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Despite recent drug approvals for the treatment of inflammatory bowel diseases (IBDs), there remains a high unmet need for new technologies that can increase drug efficacy by improving site-specific drug delivery while reducing systemic exposure. These technologies must address challenges with formulation; in particular, drugs that are liquid, peptides, or proteins are difficult to formulate using existing delayed and extended oral release technologies. They also have the potential to improve efficacy and reduce systemic exposure for certain drugs by delivering higher doses directly to the site of inflammation. A novel drug delivery system is being developed for delivery at a prespecified part of the gastrointestinal (GI) tract. This autonomous mechanical capsule uses an algorithm based on reflected light to deliver soluble formulations of drugs to the predefined location. This system has significant advantages over other traditional delayed release oral formulations because it functions independently of human physiological variables such as pH and transit time and can deliver liquid formulations, peptides, and proteins. Such a system can ensure a predictable high luminal drug exposure and limited degradation or systemic absorption in the upper GI tract and would therefore be ideal for treatment of disorders such as IBD and colon cancer.

Background The increase in therapeutic choices in inflammatory bowel diseases (IBD) imposed the identification of personalized therapeutic strategy. Confocal laser endomicroscopy (CLE) is a new endoscopic tool developed to obtain virtual in vivo histology. This study aimed to identify CLE in vivo and ex vivo features predictive of response for patients starting biologics. Methods We performed a prospective observational study at a single tertiary referral centre. 29 IBD patients (14 ulcerative colitis-UC and 15 Crohn’s Disease-CD) underwent colonoscopy with CLE before and 12-14 weeks after starting anti -TNF or 16 weeks after anti α4β7 integrin. CLE parameters analyzed were: crypt distribution along the mucosal surface, crypt area (CA), eccentricity, diameter, inter-cryptic distance (ICD), vessel tortuosity (VT), fluorescein leakage through the colonic mucosa (FLCM). Ex-vivo binding activity of fluorescein labelled biologics on corresponding biopsies was also assessed. Mosaicism reconstruction of CLE images were analyzed using a dedicated software algorithm (CellvizioViewer, Mauna Kea Technologies, ParisFrance). A dedicated Graphical User Interface was designed to enable a semiautomated analysis. Results After treatment, VT resulted significantly changed in overall IBD population (p Conclusion FLCM and ICD were the best discriminants of response in UC, while VT, CA and ICD in CD. A higher mucosal binding to a biological agent before treatment was observed in responders UC patients but not in CD patients.

Background Conventional colonoscopy is gold standard for the diagnosis and monitoring of patients with suspected or known inflammatory bowel disease (IBD). Nevertheless, it is a potentially painful procedure with risk of complications, including bleeding and perforation. Colon capsule endoscopy (CCE) is a minimally invasive alternative for patients unwilling to undergo colonoscopy or when it is contraindicated or unfeasible. However, CCE produces thousands of frames and their revision is a time-consuming and monotonous task. The detection of ulcers and erosions is paramount for the diagnosis and assessment of the activity of IBD. However, these lesions may appear in a very small number of frames, thus increasing the risk of overlooking significant lesions. Our aim was to develop an Artificial Intelligence (AI) algorithm, based on a multilayer Convolutional Neural Network (CNN) for automatic detection of ulcers and erosions in CCE exams. Methods A total of 24 CCE exams (PillCam COLON 2®) performed at a single centre between 2010–2020 were analysed. From these exams, 3 635 frames of the colonic mucosa were extracted, 770 containing colonic ulcers or erosions and 2 865 showing normal colonic mucosa. These images were used for construction of training (80% of the frames) and validation (20% of the frames) datasets. For automatic identification of these lesions, these images were inputted in a CNN model with transfer learning. The output provided by the CNN (Figure 1) was compared to the classification provided by a consensus of specialists. Performance marks included sensitivity, specificity, positive and negative predictive values, accuracy and area under the receiving operator characteristics curve (AUROC). Results After the optimization of the neural architecture of the CNN, our model automatically detected colonic ulcers and erosions with a sensitivity of 90.3%, specificity of 98.8% and an accuracy of 97.0% (Figure 2). The AUROC was 0.99 (Figure 3). The mean processing time for the validation dataset was 11s (approximately 66 frames/s). Conclusion We developed a CNN model which demonstrated high levels of efficiency for the automatic detection of ulcers and erosions in CCE images. Our study lays the foundations for the development of effective AI tools for application to CCE exams. These systems may enhance the diagnostic accuracy and reading efficiency of CCE, thus expanding the role of minimally-invasive colonic exploration in the management of IBD patients.

Background Intestinal Behçet’s disease (BD) and Crohn’s disease (CD) present similar manifestations, but there are no specific pathognomonic clinical, laboratory, or histological diagnostic tests to differentiate intestinal BD from CD. We used a proteomic approach to discover a novel diagnostic biomarker specific to intestinal BD. Methods The colon mucosa tissue samples were obtained using colonoscopy-guided biopsy of the affected bowel from patients with intestinal BD or CD at the Inflammatory Bowel Disease Clinic of Severance Hospital, Seoul, Korea. Peptides from seven intestinal BD and seven CD patients were extracted and labeled using tandem mass tag (TMT) reagents. The labeled peptides were identified and quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The differentially expressed proteins were further validated using immunohistochemical (IHC) analysis with tissue samples and an ELISA test with serum samples from 20 intestinal BD and 20 CD patients. Results A total of 3,266 proteins were identified using TMT/LC-MS/MS-based proteomic quantification, including 39 candidate proteins differentially expressed between intestinal BD and CD. Beta-2 glycoprotein 1 (APOH) and maltase-glucoamylase (MGAM) showed significantly higher intensity in the IHC staining of the intestinal BD tissues than that of CD tissues. Furthermore, the serum MGAM level was significantly higher in patients with intestinal BD than in patients with CD. Conclusion Our proteomic analysis revealed that some proteins were differentially expressed in intestinal BD patients compared to CD patients. Differential MGAM expression in intestinal BD suggests its role as a potential novel diagnostic biomarker in the differentiation of intestinal BD from CD.

Introduction/Objective Mastocytosis is a rare disease in which there are abnormal mast cell accumulation in one or more tissue sites. Multifocal dense mast cell aggregates with atypical morphology or immunohistochemistry are considered as systemic mastocytosis (SM) based on WHO criteria. SM usually involves bone marrow and majority of them also have KIT mutation. There are rare case reports of atypical enterocolic mast cell aggregates (EMCA) confined to gastrointestinal (GI) only with mild or no symptoms. Here we present a case with extensive atypical mast cell aggregates in lower GI tract yet no evidence of involvement of other organs. Methods/Case Report A 34-year-old woman presented with abdominal bloating, diarrhea along with pruritis but no cutaneous lesion. Biopsies from the ascending and descending colons, caecum and rectum consistently showed increased eosinophils and multifocal infiltrates of atypical spindle shaped mast cells which are positive for CD117/tryptase but negative for CD2 and CD25. This is consistent with SM by WHO criteria based on morphology. Bone marrow biopsy showed normal amount of mast cells with normal morphology. Upper gastrointestinal biopsy was unremarkable. Serum tryptase level was normal. No KIT mutation was detected in exon 9, 11, 13 or 17 from colonic mucosa. Patient has been treated with antihistamine and Montelukast and symptoms resolved. Results (if a Case Study enter NA) N/A Conclusion This case met the criteria of SM based on the presence of multifocal mast cell aggregates and atypical spindle morphology >25%. Johncilla et al. previously reported 16 cases of EMCA with atypical morphology or immunohistochemistry, absent to mild localized symptoms, and negative KIT mutation. Based on lack of generalized disease, the authors preferred using descriptive terminology instead of ‘systemic mastocytosis’ for those cases. Our case has broader involvement of lower gastrointestinal tract than any reported case and the patient needs treatment for the symptoms. However, there is no ‘systemic’ involvement of bone marrow or any other organ. The diagnosis of ‘Systemic Mastocytosis’ would cause potential confusion and/or unnecessary anxiety. Further study of more cases is needed to better characterize and categorize the cases of atypical mast cell aggregates localized only to the GI.

Ulcerative colitis (UC) pathogenesis includes the altered gut microbiota, environmental factors, and human immune and genetic predisposition. Recently, its association with reduced bifidobacteria quantity in the microbiota is reported.Xyloglucan, a plant based prebiotic oligosaccharide, causes increase in bifidobacteria quantity. In this article we share the results of our UC cases treated by intracolonic single dose administration of Bifidobacterium animalis subsp. Lactis and xyloglucan combination. Intracolonic single dose administration of 200 billion CFUs of Bifidobacterium animalis subsp. lactis and 4 gr of xyloglucan combination was administrated to ten severe UC patients, who were either unresponsive or had inadequate response to treatment. All patients continued treatment after the procedure. Treatment responses were evaluated by colonoscopic, laboratory and clinical examination after 6 weeks. Intracolonic single dose administration of Bifidobacterium animalis subsp. lactis and xyloglucan was found effective in the mucosal healing and resolution of colonic symptoms in ulcerative colitis patients. Intracolonic administration of Bifidobacterium animalis subsp. lactis and xyloglucan in UC is a new single strain and strain specific prebiotic combination method. It is easy to apply and has no observable side effect. Its effectiveness on mucosal healing could be attributed to the enhancement of non-stimulatory status and biodiversity in colonic mucosa. Nonetheless, it is still necessary to develop diagnostic strategies to determine the patients to whom this method would be the most applicable.

Background The mechanisms of ulcerative colitis (UC) progression require detailed study. Modern achievements of proteomic methods of analysis are ideal for research that is free from hypotheses and allows us to define molecular characteristics of inflammation in colon mucosa of UC patients. Methods The study was comparative cohort with parallel design and included 88 patients (range from 22 to 35 years, 37 men and 51 women): 53 (60.2%) pancolitis and 35 (39.8%) left-sided UC, mild and moderate activity. The control group included 30 healthy individuals. Biosamples of colon mucosa in patients with UC in the active stage and in healthy persons were received by ileocolonoscopy with colon mucosa biopsy. The separation of individual proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA). Automated mass spectrometry imaging was performed by MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database. Results We identified following functional groups of peptides and proteins in molecular patterns of colon mucosa in UC patients: SMAD family member 2 (SMAD2) activates the transcription of TFG1β, that leads to specific regulation of the CCN2 gene in cells and the development of fibrosis in colon submucosa in UC patients; the stimulation of the expression of apoС-III in affected colon mucosa in UC is associated with the activation of the FOXO1 signaling pathway that supports inflammatory processes in colon mucosa; the second small heat shock protein (HSP2) controls the apoptosis of colonocytes, is also responsible for the mucosa resistance to therapeutic strategies; caspase 8 protects colonocytes from TNFα-induced cell death through a necroptosis mechanism via the blockade of the RIP3 expression; the expression of prohibitin maintains optimal activity of the electronic transport chain through the activity of transcription factor STAT3 and the decrease in the TNFα expression; significant decrease of the PPARγ expression promotes the activation of STAT and AP-1 signaling pathways, which promotes the activity of immune and inflamation processes in colon mucosa and a significant increase in the NF-kB expression in colon mucosa is associated with the activation of TNFα and IL-1, which promotes the increase of immune processes in colon mucosa. Conclusion Bioinformatics analysis revealed the presence of molecules that are the participants in the universal pathways of UC in the active stage, and the molecular interactions involved. This information may provide new avenues for the development of novel diagnostic tests for UC.

Background Oral mesalazine is the mainstay treatment of ulcerative colitis (UC). Mesalazine exerts its anti-inflammatory effect locally in the colonic mucosa. The mucosal mesalazine concentration is inversely correlated with the degree of inflammation and previous studies have found that mucosal drug concentrations differ between various oral mesalazine preparations. In the current study we have examined the drug persistence of oral mesalazine preparations in a national cohort of UC patients. Methods Patients with newly diagnosed UC from 2010 to 2014 using oral mesalazine as anti-inflammatory monotherapy 3 months after the time of diagnosis were identified by combining data from the Norwegian Patient Registry and the Norwegian Prescription Database. The patients were retrospectively followed through 2017, median follow-up time was 1029 days. Treatment failure was defined as start of topical mesalazine or glucocorticoid preparations, systemic glucocorticoids, immunomodulators and biologic treatment or a change to another oral mesalazine preparation. Drug persistence was defined as duration of oral mesalazine preparation in monotherapy. Disease was categorised as more severe in patients who had dispensed systemic glucocorticoids the first three months after diagnosis. Drug persistence at national and regional level was stratified by mesalazine preparation (Mezavant (MEZ), Asacol (ASA), Pentasa (PEN), Salofalk (SAL)) and disease severity. Consumption was estimated based on defined daily doses (DDD = 1.5 g) of mesalazine dispensed from pharmacies. Results A total of 3421 patients were identified. Overall median mesalazine drug persistence was 311 days. The persistence differed between the preparations in descending order: MEZ (398 days), SAL (374 days), PEN (273 days), ASA (266 days), and the order was similar in the four regions. Patients with more severe disease at diagnosis had shorter drug persistence (193 vs. 407 days). Systemic glucocorticoids were given to similar proportion of patients for ASA (0.60) and PEN (0.61), while this proportion of MEZ users was lower (0.52) and even lower for SAL users (0.43). The number of prescribed DDD the first year after diagnosis was slightly higher in MEZ users (MEZ 1.75, ASA 1.36, PEN 1.42, SAL 1.40). Conclusion There were significant differences in drug persistence between oral preparations that were not explained by differences in prescription at regional level, but could partially be related to differences in disease severity. These differences could have clinical implications and bear further investigations.

Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/−) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC., The genome-wide expression profiling indicates that cancer preceding changes can be detected already in histologically normal mucosa and that decreased expression of specific chromosomal segregation genes are the most initiative cancer preceding markers in colon mucosa.

Background Endoscopic mucosal healing is considered as an important therapeutic goal in ulcerative colitis (UC) patients, and several endoscopic evaluations for colonic mucosa such as Mayo endoscopic subscore (MES) and Colitis Endoscopic Index of Severity (UCEIS) are used in clinical practice. Though the strict mucosal healing is defined as MES 0, the relapse of UC has been shown in the patients diagnosed as MES 0. In the present study, we aimed to investigate the efficacy of Linked Color Imaging (LCI), a novel endoscopic enhancement system, to predict long-term prognosis in UC patients diagnosed with MES 0. Methods Twenty-six patients with UC in clinical remission and diagnosed with MES 0 were enrolled. Endoscopic colonic images were assessed by LCI and UCEIS, using a LASEREO endoscopic system (FUJIFILM Co., Tokyo, Japan). Endoscopic LCI images were classified into three subgroups by LCI classification as previously reported. Briefly, LCI patterns were classified as A, no redness; B, redness with visible vessels; and C, redness without visible vessels. Forty months was defined as the time interval between endoscopic diagnosis and relapse of UC. Histological activity was scored according to the Geboes’ score (GS) and the active mucosa was defined by GS>2B.1. Results LCI classification can further subdivide the colonic mucosa diagnosed as MES 0. The patients with LCI-A showed no relapse and the non-relapse rates compared with the patients with LCI-B showed significantly higher (p = 0.033), while the relapse rates of the patients with UCEIS 0 showed no difference compared with UCEIS 1 (p = 0.148). There was no statistical difference in the composition of LCI-A and relapse rate between active and inactive mucosa diagnosed by GS score. Conclusion Endoscopic LCI classification can further subdivide samples diagnosed MES 0. LCI can be a novel and surpassing approach to evaluate mucosal healing and predict the outcome in UC patients.

Several different groups have recently reported the presence of pathogenic E. coli associated with ileal and/or colonic mucosa of patients with inflammatory bowel diseases. Given the important role of the gut microflora and enteropathogens in the initiation and perpetuation of intestinal inflammation, important issues now arise. Are these IBD associated E. coli pathogenic? Have they evolved from commensal bacteria? What is their reservoir? Are these bacteria sufficient to drive IBD pathogenesis? Which immunological defects may predispose to colonization by such bacteria? In June 2007, clinicians and basic scientists met in Lille, France with the goal of exchanging ideas and materials on this emerging topic. State-of-the-art lectures given by widely recognized international experts were associated with debates, case discussions and expert opinions. This paper summarizes most data that were exchanged during this day and represents an update on the potential role of pathogenic E. coli in inflammatory bowel diseases.

P248 Endoscopic evaluation of colonic mucosa in ulcerative colitis patients in clinical remission O. Shchukina1 *, E. Kondrashina2, O. Orlov3, A. Vladimirova4, A. Botina5, E. Markova6, A. Kharitidis7. 1North-West State Medical University, Chair of Gastroenterology and Dietology, Saint-Petersburg, Russian Federation, 2North-West State University, Chair of Gastroenterology and Dietology, SaintPetersburg, Russian Federation, 3City clinical hospital #3, Saint-Petersburg, Russian Federation, 4Irkutsk Diagnostic Center, Irkutsk, Russian Federation, 5Saint-Petersburg state medical university named after I.P. Pavlov, Saint-Petersburg, Russian Federation, 6City clinical hospital #31, SaintPetersburg, Russian Federation, 7City Clinical Hospital #31, City Centre of IBD, Saint-Petersburg, Russian Federation

Conclusions: IFX acts locally at mucosa level, as shown by the decrease in inflammatory infiltrate and cytokines contents. The effect of IFX is partially dependent on direct effect on epithelial cells. IFX seems to ameliorate epithelial cell healing by blocking the detrimental capacity of TNF-a pre-treated fibroblast on intestinal epithelial cells. More data are necessary to unravel molecular pathways of these observations, in order also to clarify mechanisms of loss of responses to it as well as new targets for potential new therapies.

Typhlitis caused by Balantidium coli and requiring surgical resection occurred in three captive lowland gorillas over a 30-month period. Not one of the other gorillas in the colony or their keepers was ill. B. coli is distributed widely geographically and widely among mammals. Asymptomatic commensalism predominates, but invasion of the colonic mucosa can produce diarrhea and dysentery and set the stage for local or systemic spread.

The en face histopathologic technic for examining colonic mucosa in the plane of the luminal surface is described and analyzed. Grossly normal colonic mucosa from 56 resection specimens was embedded en face and sectioned. The en face histopathologic slides showed sheets of mucosa with the crypts in cross section surrounded by lamina propria, an orientation to mucosal topography analogous to gross examination. A total of 1,931 cm2 of mucosa was embedded en face in 640 paraffin blocks, a mean of 3.0 +/- 0.8 (SD) cm2 per block. With routine processing of the same surface area, approximately 2,365 blocks (nearly four times as many as for the en face technic) would have been required. A total of 1,217 cm2 of mucosa appeared in the slides from the en face blocks, comprising 63 +/- 23% of the submitted tissue, compared with 0.3% in routine sections. Our analysis demonstrated that the en face technic is a useful tool in histopathologic studies of large areas of grossly normal colonic mucosa, particularly for quantitation and mapping of the findings.

1. 1. In the vast majority of cases of abdominal actinomycosis, the infection is secondary to perforative gastrointestinal disease. 2. 2. A case is presented of primary actinomycosis of the transverse mesocolon without evidence of pre-existing colonic disease or a break in continuity of the underlying colonic mucous membrane. 3. 3. A review of the literature reveals that this case represents the second reported instance of primary involvement of the transverse mesocolon. 4. 4. Although the usual treatment of abdominal actinomycosis combines operation and massive penicillin therapy, because of the localized nature of the fungal disease in the present case, only resectional therapy was employed.