Fibrotic Strictures Research Articles

The Value of Magnetic Resonance Enterography Activity Indices in Evaluation of Crohn’s Disease Clinical Activity

Abstract Background Crohn’s disease is a chronic inflammatory segmental bowel disorder characterized by attacks of remission and exacerbation that can significantly affect the patients’ quality of life. Hence monitoring the disease activity is crucial to achieve longer symptom free intervals which may result either from active inflammation and its complications as deep ulceration, fistulae formation and abscesses or sequelae from longstanding inflammatory process as fibrotic scarring and strictures. Aim of the Work to compare the performance of the currently available scoring systems Maria, Clermont, CDMI and MEGS to the clinical disease activity index and endoscopic indices Patients and Methods the study was conducted at the Diagnostic Radiology Unit; Radiology Department, Ain Shams University Hospitals. Over a period of 9 months. Convenience sample of proven cases of Crohn’s disease based on clinical suspicion, biomarkers, endoscopy and histopathological specimens who were referred for MRE enterography at our institution. Results We studied the relevance of 18 different single MR parameters and 5 indices in conjunction with clinical and endoscopic based scores. Our aim was to identify if any of the MR parameters can be used solely or in combination with others (indices) as predictors of disease activity. In our study, we identified that the presence of ulcers reflected the clinical rather than the endoscopic severity. Other individual MR parameters couldn’t predict either the clinical or endoscopic severity. The MaRIA score showed significant correlation with the clinical but not endoscopic score. The simplified MaRIA score reflected both the endoscopic and clinical severity scores regarding their absolute values and severity grade. Neither Diffusion- MaRIA/Clermont nor the CDMI scores could predict the degree of clinical and endoscopic disease severity. MEGS score was the most reliable score in determining the endoscopic activity despite being a consuming score with relative subjectivity in comparison to the forementioned scores. Conclusion MR indices provide an adjunct tool for evaluation of disease activity and identifying the severe disease evidenced by MaRIA, simplified MaRIA and MEGS scores. However, the use of a single MR parameter doesn’t provide a true reflection of the ongoing disease process, even the presence of ulcers and haustral loss may be associated with chronic disease.

Naringin Alleviates Intestinal Fibrosis by Inhibiting ER Stress-Induced PAR2 Activation.

Fibrosis characterized by intestinal strictures is a common complication of Crohn's disease (CD), without specific antifibrotic drugs, which usually relies on surgical intervention. The transcription factor XBP1, a key component of endoplasmic reticulum (ER) stress, is required for degranulation of mast cells and linked to PAR2 activation and fibrosis. Many studies have confirmed that naringin (NAR) can inhibit ER stress and reduce organ fibrosis. We hypothesized that ER stress activated the PAR2-induced epithelial-mesenchymal transition process by stimulating mast cell degranulation to release tryptase and led to intestinal fibrosis in CD patients; NAR might play an antifibrotic role by inhibiting ER stress-induced PAR2 activation. We report that the expression levels of XBP1, mast cell tryptase, and PAR2 are upregulated in fibrotic strictures of CD patients. Molecular docking simulates the interaction of NAR and spliced XBP1. ER stress stimulates degranulation of mast cells to secrete tryptase, activates PAR2-induced epithelial-mesenchymal transition process, and promotes intestinal fibrosis in vitro and vivo experiments, which is inhibited by NAR. Moreover, F2rl1 (the coding gene of PAR2) deletion in intestinal epithelial cells decreases the antifibrotic effect of NAR. Hence, the ER stress-mast cell tryptase-PAR2 axis can promote intestinal fibrosis, and NAR administration can alleviate intestinal fibrosis by inhibiting ER stress-induced PAR2 activation.

Intestinal Adipocytes Transdifferentiate into Myofibroblast-like Cells and Contribute to Fibrosis in Crohn's Disease.

Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD. The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-β signalling was also studied to explore the underlying mechanism. Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. Lipopolysaccharide [LPS]-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-β signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue. Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-β signalling.

Current Approach to Risk Factors and Biomarkers of Intestinal Fibrosis in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD), especially Crohn's disease (CD), characterized by a chronic inflammatory process and progressive intestinal tissue damage, leads to the unrestrained proliferation of mesenchymal cells and the development of bowel strictures. Complications induced by fibrosis are related to high rates of morbidity and mortality and lead to a substantial number of hospitalizations and surgical procedures, generating high healthcare costs. The development of easily obtained, reliable fibrogenesis biomarkers is essential to provide an important complementary tool to existing diagnostic and prognostic methods in IBD management, guiding decisions on the intensification of pharmacotherapy, proceeding to surgical methods of treatment and monitoring the efficacy of anti-fibrotic therapy in the future. The most promising potential markers of fibrosis include cartilage oligomeric matrix protein (COMP), hepatocyte growth factor activator (HGFA), and fibronectin isoform- extra domain A (ED-A), as well as antibodies against granulocyte macrophage colony-stimulating factor (GM-CSF Ab), cathelicidin (LL-37), or circulatory miRNAs: miR-19a-3p and miR-19b-3p. This review summarizes the role of genetic predisposition, and risk factors and serological markers potentially contributing to the pathophysiology of fibrotic strictures in the course of IBD.

DOP61 Up-regulated Gremlin 1 in fibroblasts from Crohn’s Disease fibrotic strictures: A potential therapeutic target

Abstract Background Fibrosis is a common complication in Crohn’s disease (CD), often leading to intestinal strictures that are refractory to available biologic drugs and require surgery. Addressing this complication remains a significant unmet need. This study aims to explore the transcriptomic signature of fibrostenotic ileal CD to identify novel therapeutic targets. Methods 9 CD patients undergoing surgery for fibrotic strictures were prospectively recruited. All patients underwent magnetic resonance enterography, ileoscopy, and assessment of C-reactive protein and faecal calprotectin. A multidisciplinary team adjudicated the presence of fibrotic strictures, warranting surgical resection. Resected specimens were harvested directly from the operating theatre and delivered fresh to pathologists, who dissected samples from the strictured area, and the proximal and distal non-strictured regions. RNA was extracted from all samples for bulk-transcriptomic and single-cell RNA sequencing (scRNAseq) analysis, using the 10x Chromium Controller® platform. Differentially expressed genes (adj. p-value <0.05) were identified. Machine learning analyses, including PCA and PLS-DA, were employed to compare gene expression patterns among different tissue segments. Pathway enrichment analysis pinpointed relevant pathways. Further, the random forest model was constructed to evaluate the predictive significance of genes in relation to strictures, and the resulting ranked list of genes was subsequently validated through qPCR, confirming the significance of selected genes. Results Bulk-transcriptomic analysis revealed 64 significantly up-regulated genes in strictures, associated with inflammation, matrix remodeling, adipogenesis and cellular stress. Furthermore, 17 down-regulated genes were linked to epithelial barrier integrity. Normalised gene expression of GREM1, SERPINE1, FGF2, HDAC1 AND LY96 showed high predictive value for strictures compared to distal and proximal segments. Notably, qPCR confirmed the significant up-regulation of GREM1 expression exclusively in the ileal stricture samples (non-stricture vs. stricture: AUC 0.88, 95% CI 0.77-0.95). scRNAseq linked up-regulated GREM1 exclusively to the fibroblast cell population (THY1+, COL1A1+,ACTA2+). Conclusion Bulk and single-cell transcriptomics, along with qPCR validation of resected CD ileal strictures, showed the up-regulation of GREM1 in fibroblasts within stricture compared to adjacent proximal and distal intestinal samples. These findings confirmed in ileal CD previous reports from animal models, highlighting the role of GREM1 in promoting intestinal fibrosis. Therefore, GREM1 emerges an attractive target for the treatment of fibrotic strictures in CD.

P387 Short and long-term outcomes of surgery for inflammatory (uncomplicated) ileocecal Crohn’s disease: multicentric retrospective analysis of 211 patients

Abstract Background Surgical management for patients with inflammatory ileocecal Crohn’s disease (CD) could be a reasonable alternative to second-line medical treatment. Methods A retrospective analysis of patients intervened for primary ileocecal CD with uncomplicated (inflammatory) phenotype at four referral hospitals during 2012-2021 was performed. The objective was to assess short and long-term outcomes of patients operated on for inflammatory, ileocecal CD. Patients operated on due to inflammatory ileocecal CD (last 50 cm of the terminal ileum and cecum), were considered eligible to participate in this study. Operations performed during a 9-year period (2012-2021) were considered for the study. Patients who were operated for CD for advanced structural bowel damage (fibrotic strictures or penetrating phenotype), those who had had previous abdominal CD-related procedures, and patients who had disease activity in other anatomical regions at the time of surgery, were excluded from the study. Results 211 patients were included. 43% of patients underwent surgery more than 5 years after diagnosis, and 49% had been exposed to at least one biologic agent preoperatively. 89% were operated by laparoscopy, with 1.6% conversion rate. The mean length of stay for patients was 5 days, with only 24 patients (11%) requiring a prolonged hospitalization. The complication rate was 23.7% (50 patients), but most complications were minor (Clavien-Dindo < IIIa), with only 11 patients (5%) presenting with major complications. Leak rate for patients who received a primary anastomosis was 2.9%. The median length of the resected bowel was 25 cm (7-92) and three patients (1.43%) received a stoma. Median follow-up was 36 (17-70) months. The endoscopic recurrence-free survival proportion at 24, 48, 72, 96, and 120 months was 56%, 52%, 45%, 38%, and 33%, respectively. The clinical recurrence-free survival proportion at 24, 48, 72, 96, and 120 months was 83%, 79%, 76%, 74%, and 74%, respectively. In multivariate analysis, previous biological treatment (HR=2.01; p=0.001) was associated with a higher risk of overall recurrence. Conclusion In this study, surgery in patients with primary inflammatory ileocecal CD is associated with good postoperative outcomes, low postoperative morbidity with reasonable recurrence rates. Further studies need to validate the present results.

P243 Multi-modality intestinal ultrasound is accurate and reproducible to distinguish inflammatory from chronic fibrotic strictures in Crohn’s disease – results from the STRICTURE study

Abstract Background In 30%-50% of patients with Crohn’s disease (CD) stenotic complications occur1. There is currently no imaging modality to identify stricture composition, which would allow early targeted (anti-inflammatory vs surgical) treatment. Intestinal ultrasound (IUS) and advanced modalities (contrast-enhanced ultrasound (CEUS) and shear-wave elastography (SWE)) have the potential for transmural disease evaluation. The STRICTURE study investigated whether (advanced) IUS techniques could distinguish between inflammatory- (IP) and non-inflammatory phenotypes (non-IP) of stricturing CD. Methods In this prospective, cross-sectional study consecutive patients with small bowel CD undergoing surgery were included. Patients were eligible if they had a non-passable stricture during endoscopy in the small bowel and/or a stricture at cross-sectional imaging (IUS or MRE)2. Prior to surgery, IUS, CEUS and SWE were performed. Two blinded sonographers scored the cine-loops for IUS and CEUS. After surgery, histological slides were retrieved and location matched with IUS. Two blinded pathologists scored for inflammation, adipocytes and fibrosis. Subsequently the predominant phenotype was determined as: [1] inflammatory (IP; Nancy score 4 with no marked fibrosis/adipocytes), [2] fibrotic (FP; structural changes due to marked fibrosis/adipocytes3) or [3] mixed phenotype (MP; inflammatory and fibrotic aspects but no predominant phenotype). FP and MP were both classified as non-IP. Results A total of 36 patients (age: 42±18 years) with a mean BWT of 6.7±1.7 mm were included. Median time between IUS and surgery was 14 [3-50] days. A total of 7 patients had an IP, 18 a FP and 11 a MP. For the conventional IUS parameters, loss of wall layer stratification (WLS) was more frequently found in IP strictures(OR: 7.87 [1.24-50.00], p=0.029). For CEUS, most parameters were significantly higher in IP versus non-IP (Table 1) and at multi-variable logistic regression Wash-in area under the curve remained the only accurate parameter to distinguish IP from non-IP (OR:1.55 [1.03-2.34], p=0.035) [Figure 1]. SWE inversely correlated with CEUS (Table 1, Figure 1) but did not differentiate between IP and non-IP (33.30 kPa vs 43.49 kPa, p=0.48). The agreement for BWT and loss of WLS was good (ICC: 0.77, p<0.001) and moderate (κ: 0.56, p<0.001), respectively. For CEUS, the most accurate parameters had good to excellent agreement [Table 1]. Conclusion Loss of WLS and CEUS are accurate to distinguish an IP from a non-IP stricture in CD and CEUS inversely correlates with SWE. In addition to accuracy, reproducibility was high and multi-modality IUS could be of additional value in this specific population to select patients most suitable for anti-inflammatory treatment. Table 1 Figure 1

OP30 Endothelial cell-mediated smooth muscle hyperplasia in Crohn’s disease intestinal strictures: Caveolin 1 as a potential therapeutic target

Abstract Background Intestinal stricture is a severe and common complication of Crohn’s disease (CD). Current therapies offer limited success and surgery is often needed. Smooth muscle hyperplasia and hypertrophy play a key role in CD stricture development. This study explores the transcriptomic features of fibrostenotic CD, focusing on the endothelial contribution to smooth muscle changes within intestinal strictures. Methods 9 CD patients undergoing surgery for fibrotic strictures were prospectively enrolled. Dissected samples from the stricture and the adjacent proximal and distal non-strictured areas were obtained from fresh specimens collected directly from the operating theatre. RNA was extracted from all samples for bulk-transcriptomic analysis. Differentially expressed genes (adj. p-value <0.05) were identified and pathway enrichment analysis pinpointed relevant pathways. Subsequently, single-cell RNA sequencing (scRNAseq) analysis was performed using the 10x Chromium Controller® platform. A total of 31.195 cells were sequenced and bioinformatic analysis revealed 13 distinct clusters based on the expression of key lineage target genes. To better characterise the nature of clusters expressing stromal like markers and positioned closely in the UMAP plot, a further subclustering was performed. This resulted in 5 groups, including plasma cells, endothelial cells, fibroblasts, epithelial cells and dendritic like cells. Results Bulk-transcriptomic analysis identified 81 genes differentially expressed in strictures compared to both proximal and distal regions. Notably, genes associated with leukocyte and macrophage recruitment and chemotaxis, namely Platelet and Endothelial Cell Adhesion Molecule 1 (PECAM1), C-C motif Chemokine Ligand 2 (CCL2), and Endothelin Receptor Type B (EDNRB), resulted overexpressed in strictures. scRNAseq identified a distinct subset of endothelial cells (CD34+, PECAM1+). Caveolin 1 (CAV1), a gene encoding for a structural protein predominantly expressed in smooth muscle cell plasma membrane invaginations, was exclusively up-regulated in endothelial cells of ileal stricture samples. Previous research linked CAV1 to smooth muscle proliferation and fibrosis in various organs. Conclusion This study highlights the pivotal role of endothelial cells in CD strictures. The transcriptomic analysis shows the involvement of inflammatory targets featured genes involved in transendothelial immune cell migration. Furthermore, the up-regulation of CAV1 in endothelial cells within stricture segments suggests a mechanistic connection between endothelial cells and smooth muscle hyperplasia in intestinal strictures. CAV1 holds promise as a potential therapeutic target in fibrostenotic CD.

P823 Real-world effectiveness of upadacitinib in Crohn's disease; a UK multicentre retrospective cohort study

Abstract Background Upadacitinib is a Janus kinase inhibitor which has recently been approved for the treatment of Crohn’s disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn’s disease. Our aim was to evaluate the outcomes of upadacitinib in a real-world cohort. Methods We conducted a retrospective, multicentre, cohort study. Our primary outcome was treatment persistence at week 24. Our secondary endpoints were corticosteroid-free clinical remission (Harvey-Bradshaw Index ≤4), and biomarker remission (CRP ≤5 mg/L and FCAL <250 µg/g). We measured outcomes at 12 weeks, 24 weeks and at last observation. We recorded adverse events. Results We included 74 patients who commenced upadacitinib over a two-year period for analysis, with a median follow-up time of 23 weeks (IQR, 15-39 weeks). All patients had failed anti-TNF therapy, with 78% and 58% additionally failing prior IL12/23 and vedolizumab (Table 1). Treatment persistence was 83.6% at week 12, and 76.6% at week 24 (Figure 1). Reasons for treatment cessation included primary non-response 15% (11/74), secondary loss of response 1% (1/74), and adverse events 12% (9/74). Rates of clinical remission were 58% (32/55) at week 12, 43% (16/37) at week 24, and 52% (35/67) at last observation. CRP remission rates were 45% (27/60) at week 12, 35% (12/34) at week 24, and 44% (30/69) at last observation. FCAL remission rates were 40% (17/42) at week 12, 31% (9/29) at week 24, and 36% (19/53), at last observation. There was a significant reduction in HBI, CRP and FCAL during follow-up (Figure 1). During the maintenance period, 11% (7/61) of the cohort who continued therapy were prescribed corticosteroids. Ten patients (19%) had a hospitalisation due to a Crohn’s flare. Five patients (7%) underwent Crohn’s disease related resectional surgery during the study period. Two were emergency surgeries (3%), and three (4%) were elective surgeries for symptomatic fibrotic strictures, which were present prior to commencing upadacitinib. Thirty-four adverse events were recorded across 29 patients (39%). Serious adverse events occurred in 9 patients (12%), three of which (4%) led to hospitalisation. Conclusion Upadacitinib was effective in a real-world, medically refractory, moderate to severe Crohn’s disease cohort with good persistence.

P670 Intestinal Motility Changes in Patients Undergoing Removable Stent Treatment for Focal Crohn’s Disease Strictures

Abstract Background Management and assessment of fibrostenotic Crohn’s disease(CD) is a research priority. Deep phenotyping is key for effective therapeutic development. In this study, we explore MRI assessed bowel motility before and after endoscopic stent treatment of focal fibrotic strictures in patients with CD. Methods Patients (n = 12, median age = 51 y) undergoing removable stent treatment were recruited as part of an approved study. Average CD diagnosis was 31y (range 16-57 y). All strictures were fibrotic in nature- three were de novo, while the remaining were anastomotic (ileocolonic). All patients had symptoms attributable to focal stricturing. Each patient had an MR – Enterography (MRE) scan (median 21 weeks) before and after (median 17 weeks) stent dilation. MR – Enterography (MRE) protocol included oral preparation, anatomical and cine ‘motility’ sequences across the abdomen in 20s breath hold (1 image/second). Motility sequences were processed with CE/FDA cleared GIQuant (Motilent, UK) to produce a quantitative map from which, objective data could be generated across the bowel. Stricture assessment was performed by a consultant radiologist. Non parametric statistics were used to investigate the following questions: 1. Was the baseline regional motility (mean, range) at stricture, dilation and morphologically normal bowel different across patients (Kruskal-Wallis)? 2. What were the changes in stricture motility pre and post stent placement (Wilcoxin Rank)? 3. Was stricture motility associated with stricture morphology (Spearman’s Rho)? Results 1. Motility at the stricture (126, range 62 to 139), pre-stenotic terminal ileum (252, range 80 to 478) and the global small bowel (269, range 166 to 339) was varied across the cohort (P < 0.001). 2. All patients had improvement in symptom scores & reporting, without change in stricture motility (P = 0.94). 3. A positive change in stricture motility was associated with reduced length of pre stricture dilatation (R = 0.64, P = 0.02) Conclusion Strictured intestine displayed reduced motility compared with adjacent bowel segments. While reduced, peristalsis was still present although paired analysis suggested no change pre and post stent stricture management. This implies that symptomatic relief was not related to altered peristalsis across the study. Finally, the length of dilation did appear to be associated with dynamic changes in stricture motility. In summary, as noted in stent-treated CD strictures, a dynamic physiological environment exists which can be captured with Cine MRI. These motility assessments, which have been studied as a proxy indicator of active CD, represent the first reported dynamic motility outcomes following stricture intervention.

P482 Diagnostic accuracy of contrast-enhanced ultrasound for fibrotic strictures of Crohn’s disease: a systematic review and meta-analysis of individual participant data

Abstract Background Crohn's disease (CD) often leads to the development of intestinal strictures, requiring effective differentiation between inflammatory and fibrotic for the optimal treatment strategies. Despite recent advances in drug development targeting fibrosis, current evaluation methods remain insufficient. Contrast-enhanced ultrasound (CEUS) is a promising modality for assessing vascularity and inflammation, yet its accuracy in fibrosis detection needs more validation. Methods A systematic review and meta-analysis were conducted using IPD to determine the diagnostic accuracy of CEUS in identifying intestinal fibrosis in CD. Our search included databases such as MEDLINE, EMBASE, and Web of Science up until March 23, 2023. Inclusion criteria required a confirmed diagnosis of CD and studies that evaluated the accuracy of CEUS parameters, including total area under the curve (AUC), wash-in AUC, wash-out AUC, peak enhancement, wash-in perfusion index, wash-in rate, wash-out rate, rise time, fall time, and mean transit time related to fibrosis in CD (Figure 1 (A)). The quality of included studies was assessed using the QUADAS-2 tool, with each study mandatorily using surgical specimen pathology as a reference standard in at least one instance. Results Our qualitative synthesis included eight studies encompassing 306 patients. These studies were generally assessed to have a high risk of bias. It is important to note that while peak enhancement and AUC were frequently examined across studies, neither parameter had established absolute cutoff values for the diagnosis of fibrosis. From the three studies where IPD was available, detailed data from 80 patients were included in the meta-analysis (colon n=11 and small bowel n= 69). Among them, 54 underwent surgical intervention with fibrosis being confirmed in 31. The highest diagnostic accuracy was observed for total AUC and wash-in AUC, with pooled sensitivity and specificity for predicting fibrosis at 0.86 (95% CI, 0.59–0.97) and 0.25 (95% CI, 0.03–0.76), respectively (Figure 1 (B)). Conclusion This meta-analysis with IPD pioneers the exclusive evaluation of CEUS for fibrotic strictures in CD. It reveals a significant risk of bias in the primary research and a notable absence of consensus on the CEUS parameters' threshold values for distinguishing fibrosis from inflammation. The observed low specificity highlights the need for innovative strategies in future research, such as integrating CEUS with techniques like elastography, to enhance the precision of fibrosis detection in CD. PROSPERO 2020 CRD42020214472. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020214472

Radical Surgical Treatment of Idiopathic Tracheal Stenosis. A Clinical Observation

Introduction. Idiopathic cicatricial tracheal stenosis (ICTS) comprises a rare and dangerous disease of unknown etiology. Its morphological substrate consists in the formation of circular fibrotic stenosis, usually at the level of the cricoid cartilage and the first two С-shaped rings of the trachea. The first cases of the disease were described by Brandenburg only in 1972. Progression of the disease is slow, right up to severe respiratory failure and asphyxia. Treatment methods for idiopathic cicatricial tracheal stenosis include both endoscopic and open surgical techniques. However, endoscopic treatment fails to produce the desired effect. Materials and methods. The authors of the present paper performed tracheo-laryngeal resection as a radical method for treating idiopathic tracheal stenosis in a 54-year-old patient against the background of prolonged unsuccessful endoscopic treatment. The follow-up period accounted for 45 days. Examinations in the postoperative period showed complete epithelialization of the anastomosis line without inflammation. Results and discussion. Idiopathic cicatricial tracheal stenosis is considered to be a dangerous disease without significant causes of development. However, it is claimed to be a potentially curable disease, though its treatment is a difficult task. Some authors report satisfactory results of endoscopic treatment of ICTS, but most publications on this issue consider a single tracheo-laryngeal resection with anastomosis as the most optimal method of treatment, thereby correlating with the results of the present study. Conclusion. The present observation characterizes the peculiarity and possibility of radical treatment of ICTS, since the endoscopic method of treatment produces only a temporary effect. Small number of observations and lack of a coherent pathogenetic theory necessitate further research into this problem.

Evaluating the diagnostic accuracy of magnetic resonance imaging in distinguishing strictures in Crohn's disease: a systematic review and meta-analysis.

This systematic review and meta-analysis sought to assess the diagnostic accuracy of magnetic resonance imaging (MRI) in distinguishing fibrotic from inflammatory strictures in Crohn's disease (CD) patients. A rigorous and systematic exploration of five key databases yielded studies that met predefined criteria. Data were extracted for a comprehensive meta-analysis using MetaDiSC and MetaDTA software, providing diagnostic accuracy measures. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was utilized for evaluating the methodological quality and potential bias within the studies. The systematic review involved the evaluation of 7437 records, culminating in the inclusion of 22 studies. In detecting fibrotic strictures in CD patients, MRI exhibited a pooled sensitivity of 85.20% (95% CI: 76.10-91.20%) and specificity of 96.00% (95% CI: 87.80-98.70%). For differentiating fibrotic strictures from inflammatory stenosis, the sensitivity was 81.5% (95% CI: 70.2-89.20%), and the specificity was 97.2% (95% CI: 90.0-99.3%). In terms of assessing the severity of strictures, sensitivity stood at 90.4% (95% CI: 78.1-96.1%) and specificity at 89.4% (95% CI: 57.4-98.2%). The consistency of the diagnostic accuracy was observed across different geographical locations and the various reference tests applied in the studies. The results of this meta-analysis underscore the robust diagnostic accuracy of MRI in detecting fibrotic strictures, distinguishing between fibrotic and inflammatory strictures, and evaluating stricture severity in CD patients. These findings support the integration of MRI into standard diagnostic protocols for patients with CD. Further large-scale, multicenter trials are warranted to confirm these results and to identify any potential limitations associated with the application of MRI in this clinical setting.

Extracellular matrix remodeling proteins as biomarkers for clinical assessment and treatment outcomes in eosinophilic esophagitis

BackgroundEosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted.AimsTo investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients.MethodsProtein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention.ResultsPatients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p < 0.01), whereas low CTX-III levels were observed in patients achieving histological remission (< 15 eos/hpf) (vs. no histological remission (p < 0.05). Progression of endoscopic fibrosis after intervention was associated with increased levels of type-III (PRO-C3) and -VI collagen (PRO-C6) formation (all; p < 0.05). A baseline EREFS inflammatory subscore ≥ 2 correlated with higher neutrophilic activity (Cpa9-HNE) at week 6 (p < 0.05). Moreover, increased degradation of type-III (C3M) and -IV (C4M/PRO-C4) collagens were associated with remission of food impaction after intervention (all; p < 0.05).ConclusionSerum extracellular matrix remodeling proteins demonstrated potential as surrogate biomarkers for assessing histological disease remission, endoscopic fibrosis, and remission of symptoms of food impaction after diet intervention in adult EoE patients.

The Hypermetabolic Response to Burns and its Treatment: A Literature Review

Abstract: Major burn injuries provoke a profound stress response marked by extreme hypermetabolism and impaired immune function. The physiological alterations to glucose, protein and lipid metabolism can be detected even years after the inciting burns injury and when untreated can lead to profound wasting, fatty liver, and even death. Therapeutic strategies which target these physiological disturbances are of paramount importance. Treating burn injuries begins with active cooling, to minimize loss of heat and water, and nutrition, to counteract the extensive catabolism. Providers should follow the strict guidelines published to ensure caloric requirements are met in adult and pediatric patients, with supplementation as indicated. Several pharmacotherapies have proven beneficial in helping to counteract and reverse these physiological changes by lowering insulin resistance, slowing catabolism, and minimizing loss of lean body mass. The most promising drugs include anabolic agents such as insulin, recombinant human growth hormone (rhGH), insulin-like growth factor 1 (IGF-1), metformin, beta-blockers, oxandrolone, and fenofibrate. Surgery is a necessary adjunct, either in the acute phase to debride compromised soft tissue and prevent compartment syndromes, but also in the chronic setting to release contractures and fibrotic strictures which may impair function. This narrative literature review provides a synopsis of our understanding of the hypermetabolic response to burn injury and discusses the different treatment options aiming to control postburn hypermetabolism and ultimately improve patient outcomes.

Long-term follow-up results of ipilimumab and nivolumab for the treatment of mismatch repair deficient locally advanced rectal cancer.

e15652 Background: Mismatch repair deficient (dMMR) colorectal cancers have unique biology and responses to therapy. In the advanced setting, first line immunotherapy has superior activity compared to chemotherapy. Recent studies have demonstrated improved responses with neoadjuvant anti-PD1 therapy for dMMR locally advanced rectal cancer (LARC). In this study, we review our experience with the combination of ipilimumab (ipi) and nivolumab (nivo) for the treatment of dMMR LARC. Methods: Patients (pts) with dMMR LARC treated with ipi/nivo at the University of Wisconsin Carbone Center were identified under an IRB-approved protocol. Baseline demographics, molecular testing, treatment history, clinical imaging, and pathological evaluations were collected and summarized. Pts were followed with serial imaging (CT/MRI), endoscopic evaluations, and ctDNA MRD assays. Results: Fours pts (median age: 63 [range: 59-68]; 50% female) with dMMR LARC treated with ipi/nivo were identified. 3 pts had T4 tumors and were node positive. 1 patient had a mutation in MSH6, 1 patient had 2 mutations in MSH2, another had loss of MLH1/PMS2 on IHC, and the last patient had loss of MSH2/MSH6 on IHC. None of the patients have known germline variants. 2 patients were treated initially with FOLFOX chemotherapy and had progressive disease prior to conversion to ipi/nivo. Median follow-up is 25.5 months [range: 9-42] and 1 pt continues on nivo treatment. Pts were treated with 1-4 infusions of ipi and 2-24 months of nivolumab. All patients achieved a complete clinical/pathologic response and remain without evidence of disease recurrence. None of the pts required additional surgery or radiation therapy for cancer recurrence/progression. 3 of the 4 patients developed grade 3/4 immune-related adverse events, including 2 patients with adrenal insufficiency and 1 patient with immune hepatitis. 1 pt developed a fibrotic stricture at the site of the prior cancer requiring resection. Conclusions: dMMR LARC is a unique subtype of rectal cancer sensitive to combination immunotherapy with high potential for complete responses and organ preservation. The use of ipi/nivo in this cohort of pts resulted in complete pathogenic responses for all that remain durable over an extended period of time, though with increased immune-related adverse events compared to anti-PD1 therapies alone. This regimen is currently being studied further in prospective studies.

Transoral Sialodochoplasty Assisted With Sialendoscopy for the Treatment of Parotid Duct Stenosis With a Megaduct: Case Report

Salivary megaduct with stricture is characterized by recurrent pain, cheek and parotid swelling. We report on a case of circular web type fibrotic stenosis accompanying a large megaduct found by sialendoscopy. Although, sialendoscopy enabled minimally invasive diagnosis and treatment of stenotic lesion of the Stensen’s duct, bougination is not effective for severe fibrotic stenosis. Transoral sialodochoplasty assisted with sialendoscopy can be an additional treatment option for the parotid duct stenosis with a memegaduct. Sialendoscopy assisted stent insertion can be helpful to prevent the scaring of neo opening and recurrence.

MR enterography in small bowel diseases, adding multipoint Dixon sequence, is it worth?

BackgroundMR enterography (MRE) has been increased in the last decade as a modality of choice in diagnosis and evaluation of small bowel diseases in both children and adults. Lacking ionizing radiation, non-invasiveness, excellent soft tissue resolution, adequate luminal distension of small bowel loops are the advantages of this technique. Acquisition of images was used to be: T2WI, steady-state free precession, and T1WI, fat-suppressed gadolinium contrast-enhanced sequences. Multipoint Dixon sequence was added recently to the routine MR enterography protocol. The current study aimed to evaluate the added value of multipoint Dixon sequence as a valuable modification of MR enterography protocol for better assessment of small bowel lesions as activity of Crohn’s disease, small bowel polyps, fibrotic strictures, with modification of MRE protocol in the future with less time consumption and better radiological evaluation.MethodsThe current research was a prospective cross-sectional study. Data were collected prospectively after getting ethical approval from the ethical committee of the faculty of medicine, in our university.Study populationThe sample size was 69 adult patients with suspected small bowel lesions, within the period from January 2022 to 30th December 2022. Written informed consent was obtained from all studied cases before the study, who were enrolled in this study. This number was calculated by using MedCalc 19 program by setting alpha error significance of 0.05%, 95% confidence level, and 80% power sample.ResultsThis study enrolled 69 patients with recurrent abdominal pain and/or bleeding in stool. The patients’ age ranged from 18 to 50 years, with a mean of 32.6 ± 8.8. There is slightly higher female prevalence. The most common positive imaging findings in the studied patients were mucosal thickening in terms of submucosal fat deposition (36.23% of the MRE examination and 39.13% of the MRE with added Dixon sequence). Adding Dixon sequence yielded significantly higher AUC (97.2% vs. 90.5%, p = 0.047), higher sensitivity (100% vs. 92.16%), specificity (94.4% vs. 88.89%), accuracy (98.55% vs. 91.3%), positive predictive value (98.08% vs. 95.92%), and negative predictive value (100% vs. 80%).ConclusionsMRE is an excellent imaging modality in the assessment of small bowel diseases without the use of ionizing radiation. Developing MR-based sequences as multi-point Dixon sequence have the potential to improve the ability of MRE to image the subtle changes as Crohn’s accompanying early inflammatory changes and fibrosis, as well as small intestinal polyps. Familiarity with MR enterography is essential for radiologists and gastroenterologists who participate in the clinical management of small intestinal diseases.

A novel tetra-PEG based hydrogel for prevention of esophageal stricture after ESD in a porcine model

Endoscopic submucosal dissection (ESD) is an accepted treatment for early esophageal cancer and precancerous lesions, but resection of a large mucosal area often leads to postoperative esophageal stricture. Biomaterials provide a new option for the treatment of post-ESD ulcers. In this study, we developed a well-defined ammonolysis-based tetra-armed poly (ethylene glycol) (Tetra-PEG) hydrogel and investigated its efficacy and related mechanisms for preventing esophageal ESD-induced stricture in a porcine model. In terms of material properties, Tetra-PEG hydrogel present great biocompatibility，great capability to retain moisture, strong tissue adhesion and high mechanical strength. Then, six domestic female pigs were randomly divided into PEG (n = 3) and control groups (n = 3). A 3/4 of the esophageal circumference ESD was performed in all pigs. In PEG group, Tetra-PEG hydrogel was easily delivered via endoscopy and adhered to the ulcer bed tightly. Compared to control group, Tetra-PEG hydrogel accelerated esophageal ulcer healing at an early stage with enhanced epithelium regeneration, milder inflammation and lesser fibrosis by regulating TGF-β/Smad2 signaling. Taken together, our findings reveal Tetra-PEG hydrogel is a promising and attractive candidate for preventing the formation of fibrotic stricture in the process of esophageal ESD-induced ulcer repair.

A38 INVESTIGATION OF POST-TRANSLATIONAL MODIFICATIONS IN SERUM OF CROHN’S DISEASE PATIENTS USING A PROTEOMICS APPROACH

Abstract Background Canada has one of the highest prevalences of Crohn’s disease (CD) worldwide. More specifically, fibrostenotic CD is a phenotype with prolonged chronic inflammation and fibrotic strictures often resistant to anti-inflammatory therapies and characterized by luminal narrowing that ultimately requires surgery. Proteins play an essential role in disease pathogenesis, and post-translational modifications (PTMs) can alter their properties. PTMs have been frequently implicated in human diseases. However, they have yet to be explored in the context of CD, which could lead to new avenues for a better understanding of disease mechanisms and the discovery of biomarkers. Purpose Identify post-translational modifications in serum proteins of CD patients. Method Serum samples from patients with strictures or inflammatory phenotype (without strictures) (n=4 per group), as diagnosed by intestinal ultrasound, were analyzed using a shotgun-proteomics approach. Protein identification and PTM prediction were performed with FragPipe. Identified mass shifts determined by an open search in FragPipe were mapped to possible PTMs and confirmed via unimod.org. Statistical significance analysis was performed with MSstatsPTM. Result(s) The prediction analysis identified 363 potential modification sites, including artifacts and chemical derivatives. The addition of all potential PTMs in the analysis would lead to false positives; therefore, it was selected five of the most abundant mass shifts mapped to true PTMs: cysteine oxidation, serine methylation, and three modifications of the protein n-termini (formaldehyde adduct, carbamylation, and formylation). Standard proteomics analysis identified 3635 unique peptides and 317 unique proteins. The addition of the predicted PTMs increased the number of peptides by 9.8%, reaching 3994 unique sequences. Interestingly, a very subtle increase was observed on the protein level, where only two additional proteins were identified. Of the PTMs identified, methylation of a serine residue on the variable chain of immunoglobulin (IGLV1-47) was statistically enriched in inflammatory samples (5.74 fold change, adj. p-value = 0.041). The variable chain participates in the antigen recognition process, and modification of its amino acids could impact antibody specificity. Additionally, structuring patients showed two modifications on thrombin: oxidation of cysteine and methylation of serine. Thrombin was previously shown to be elevated in CD patients compared to healthy controls. As both modifications were not present in inflammatory patients, they constitute potential biomarkers for specific diagnosis of the structuring disease. Conclusion(s) The observed gain in peptide identification demonstrates the diversification promoted by PTMs and exhibits their importance in proteomics studies. Even though the identified modifications require further validation, they can shed light on new players of CD pathogenesis and suggest novel biomarkers for disease diagnosis. Disclosure of Interest None Declared