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BACKGROUND & AIMS: Microscopic inflammation has significant prognostic value in ulcerative colitis (UC); however, its assessment is complex with high interobserver variability. We aimed to develop and validate an artificial intelligence (AI) computer-aided diagnosis system to evaluate UC biopsies and predict prognosis. METHODS: A total of 535 digitalized biopsies (273 patients) were graded according to the PICaSSO Histologic Remission Index (PHRI), Robarts, and Nancy Histological Index. A convolutional neural network classifier was trained to distinguish remission from activity on a subset of 118 biopsies, calibrated on 42 and tested on 375. The model was additionally tested to predict the corresponding endoscopic assessment and occurrence of flares at 12 months. The system output was compared with human assessment. Diagnostic performance was reported as sensitivity, specificity, prognostic prediction through Kaplan-Meier, and hazard ratios of flares between active and remission groups. We externally validated the model in 154 biopsies (58 patients) with similar characteristics but more histologically active patients. RESULTS: The system distinguished histological activity/remission with sensitivity and specificity of 89% and 85% (PHRI), 94% and 76% (Robarts Histological Index), and 89% and 79% (Nancy Histological Index). The model predicted the corresponding endoscopic remission/activity with 79% and 82% accuracy for UC endoscopic index of severity and Paddington International virtual ChromoendoScopy ScOre, respectively. The hazard ratio for disease flare-up between histological activity/remission groups according to pathologist-assessed PHRI was 3.56, and 4.64 for AI-assessed PHRI. Both histology and outcome prediction were confirmed in the external validation cohort. CONCLUSION: We developed and validated an AI model that distinguishes histologic remission/activity in biopsies of UC and predicts flare-ups. This can expedite, standardize, and enhance histologic assessment in practice and trials. ispartof: GASTROENTEROLOGY vol:164 issue:7 pages:1180-+ ispartof: location:United States status: published

ObjectiveUlcerative colitis (UC) is a chronic, debilitating immune-mediated disease driven by disturbed mucosal homeostasis, with an excess of intestinal effector T cells and an insufficient expansion of mucosal regulatory T cells (Tregs). We here report on the successful adoptive transfer of autologous, ex vivo expanded Tregs in a patient with refractory UC and associated primary sclerosing cholangitis (PSC), for which effective therapy is currently not available.DesignThe patient received a single infusion of 1×106autologous, ex vivo expanded, polyclonal Tregs per kilogram of body weight, and the clinical, biochemical, endoscopic and histological responses were assessed 4 and 12 weeks after adoptive Treg transfer.ResultsThe patient showed clinical, biochemical, endoscopic and histological signs of response until week 12 after adoptive Treg transfer, which was associated with an enrichment of intestinal CD3+/FoxP3+and CD3+/IL-10+T cells and increased mucosal transforming growth factor beta and amphiregulin levels. Moreover, there was marked improvement of PSC with reduction of liver enzymes. This pronounced effect lasted for 4 weeks before values started to increase again.ConclusionThese findings suggest that adoptive Treg therapy might be effective in refractory UC and might open new avenues for clinical trials in PSC.Trial registration numberNCT04691232.

Background Motorized spiral enteroscopy (MSE) has been shown to be safe and effective for deep enteroscopy in studies performed at expert centers with limited numbers of patients without previous abdominal surgery. This study aimed to investigate the safety, efficacy, and learning curve associated with MSE in a real-life scenario, with the inclusion of patients after abdominal surgery and with altered anatomy. Methods Patients with indications for deep enteroscopy were enrolled in a prospective observational multicenter study. The primary objective was the serious adverse event (SAE) rate; secondary objectives were the diagnostic and therapeutic yield, procedural success, time, and insertion depth. Data analysis was subdivided into training and core (post-training) study phases at centers with different levels of MSE experience. Results 298 patients (120 women; median age 68, range 19–92) were enrolled. In the post-training phase, 21.5 % (n = 54) had previous abdominal surgery, 10.0 % (n = 25) had surgically altered anatomy. Overall, SAEs occurred in 2.3 % (7/298; 95 %CI 0.9 %–4.8 %). The SAE rate was 2.0 % (5/251) in the core group and 4.3 % (2/47) in the training group, and was not increased after abdominal surgery (1.9 %). Total enteroscopy was achieved in half of the patients (n = 42) undergoing planned total enteroscopy. In 295/337 procedures (87.5 %), the anatomical region of interest could be reached. Conclusions This prospective multicenter study showed that MSE was feasible and safe in a large cohort of patients in a real-life setting, after a short learning curve. MSE was shown to be feasible in postsurgical patients, including those with altered anatomy, without an increase in the SAE rate.

[EN] Background and Objective: Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) affecting the colon and the rectum characterized by a remitting-relapsing course. To detect mucosal inflammation as-sociated with UC, histology is considered the most stringent criteria. In turn, histologic remission (HR) correlates with improved clinical outcomes and has been recently recognized as a desirable treatment target. The leading biomarker for assessing histologic remission is the presence or absence of neutrophils. Therefore, the finding of this cell in specific colon structures indicates that the patient has UC activity. However, no previous studies based on deep learning have been developed to identify UC based on neu-trophils detection using whole-slide images (WSI). Methods: The methodological core of this work is a novel multiple instance learning (MIL) framework with location constraints able to determine the presence of UC activity using WSI. In particular, we put forward an effective way to introduce constraints about positive instances to effectively explore additional weakly supervised information that is easy to obtain and enjoy a significant boost to the learning process. In addition, we propose a new weighted embedding to enlarge the relevance of the positive instances. Results: Extensive experiments on a multi-center dataset of colon and rectum WSIs, PICASSO-MIL, demon-strate that using the location information we can improve considerably the results at WSI-level. In com-parison with prior MIL settings, our method allows for 10% improvements in bag-level accuracy. Conclusion : Our model, which introduces a new form of constraints, surpass the results achieved from current state-of-the-art methods that focus on the MIL paradigm. Our method can be applied to other histological concerns where the morphological features determining a positive WSI are tiny and similar to others in the image., This work has received funding from Horizon 2020, the European Unions Framework Programme for Research and Innovation, under grant agreement No. 860627 (CLARIFY) , the Spanish Ministry of Economy and Competitiveness through project PID2019-105142RB-C21 (AI4SKIN) and GVA through projects PROMETEO/2019/109 and INNEST/2021/321 (SAMUEL) . Roco del Amor and Adrin Colomer work have also been supported by the Spanish Government under FPU Grant (FPU20/05263) and the Universitat Politcnica de Valncia (PAID-10-21-Subprograma 1), respectively. We gratefully acknowledge the support from the Generalitat Valenciana (GVA) with the donation of the DGX A100 used for this work, action co-financed by the European Union through the Operational Program of the European Regional Development Fund of the Comunitat Valenciana 2014¿2020 (IDIFEDER/2020/030).

Marcel Vetter1 12 2, Timo Rath1 12 2, Jürgen Siebler1 12 2, Maximilian Waldner1 12 2, Markus F Neurath1 12 2, Lukas Pfeifer3 3 1Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 2Deutsches Zentrum Immuntherapie, DZI, Erlangen, Germany; 3Department of Gastroenterology and Interventional Endoscopy, Krankenhaus Barmherzige Brüder, Regensburg, GermanyCorrespondence: Lukas PfeiferDepartment of Gastroenterology and Interventional Endoscopy, Krankenhaus Barmherzige Brüder, Prüfeninger Straße 86, Regensburg, Bavaria, 93049, GermanyTel +49 941 369 2051Fax +49 941 369 2055Email Lukas.Pfeifer@barmherzige-regensburg.deBackground: Ingestion of alkaline fluids is a common problem, which can lead to perforations, strictures and malignancy. We present a rare case series of several patients who accidentally ingested the same alkaline substance in different doses.Methods: We investigated four patients with accidental ingestion of dishwashing liquid. All patients underwent gastroscopy within 24h after inpatient admission. Gastroesophageal lesions were classified according to the Zargar classification for corrosive ingestions.Results: Esophagogastric lesions were predominantly found at the distal esophagus and the small curvature of the stomach. The severity of these lesions ranged from mild erosions (Zargar 2A) to marked necrosis (Zargar 3A). Our data suggest that the degree of these lesions correlated with the amount of ingested toxin and duration of the inpatient stay. However, a low symptom severity or inconspicuous otolaryngologic examination did not exclude severe gastroesophageal lesions.Conclusion: Our data suggest that the severity of gastroesophageal lesions correlates with the amount of ingested alkaline substance. Symptom burden and an otolaryngologic examination are not sufficiently predictive for the severity of gastroesophageal lesions. The composition and quantity of the swallowed liquid should be determined.Keywords: alkali ingestion, gastroscopy, toxin dose, case series

Background and Aims Buried bumper syndrome (BBS) is a rare adverse event of percutaneous endoscopic gastrostomy (PEG) placement in which the internal bumper migrates through the stomal tract to become embedded within the gastric wall. Excessive tension between the internal and external bumpers, causing ischemic necrosis of the gastric wall, is believed to be the main etiologic factor. Several techniques for endoscopic management of BBS have been described using off-label devices. The Flamingo set is a novel, sphincterotome-like device specifically designed for BBS management. We aimed to evaluate the effectiveness of the Flamingo device in a large, homogeneous cohort of patients with BBS. Methods A guidewire was inserted through the external access of the PEG tube into the gastric lumen. The Flamingo device was then introduced into the stomach over the guidewire. This dedicated tool can be flexed by 180 degrees, exposing a sphincterotome-like cutting wire, which is used to incise the overgrown tissue until the PEG bumper is exposed. A retrospective, international, multicenter cohort study was conducted on 54 patients between December 2016 and February 2019. Results The buried bumper was successfully removed in 53 of 55 procedures (96.4%). The median time for the endoscopic removal of the buried bumper was 22 minutes (range, 5-60). Periprocedural endoscopic adverse events occurred in 7 procedures (12.7%) and were successfully managed endoscopically. A median follow-up of 150 days (range, 33-593) was performed in 29 patients (52.7%), during which no significant adverse events occurred. Conclusions Through our experience, we found this dedicated novel device to be safe, quick, and effective for minimally invasive, endoscopic management of BBS.

Aim The use of artificial intelligence represents an objective approach to increase endoscopist's adenoma detection rate (ADR) and limit interoperator variability. In this study, we evaluated a newly developed deep convolutional neural network (DCNN) for automated detection of colorectal polyps ex vivo as well as in a first in-human trial. Methods For training of the DCNN, 116 529 colonoscopy images from 278 patients with 788 different polyps were collected. A subset of 10 467 images containing 504 different polyps were manually annotated and treated as the gold standard. An independent set of 45 videos consisting of 15 534 single frames was used for ex vivo performance testing. In vivo real-time detection of colorectal polyps during routine colonoscopy by the DCNN was tested in 42 patients in a back-to-back approach. Results When analyzing the test set of 15 534 single frames, the DCNN's sensitivity and specificity for polyp detection and localization within the frame was 90% and 80%, respectively, with an area under the curve of 0.92. In vivo, baseline polyp detection rate and ADR were 38% and 26% and significantly increased to 50% (P = 0.023) and 36% (P = 0.044), respectively, with the use of the DCNN. Of the 13 additionally with the DCNN detected lesions, the majority were diminutive and flat, among them three sessile serrated adenomas. Conclusion This newly developed DCNN enables highly sensitive automated detection of colorectal polyps both ex vivo and during first in-human clinical testing and could potentially increase the detection of colorectal polyps during colonoscopy.

During the past decade, molecular imaging has emerged as a new and innovative field combining clinical endoscopy with methods prior used in basic science. Through the labeling of cellular targets with certain molecular probes and their subsequent detection with dedicated endoscopic devices, molecular imaging enables the visualization of single molecules or receptors during ongoing endoscopy. Early studies in the field have provided proof-of-principle that molecular imaging can improve visualization, or even unmask, previously unrecognized early dysplasia or cancer. Building on this, further studies then used molecular imaging for grading and detecting inflammation and inflammation associated cancer. Most recently, molecular imaging has been used to phenotype the expression of single receptors and targets of biological therapy and thereby enables molecular tissue profile in vivo. With this live molecular fingerprinting, molecular imaging can be used to guide expression-tailored individualized therapy, and due to the diversification of biological therapy in both cancer and intestinal inflammation, it can be expected that molecular imaging will gain further traction in the foreseeable future. Within this review, we first summarize the technical components commonly used for molecular imaging and then review preclinical and clinical studies and possible and evolving clinical applications on molecular imaging within the entire the GI tract.

Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity.MethodsUsing a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies.ResultsPHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients’ risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy.ConclusionsPHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.

Apart from endoscopic healing as an established treatment goal in patients with inflammatory bowel disease (IBD), histologic remission is an emerging endpoint that might even better predict disease outcome, especially in ulcerative colitis (UC). Within this study, we aimed to evaluate whether endocytoscopy (EC) as an in vivo contact microscopy technology can accurately assess histologic inflammation and predict the further course of disease in UC patients.Initially, a new and intuitive EC score reflecting the entire spectrum of microscopic disease activity in UC was consensually developed. Subsequently, this score was independently validated in 46 patients with UC who underwent close-meshed follow-up during which major adverse outcomes (MAOs; defined as disease flare, IBD-related hospitalization, IBD-related surgery, necessity for initiation or escalation therapy) were recorded. Results of EC grading of inflammatory activity were compared against 2 validated histologic scores in UC. Diagnostic performance of endoscopic remission under white-light endoscopy (Mayo Endoscopic Score and Ulcerative Colitis Endoscopic Index of Severity), EC, and histology were compared for the prediction of MAOs.Endocytoscopic assessment of inflammatory activity in UC based on the newly developed ErLangen Endocytoscopy in ColiTis score showed strong correlation with histopathologic scoring (Robarts Histopathology Index, r = .70; Nancy Histologic Index, r = .73) and was superior to white-light endoscopy for grading of microscopic disease activity, with a sensitivity of 88%, specificity of 95.2%, and area under the curve of .916. Furthermore, EC exhibited a high interobserver agreement for in vivo grading of microscopic inflammation and was comparably accurate as histopathology for forecasting the occurrence of MAOs in UC.Endocytoscopic grading of inflammatory activity along a newly developed scoring system enabled real-time histology in UC patients and better predicted clinical outcome in UC patients than endoscopic remission.

A composite endoscopic-histologic remission is increasingly explored as an important endpoint in ulcerative colitis (UC). We investigated combined endoscopic-histologic remission for predicting clinical outcomes at 12 months compared with endoscopic remission alone using the high definition virtual chromoendoscopy (VCE) Paddington International virtual ChromoendoScopy ScOre (PICaSSO) and histology scores.Ulcerative colitis patients, prospectively enrolled from 11 international centres, underwent VCE with targeted biopsies and followed up for 12 months. Endoscopic activity was assessed by Mayo Endoscopic Score (MES), Ulcerative Colitis Endoscopic Index Severity (UCEIS) followed by VCE-PICaSSO. Robarts Histopathological Index|Robarts Histological index≤3 without neutrophils in mucosa, and Nancy Histological index (NHI)≤ 1 were used to define histologic remission. Combined endoscopic-histologic remission was compared with endoscopic remission alone by Cox proportional hazards model and by two- and three-proportion analysis using pre-specified clinical outcomes.307 patients were recruited and 302 analysed. There was no difference in survival without specified clinical outcomes between PICaSSO defined endoscopic remission alone and endoscopic plus histologic remission in the rectum (HR 0.42, 95%CI 0.16-1.11 and HR 1.03, 95%CI 0.42-2.52 for Robarts Histological index and NHI respectively) at 12 months. There was however a significant survival advantage without specified clinical outcome events for UCEIS combined with histology compared with UCEIS alone (HR 0.30, 95%CI 0.12-0.75, p = 0.02) at 12 months (but not combined with NHI). For MES there was no advantage for predicting specified clinical outcomes at 12 months for endoscopy alone versus endoscopy plus histology, but there were differences in two and three proportion analysis at 6 months.Endoscopic remission by VCE-PICaSSO alone was similar to combined endoscopic and histologic remission for predicting specified clinical outcomes at 12 months. Larger studies with specific therapeutic interventions are required to further confirm the findings.

Background The adenoma detection rate (ADR) is inversely associated with the incidence of interval colorectal cancer and serves as a benchmark quality criterion during screening colonoscopy. However, adenoma miss rates reach up to 26% and studies have shown that a second inspection of the right colon in retroflected view (RFV) can increase ADR. Aim To assess whether inspection of the whole colon in RFV compared to standard forward view (SFV) can increase ADR. Methods Patients presenting for screening or surveillance colonoscopy were invited to participate in this randomized controlled trial and randomized into two arms. In RFV arm colonoscopy was initially performed with SFV, followed by a second inspection of the whole colon in RFV. In the SFV arm first withdrawal was performed with SFV, followed by a second inspection of the whole colon again with SFV. Number, size and morphology of polyps found during first and second inspection in each colonic segment were recorded and all polyps were removed and sent for histopathology in separate containers. Results Two hundred and five patients were randomly assigned to the RFV (n = 101) and SFV (n = 104) arm. In the RFV arm, both polyp detection rate (PDR) and ADR were increased under second inspection in RFV (PDR 1st SFV: 39.8%, PDR 2nd RFV: 46.6%; ADR 1st SFV: 35.2%, ADR 2nd RFV: 42%). Likewise, in the SFV arm, PDR and ADR were increased under second inspection (PDR 1st SFV: 37.5%, PDR 2nd SFV: 46.6%; ADR 1st SFV: 34.1%, ADR 2nd SFV: 44.3%) with no significant differences in ADR and PDR between the SFV and RFV arm. Mean number of adenomas per patient (APP) was increased in the RFV and SFV (APP RFV arm: 1st SFV: 1.71; 2nd RFV: 2.38; APP SFV arm: 1st SFV: 1.83, 2nd SFV:2.2). The majority of adenomas additionally found during second inspection in RFV or in SFV were located in the transverse and left-sided colon and were > 5 mm in size. Conclusion Second inspection of the whole colon leads to increased adenoma detection with no differences between SFV and RFV. Hence, increased detection is most likely a feature of the second inspection itself but not of the inspection mode.

Background: The advancement of innovative endoscopic technology in terms of improving the visualization of the mucosa has been of significant benefit. Summary: Advancements in image resolution, software processing, and optical filter technology have resulted in several techniques complemental to traditional white light endoscopy. These new techniques provide a real-time optical diagnosis as well as virtual histology of detected lesions. Optical molecular imaging permits a functional assessment within cells. Key Message: Optical molecular imaging provides an understanding of cellular processes and permits validation of the specificity of fluorescent tracers and the possibility of quantifying the signal.

Background: Endoscopic imaging is a rapidly evolving field with a constant influx of new concepts and technologies. Since the introduction of video endoscopy and subsequently high-definition imaging as the first revolutions in gastrointestinal endoscopy, several technologies of virtual chromoendoscopy have been developed and brought to the market in the past decade, which have shaped and revolutionized for a second time our approach to endoscopic imaging. In parallel to these developments, microscopic imaging technologies, such as endomicroscopy and endocytoscopy, allow us to examine single cells within the mucosa in real time, thereby enabling histological diagnoses during ongoing endoscopy. Summary: In this review, we provide an overview on the technical background of different technologies of advanced endoscopic imaging, and then review and discuss their role and applications for the diagnosis and management of colorectal neoplasms as well as limitations and challenges that exist despite all technological improvements. Key Messages: Technologies of advanced endoscopic imaging have profound impact not only on our imaging capabilities, they are also about to fundamentally change our approach to managing lesions in the gastrointestinal tract: not every lesion found during colonoscopy has to be excised or sent for histopathologic evaluation. However, before this becomes widespread reality, major obstacles such as patient acceptance, adoption by less trained endoscopists, and also legal aspects need to carefully addressed. The development of computer-aided diagnosis and artificial intelligence algorithms hold the potential to overcome the obstacles associated with the concept of optical biopsy and will most likely fundamentally facilitate, shape, and change decision making in the management of colorectal lesions.

Purpose Patients with inflammatory bowel disease (IBD) have an increased risk for colorectal cancer (CRC). In IBD patients, cancer is often diagnosed in advanced stages and conflicting data on survival compared to sporadic CRC have been reported. The aim of this study was to directly compare clinical characteristics and prognosis of patients with IBD-CRC and sporadic CRC. Methods The clinical and pathological data of 63 patients with IBD-CRC and 3710 patients with sporadic CRC treated at the University Hospital of Erlangen between 1995 and 2015 were compared. Forty-seven M0 patients with IBD were matched with sporadic CRC patients after curative resection (R0) according to tumor localization, stage, sex, and year of treatment. Overall and disease-free survival were compared. Results Sixty-three patients presented IBD-CRC. Fifty were affected with ulcerative colitis (UC) and 13 with Crohn’s disease (CD). CRC was diagnosed within 1.45 years since last endoscopic surveillance. Twelve patients (19%) had a diagnosis of primary sclerosing cholangitis. In matched analysis, IBD patients were diagnosed with CRC at younger age compared to sporadic CRC and were more likely to have right-sided CRC (40% versus 23.3%) and rare histological subtypes (19% versus 9.2%). No differences in 5-year overall (78.7 versus 80.9 months) and 5-year disease-free survival (74.5 versus 70.2 months) were noted. Conclusion IBD-CRC patients were younger and more frequently had right-sided carcinomas compared to sporadic CRC. CRC in IBD patients did not show survival difference compared to matched-pair sporadic CRC patients without distant metastases after curative resection. Surveillance might be important for early detection of CRC in IBD patients.

Endoscopic and histologic remission have emerged as key therapeutic goals in the management of inflammatory bowel diseases (IBD) that are associated with favorable long-term disease outcomes. Here, we prospectively compared the predictive value of barrier healing with endoscopic and histologic remission for predicting long-term disease behavior in a large cohort of patients with IBD in clinical remission.At baseline, patients with IBD in clinical remission underwent ileocolonoscopy with assessment of intestinal barrier function by confocal endomicroscopy. Endoscopic and histologic disease activity, as well as barrier healing, was prospectively assessed along established scores. During subsequent follow-up, patients were closely monitored for clinical disease activity and the occurrence of major adverse outcomes (MAOs): disease flares, IBD-related hospitalization or surgery, and initiation or dose escalation of systemic steroids, immunosuppressants, small molecules, or biological therapy.The final analysis included 181 patients, 100 with Crohn's disease [CD] and 81 with ulcerative colitis (UC). During a mean follow-up of 35 (CD) and 25 (UC) months, 73% of patients with CD and 69% of patients with UC experienced at least 1 MAO. The probability of MAO-free survival was significantly higher in patients with IBD with endoscopic remission compared with endoscopically active disease. In addition, histologic remission predicted MAO-free survival in patients with UC but not CD. Barrier healing on endomicroscopy was superior to endoscopic and histologic remission for predicting MAO-free survival in both UC and CD.Barrier healing is associated with decreased risk of disease progression in patients with clinically remittent IBD, with superior predictive performance compared with endoscopic and histologic remission. Analysis of barrier function might be considered as a future treatment target in clinical trials.gov number, NCT05157750.

International audience; Background & Aims: The molecular checkpoints driving T cell activation and cytokine responses in ulcerative colitis are incompletely understood. Here, we studied the Tec kinase ITK in ulcerative colitis and explored the link between Cyclosporine A (CsA) function and ITK activation. Methods: We analyzed patients with inflammatory bowel disease (n=202) and evaluated ITK expression and activity as well as the functional effects of CsA. Moreover, three independent murine colitis models were used to investigate the functional role of ITK. Finally, the activity of ITK was blocked via pharmacological inhibitors and genetically engineered mice. Readout parameters were mini-endoscopy, histopathology, mucosal T cell apoptosis and cytokine production. Results: We found an expansion of ITK expressing mucosal CD4+ T cells in ulcerative colitis rather than Crohn ́s disease that correlated with disease severity. CsA suppressed activation of ITK in cultured CD4+ T cells and calcineurin-containing microclusters adjacent to the T cell receptor signaling complex. Functionally, the capacity of CsA to suppress activity of experimental colitis was critically dependent on ITK. Moreover, genetic inactivation of Itk via gene targeting or induction of allele-sensitive Itk mutants suppressed experimental colitis in three colitis models, while pharmacological ITK blockers could be used for treatment of established colitis and triggered resolution of inflammation. Hereby, ITK controlled apoptosis and activation of mucosal Th2 and Th17 lymphocytes via NFATc2 signaling pathways. Conclusion: ITK activation was detected in ulcerative colitis and could be downregulated in cultured T cells by CsA administration. Selective targeting of ITK emerges as an attractive approach for treatment of chronic intestinal inflammation and potentially ulcerative colitis by driving resolution of mucosal inflammation

Background and Aims The topically applied Toll-like receptor 9 [TLR9] agonist cobitolimod is a first-in-class DNA-based oligonucleotide with demonstrated therapeutic efficacy in clinical trials with ulcerative colitis [UC] patients. We here characterized its anti-inflammatory mechanism in UC. Methods Luminal cobitolimod administration was evaluated in an experimental dextran sodium sulfate [DSS]-induced colitis model. Cultured blood and mucosal cells from UC patients were treated with cobitolimod and analysed via microarray, quantitative real-time PCR, ELISA and flow cytometry. Intestinal slides of cobitolimod-treated UC patients were analysed by immunohistochemistry. Results Cobitolimod administration markedly suppressed experimental colitis activity, and microarray analyses demonstrated mucosal IL10 upregulation and suppression of IL17 signalling pathways. Cobitolimod treatment was associated with significant induction of mucosal IL10+Tr1 and Treg cells and suppression of Th17 cells. TLR9 knockout mice indicated that cobitolimod requires TLR9 signalling for IL10 induction. In UC patients, mucosal TLR9 levels correlated with severity of inflammation. Cobitolimod inhibited IL17A and IL17F, but increased IL10 and FoxP3 expression in cultured intestinal UC T cells. Cobitolimod-mediated suppression of intestinal IL17+T cells was abrogated by IL10 blockade. Furthermore, cobitolimod led to heightened IL10 production by wound healing macrophages. Immunohistochemistry in intestinal biopsies of cobitolimod-treated UC patients indicated increased presence of IL10+mononuclear and regulatory T cells, as well as reduction of IL17+cells. Conclusion Activation of TLR9 via cobitolimod might represent a novel therapeutic approach in UC, as it suppresses Th17 cells and induces anti-inflammatory IL10+macrophages and regulatory T cells, thereby modifying the dysregulated intestinal cytokine balance. Podcast This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.

Background and study aims Apart from mucosal healing as an established treatment goal in inflammatory bowel diseases (IBD), recent evidence suggests that histologic healing may become another key prognostic parameter in IBD patients. We aimed to evaluate whether magnification endoscopy with optical chromoendoscopy can accurately assess histologic inflammation in IBD patients. Patients and methods In this prospective study, 82 patients with IBD (30 UC, 52 CD) were included. In all patients, magnification endoscopy in conjunction with optical chromoendoscopy was performed and rated on a novel magnification endoscopy score by three independent endoscopists. Targeted biopsies of the imaged areas were obtained and results were compared against two histological scores in UC (Robarts Histopathology Index, RHI; Nancy Histology Index, NHI) and one score in CD (modified Riley index, mRI). Moreover, interobserver agreement was calculated. Results Magnification endoscopy showed strong correlation with histopathologic scoring in both UC (RHI: r = 0.83, NHI: r = 0.78, P 0.7). Conclusion Magnification endoscopy in combination with optical chromoendoscopy shows strong correlation with histologic inflammation in patients with IBD. This approach has potential to reduce physical biopsies for monitoring of inflammatory activity in patients with IBD during colonoscopy.

Background Gastrointestinal (GI) bleeding is a common indication for endoscopy. For refractory cases, hemostatic powders (HP) represent "touch-free" agents. Aim To analyze short term (ST-within 72 h-) and long-term (LT-within 30 d-) success for achieving hemostasis with HP and to directly compare the two agents Hemospray (HS) and Endoclot (EC). Methods HP was applied in 154 consecutive patients (mean age 67 years) with GI bleeding. Patients were followed up for 1 mo (mean follow-up: 3.2 mo). Results Majority of applications were in upper GI tract (89%) with following bleeding sources: peptic ulcer disease (35%), esophageal varices (7%), tumor bleeding (11.7%), reflux esophagitis (8.7%), diffuse bleeding and erosions (15.3%). Overall ST success was achieved in 125 patients (81%) and LT success in 81 patients (67%). Re-bleeding occurred in 27% of all patients. In 72 patients (47%), HP was applied as a salvage hemostatic therapy, here ST and LT success were 81% and 64%, with re-bleeding in 32%. As a primary hemostatic therapy, ST and LT success were 82% and 69%, with re-bleeding occurring in 22%. HS was more frequently applied for upper GI bleeding (P = 0.04). Conclusion Both HP allow for effective hemostasis with no differences in ST, LT success and re-bleeding.

Chronic idiopathic inflammatory bowel disease (IBD) cases are on the rise, with approximately 6.8 million people diagnosed in 2017 [1]. Diagnosing the two main forms of IBD, ulcerative colitis (UC) and Crohn’s disease (CD), involves a combination of clinical history, laboratory findings, imaging, endoscopy and histology [2]. The histopathological diagnosis of IBD is based on a combination of microscopic findings, with consideration of clinical data that include the patient’s age, symptoms, duration of symptoms and endoscopic results [3–17]. CD is a chronic, progressively destructive disease with an intermittent course in most cases. UC is most often described as relapsing and remitting, with symptoms of active disease that alternate with periods of clinical quiescence called remission [18, 19]. Until recently, therapeutic strategies in both diseases aimed to achieve adequate control of gastrointestinal inflammation. In recent years, however, mucosal healing has become the key treatment goal in IBD. It is associated with improved clinical outcomes, prolonged remission, fewer hospitalizations and decreased probability for surgery [20–36]. Patients with mucosal healing have lower rates of clinical relapse compared to those with evidence of active or quiescent disease. Endoscopic evaluation without histology, however, may be insufficient to deem treated IBD mucosa as completely healed [34, 36]. Furthermore, histologic identification of active disease has also been shown to better predict the development of neoplasia in patients with UC compared to endoscopic assessment of activity [30–32, 34, 37]. The fact that concordance between endoscopic and histological remission is moderate only—with histological remission being superior—underscores the necessity of incorporating histologic methods of activity scoring into clinical trials [34]. In fact, in 2016, the Food and Drug Administration (FDA) of the United States Department of Health and Human Services recommended that histologic assessment be used in conjunction with endoscopy [38]. A number of histologic indices for assessing activity in UC and CD exist. Nevertheless, they all have limitations, including lack of full validation, difficulty of usage and heterogeneity in their standards for distinguishing between quiescent disease and histologic normalization [39, 40]. Moreover, there is also a need for standardization of biopsy procedures in UC and CD on the endoscopic end. Recommendations for biopsy procedures and IBD scoring exist from many internationally recognized organizations, such as the European Crohn’s and Colitis Organisation (ECCO), the World Gastroenterology Organisation (WGO), the British Society of Gastroenterology (BSG), the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD), the American College of Gastroenterology (ACG) and the American Society for Gastrointestinal Endoscopy (ASGE). Some of them have recently been updated [17, 19, 28, 41–51]. However, in practice, these existing recommendations are not widely adhered to and there is still a need for standardizing the number of IBD biopsies, the locations they are taken from and an accepted validated IBD histologic assessment tool for daily practice. For these reasons, the objectives of the 2020 International Consensus Conference on IBD Activity Scoring were (i) to review existing recommendations and to agree upon ten recommendations with the highest impact to maximize diagnostic information from biopsies for UC and CD and (ii) to agree on a simple, histologic scoring system for both types of IBD that is able to distinguish between quiescent disease and mucosal healing and has potential for use in daily routine practice as well as for clinical trials.

BACKGROUND & AIMS: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. METHODS: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. RESULTS: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission. CONCLUSION: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC. ispartof: GASTROENTEROLOGY vol:160 issue:5 pages:1558-+ ispartof: location:United States status: published