Fibrotic Strictures Research Articles

Self-expandable metal stents versus endoscopic balloon dilation for the treatment of strictures in Crohn's disease (ProtDilat study): an open-label, multicentre, randomised trial

Endoscopic balloon dilation (EBD) is the established endoscopic treatment for short strictures in Crohn's disease. Fully covered self-expandable metal stents (FCSEMS) have been used for endoscopic treatment of patients for whom EBD was unsuccessful. We aimed to determine the efficacy and safety of the two endoscopic treatments in patients with Crohn's disease with stenosis and compare the mean cost of both treatments. This multicentre, open-label, randomised trial was done in 19 tertiary and secondary hospitals in Spain. Patients with Crohn's disease with obstructive symptoms and predominantly fibrotic strictures of less than 10 cm in length were eligible for inclusion. We excluded patients with stenosis treated with SEMS or EBD in the previous year and stenosis not accessible to a colonoscope. Patients were randomly assigned (1:1) to receive either EBD (EBD group) or FCSEMS (FCSEMS group) using a digital en-block randomisation system (block size of four). In the EBD group, dilation was done with a CRE Boston Scientific (Marlborough, MA, USA) pneumatic balloon with the diameter set at the discretion of the endoscopist; a maximum of two sessions of dilation were allowed with a minimum interval of 15-30 days between them. In the FCSEMS group, a 20 mm diameter Taewoong (Gimpo-si, South Korea) fully covered metal stent was placed; stent length was set at the discretion of the endoscopist. The primary outcome was to assess the efficacy of the endoscopic treatment, defined by the proportion of patients free of a new therapeutic intervention (EBD, FCSEMS, or surgery) due to symptomatic recurrence at 1 year of follow-up. Patients were analysed according to the intention-to-treat principle. Adverse events were recorded for all the patients; events were considered associated to be with the procedure when a causal association was possible, probable, or definite. This trial is registered with ClinicalTrials.gov, NCT02395354. From Aug 28, 2013, to Oct 9, 2017, we assessed the eligibility of 99 patients, of whom 19 (19%) patients were excluded. Thus, 80 (81%) patients were randomly assigned to treatment: 39 (49%) patients to the FCSEMS group and 41 (51%) patients to the EBD group. 33 (80%) of 41 patients in the EBD group and 20 (51%) of 39 patients in the FCSEMS group were free of a new therapeutic intervention at 1 year (odds ratio [OR] 3·9 [95% CI 1·4-10·6]; p=0·0061). Two (3%) of 80 patients had severe adverse events (one [2%] patient in the EBD group and one [3%] patient in the FCSEMS group); both patients had perforations. EBD is more effective than FCSEMS for Crohn's disease strictures, with a good safety profile for both treatments. Spanish National Institute of Health, Foundation of Spanish Society of Digestive Endoscopy, Catalan Society of Gastroenterology, and Taweoong.

Intestinal strictures in Crohn's disease: a 2021 update.

Intestinal strictures remain one of the most intractable and common complications of Crohn’s disease (CD). Approximately 70% of CD patients will develop fibrotic strictures after 10 years of CD diagnosis. Since specific antifibrotic therapies are unavailable, endoscopic balloon dilation and surgery remain the mainstay treatments despite a high recurrence rate. Besides, there are no reliable methods for accurately evaluating intestinal fibrosis. This is largely due to the fact that the mechanisms of initiation and propagation of intestinal fibrosis are poorly understood. There is growing evidence implying that the pathogenesis of stricturing CD involves the intricate interplay of factors including aberrant immune and nonimmune responses, host-microbiome dysbiosis, and genetic susceptibility. Currently, the progress on intestinal strictures has been fueled by the advent of novel techniques, such as single-cell sequencing, multi-omics, and artificial intelligence. Here, we perform a timely and comprehensive review of the substantial advances in intestinal strictures in 2021, aiming to provide prompt information regarding fibrosis and set the stage for the improvement of diagnosis, treatment, and prognosis of intestinal strictures.

Total Flavone of Abelmoschus manihot Ameliorates TNBS-Induced Colonic Fibrosis by Regulating Th17/Treg Balance and Reducing Extracellular Matrix.

Background and Aims: Surgery remains the major available strategy in inflammatory bowel disease (IBD) fibrotic strictures because no available drugs have sufficient prevention and treatment in this complication. This study aimed to evaluate the efficacy of the total flavone of Abelmoschus manihot L. Medic (TFA) on the development of colonic fibrosis in mice and its possible mechanism. Methods: The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colonic inflammation-associated fibrosis mice were used to evaluate anti-fibrosis of TFA using macroscopic, histological, immunohistochemical analyses, ELISA, Masson staining, Verhoeff’s von Gieson staining, transcription-quantitative polymerase chain reaction, and immunoblot analysis. Results: Oral administration of TFA attenuated body weight loss, reduced colon length shortening, lowered the morphological damage index score, and notably ameliorated the inflammatory response. TFA downregulated proinflammatory cytokines IL-6, IL-17, TNF-α, IFN-γ productions, and increased the levels of anti-inflammatory cytokine IL-10 and TGF-β. The histological severity of the colonic fibrosis was also notably improved by the TFA treatment and associated with a significant reduction in the colonic expression of col1a2, col3a2, and hydroxyproline. TFA inhibits α-SMA, TGF-β, vimentin, TIMP-1 expression, increasing MMPs, thereby inhibiting activated intestinal mesenchymal cells and extracellular matrix (ECM) deposition. Conclusion: Together, we herein provide the evidence to support that TFA may restore the imbalance of Th17/Treg and decrease the generation of ECM. This may be a potential mechanism by which TFA protects the intestine under inflammatory conditions and acts as a therapeutic agent for the treatment of intestinal fibrosis in Crohn’s disease.

Mucosal gene expression profile of stricturing Crohn's disease: A preliminary study.

Intestinal strictures are an important complication of Crohn's disease (CD), with ~40% of patients developing symptomatic obstruction within 10 years of diagnosis. However, there is a paucity of research examining the mechanisms driving the development of fibrotic strictures in CD. The present study aimed to identify the mucosal markers associated with stricturing complications by examining the differences in the gene expression profiles of two patient cohorts: Patients diagnosed with inflammatory CD (n=12) and patients with stricturing CD (n=9). For each patient, a paired sample of inflamed and uninflamed mucosa was isolated and assessed by quantitative PCR using a large panel of genes associated with inflammatory bowel disease. The presents study revealed a significantly increased level of four genes in the mucosa of patients with strictures compared with the inflammatory pattern of the disease: Formyl-peptide receptor 1 [P=0.019; fold change (FC)=11.6], C-C chemokine receptor type 1 (P=0.035; FC=5.44), IFN-γ-inducible protein 10 (P=0.037; FC=3.8) and C-C chemokine ligand 25 (P=0.048; FC=3.56). The augmented expression of these four genes in the CD stricturing phenotype, if confirmed in larger cohorts of patients, could help elucidate the mechanisms leading to disease-associated complications.

In vivo performance of decellularized tracheal grafts in the reconstruction of long length tracheal defects: Experimental study

The repair of long-segment tracheal lesions remains an important challenge. Nowdays no predictable and dependable substitute has been found. Decellularized tracheal scaffolds have shown to be a promising graft for tracheal transplantation, since it is non-immunogenic. Evaluate in vivo decellularized tracheal allografts performance to replace long tracheal segment. Forty-five swines underwent surgery as follows: Fifteen trachea donors and 30 receptors of decellularized trachea allografts. The receptors were randomly divided in five groups (n = 6). In groups I and II, donor trachea segment was decellularized by 15 cycles with sodium deoxycholate and deoxyribonuclease, in group II, the allograft was reinforced with external surgical steel wire. Groups, III, IV, and V decellularization was reduced to seven cycles, supplemented with cryopreservation in group IV and with glutaraldehyde in group V. A 10 rings segment was excised from the receptor swine and the decellularized trachea graft was implanted to re-establish trachea continuity. Both decellularization cycles caused decreased stiffness. All trachea receptors underwent euthanasia before the third post-implant week due to severe dyspnea and trachea graft stenosis, necrosis, edema, inflammation, hemorrhage, and granulation tissue formation in anastomotic sites. Histologically all showed total loss of epithelium, separation of collagen fibers, and alterations in staining. Both decellularization techniques severely damaged the structure of the trachea and the extracellular matrix of the cartilage, resulting in a no functional graft, in spite of the use of surgical wire, cryopreservation or glutaraldehyde treatment. An important drawback was the formation of fibrotic stenosis in both anastomosis.

A patient-like swine model of gastrointestinal fibrotic strictures for advancing therapeutics

Gastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans.

Bowel stiffness associated with histopathologic scoring of stenosis in patients with Crohn's disease

Background and aims: Intestinal stenosis is a common complication of Crohn's Disease (CD). Stenosis is associated with alteration of bowel mechanical properties. This study aims to quantitate the mechanical properties of the intestinal stenosis and to explore associations between histology and mechanical remodeling at stenotic intestinal sites in CD patients. Methods: Intestinal segments from stenotic sites were studied in vitro from 19 CD patients. A luminal catheter with a bag was used to stepwise pressurize the intestinal segments from 0-100 cmH2O with 10 cmH2O increments. B-mode ultrasound images were obtained at the narrowest part of the stenosis at each pressure level and morphometric parameters were obtained from ultrasound images. The mechanical behavior of the stenotic tissue were characterized by using an isotropic three dimensional strain energy function in Demiray model form, the mechanical constants were obtained by fitting the model to the recorded intraluminal pressure and the inner radius of the stenotic segment of the small bowel. Grading scores were used for histological analysis of inflammation, fibrosis, muscular hypertrophy and adipocyte proliferation in the intestinal layers. The collagen area fraction in intestinal layers was also calculated. Associations between histological and the mechanical constants (stiffness) were analyzed. Results: Chronic inflammation was mainly located in mucosa whereas fibrosis was found in submucosa. The mechanical remodeling was performed with changed mechanical constants ranged between 0.35-13.68kPa. The mechanical properties changes were associated mainly with chronic inflammation, fibrosis and combination of inflammation and fibrosis (R>0.69, P<0.001). Furthermore, the mechanical properties correlated with the collagen fraction in submucosa and muscular layers (R>0.53, P<0.05). Conclusions: We quantitated the intestinal stenosis stiffness. Associations were found between bowel mechanical remodeling and histological changes at the stenotic site in CD patients. Statement of significanceAlthough intestinal ultrasonography, CT and MRI can be used to diagnose Crohn's Disease (CD)-associated bowel strictures, these techniques may not have sufficient accuracy and resolution to differentiate predominantly inflammatory strictures from predominantly fibrotic strictures. The present study aims to quantitate the mechanical remodeling of intestinal stenosis and to explore the associations between histological parameters and mechanical properties at the intestinal stenotic sites in CD patients. For the first time, we quantitatively demonstrated that the mechanical properties of the intestinal wall in CD stenosis are associated with the chronic inflammation, fibrosis and collagen fraction in the intestinal layers. The results of this study may facilitate design and development of artificial biomaterials for gastrointestinal organs. The potential clinical implication of this study is that the histological characteristics in patients with CD can be predicted clinically by means of inflammation and fibrosis assessment in conjunction with tissue stiffness measurement.

Experimental Tracheal Replacement: Angiogenesis and Null Apoptosis Promote Stenosis

BackgroundTracheal replacement is a challenge for thoracic surgeons due to stenosis in the trachea-prosthesis anastomosis. We propose that stenosis occurs due to fibrosis as a result of an abnormal healing process, characterized by an increased expression of wound healing growth factors (vascular endothelial growth factor [VEGF], survivin, and CD31), which promote angiogenesis and decrease apoptosis. We analyzed the immunoreactivity of VEGF, survivin, CD31, and caspase-3 in the development of fibrotic stenosis in prosthetic tracheal replacement.MethodsFourteen dogs were operated on group I (n=7) received a 6-ring cervical tracheal segment autograft, while in group II (n=7), a 6-ring segment of the cervical trachea was resected and tracheal continuity was restored with a Dacron prosthesis. The follow-up was 3 months. Immunoreactivity studies for VEGF, survivin, CD31, and caspase-3 were performed. A statistical analysis was done using the Wilcoxon signed rank test.ResultsFour animals in group I were euthanized on the 10th postoperative day due to autograft necrosis. Three animals completed the study without anastomotic stenosis. Moderate expression of VEGF (p=0.038), survivin (p=0.038), and CD31 (p=0.038) was found. All group II animals developed stenosis in the trachea-prosthesis anastomotic sites. Microscopy showed abundant collagen and neovascularization vessels. Statistically significant immunoreactive expression of VEGF (p=0.015), survivin (p=0.017), and CD31 (p=0.011) was observed. No expression of caspase-3 was found.ConclusionWe found a strong correlation between fibrosis in trachea-prosthesis anastomoses and excessive angiogenesis, moderate to intense VEGF, CD31, and survivin expression, and null apoptotic activity. These factors led to uncontrolled collagen production.

P013 Potential Role of Epithelial Protein Disulphide Isomerases in Crohn’s Disease Fibrosis

Abstract Background Intestinal fibrosis is a common complication of Crohn’s disease (CD) characterized by an accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. In in-vitro experiments, this myofibroblastic differentiation is elicited by a whole series of factors among which transforming growth factor-β1 (TGF-β1) seems to play a key role. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser-capture microdissection in normal and fibrotic zones of resected ileal CD strictures (13 zones collected in 5 patients). The pro-fibrotic role of selected epithelial proteins was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. Results Proteomic study revealed an endoplasmic reticulum (ER) stress proteins increase in the epithelium of CD ileal fibrotic strictures, including Anterior gradient protein 2 homolog (AGR2), Protein disulphide isomerase A6 (PDIA6) and Endoplasmic reticulum resident protein 44 (ERP44) which are 3 protein disulphide isomerases. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2, PDIA6, ERP44 as well as TGF-β1 intracellular expression and their secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin (Tm), led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. The application of blocking agents for AGR2, PDIA6, ERP44 or TGF-β1 in the supernatant of these Tm-pre-conditioned HT-29 cells, attenuated the myofibroblastic differentiation induced by this supernatant, suggesting a pro-fibrotic role of these secreted epithelial proteins. Conclusion The development of CD fibrotic strictures may involve ER stress in epithelial cells, releasing a whole set of proteins into their environment, including AGR2, PDIA6, ERP44 as well as TGF-β1, which could exercise a pro-fibrotic role through a paracrine action.

Crohn Disease

The role of surgery in the management of Crohn disease has undergone a dramatic evolution over the past 50 years. Currently, surgical treatment of Crohn disease is seldom performed in the emergency setting; it is nearly always performed after failed medical therapy. The general indications for surgical treatment are described and include specific attention to complications of the disease, including obstruction, symptomatic fistulas, abscess formation, cancer or dysplasia, and failure to grow. The special considerations of surgical therapy are also described, including pregnancy, the marking of stoma sites, and the choice of incision, which may involve laparoscopy. Surgical management of Crohn disease is evaluated in terms of therapy at specific sites, including esophageal, gastric, and duodenal disease; jejunoileal disease; ileocolic disease; colonic disease; and anal disease. Chemoprophylaxis is also described, as is surveillance and behavioral modification. Tables outline the Vienna Classification System, Crohn Disease Activity Index, Harvey-Bradshaw Index, extraintestinal manifestations, and the medical treatment of Crohn disease. Figures show endoscopic images of Crohn disease, computed tomographic enterography, a capsule endoscopy showing large Crohn structures, surgery rates over time, caput medusa, an example of stenotic ileocolic Crohn disease, an enterocutaneous fistula, Heineke-Mikulicz strictureplasty, Finney strictureplasty, a fibrotic stricture, an example of a large ulcer, pyoderma gangrenosum, a sigmoid colon stricture, toxic megacolon, and vessel loops for drainage of abscesses. This review contains 15 figures, 5 tables, and 76 references.

A case report of portal vein thrombosis and common bile duct compression in the patient having pseudocyst of pancreas and its management by percutaneous trans-hepatic biliary drainage

Pancreatitis is a systemic disease owing to release of inflammatory mediators and digestive enzymes. Acute pancreatitis is sudden inflammation of the pancreas. Alcohol and gallstones are main cause of acute pancreatitis. Chronic pancreatitis is the persistent inflammation and irreversible fibrosis associated with atrophy of pancreatic parenchyma. There are various complications associated with pancreatitis such as strictures, pancreatic necrosis, pseudo-cyst of pancreas, pancreato-cutaneous fistulas, venous thrombosis, arterial aneurysm in various arteries around pancreas etc. Common bile duct (CBD) strictures are a common complication in patients with advanced chronic pancreatitis and have a variable clinical presentation ranging from an incidental finding to overt jaundice and cholangitis. CBD strictures occur as a consequence of recurrent acute inflammatory episodes which may ultimately result in a periductal fibrotic stricture. CBD can be compressed as a result of extrinsic compression by large pseudocyst or aneurysm. The diagnosis is mostly made during investigations for abdominal pain but jaundice may be the initial clinical presentation. The jaundice is typically transient but may be recurrent with a small risk of secondary biliary cirrhosis in longstanding cases. Vascular complications in chronic pancreatitis are rare. Venous thrombosis is the most common complication of pancreatitis affecting venous system. It occurs as consequences of an inflammatory mass in head of pancreas, and splenic vein thrombosis occurs in association with chronic pancreatitis in 4-8% cases. Present case is a case of acute pancreatic collection in head of pancreas with aneurysmal small bleeding causing complete CBD compression and extensive venous thrombosis involving superior mesenteric vein, portal vein, splenic.

Potential Role of Epithelial Endoplasmic Reticulum Stress and Anterior Gradient Protein 2 Homologue in Crohn's Disease Fibrosis.

Intestinal fibrosis is a common complication of Crohn's disease [CD]. It is characterised by an accumulation of fibroblasts differentiating into myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. We performed a pilot proteomic study comparing the proteome of surface epithelium, isolated by laser-capture microdissection, in normal and fibrotic zones of resected ileal CD strictures [13 zones collected in five patients]. Proteins of interests were validated by immunohistochemistry [IHC] in ileal and colonic samples of stricturing CD [n = 44], pure inflammatory CD [n = 29], and control [n = 40] subjects. The pro-fibrotic role of one selected epithelial protein was investigated through in-vitro experiments using HT-29 epithelial cells and a CCD-18Co fibroblast to myofibroblast differentiation model. Proteomic study revealed an endoplasmic reticulum [ER] stress proteins increase in the epithelium of CD ileal fibrotic strictures, including anterior gradient protein 2 homologue [AGR2] and binding-immunoglobulin protein [BiP]. This was confirmed by IHC. In HT-29 cells, tunicamycin-induced ER stress triggered AGR2 intracellular expression and its secretion. Supernatant of these HT-29 cells, pre-conditioned by tunicamycin, led to a myofibroblastic differentiation when applied on CCD-18Co fibroblasts. By using recombinant protein and blocking agent for AGR2, we demonstrated that the secretion of this protein by epithelial cells can play a role in the myofibroblastic differentiation. The development of CD fibrotic strictures could involve epithelial ER stress and particularly the secretion of AGR2.

Can Conventional and Diffusion-Weighted MR Enterography Biomarkers Differentiate Inflammatory from Fibrotic Strictures in Crohn's Disease?

Background and Objectives: To retrospectively assess the value of magnetic resonance enterography (MRE) parameters derived from conventional and diffusion weighted imaging (DWI) sequences to differentiate fibrotic strictures from inflammatory ones in adult patients with Crohn’s disease (CD), using surgical specimens as the histopathological reference standard. Material and Methods: Twenty-three patients with CD who had undergone surgical resection of ileal strictures with full-thickness histopathologic analysis within 3 months from preoperative MRE were included. Two radiologists blinded to histopathology in consensus evaluated the following biomarkers on MRE images matched to resected pathological specimens: T1 ratio, T2 ratio, enhancement pattern, mural thickness, pre-stenotic luminal diameter, and apparent diffusion coefficient (ADC). A blinded pathologist graded stricture histological specimens with acute inflammation score (AIS) and fibrosis score (FS). MRE measurements were correlated with the reference standard. Results: Inflammation and fibrosis coexisted in 78.3% of patients. T2 ratio was reduced in patients with severe fibrosis (p = 0.01). Pre-stenotic bowel dilatation positively correlated with FS (p = 0.002). The ADC value negatively correlated with FS (p < 0.001) and was different between FS grades (p < 0.05). The area under the receiver operating characteristic curve for discriminating between none and mild/moderate–severe bowel wall fibrosis was 0.75 for pre-stenotic bowel dilatation (sensitivity 100%, specificity 44.4%) and 0.97 for ADC (sensitivity 80%, specificity 100%). Conclusions: Inflammation and fibrosis often coexist in CD bowel strictures needing surgery. The combination of parameters derived from conventional MR sequences (T2 ratio, pre-stenotic dilatation) and from DWI (ADC) may provide a contribution to detect and grade bowel fibrosis in adult CD patients.

A37 EXPLORING THE PROTEOMICS DIFFERENCES IN CROHN’S DISEASE PATIENTS

Abstract Background Canada has the highest prevalence rate of Crohn’s disease (CD) in North America. In Alberta, the yearly cost of anti-inflammatory drugs can be more than $25,000 per person; however, half of the patients do not respond to medication. CD is characterized by lesions in the small intestine due to inflammation, promoting diarrhea and abdominal pain. Prolonged chronic inflammation results in fibrotic strictures that are resistant to anti-inflammatory therapies and promote narrowing of the luminal space that ultimately require surgery. Currently, there is no biomarker to distinguish between the inflammatory or stricturing phenotype. Aims AIM 1: Profile serum samples from CD patients using a label-free shotgun-proteomics. AIM 2: Identify signatures and biomarkers that distinguish inflammatory and fibrotic strictures using a bioinformatics approach. Methods Serum samples from 15 CD patients with strictures and 15 CD patients without strictures (inflammatory phenotype), as diagnosed by ultrasound imaging, were analyzed by a standard shotgun-proteomics approach. Briefly, 200 µg of serum proteins were processed in a label-free protocol in combination with the filter-aided sample preparation (FASP) method. Liquid chromatography-tandem mass spectrometry was performed on an Orbitrap Fusion Lumos. Protein identification was accomplished by MaxQuant at a 1% false-discovery rate. Statistical significance was determined by the MSstats package, in the R software. To identify the biological significance of disturbed pathways, it was characterized by the protein-protein interactions and pathway enrichment analysis using String-DB and Metascape. Results It was identified a statistically significant protein panel between the two phenotypes. Proteins identified in the strictured group include JAK1 (Tyrosine-protein kinase), CD5 antigen-like protein (regulates inflammatory gene expression in Th17 cells), and neogenin (cell adhesion). Of the inflammatory patients, there was a significant elevation of PFK/FBPase 2 (synthesis and degradation of fructose 2,6-bisphosphate), vinculin (cell-matrix adhesion) and MMP-16/MT3-MMP (matrix metalloproteinase). Conclusions The identification of a distinct signature between both phenotypes provide important biological information about the disease progression and are a good sign that a biomarker discovery platform will be capable to differentiate between inflammatory and fibrostenotic strictures from serum samples of CD patients. Funding Agencies CAG, CIHRNSERC

Rapamycin is Effective for Upper but not for Lower Gastrointestinal Crohn's Disease-Related Stricture: A Pilot Study.

Crohn’s disease (CD)-related fibrotic stricture remains a clinical challenge because of no effective treatments. This study aimed to evaluate the potential efficacy of rapamycin in patients with CD-related strictures in different locations in gastrointestinal tract. A pilot prospective study on using rapamycin for CD-related stricture was performed from April 2015 to August 2020 in a single center in China. Fifteen patients were enrolled into the study. The clinical efficacy was evaluated by diet score and gastrointestinal obstruction symptoms score. Clinical responses were defined as the ability to tolerate the regular diet with vegetable fiber combined with a reduction of ≥75% in overall target score and a score of less than two points for each item. Three patients discontinued rapamycin for less than 1-month due to intolerance to adverse events, then, 12 patients received ≥1 dose of the rapamycin and provided ≥1 post-baseline target score after baseline were included for intent-to-treat (ITT) analysis. 100% (5/5) of patients with upper gastrointestinal strictures achieved clinical response after using rapamycin. However, no clinical response was observed in those patients with CD lesions in lower gastrointestinal tract. Adverse events occurred in 40% (6/15) of patients. No death or serious opportunistic infections were observed in the present study. This study firstly reported that rapamycin might be effective for CD-related stricture in the upper, but not in lower gastrointestinal tract.

MINIMAL INVASIVE MANAGEMENT OF PEDIATRIC CROHN’S ANORECTAL STRICTURE, LESS IS MORE

Abstract Background Anorectal stricture (ARS) is an uncommon but potentially disabling manifestation of perianal Crohn disease (CD) in pediatric patients. Various treatment options are available but there is little data regarding their efficacy, particularly in the pediatric population. We present three case reports of patients with symptomatic ARS treated with serial dilation and biologic therapy. Methods An institutional review board-approved retrospective review was performed using electronic health records. Three patients with ileocolonic CD and perianal involvement with symptomatic ARS were identified. All patients were treated with serial rectal dilations under general anesthesia using Hegar dilators. Results All patients are currently asymptomatic at follow-ups ranging from 1 to 3.5 years since the last dilation. Patient demographics and details of ARS management are presented in Table 1. All patients tolerated the procedures well and did not experience complications such as perforation, sepsis, or fecal incontinence. Rectal biopsy in each patient showed active inflammation, suggesting type 1 stricture according to the Hughes-Cardiff Classification (vs. type 2 fibrotic stricture). Patient 1 experienced 6 recurrences, each managed with an average of 2 dilations until disease control was established with ustekinumab (USK) and eventually vedolizumab (VDZ). She underwent ileocecal resection three years after the final dilation. Patient 2 underwent ileocecal resection immediately following the first series of dilations. He later experienced one stricture recurrence at 2 years, which was managed with one dilation and increased USK dosing frequency. Patient 3 received steroid suppositories prior to dilation and has been self-dilating at home. He has had no recurrences requiring operative dilation. Self-dilation was not feasible in patients 1 and 2. Conclusion Inflammatory anorectal stricture associated with perianal Crohn disease in pediatric patients can be managed successfully with dilation until disease control with biologic therapy. Recurrences of stricture can also be managed with dilation and modification of biologic therapy. If tolerated, self-dilation may reduce recurrence. Background Anorectal stricture (ARS) is an uncommon but potentially disabling manifestation of perianal Crohn disease (CD) in pediatric patients. Various treatment options are available but there is little data regarding their efficacy, particularly in the pediatric population. We present three case reports of patients with symptomatic ARS treated with serial dilation and biologic therapy. Crohn’s rectal stricture pre and post dilation

Degree of Creeping Fat Assessed by Computed Tomography Enterography is Associated with Intestinal Fibrotic Stricture in Patients with Crohn's Disease: A Potentially Novel Mesenteric Creeping Fat Index.

Emerging evidence points to a link between creeping fat and the pathogenesis of Crohn's disease [CD]. Non-invasive assessment of the severity of creeping fat on cross-sectional imaging modality has seldom been investigated. This study aimed to develop and characterize a novel mesenteric creeping fat index [MCFI] based on computed tomography [CT] in CD patients. MCFI was developed based on vascular findings on CT in a retrospective cohort [n = 91] and validated in a prospective cohort [n = 30]. The severity of creeping fat was graded based on the extent to which mesenteric fat extended around the intestinal circumference using the vessels in the fat as a marker. The accuracy of MCFI was assessed by comparing it with the degree of creeping fat observed in surgical specimens. The relationship between MCFI and fibrostenosis was characterized by determining if these correlated. The accuracy of MCFI was compared with other radiographic indices [i.e. visceral to subcutaneous fat area ratio and fibrofatty proliferation score]. In the retrospective cohort, MCFI had moderate accuracy in differentiating moderate-severe from mild fibrostenosis (area under the receiver operating characteristic [ROC] curve [AUC] = 0.799; p = 0.000). ROC analysis in the retrospective cohort identified a threshold MCFI of > 3 which accurately differentiated fibrostenosis severity in the prospective cohort [AUC = 0.756; p = 0.018]. An excellent correlation was shown between MCFI and the extent of fat wrapping in specimens in the prospective cohort [r = 0.840, p = 0.000]. Neither visceral to subcutaneous fat area ratio nor fibrofatty proliferation score correlated well with the degree of intestinal fibrosis. MCFI can accurately characterize the extent of mesenteric fat wrapping in surgical specimens. It may become another non-invasive measure of CD fibrostenosis.

Congenital stricture of the vestibulo‐vaginal fold in a mare with normal karyotype

SummaryA diagnosis of congenital stricture of the vestibulo‐vaginal fold was reached in an 11‐year‐old mare without previous reproductive records, during a breeding soundness examination. The mare had an annular stricture of the vestibule–vaginal fold that did not allow palpation or vaginoscopic visual examination of the anterior portion of the vagina. Endoscopic evaluation of both anterior and posterior portions of the vagina revealed a normal mucosa without scar tissue. Ultrasound examination of the cervix, uterus and ovaries did not reveal any other abnormality. The mare had a normal karyotype – 64 XX. Vestibulo‐vaginal stricture or stenosis is a congenital anomaly that occurs when there is an incomplete perforation of the hymen or occurs in association with hypoplasia of the genital canal that results in the formation of an annular fibrotic stenosis at the vestibule–vaginal junction. To our knowledge, this is the first report of vestibulo‐vaginal stricture in a mare with confirmed normal karyotype, 64,XX.

A Rare Nidus for Biliary Stone Formation: Post-Cholecystectomy Clip Migration

A 54-year-old woman presented with one month of recurrent postprandial right sided and epigastric abdominal pain, associated with intermittent anorexia and vomiting. Her past medical history includes Crohn’s disease diagnosed in 1976, requiring total colectomy and end ileostomy in 1977 and small bowel resection for fibrotic stricture in 1980. A cholecystectomy for biliary pancreatitis was performed in 2004.

Fibrotic Strictures in Crohn's Disease: Mechanisms and Predictive Factors.

Fibrotic strictures are one of the most severe complications of Crohn's Disease (CD). They occur in about 50% of patients at five years and in 70% at ten years of the diagnosis. The only treatment available for symptomatic fibrotic strictures is surgical resection and endoscopic dilation. Both strategies are associated with a high rate of recurrence, and with multiple surgical resections, which pose the threat of surgical morbidity and short bowel syndrome. Therefore, it is crucial to identify, early, the patients more prone to develop intestinal fibrosis to intensify follow-ups, switch to more aggressive treatments, and suggest lifestyle modifications. Scarce data are available concerning biomarkers and genetic determinants to predict which patient will develop intestinal fibrosis. Biologic or clinical markers would be useful to determine this subgroup of CD patients and to predict the onset of intestinal fibrosis and, ideally, its severity. Furthermore, the identification of environmental risk factors may suggest lifestyle changes aimed at modifying the natural course, thus decreasing the risk of complicated CD. In this review, we will critically revise clinical, environmental, genetic, and serologic factors that have been associated with a complicated CD course with a particular focus on the fibrostenosing phenotype and their possible implications as predictive factors of intestinal fibrosis.