Extent Of Colitis Research Articles

Ulcerative colitis complicated with hypermucinous dysplasia.

Patients with ulcerative colitis are at increased risk for colorectal neoplasia compared to the general population. The risk factors include family history of colorectal cancer, wide extent of colitis, disease duration, cumulative inflammatory burden, and primary sclerosing cholangitis. Here, we report a case of colorectal neoplasia developed in a patient with ulcerative colitis.

A181 HIGHER CUMULATIVE HISTOLOGIC INFLAMMATORY BURDEN SCORE IS ASSOCIATED WITH THE RISK OF DEVELOPMENT OF COLORECTAL NEOPLASIA IN ULCERATIVE COLITIS

Abstract Background Ulcerative colitis (UC) patients have an elevated risk of colorectal neoplasia (CRN). Younger age at diagnosis, extent of colitis, and longer duration of colitis, as well as increased severity, which is a component of the cumulative inflammatory burden score (CIB), have been associated with the development of CRN. CIB was developed based on a large cohort of UC patients from St. Mark’s Hospital (UK) but needs further validation in independent cohorts. Purpose We analyzed the association between higher histologic CIB and development of CRN in longstanding UC patients. Method A matched case-control cohort of UC patients with at least 8 years of disease duration was analyzed at Mount Sinai Hospital. Patients with primary sclerosing cholangitis were excluded. Cases consisted of UC patients with colitis-associated neoplasia defined as indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or colorectal cancer (CRC). Each case was matched to two controls by age at disease onset, disease duration, and histological extent of colitis. Histologic reports obtained by colonoscopy were reviewed and histological activity was assessed as quiescent/normal (0), mild (1), moderate (2), and severe (3). The colonic area with the higher score was utilized and the CIB was calculated by summing each score and multiplying it by the interval of surveillance. A mean CIB (mCIB) was also calculated for each patient dividing the CIB by the number of colonoscopies. Continuous variables including CIB scores and mCIB scores were summarized as median and interquartile range (IQR) and differences between groups were compared by Mann-Whitney test. Result(s) Fifty-four UC patients were analyzed with 18 having CRN (6 CRC, 2 HGD, 3 LGD and 7 IND) and 36 controls without CRN. The clinical characteristics of the total cohort, cases and controls are depicted in the Table. Median age at last colonoscopy assessed was 45 years (36-55) and 40.7% were female. The median age at onset of UC was 23 years (19-37) and median duration of UC was 16 years (11-23). All patients had extensive histologic colonic disease. There were no differences between cases and controls in interval of surveillance evaluated (7.5 vs 7.8 years, p = 0.7) and median number of colonoscopies with histologic assessment (4 vs 4, p =0.6). Cases with CRN had significantly higher CIB (11.4 vs 7.9, p = 0.02) and mCIB (2.9 vs 2.0, p = 0.02) compared to controls. Image Conclusion(s) The histologic CIB score is associated with an increased risk of developing CRN in UC patients with similar age at onset of disease, disease duration and colitis extent. Given CIB reflects the severity of histologic inflammation over the years, treatment strategies to improve histologic inflammation could reduce the incidence of CRN in UC. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

Risk Factors for Colorectal Cancer in Patients with Inflammatory Bowel Disease and Management During Cancer Treatment: A Systematic Review

Introduction: Inflammatory bowel disease (IBD) is a group of conditions involving inflammation of the gastrointestinal tract. Patients with IBD are at an increased risk of developing colorectal cancer (CRC). Current evidence regarding risk factors for CRC in IBD patients and guidelines for IBD treatment upon cancer diagnosis is inconclusive. A systematic review was conducted to evaluate evidence on risk factors resulting in an increased incidence of CRC among IBD patients and modifications made to IBD management during cancer treatment. Methods: The PubMed database was searched from inception to 2019 with an English-language restriction, and two independent reviewers screened the articles for inclusion according to established criteria. Results: Eight studies (five literature reviews and three retrospective cohort studies) were included. Of the eight articles, six reported several risk factors for CRC in IBD patients such as duration of IBD, extent of IBD, co-existing primary sclerosing cholangitis, family history of CRC, age at IBD onset, vitamin D deficiency, and gender. The other two articles discussed IBD management during cancer treatment in the form of suspending immunosuppressive medications and administering those of an anti-inflammatory nature. Discussion: An individualized, case-by-case approach for IBD patients diagnosed with cancer was recommended. No standardized course of treatment was found. Conclusion: Despite the limitations of this review, numerous potential risk factors for CRC in IBD patients were identified. However, a lack of definitive evidence pertaining to modifications made to IBD management during cancer treatment suggests that additional research is needed to draw material conclusions.

Surveillance for Colorectal Neoplasia in Inflammatory Bowel Disease: When to Stop.

Patients with chronic ulcerative and Crohn's colitis are at increased risk for colorectal neoplasia(CRN [dysplasia and cancer]) compared to the general population. Risk factors for CRN include extent of colitis, cumulative inflammatory burden, family history of colorectal cancer, and primary sclerosing cholangitis. Best practices to prevent CRN include control of colonic inflammation, high quality surveillance colonoscopy with or without enhanced imaging techniques, resection of visible dysplasia if possible, and colectomy in patients with unresectable dysplasia, invisible multifocal low grade dysplasia, or invisible high grade dysplasia. Cessation of dysplasia surveillance is individualized and should involve shared decision making based on factors including but not limited to chronologic age, frailty, co-morbid conditions, life expectancy, results of prior surveillance exams, and risk factors for CRN.

Clinical significance and long-term prognosis of ulcerative colitis patients with appendiceal orifice inflammation

BackgroundAppendiceal orifice inflammation (AOI) or peri-appendiceal red patch is a skip lesion with segments of continuous colitis from the rectum. Frequently observed in ulcerative colitis (UC) patients, this lesion might be associated with proximal extension in some studies. However, the clinical significance of this lesion and long-term outcomes including therapy remain unclear. Thus, the aim of this study was to evaluate the clinical implication of AOI during long-term periods in patients with UC.MethodsWe retrospectively reviewed 376 patients with UC who performed complete colonoscopic examinations between April 2000 and December 2020. We compared clinical characteristics and outcomes of patients manifesting AOI with those who did not show AOI during a mean follow-up period of 66.1 months. Long-term outcomes included maximal extent of colitis, proximal extension, therapeutic medical histories, UC-related hospitalization, and relapse.ResultsNinety-eight (26.1%) patients showed AOI without evidence of inflammation in the right colon. Mild disease activity at the diagnosis of UC was more included in patients with AOI than in those without AOI. Other baseline characteristics including disease extent, smoking history, external intestinal manifestation, and terminal ileal ulceration were not significantly different between the two groups. During follow-up periods, patients with and without AOI showed no significant difference in proximal extension, Mayo endoscopic score at the last endoscopic examination, UC-related hospitalization, or relapse. Of medication history, patients with AOI were less included in the group treated with high-dose aminosalicylates than those without AOI. However, therapeutic histories of steroids, immunosuppressive agents, and biologics were not significantly different. Of 62 patients with AOI who underwent follow-up colonoscopy, 36 (58.1%) showed resolution of AOI. Clinical outcomes of the resolution group were not different than those of the non-resolution group. Biopsy results of 77 patients with AOI showed chronic active or erosive colitis.ConclusionsLong-term outcomes of UC patients with AOI were not different from those without AOI. Outcomes of resolution and non-resolution groups of AOI patients were not different either. Thus, AOI might have no prognostic implication in distal UC patients.

Primary sclerosing cholangitis-A long night's journey into day.

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Methylation of RUNX3 Promoter 2 in the Whole Blood of Children with Ulcerative Colitis.

Ulcerative colitis (UC) results from a complex interplay between the environment, gut microbiota, host genetics, and immunity. Runt-related transcription factor 3 (RUNX3) regulates Th1/Th2 balance and, thus, the synthesis of cytokines and inflammation. We aimed to analyze the dependence of RUNX3 promoter 2 (P2) methylation level on: age, sex, body mass index (BMI), C-reactive protein (CRP), serum albumin, disease duration, Pediatric Ulcerative Colitis Activity Index (PUCAI), the Paris classification, and exposure to medications. This multicenter, cross-sectional study recruited hospitalized children with UC. Methylation of RUNX3 P2 was measured with methylation-sensitive restriction enzymes in the whole blood DNA. Sixty-four children were enrolled, with a mean age of 14.5 ± 2.8 years. Half of them were female (51.6%), and the average BMI Z-score was −0.44 ± 1.14. The mean methylation of RUNX3 P2 was 54.1 ± 13.3%. The methylation level of RUNX3 P2 did not correlate with age, sex, nutritional status, CRP, albumin, PUCAI, or the extent of colitis (Paris E1–E4). RUNX3 P2 methylation did not differ between patients recruited within two and a half months of diagnosis and children who had UC for at least a year. Current or past exposure to biologics, immunosuppressants, or steroids was not associated with RUNX3 P2 methylation. Methylation of RUNX3 promoter 2 in whole blood DNA does not seem to be associated with the characteristics of UC in children.

Association of young age and male sex with primary sclerosing cholangitis in Taiwanese patients with inflammatory bowel disease.

Background/AimsPrimary sclerosing cholangitis (PSC) is associated with inflammatory bowel disease (IBD). We aimed to evaluate the prevalence, clinical manifestation, and outcomes of PSC in Taiwanese patients with IBD.MethodsThis retrospective study enrolled patients with IBD admitted from January 1, 1996, to December 31, 2018, to National Taiwan University Hospital. A case-matched analysis was performed comparing patients with IBD with and without PSC according to age, sex, and time of admission, with ratios of 1:4 and 1:2 in the adult and pediatric groups, respectively.ResultsIn total, 763 patients with IBD were enrolled, 12 of whom were also diagnosed with PSC (1.57%). All these patients had ulcerative colitis (UC). A greater incidence of IBD with PSC was observed in younger patients than in older patients. Male sex was a risk factor for PSC in pediatric patients with IBD (P=0.015); 75% of these patients were diagnosed with PSC along with or after the diagnosis of UC. There was no significant difference in colitis extent and severity between the groups; however, a higher proportion of rectal sparing was observed in patients with PSC (P=0.001). There was no significant difference in cancer development between the groups (P=0.679).ConclusionsA 1.57% prevalence of PSC was observed in Taiwanese patients with IBD. The majority of patients with IBD and PSC were men and were diagnosed at a younger age. Hence, routine evaluation of biliary enzymes and liver imaging is recommended in young male patients with IBD.

Comparison of the extent of pediatric inflammatory bowel disease based on endo-colonoscopy and histological findings

Introduction: Paris classification for the extent of inflammatory bowel disease (IBD) in children is based solely on macroscopic findings obtained via endo-colonoscopy. However, in some cases histologic findings may indicate more severe cases. Objectives: The aim of the present study was to compare the extent of pediatric IBD based on endo-colonoscopy and pathological findings. Patients and Methods: Data on 67 hospitalizations were collected from 51 children with IBD who had been admitted to the children’s medical center of Tehran. All patients underwent endoscopy or colonoscopy and had a histological report. Results: Comparison of the endoscopic and histological findings in ulcerative colitis showed that, in 37% of cases, gastric involvement was reported in histology, while these cases were reported normal in endoscopy. In colonoscopy, the transverse colon was more involved, as compared with the results of histology, while in other parts of the colon, the histological involvement showed more severe findings. Considering Paris classification, in 25% of cases, the extent of the disease was higher in colonoscopy, and in 16% of cases, it was higher in histology. Of all children with Crohn’s disease, gastric involvement in 20% of cases and esophageal and duodenal involvement in 13% of cases were more reported in histology than in endoscopy. In the ascending colon, descending colon, and rectosigmoid, histological involvement was more than that observed in colonoscopy. Considering Paris classification, in 5% of cases, the extent of the disease was higher in colonoscopy, and in 9% of cases, it was higher in histology. Conclusion: Concurrent use of histological findings and endoscopic findings may help to better determine the severity and extent of the disease and facilitate the process of treatment.

P109 Impact of ethnicity on colorectal cancer incidence in a cohort of colitis-associated dysplasia patients

Abstract Background Racial disparities in inflammatory bowel disease (IBD) phenotypic presentations and outcomes are recognised. However, there are conflicting data from Western population-based cohort studies as to whether racial differences in colitis-associated colorectal cancer (CRC) incidence exists. To our knowledge this is the first study to investigate the impact of ethnicity on the natural history of dysplasia in ulcerative colitis (UC). Methods We performed a retrospective multi-centre cohort study of adult patients with UC whose first low-grade dysplasia (LGD) diagnosis within the extent of colitis was made between 1 January 2001 and 30 December 2018. Only patients with at least one follow-up colonoscopy or colectomy by 30 August 2019 were included. The study end point was time to CRC or end of follow-up. Statistical differences between groups were evaluated using Mann-Whitney U tests and Chi-squared tests. Survival analyses were performed using Kaplan-Meier estimation and multivariate Cox proportional hazards models. Results 408 patients met the inclusion criteria (see Figure 1 for patient and clinical demographics). More patients from a Black or Asian (BAME) background progressed to CRC [13.4% vs. 6.4%; p=0.036] compared to their White Caucasian counterparts, despite having surveillance follow-up. Figure 2 displays Kaplan-Meier curves demonstrating the probability of remaining CRC-free after LGD diagnosis and categorised by ethnicity. BAME patients were more likely to have moderate-severe inflammatory activity on colonic biopsy within the 5 preceding years [42.0% vs. 28.9%; p=0.023], but no significant differences in medication use and a longer median time interval from LGD diagnosis to colectomy date [32 months vs. 11 months; p=0.021]. After adjusting for sex, age and UC duration at time of LGD diagnosis and presence of moderate-severe histological inflammation, being Black or Asian was a predictive factor for CRC progression on multivariate Cox proportional hazard analysis [HR 2.97 (95% CI 1.22 – 7.20); p = 0.016]. However, ethnicity was no longer predictive of CRC progression on sub-analysis of the 317 patients who did not have a colectomy during the follow-up period. Conclusion In this UK multi-centre cohort of UC surveillance patients diagnosed with LGD, delays in receiving cancer preventative colectomy may contribute to an increased CRC incidence in certain ethnic groups. Further work is required to elucidate whether these delays are related to institutional factors (e.g. inequity in the content of decision-making support given or access to healthcare) or cultural factors.

Clinicopathologic Characteristics and Neoplasia Risk of Colorectal Inflammatory Polyposis in Inflammatory Bowel Disease.

Inflammatory polyps (IPs) in inflammatory bowel disease may have been associated in the past with increased neoplasia risk. Additionally, colonic mucosa in filiform polyposis and giant inflammatory polyposis may be difficult to visualize during endoscopic surveillance, perhaps contributing to early colectomy in these patients. To examine the clinicopathologic characteristics and significance of IPs and inflammatory polyposis in inflammatory bowel disease. We identified 336 resections from inflammatory bowel disease patients (212 [63.1%] male; mean age, 40.3 years; 175 [52.1%] with ulcerative colitis), including 78 with rare/few (<10) IPs, 141 with multiple (≥10) IPs, and 117 with inflammatory polyposis (including 30 with filiform polyposis/giant inflammatory polyposis) and compared them with 100 controls without IPs along various parameters, including overall and occult (unexpected) dysplasia. There was no increased neoplasia in resections with IPs compared with controls, given similar age, disease duration, degree of inflammation, anatomical extent of colitis, prevalence of primary sclerosing cholangitis, and tissue sampling. Increasing numbers of IPs and inflammatory polyposis were significantly associated in multivariate analysis with ulcerative and indeterminate colitis (P = .003) and shorter disease duration (P = .01), but also, and independently, with lower rates of dysplasia overall, including all grades (P = .001) and advanced neoplasia (P = .04). There were no instances of occult dysplasia (any grade) among inflammatory polyposis cases. These findings support the conclusion that the presence of IPs per se, and inflammatory polyposis in particular (including filiform polyposis and giant inflammatory polyposis), should not be considered an independent risk factor for the development of neoplasia in inflammatory bowel disease patients, outside the context of disease duration and inflammatory burden.

5-aminosalicylate-intolerant patients are at increased risk of colectomy for ulcerative colitis.

Although 5-aminosalicylate (5-ASA) is the therapy of first choice in ulcerative colitis (UC), some patients cannot tolerate it because of side effects. Previous reports have not investigated whether 5-ASA intolerance is associated with the risk of colectomy. To investigate the associations between 5-ASA tolerance and colectomy among UC patients METHODS: The data of UC patients who visited any of three hospitals during 2014-2018 in and around Tokyo, Japan, were retrospectively obtained from the medical records. Patients were categorized as (a) tolerant to any 5-ASA compounds ("tolerant to 5-ASA") and (b) patients who were intolerant to one or more 5-ASA compounds leading to refrainment from their further use ("intolerant to 5-ASA"). The association between 5-ASA tolerance and colectomy was examined by Cox proportional hazards model adjusted for sex, age, smoking and extent of colitis. Of 1788 patients, 1684 were "tolerant to 5-ASA" while 104 were "intolerant to 5-ASA". Colectomy was performed in 43 (2.6%) of the patients tolerant to 5-ASA and 12 (11.5%) of the patients intolerant to 5-ASA. After adjusting for all covariates, the risk of undergoing colectomy was higher in the "intolerant to 5-ASA" group than in the "tolerant to 5-ASA" group (hazard ratio: 4.92; 95% confidence interval: 2.58-9.38). Patients in whom 5-ASA was discontinued due to intolerance had a higher risk of undergoing colectomy than patients tolerant to their first, second or third 5-ASA compounds.

Finger clubbing in inflammatory bowel disease: association with upper small bowel lesions and need of surgery in Crohn's disease.

Finger clubbing has been associated with inflammatory bowel disease (IBD). In a prospective single-center study, we aimed to assess the frequency of finger clubbing in a cohort of IBD patients. Whether finger clubbing is associated with clinical characteristics of IBD was also investigated. IBD patients with a detailed clinical history were enrolled. Finger clubbing was assessed by visual inspection. Data were expressed as median (range), chi-square, t-test. Multivariate logistic regression analysis was used to assess risk factors for finger clubbing, when considering demographic and clinical characteristics, smoking habits and chronic pulmonary diseases (CPD). Finger clubbing was searched in 470 IBD patients: 267 Crohn's disease and 203 ulcerative colitis. Finger clubbing was more frequent in Crohn's disease than in ulcerative colitis: 45/267 (16.8%) vs. 15/203 (7.3%) [odds ratio (OR), 2.54 (1.37-4.70); P = 0.003]. Crohn's disease involved the ileum (59.9%), colon (4.5%), ileum-colon (25.8%) and upper gastrointestinal (GI) (9.8%). Ulcerative colitis extent included proctitis (E1) (13.4%), left-sided (E2) (43.3%) and pancolitis (E3) (43.3%). Upper GI lesions, but not other Crohn's disease localizations, were more frequent in patients with finger clubbing [9/45 (20%) vs. 17/222 (7.7%); P = 0.032]. Crohn's disease-related surgery was more frequent in patients with finger clubbing [36/45 (80%) vs. 107/222 (48.1%); P < 0.001]. In Crohn's disease, the only risk factors for finger clubbing were upper GI lesions and Crohn's disease-related surgery [OR, 2.58 (1.03-6.46), P = 0.04; OR, 4.07 (1.86-8.91), P = 0.006]. Ulcerative colitis extent was not associated with finger clubbing [E1: OR, 0.27 (0.02-3.44), P = 0.33; E2: OR, 0.93 (0.24-3.60), P = 0.92; E3:OR, 0.64 (0.22-1.86), P = 0.59]. In ulcerative colitis, but not in Crohn's disease, finger clubbing was more frequent in smokers [13/15 (86.6%) vs. 99/188 (52.6%); P = 0.01] and in patients with CPD [5/15 (33.3%) vs. 16/188 (8.5%); P = 0.002]. Smoking and CPD were the only risk factors for finger clubbing in ulcerative colitis [OR, 7.18 (1.44-35.78), P = 0.01; OR, 10.93 (2.51-47.45), P = 0.001]. In the tested IBD population, finger clubbing was more frequent in Crohn's disease than in ulcerative colitis. In Crohn's disease, upper GI lesions and history of Crohn's disease-related surgery were risk factors for finger clubbing, suggesting the possible role of finger clubbing as a subclinical marker of Crohn's disease severity.

Abstract 585: Colitis in tumor-bearing mice undergoing checkpoint inhibitor therapy

Abstract Checkpoint inhibitor (CPI) therapy represents an exciting new treatment option for patients with advanced malignancies. However, several adverse events (AEs) that affect multiple body systems are associated with CPI treatment, including colitis. The mechanisms mediating these AEs remain to be fully elucidated. That mice treated with CPI fail to develop the spectrum of AEs observed in patients hampers the field's ability to develop supportive care treatment options. Here we sought to examine colitis in tumor bearing mice undergoing CPI therapy. Briefly, naïve TH cells and Treg cells were harvested from C57Bl/6 donor mice and were adoptively transferred into RAG2−/- recipients. Animals were inoculated with B16F10 cells into the left flank seven days later. T cell engraftment was assessed after 13 days, and animals were randomized into treatment groups by rate of T cell engraftment; animals were treated Q3D with either vehicle or anti-CTLA4 for an additional four weeks. Animals were monitored for body weight loss and systemic AEs (gastrointestinal, pulmonary, neurological) daily and tumor volume was measured by digital caliper three times per week. Extent of colitis was evaluated by video endoscopy at several timepoints and colitis severity was scored using a 0-4 scale. Animals developed body weight loss approximately two weeks after T cell transfer and CPI treatment increased the severity of body weight loss observed. Colitis was seen by video endoscopy within a similar timeframe. Mean tumor volume was decreased in animals treated with CPI as compared to those treated with vehicle. Diarrhea, pulmonary symptoms, and neurological symptoms were observed in a subset of animals over the study period; anti-CTLA4 treatment increased the overall incidence of pulmonary symptoms. These data demonstrate the utility of this system for assessment of colitis or other AE supportive care treatment options in the context of CPI-treated, tumor-bearing mice. Citation Format: Caitlin S. Parello, Benjamin G. Cuiffo, Kasey Reardon, Alexandria Fusco, Brett Van Dam, Gregory D. Lyng, Stephen T. Sonis. Colitis in tumor-bearing mice undergoing checkpoint inhibitor therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 585.

Characterising the role of Proline Tyrosine Kinase 2 during Adherent-invasive Escherichia coli infection of macrophages

Studies have implicated that Adherent-invasive Escherichia coli (AIEC) in the aetiology of Crohn’s Disease (CD), a chronic inflammatory bowel disease (IBD). CD-associated AIEC are characterised by an ability to adhere to and invade intestinal epithelial cells and replicate intracellularly in macrophages. This occurs as AIEC form vacuoles within phagolysosomes, preventing macrophage-mediated killing. However, little is known about the interaction of macrophage proteins with AIEC. In this study, we used an in vitro infection model to identify macrophage proteins associated with AIEC intracellular replication. We identified the importance of proline-rich tyrosine kinase 2 (PYK2) in AIEC infection. PYK2 is widely expressed in epithelial cells and hematopoietic cells and plays essential roles in tumorigenesis and tumour progression. PYK2 is also overexpressed in patients with intestinal and colorectal cancer (CRC). CRC is one of the major long-term complications of IBD, especially in patients with long disease duration, a large extent of colitis, and uncontrolled inflammation. Moreover, PYK2 has been identified as an IBD risk loci via large scale genome-wide association studies. Our in vitro models have demonstrated that the addition of PYK2 inhibitor PF-431396 during infection results in a significant decrease in intracellular replication of AIEC. This has been quantified using fluorescence immunostaining and imaging flow cytometry. These results suggest that PYK2 may play a role in intracellular bacteria survive and replication. Our future work aims to further understand the relationship between PYK2, AIEC and CD.

Saccharin Supplementation Inhibits Bacterial Growth and Reduces Experimental Colitis in Mice.

Non-caloric artificial sweeteners are frequently discussed as components of the “Western diet”, negatively modulating intestinal homeostasis. Since the artificial sweetener saccharin is known to depict bacteriostatic and microbiome-modulating properties, we hypothesized oral saccharin intake to influence intestinal inflammation and aimed at delineating its effect on acute and chronic colitis activity in mice. In vitro, different bacterial strains were grown in the presence or absence of saccharin. Mice were supplemented with saccharin before or after induction of acute or chronic colitis using dextran sodium sulfate (DSS) and the extent of colitis was assessed. Ex vivo, intestinal inflammation, fecal bacterial load and composition were studied by immunohistochemistry analyses, quantitative PCR, 16 S RNA PCR or next generation sequencing in samples collected from analyzed mice. In vitro, saccharin inhibited bacterial growth in a species-dependent manner. In vivo, oral saccharin intake reduced fecal bacterial load and altered microbiome composition, while the intestinal barrier was not obviously affected. Of note, DSS-induced colitis activity was significantly improved in mice after therapeutic or prophylactic treatment with saccharin. Together, this study demonstrates that oral saccharin intake decreases intestinal bacteria count and hence encompasses the capacity to reduce acute and chronic colitis activity in mice.

Combined IMIG and immune Ig attenuates inflammatory colitis in mice

BackgroundUsing a combination of homologous and heterologous (mouse/human) polyclonal anti-idiotypic Igs and immune Igs in BALB/c mice we have previously reported attenuation of allergic type responses following OVA immunization. We have now investigated attenuation of an inflammatory colitis in C57BL/6 mice receiving dextran sodium sulfate (DSS) in their drinking water, using additional treatment of DSS-exposed mice with combined human Igs, commercial IVIG (given IM, hence hereafter IMIG) as a source of pooled anti-idiotype Ig, and human anti-Tet as immune Ig. MethodsAcute or chronic colitis was induced by DSS in groups of C57BL/6 mice. Mice also received weekly immunotherapy with im injections of polyclonal immune Ig, polyclonal anti-idiotype Ig, or the combined Igs, for a total of 5 injections, beginning with DSS treatment or after 2 cycles of DSS. Weight loss and mortality were monitored daily, and the extent of colitis was determined further using colonic length measurement, and by ELISA measurement of inflammatory cytokines in supernatants from colonic explant cultures. ResultsMice developed colitis in both the acute and chronic models with loss of body weight, shortened colon lengths, and increased expression of inflammatory cytokines in colonic tissue. Loss of body weight, and inflammatory cytokine production, was attenuated only in chronic colitis, and only after combined IMIG and immune Ig treatment, and not in groups receiving only IMIG or immune Ig alone. ConclusionHeterologous combinations of polyclonal IMIG and immune Ig can attenuate inflammatory colitis in mice. Given the described efficacy of this treatment for allergic desensitization, we hypothesize this methodology may have widespread clinic utility.

Risk of colorectal cancer in a population-based study 20 years after diagnosis of ulcerative colitis: results from the IBSEN study

ObjectiveThe association between ulcerative colitis (UC) and colorectal cancer (CRC) is widely accepted, although attenuated risk has been reported in recent years. Colonoscopic surveillance is recommended with intervals based on...

A41 LOSS OF SATB2 EXPRESSION IN COLORECTAL CANCER IS ASSOCIATED WITH DURATION OF INFLAMMATORY BOWEL DISEASE

Abstract Background Patients with inflammatory bowel disease (IBD) are at higher risk for developing colitis-associated colorectal cancer (CAC). Clinical and endoscopic features are used to stratify the risk of CAC, but new biomarkers are necessary to improve this stratification. Recent studies have shown that loss of expression of special AT-rich sequence binding protein 2 (SATB2) is frequent in CAC compared to sporadic colorectal cancer and this SATB2 status is found in pre-cancerous dysplastic lesions as well. However, the relationship of known clinical risk factors for CAC and loss of SATB2 has not been explored. Aims To assess the association of loss of SATB2 expression in CAC with clinical characteristics of IBD. Methods Patients with a known diagnosis of ileocolonic or colonic Crohn’s disease (CD), ulcerative colitis (UC), or IBD unclassified (IBDU) who underwent colectomy between October 2010 and December 2017 for CAC were included. SATB2 expression in neoplastic tissue was evaluated using immunohistochemistry (IHC), where less than 5% of tumor cells showing staining was considered loss of SATB2. Tumor grade, P53 and mismatch repair (MMR) status were assessed as well. Available clinical data such as sex, smoking status, IBD diagnosis (CD, UC or IBDU), age at IBD diagnosis, duration of IBD, extent of colitis and previous medications were collected. We used a generalized linear model to assess the association between these biomarkers and clinical data. Results A total of 58 patients with mean age at CAC diagnosis of 50.3 ±13 years, 27 (46%) females were analyzed. Mean IBD duration was 17.6 ±10 years and 22 (37.9%), 34 (58.6%) and 2 (3.4%) were CD, UC and IBDU, respectively. Thirty-two (55.2%) CACs had loss of SATB2 expression. There was no association between age at CAC diagnosis or grade of the tumor and loss of SATB2. However, longer duration of IBD (21.2 ± 9 years vs 13.7 ± 9 years, p = 0.01) was significantly associated with loss of SATB2. There was no association between SATB2 status and other explored clinical or endoscopic variables. Tumors with P53 mutation were associated with a younger age at diagnosis of CAC (47.2 ±13 vs 55.0 ±12 years, p = 0.03), but no other associations of this marker or MMR with clinical or endoscopic variables of IBD were found. Conclusions Loss of SATB2 expression is significantly associated with IBD duration, a well-known risk factor for CAC. This association with duration of IBD could denote an effect of longer chronic inflammation on SATB2 status. Given the previously reported association of loss of expression of SATB2 with pre-cancerous lesions in IBD patients, this could be a potential biomarker for risk of CAC. Funding Agencies National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

DOP41 Low-grade dysplasia prognosis and predictive factors for advanced neoplasia progression in the 21st century: A large multi-centre retrospective cohort study

Abstract Background Recent advances in ulcerative colitis (UC) endoscopic surveillance such as high-definition imaging and greater chromoendoscopy (CE) use have led to an increase in detection and resection of visible dysplasia. An updated study of prognosis of low-grade dysplasia (LGD) is needed to address uncertainty as to the accuracy of progression rates based on historical studies. Methods This retrospective cohort study involved four UK IBD centres. Hospital and endoscopy pathology databases were searched between 1 January 2001 and 30 December 2018 to identify adult patients with UC who had their first LGD diagnosis diagnosed within the extent of colitis. Only patients followed up with at least one colonoscopy or colectomy by 30 August 2019 were included. The study endpoint was time to high-grade dysplasia (HGD) or cancer (CRC), i.e. advanced neoplasia (AN), or end of follow-up. Survival analyses were performed using Kaplan–Meier estimation and Cox proportional hazards (PH) models. Results In total, 460 patients met the inclusion criteria and were followed up for a median of 4.1 years (IQR 6), equating to 2,232 patient-years. A mean of 3.7 (range 0–17) subsequent colonoscopies was performed per patient. Seventy-seven per cent of patients had CE surveillance. Complete endoscopic resection was achieved in 94% and 64% of the polypoid and non-polypoid LGD, respectively. There was progression to AN in 88 cases (19%) during follow-up. There was no significant difference in AN progression between centres. Unresectable non-polypoid or invisible LGD carried the greatest risk of AN development (Figure 1). On univariate Cox PH analysis, CE use was protective against AN progression (HR 0.5; 95% CI 0.3–1.0; p = 0.04). However, only highly significant predictors of LGD progression to AN on univariate analysis (Bonferroni adjusted p &amp;lt; 0.003), were entered into the multivariate model: Cumulative risk of AN increased with the number of risk factors (Figure 2). Conclusion This is the largest study examining prognosis of LGD, based on endoscopic features, in this century. Five-year cumulative incidence of AN is low after complete endoscopic resection of visible LGD without surrounding dysplasia. Lesion size of 1 cm or more, invisibility, multifocality and unresectability of LGD are significant risk factors for progression to AN. These factors should be taken into consideration when discussing management options with patients.