Standardizing Randomized Controlled Trials in Celiac Disease: An International Multidisciplinary Appropriateness Study.

BACKGROUND & AIMS: There is a need to develop safe and effective pharmacologic options for the treatment of celiac disease (CeD); however, consensus on the appropriate design and configuration of randomized controlled trials (RCTs) in this population is lacking. METHODS: A 2-round modified Research and Development/University of California Los Angeles Appropriateness Method study was conducted. Eighteen gastroenterologists (adult and pediatric) and gastrointestinal pathologists voted on statements pertaining to the configuration of CeD RCTs, inclusion and exclusion criteria, gluten challenge, and trial outcomes. Two RCT designs were considered, representing the following distinct clinical scenarios for which pharmacotherapy may be used: trials incorporating a gluten challenge to simulate exposure; and trials evaluating reversal of histologic changes, despite attempted adherence to a gluten-free diet. Each statement was rated as appropriate, uncertain, or inappropriate, using a 9-point Likert scale. RESULTS: For trials evaluating prevention of relapse after gluten challenge, participants adherent to a gluten-free diet for 12 months or more with normal or near-normal-sized villi should be enrolled. Gluten challenge should be FODMAPS (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) free, and efficacy evaluated using histology with a secondary patient-reported outcome measure. For trials evaluating reversal of villus atrophy, the panel voted it appropriate to enroll participants with a baseline villus height to crypt depth ratio ≤2 and measure efficacy using a primary histologic end point. Guidance for measuring histologic, endoscopic, and patient-reported outcomes in adult and pediatric patients with CeD are provided, along with recommendations regarding the merits and limitations of different end points. CONCLUSIONS: We developed standardized recommendations for clinical trial design, eligibility criteria, outcome measures, gluten challenge, and disease evaluations for RCTs in patients with CeD.

Features of colorectal adenomas among young patients with Lynch syndrome according to path_MMR: Results from the PRED-IdF registry.

BACKGROUND: Lynch syndrome (LS) is the most frequent inherited colorectal cancer syndrome. AIM: To assess the burden of adenoma in LS patients under 50 years-old followed in the PRED-IdF network. METHODS: From January 2010 to January 2019, all patients under 50 years of age with a confirmed LS germline mutation were included. The main objective was the description of adenomas characteristics according to path_MMR. RESULTS: We analyzed data from 708 patients (mean age 34.8 ± 8.6), of which 41.8 % were male. Among these patients, 37.6% had path_MLH1, 45.4% path_MSH2, 13.9% path_MSH6, 2.9% path_PMS2, and 1.2% path_EpCAM. The analysis included 1721 (70.9%) follow-up colonoscopies. A total of 682 adenomas were detected, including 140 (20.5%) advanced adenomas. The adenoma detection rates during the first and follow-up colonoscopies were 19.2% and 20.5%, respectively. Most adenomas were <10 mm (57.9%), located in the proximal colon (334, 48.9%), and presented as non-polypoid lesions (493, 72.3%). The median growth time for adenomas was 23 months (range 9-114) irrespective of the path_MMR mutation (p = 0.62). CONCLUSION: LS patients under 50 years of age have a high burden of adenomas, particularly small non-polypoid adenomas located in the proximal colon. These results highlight the need for intensive screening, with a particular focus on the proximal colon.

PERcutaneous transhepatic CHOLangioscopy using a new single-operator short cholangioscope (PERCHOL): European feasibility study.

OBJECTIVES: A new short device for percutaneous endoscopic cholangioscopy was recently developed. However, feasibility and safety has not yet been evaluated. The aim of this study was to assess clinical success, technical success, and adverse events (AEs). METHODS: This observational multicenter retrospective study included all patients who underwent percutaneous cholangioscopy using a short cholangioscope between 2020 and 2022. The clinical success, defined as the complete duct clearance or obtaining at least one cholangioscopy-guided biopsy, was assessed. The histopathological accuracy, technical success, and the AE rate were also evaluated. RESULTS: Fifty-one patients (60 ± 15 years, 45.1% male) were included. The majority of patients had altered anatomy (n = 40, 78.4%), and biliary stones (n = 34, 66.7%) was the commonest indication. The technique was predominantly wire-guided (n = 44, 86.3%) through a percutaneous sheath (n = 36, 70.6%) following a median interval of 8.5 days from percutaneous drainage. Cholangioscopy-guided electrohydraulic lithotripsy was performed in 29 cases (56.9%), combined with a retrieval basket in eight cases (27.6%). The clinical success was 96.6%, requiring a median of one session (range 1-3). Seventeen patients (33.3%) underwent cholangioscopy-guided biopsies. There were four (7.8%) cholangioscopy-related AEs (cholangitis and peritonitis). Overall, the technical success and AE rates were 100% and 19.6%, respectively, in a median follow-up of 7 months. CONCLUSION: Percutaneous endoscopic cholangioscopy with a new short device is effective and safe, requiring a low number of sessions to achieve duct clearance or accurate histopathological diagnosis.

Endoscopic ultrasound-guided gastroenterostomy with lumen-apposing metal stents: a retrospective multicentric comparison of wireless and over-the-wire techniques.

BACKGROUND: Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) using lumen-apposing metal stents (LAMSs) appears to be effective and safe in gastric outlet obstruction (GOO); however, the EUS-GE procedure is not standardized, with the use of assisted or direct methods still debated. The aim of this study was to compare the outcomes of EUS-GE techniques focusing on an assisted with orointestinal drain wireless endoscopic simplified technique (WEST) and the nonassisted direct technique over a guidewire (DTOG). METHOD: This was a multicenter European retrospective study involving four tertiary centers. Consecutive patients who underwent EUS-GE for GOO between August 2017 and May 2022 were included. The primary aim was to compare the technical success and adverse event (AE) rates of the different EUS-GE techniques. Clinical success was also analyzed. RESULTS: 71 patients (mean [SD] age 66.2 10 years; 42.3 % men; 80.3 % malignant etiology) were included. Technical success was higher in the WEST group (95.1 % vs. 73.3 %; estimate of relative risk from odds ratio (eRR) 3.2, 95 %CI 0.94-10.9; P = 0.01). The rate of AEs was lower in the WEST group (14.6 % vs. 46.7 %; eRR 2.3, 95 %CI 1.2-4.5; P = 0.007). Clinical success was comparable between the two groups at 1 month (97.5 % vs. 89.3 %). The median follow-up was 5 months (range 1-57). CONCLUSION: The WEST resulted in a higher technical success rate with fewer AEs, with clinical success comparable with the DTOG. Therefore, the WEST (with an orointestinal drain) should be preferred when performing EUS-GE.

[Immunopathology of the small intestine]. / Immunopathologie de l'intestin grêle.

The gastrointestinal tract is the site of exciting immunological interactions between the epithelium and the mucosa-associated lymphoid tissue, leading to the immune response to food and microbial antigens in the digestive lumen. The objective of this review is to present the main dysimmune pathologies of the digestive tract leading to an enteropathy. As examples, we describe celiac and non-celiac enteropathies to clarify a florid diagnostic framework, by identifying a spectrum of elementary lesions, which must be confronted with the clinico biological context of the patient to orient the diagnosis. The microscopic lesions observed are most often non-specific and may be encountered in several diagnostic settings. Moreover, it is a set of elementary lesions in each clinical context that will orient the diagnostic framework. Celiac disease is the main etiology of enteropathy with villous atrophy, its diagnosis is multidisciplinary and there are many differential diagnoses. We will discuss celiac disease lymphomatous complications as enteropathy associated T-cell lymphoma including refractory sprue type 2. We will then present the non-celiac enteropathies. Among these, enteropathies of unknown etiology may be associated with a primary immune deficiency that may be reflected by florid lymphoid hyperplasia of the gastrointestinal tract and/or be associated with an infectious etiology that should also be constantly sought. Finally, we will discuss of induced enteropathy by new immunomodulatory treatments.

Efficacy of Organ Preservation Strategy by Adjuvant Chemoradiotherapy after Non-Curative Endoscopic Resection for Superficial SCC: A Multicenter Western Study.

BACKGROUND: In case of high risk of lymph node invasion after endoscopic resection (ER) of superficial esophageal squamous cell carcinoma (SCC), adjuvant chemoradiotherapy (CRT) can be an alternative to surgery. We assessed long-term clinical outcomes of adjuvant therapy by CRT after non-curative ER for superficial SCC. METHODS: We performed a retrospective multicenter study. From April 1999 to April 2018, all consecutive patients who underwent ER for SCC with tumor infiltration beyond the muscularis mucosae were included. RESULTS: A total of 137 ER were analyzed. The overall nodal or metastatic recurrence-free survival rate at 5 years was 88% and specific recurrence-free survival rates at 5 years with and without adjuvant therapy were, respectively, 97.9% and 79.1% (p = 0.011). Independent factors for nodal and/or distal metastatic recurrence were age (HR = 1.075, p = 0.031), Sm infiltration depth > 200 µm (HR = 4.129, p = 0.040), and the absence of adjuvant CRT or surgery (HR = 11.322, p = 0.029). CONCLUSION: In this study, adjuvant therapy is associated with a higher recurrence-free survival rate at 5 years after non-curative ER. This result suggests this approach may be considered as an alternative to surgery in selected patients.

EUS-Guided Gastroenterostomy in Malignant Gastric Outlet Obstruction: A Comparative Study between First- and Second-Line Approaches after Enteral Stent Placement.

INTRODUCTION: Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is increasingly used in the setting of malignant gastric outlet obstruction (GOO). However, little is known about the role of primary EUS-GE. The aim of the present study is to compare the outcomes of EUS-GE by using the freehand technique as a first- and second-line approach after enteral stenting (ES). METHODS: This is an observational single-center study using a prospectively collected database. All consecutive patients who underwent an EUS-GE using the freehand technique due to malignant GOO were included. Patients with previous gastric surgery, a wire-guided EUS-GE technique, or those presenting without GOO were excluded. The primary outcome was the clinical success, defined as a solid oral intake at 1 week after the procedure (GOO Score, GOOSS ≥ 2). The secondary outcomes were technical success and adverse event (AE) rates. The impact on nutritional parameters was also assessed. RESULTS: Forty-five patients underwent an EUS-GE for all indications. Finally, 28 patients (mean age: 63 ± 17.2 years, 57.1% male) with (n = 13, 46.4%) and without (n = 15, 53.6%) a previous ES were included. The technical success was achieved in 25 cases (89.3%), with no differences between the two groups (92.3% vs. 86.7%, p = 1). The median limb diameter and procedure time were 27 mm (range:15-48) and 37 min. Overall, clinical success was achieved in 22 cases (88%), with three failures due to AEs (n = 2) or peritoneal carcinomatosis (n = 1). The diet progression was quicker in patients with a previous ES (GOOSS at 48 h, 2 vs. 1, p = 0.023), but the GOOSS at 1 week (p = 0.299), albumin gain (p = 0.366), and BMI gain (0.257) were comparable in the two groups. The AE rate was 7.1%. CONCLUSIONS: EUS-GE achieves a high technical and clinical success in patients with GOO regardless of the presence of a previous ES. Patients with previous ES may have a quicker progression of their diet, but the GOOSS and nutritional status in the long term at 1 week or 1 month are comparable. Primary EUS-GE might require fewer procedures and less discontinuation of chemotherapy to achieve a comparable result.

Hybrid retroperitoneal necrosectomy using a triple-port approach under endoscopic guidance.

Complex walled-off necrosis with a retroperitoneal component represent a therapeutic challenge. Although mini-invasive approaches have been described, hybrid procedures combining surgical, endoscopic and radiological techniques have slightly been evaluated. A 58 years-old male presented with a 20-cm infected multilocular walled-off necrosis. First, endoscopic-ultrasound guided cystogastrostomy using a lumen-apposing metal stent with further necrosectomy was performed, but the access to distal retroperitoneal collection was average.

Endoscopic ultrasound-guided drainage using lumen-apposing metal stent of malignant afferent limb syndrome in patients with previous Whipple surgery: Multicenter study (with video).

OBJECTIVES: Endoscopic ultrasound-guided digestive anastomosis (EUS-A) is a new alternative under evaluation in patients presenting with afferent limb syndrome (ALS) after Whipple surgery. The aim of the present study is to analyze the safety and effectiveness of EUS-A in ALS. METHODS: This is an observational multicenter study. All patients ≥18 years old with previous Whipple surgery presenting with ALS who underwent an EUS-A using a lumen-apposing metal stent (LAMS) between 2015 and 2021 were included. The primary outcome was clinical success, defined as resolution of the ALS or ALS-related cholangitis. Furthermore, technical success, adverse event rate, and mortality were evaluated. RESULTS: Forty-five patients (mean age: 65.5 ± 10.2 years; 44.4% male) were included. The most common underlying disease was pancreatic cancer (68.9%). EUS-A was performed at a median of 6 weeks after local tumor recurrence. The most common approach used was the direct/freehand technique (66.7%). Technical success was achieved in 95.6%, with no differences between large (≥15 mm) and small LAMS (97.4% vs. 100%, P = 0.664). Clinical success was retained in 91.1% of patients. A complementary treatment by dilation of the stent followed by endoscopic retrograde cholangiopancreatography through the LAMS was performed in three cases (6.7%). There were six recurrent episodes of cholangitis (14.6%) and two procedure-related adverse events (4.4%) after a median follow-up of 4 months. Twenty-six patients (57.8%) died during the follow-up due to disease progression. CONCLUSION: EUS-A is a safe and effective technique in the treatment of malignant ALS, achieving high clinical success with an acceptable recurrence rate.

Comparison of cold biopsy forceps vs cold snare for diminutive colorectal polyp removal: A multicenter non-inferiority randomized controlled trial.

BACKGROUND: European guidelines recommends the use of cold snare polypectomy (CSP) for removal of diminutive colorectal polyps (DCP). However, for DCP < 4 mm cold biopsy forceps (CBF) may be optional. We aimed to compare the efficacy of CSP with CBF for removal of DCP in routine colonoscopy. METHODS: We conducted a multicenter non-inferiority randomized controlled trial. After screening, 123 patients were prospectively included and 180 DCPs were removed by either CBF or CSP after randomization (1:1). The primary end-point was the histological complete resection rate defined by negative additional biopsies taken from the edge of the polypectomy ulcer site. RESULTS: Among DCPs, 121 (67.2%) adenomas or sessile serrated lesions were considered for the analysis. Polyps were 4 [1-5] mm in size, mostly flat (55.4%) and located in the proximal colon (44.6%). The en bloc resection rate was higher in the CSP group than the CBF group (91.7% vs. 42.6%, p < 0.001). The histological complete resection rate was comparable in the two groups (93.33% vs 90.16%; p = 0.527), even for polyps < 4 mm (91.30% vs 91.30%; p = 1). All specimens were retrieved and there was no difference in terms of procedure times and adverse events. Finally, univariate analysis did not identify any potential factor associated with complete resection rate. CONCLUSION: In this study, CSP was comparable to CBF for the removal of DCP. Therefore, CBF may be considered as an alternative technique for resection of DCP, together with CSP, ClinicalTrials.gov registry (NCT04727918).

Oncogenetic landscape of lymphomagenesis in coeliac disease.

OBJECTIVE: Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. DESIGN: Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. RESULTS: 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. CONCLUSION: Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.

Endoscopic submucosal dissection in tumors extending to the dentate line compared to proximal rectal tumors: a systematic review with meta-analysis.

Endoscopic submucosal dissection (ESD) is a validated treatment for early rectal tumors, but whether this therapy is efficient or not for rectal tumors extending to the dentate line (RTDL) remains unclear. We performed a systematic review and meta-analysis to assess the effectiveness and safety of ESD in RTDL compared to non-RTDL. A search in PubMed, Scopus and the Cochrane library up to April 2020 was conducted to identify studies that compared ESD in both localizations (RTDL and non-RTDL), reporting at least one main outcome (en bloc, complete resection, recurrence). Secondary outcomes were adverse event occurrence. Five observational studies including 739 patients with a total of 201 RTDL and 538 non-RTDL were considered. The proportion of female sex (66% vs. 36.9%, P < 0.001) and tumor size [mean difference = 7.75, 95% confidence interval (CI): 3.01-12.49, P = 0.001] were higher in the RTDL group. There were no differences in en bloc resection rates between RTDL and non-RTDL groups [odds ratio (OR): 0.95, 95% CI: 0.50-1.79, P = 0.087]. The complete resection rate was significantly higher in the non-RTDL group (OR: 1.72, 95% CI: 1.18-2.53, P = 0.005, I2 = 0%). However, recurrence rates were comparable (RD: -0.04, 95% CI: -0.07 to 0.00, P = 0.06, I2 = 0%). Concerning adverse events, there were no differences in terms of perforation (OR: 0.9, 95% CI: 0.26-3.08, P = 0.86, I2 = 0%) or delayed bleeding (OR: 0.64, 95% CI: 0.17-2.42, P = 0.51, I2 = 35%). Anal pain rate was 28% (95% CI: 21.4-35.8%). ESD is an effective and safe therapeutic approach for RTDL with comparable recurrence rate to non-RTDL. The lower complete resection rate in RTDL needs to be clarified in studies.

Extracellular vesicles from adipose stromal cells combined with a thermoresponsive hydrogel prevent esophageal stricture after extensive endoscopic submucosal dissection in a porcine model.

In this study, we investigated the combination of extracellular (nano) vesicles (EVs) from pig adipose tissue-derived stromal cells (ADSCs) and a thermoresponsive gel, Pluronic® F-127 (PF-127), to prevent stricture formation after endoscopic resection in a porcine model. ADSC EVs were produced at a liter scale by a high-yielding turbulence approach from ADSCs 3D cultured in bioreactors and characterized in terms of size, morphology and membrane markers. The thermoresponsive property of the PF-127 gel was assessed by rheology. The pro-regenerative potency of ADSC EVs was investigated ex vivo in esophageal biopsies under starvation. In vivo tests were performed in a porcine model after extended esophageal endoscopic mucosal dissection (ESD). Pigs were randomized into 3 groups: control (n = 6), gel (n = 6) or a combination of 1.45 × 1012 EVs + gel (n = 6). Application of gel ± EVs was performed just after ESD with a follow-up finalized on day 21 post-ESD. There was a trend towards less feeding disorder in the EV + gel group in comparison with the gel and the control groups (16.67% vs. 66.7% vs. 83.33%, respectively) but without reaching a statistically significant difference. A significant decrease in the esophageal stricture rate was confirmed by endoscopic, radiological and histological examination for the EV + gel group. A decrease in the mean fibrosis area and larger regenerated muscularis mucosae were observed for the EV + gel group. In summary, the application of EVs + gel after extended esophageal endoscopic resection succeeded in preventing stricture formation with an anti-fibrotic effect. This nano-therapy may be of interest to tackle an unmet medical need considering that esophageal stricture is the most challenging delayed complication after extended superficial cancer resection by endoscopy.

Acid Reflux Is Common in Patients With Gastroesophageal Reflux Disease After One-Anastomosis Gastric Bypass.

INTRODUCTION: Patients with one-anastomosis gastric bypass (OAGB) can develop gastroesophageal reflux disease (GERD). The nature of this GERD (acid or biliary) remains unclear. OBJECTIVE: To assess the nature of GERD via impedance pH testing in patients presenting with reflux post OAGB. METHODS: Retrospective analysis of a prospectively collected database of 43 patients with OAGB backgrounds who developed postoperative GERD and were investigated with impedance pH monitoring between 2006 and 2019. RESULTS: Mean age was 52.48 ± 9 years. Mean body mass index (BMI) prior to OAGB was 46.82 kg/m2. None of these patients had clinical GERD before surgery. The median time interval between surgery and investigation with 24-h impedance pH monitoring was 64 (56) months. The mean BMI at the time of investigations was 32.67 ± 6.9 kg/m2. The type of reflux was acid in 13 (30.2%), non-acid (biliary) in 12 (27.9%), and mixed (acid and biliary) in 5 (11.6%) patients. However, it remained not confirmed in 13 (30.2%). Median DeMeester score was 48.95 (27.67) in patients with acid, 2.8 (7.4) in patients with biliary, and 28.7 (5.6) in patients with mixed reflux. Median percent of time spent with pH < 4 was 9.65 (8) in patients with acid, 0.6 (1.75) in patients with biliary, and 7.7 (3.9) in patients with mixed reflux. CONCLUSION: Acid reflux seems to be as common as bile reflux in patients presenting with GERD after OAGB. In case of revisional surgery for severe GERD post OAGB, 24-h impedance pH monitoring could be essential to determine the surgical procedure of choice.

Upper Gastrointestinal Lesions during Endoscopy Surveillance in Patients with Lynch Syndrome: A Multicentre Cohort Study.

BACKGROUND: Patients with Lynch syndrome are at increased risk of gastric and duodenal cancer. Upper gastrointestinal endoscopy surveillance is generally proposed, even though little data are available on upper gastrointestinal endoscopy in these patients. The aim of this retrospective study was to evaluate the prevalence and incidence of gastrointestinal lesions following upper gastrointestinal endoscopy examination in Lynch patients. METHODS: A large, multicentre cohort of 172 patients with a proven germline mutation in one of the mismatch repair genes and at least one documented upper gastrointestinal endoscopy screening was assessed. Detailed information was collected on upper gastrointestinal endoscopy findings and the outcome of endoscopic follow-up. RESULTS: Seventy neoplastic gastrointestinal lesions were diagnosed in 45 patients (26%) out of the 172 patients included. The median age at diagnosis of upper gastrointestinal lesions was 54 years. The prevalence of cancer at initial upper gastrointestinal endoscopy was 5% and the prevalence of precancerous lesions was 12%. Upper gastrointestinal lesions were more frequent after 40 years of age (p < 0.001). Helicobacter pylori infection was associated with an increased prevalence of gastric, but not duodenal, lesions (p < 0.001). CONCLUSIONS: Neoplastic upper gastrointestinal lesions are frequent in patients with Lynch syndrome, especially in those over 40 years of age. The results of our study suggest that Lynch patients should be considered for upper gastrointestinal endoscopic and Helicobacter pylori screening.

Probe-based Confocal Laser Endomicroscopy for In Vivo Assessment of Histological Healing in Ulcerative Colitis: Development and Validation of the ENHANCE Index.

BACKGROUND AND AIMS: Histological healing may represent the ultimate therapeutic goal in ulcerative colitis [UC], but it requires biopsies. Our aim was to develop a non-invasive index able to assess histological disease activity in ulcerative colitis, using probe-based confocal laser endomicroscopy [pCLE]. METHODS: One hundred patients with quiescent UC were prospectively included in five French centres. After fluorescein intravenous injection, during colonoscopy, the colorectal mucosa was analysed by white light imaging and pCLE, and then biopsied in different locations. Five endoscopists performed central reading of pCLE images blinded to clinical, endoscopic, and histological data. One expert pathologist performed a central histological reading [Nancy index: gold standard]. Univariate and multivariate analyses were performed to identify the endomicroscopic items associated with the presence of histologically active disease. RESULTS: Over 1000 pCLE videos sequences performed in 100 UC patients in endoscopic remission [Mayo 0 and 1] were evaluated. We observed that vessel diameter >20 µm, dilated crypt lumen, fluorescein leakage, and irregular crypt architecture were statistically associated with histologically proven inflammation according to the Nancy index. Hence, we built a pCLE index of mucosal inflammation with overall accuracy of 79.6% and overall sensitivity and specificity of, respectively, 57.8% and 82.8%. Negative predictive value, especially when a pCLE index ≤1 was observed, was high [93.1%]. CONCLUSIONS: Using a robust methodology, large vessel diameter, dilated crypt lumen, fluorescein leakage,and irregular crypt architecture are reliable endomicroscopic items defining the ENHANCE index for real-time assessment of histological disease activity in UC.

Local administration of stem cell-derived extracellular vesicles in a thermoresponsive hydrogel promotes a pro-healing effect in a rat model of colo-cutaneous post-surgical fistula.

Extracellular vesicles (EVs), especially from stem/stromal cells (SCs), represent a cell-free alternative in regenerative medicine holding promises to promote tissue healing while providing safety and logistic advantages in comparison to cellular counterparts. Herein, we hypothesize that SC EVs, administered locally in a thermoresponsive gel, is a therapeutic strategy for managing post-surgical colo-cutaneous fistulas. This disease is a neglected and challenging condition associated to low remission rates and high refractoriness. Herein, EVs from a murine SC line were produced by a high-yield scalable method in bioreactors. The post-surgical intestinal fistula model was induced via a surgical cecostomy communicating the cecum and the skin in Wistar rats. Animals were treated just after cecostomy with PBS, thermoresponsive Pluronic F-127 hydrogel alone or containing SC EVs. A PET-monitored biodistribution investigation of SC EVs labelled with 89Zr was performed. Fistula external orifice and output assessment, probe-based confocal laser endomicroscopy, MRI and histology were carried out for therapy follow-up. The relevance of percutaneous EV administration embedded in the hydrogel vehicle was indicated by the PET-biodistribution study. Local administration of SC EVs in the hydrogel reduced colo-cutaneous fistula diameter, output, fibrosis and inflammation while increasing the density of neo-vessels when compared to the PBS and gel groups. This multi-modal investigation pointed-out the therapeutic potential of SC EVs administered locally and in a thermoresponsive hydrogel for the management of challenging post-surgical colon fistulas in a minimally-invasive cell-free strategy.