgery in an in vivo animal model. Further work is necessary to determine the effect of single versus serial PRP injections on cartilage repair tissue in humans.

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.

Very Early Onset Eosinophilic Esophagitis Is Common, Responds to Standard Therapy, and Demonstrates Enrichment for CAPN14 Genetic Variants

To determine if very early onset eosinophilic esophagitis (V-EoE) represents a separate disease endotype, with worse clinical features and prognosis, distinct molecular properties, and specific risk factors, compared with that of later-onset pediatric eosinophilic esophagitis (L-EoE).In this study, researchers included patients diagnosed with eosinophilic esophagitis (EoE) at the age of ≤12 months (V-EoE: n = 57) and at the age of 14 to 18 years (L-EoE: n = 70). The diagnostic criteria for EoE included symptoms of esophageal dysfunction or inflammation and at least 15 eos/hpf in distal esophageal biopsy despite proton pump inhibitor use.A single-center retrospective chart review was focused on demographics and clinical history. Pretreatment histologic and gross endoscopic features were graded by using the EoE Histology Scoring System and the EoE Endoscopic Reference Score. RNA was extracted from a cohort of 15 pretreatment patients and analyzed via the EoE Diagnostic Panel, which is used to distinguish EoE from gastroesophageal reflux. With genetic analysis, the researchers examined whether single-nucleotide polymorphisms in CAPN14 and TSLP were associated with age of diagnosis.EoE was most commonly diagnosed at the age of 0 to 24 months. The V-EoE group was more likely to present with feeding issues, weight concerns, and vomiting, compared with that of dysphagia in the L-EoE group. Patients with V-EoE were more likely to have a history of cesarean delivery. Dietary restriction was more likely to be the initial and successful therapy in in the V-EoE group, whereas the L-EoE group was more likely to respond to swallowed steroids. Histologic remission was sustained in patients with V-EoE and was less common in patients with L-EoE, likely due to therapy nonadherence. The V-EoE group demonstrated higher levels of inflammation on histology, whereas esophageal strictures and fibrosis were more common in the L-EoE group. EDP molecular expression was similar between the 2 groups. Genetic analysis–identified single-nucleotide polymorphisms in CAPN14 were associated with V-EoE.V-EoE is associated with unique clinical, histologic, and genetic features. The increased incidence of cesarean delivery in patients with V-EoE may indicate a role of early-life dysbiosis. Patients with V-EoE can be managed successfully with standard therapy and achieve sustained remission. Fibrostenosis and esophageal dilation were more likely in L-EoE.V-EoE is a clinically important entity, requiring prompt recognition and diagnosis to initiate treatment. In a patient with recurrent emesis, feeding difficulties, and poor weight gain, consider endoscopy to evaluate for EoE. Risk factors include cesarean delivery and CAPN14 variants. Successful management of V-EoE can be attained with standard therapy and may prevent late-stage complications related to esophageal remodeling.

Measuring Histologic Activity in Inflammatory Bowel Disease: Why and How.

Histology is used to confirm the diagnosis of inflammatory bowel disease, exclude superimposed infections, and to evaluate for dysplasia. Histology has rarely been used to measure disease activity and guide therapy despite evidence that histologic measurements have value in predicting important clinical outcomes. More recently, there have been numerous studies supporting a role for histologic disease activity measurements in predicting a variety of outcomes including relapse, hospitalizations, steroid use, and dysplasia. The histologic assessment was superior to endoscopic measurements in many of these studies. This review will summarize the recent literature regarding histologic disease activity measurements in ulcerative colitis and Crohn disease. A detailed description of histologic scoring systems will also be provided to provide pathologists with the necessary tools to accurately measure disease activity.

The Effect of Single vs Serial Platelet-Rich Plasma Injections in Osteochondral Lesions Treated With Microfracture: An In Vivo Rabbit Model

Background: Biological adjuvants are used after a musculoskeletal injury to improve healing, decrease inflammation, and restore joint homeostasis. Work on 1 such adjuvant, platelet-rich plasma (PRP), has suggested a positive effect when introduced during cartilage repair. However, it remains unknown whether healing osteochondral injuries benefit from serial PRP injections. Purpose: To evaluate the effects of serial PRP injections versus a single PRP injection on reparative cartilaginous tissue, subchondral bone remodeling, and the expression of inflammatory cytokines in joint synovium. Study Design: Controlled laboratory study. Methods: A total of 48 New Zealand White rabbits were randomly assigned to receive 1 (1P), 2 (2P), or 3 (3P) PRP injections. Cylindrical full-thickness cartilage defects (2.9 × 2.9 mm) with microdrillings (0.6-mm diameter) were created on the medial condyles of both knees. PRP was injected into the right knee after closure (groups 1P, 2P, and 3P), at 2 weeks after surgery (groups 2P and 3P), and at 4 weeks after surgery (group 3P). The left knees did not receive any PRP injections. A total of 6 rabbits in each group were euthanized at 3, 6, and 12 weeks postoperatively. Cartilage repair tissue was assessed using the Goebel macroscopic and modified International Cartilage Regeneration & Joint Preservation Society (ICRS) histological scoring systems. Subchondral bone remodeling was evaluated by micro–computed tomography analysis (micro-CT). Inflammatory cytokine levels were assessed by quantitative polymerase chain reaction. Results: No significant differences were found for the mean macroscopic score between the PRP groups at 12 weeks (control, 6.1 ± 3.3; group 1P, 3.4 ± 2.7; group 2P, 4.2 ± 2.9; group 3P, 0.7 ± 1.5). All PRP groups had a significantly higher mean modified ICRS histological score compared with the control group, but no significant difference was found among the PRP groups. No significant differences were seen in outcomes for the tested micro-CT parameters or cytokine expression levels. Conclusion: Serial PRP injections conferred no apparent advantage over single injections according to evaluations of the macroscopic and histological appearance of the cartilaginous tissue, subchondral bone healing, and inflammatory cytokine expression levels in the synovium. Clinical Relevance: The use of PRP as a biological adjuvant to bone marrow stimulation for osteochondral lesions has the potential to enhance the quality of regenerative cartilaginous tissue. We recommend only a single PRP injection if the use of PRP is indicated by the operating surgeon as an adjuvant therapy for osteochondral lesions.

Loss of Endothelial TSPAN12 Promotes Fibrostenotic Eosinophilic Esophagitis via Endothelial Cell–Fibroblast Crosstalk

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 thefunctional consequences. 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 invitro. 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. 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.

Clinicopathological Differences between Eosinophilic Esophagitis and Asymptomatic Esophageal Eosinophilia.

Objective According to consensus guidelines, eosinophilic esophagitis (EoE) is defined as a clinicopathological entity whose symptoms and histology must always be considered together. However, endoscopic findings typical of EoE are often seen in asymptomatic esophageal eosinophilia (aEE). We aimed to clarify the clinicopathological features of aEE. Methods We retrospectively compared cases of aEE and those of symptomatic EoE. Materials We reviewed 146 patients who underwent upper gastrointestinal endoscopy and were confirmed histopathologically to have esophageal eosinophil infiltration of at least 15 eosinophils per high-power field. They were divided into the aEE group (n=75) and the EoE group (n=71). Patients' clinicopathological findings were then collected and examined. Results The EoE group experienced dysphagia (47.9%), heartburn (40.8%), food impaction (40.8%), chest pain (16.9%), and other symptoms (8.5%). There was no significant difference between the two groups with regard to age, sex, current smoking status, or alcohol consumption. The aEE group had a significantly higher body mass index (p<0.01) and significantly lower frequency of concurrent allergic diseases (p<0.01) than the EoE group. No significant differences were found between the two groups with regard to the mean peripheral blood eosinophil count, non-specific immunoglobulin E concentration, peak eosinophil infiltration in the biopsy specimens, EoE histology scoring system, phenotype and location of typical endoscopic findings of EoE, or thickness of the esophagus wall or the mucosal and submucosal layer as measured by endoscopic ultrasonography. Two patients in the aEE group who were followed up without treatment subsequently developed esophageal symptoms. Conclusion aEE and EoE may have the same clinicopathological features.