UC Cases Research Articles

Depression and Inflammatory Bowel Disease: A Bidirectional Two-sample Mendelian Randomization Study.

Observational studies have suggested a bidirectional association between depression and inflammatory bowel disease [IBD], including Crohn's disease [CD] and ulcerative colitis [UC]. However, it remains unclear whether the observed associations are causal due to the difficulties of determining sequential temporality. We investigated the association between depression and IBD by using bidirectional two-sample Mendelian randomization [MR]. Independent genetic variants for depression and IBD were selected as instruments from published genome-wide association studies [GWAS] among individuals of predominantly European ancestry. Summary statistics for instrument-outcome associations were retrieved from three separate databases for both depression [Psychiatric Genomics Consortium, FinnGen and UK Biobank] and IBD [the largest GWAS meta-analysis, FinnGen and UK Biobank], respectively. MR analyses included the inverse-variance-weighted method, weighted-median estimator, MR-Egger regression, and sensitivity analyses of Steiger filtering and MR PRESSO. From either direction, analyses were performed per outcome database and were subsequently meta-analysed using a fixed-effect model. Genetically predicted depression [per log-odds ratio increase] was associated with a higher risk of IBD; odds ratios [95% confidence interval] for IBD, CD and UC were 1.20 [1.05, 1.36], 1.29 [1.07, 1.56] and 1.22 [1.01, 1.47] in a combined sample size of 693 183 [36 507 IBD cases], 212 172 [13 714 CD cases] and 219 686 [15 691 UC cases] individuals, respectively. In contrast, no association was observed between genetically influenced IBD and depression in 534 635 individuals [71 466 depression cases]. Our findings corroborated a causal association of depression on IBD, which may impact the clinical decision on the management of depression in patients with IBD. Though our results did not support a causal effect of IBD on depression, further investigations are needed to clarify the effect of IBD activity on depression [with different symptomology].

Clinical characteristics and prognosis of patients with ulcerative colitis that shows rectal sparing at initial diagnosis.

BACKGROUNDUlcerative colitis (UC) is characterised by mucosal inflammation from the rectum to its proximal area in a symmetric and continuous fashion. However, although uncommon, we encounter cases of UC with rectal sparing in the initial stage.AIMTo evaluate the clinical characteristics and clinical course for rectal sparing UC compared with typical UC.METHODSWe looked at records from 2004 to 2015, and selected patients who were newly diagnosed with UC, and who could be followed up for at least 5 years in our hospital. We then retrospectively analysed the medical records and endoscopic findings of those patients. To compare the clinical course and prognosis, we matched each patient with rectal sparing UC 1:3 with controls by age, sex, and disease extent. RESULTSOf 619 UC patients, 24 (3.9%) showed rectal sparing at diagnosis. During the follow-up period (median 8 years), in two (8.3%) of the 24 patients, rectal sparing remained through follow-up inspections; but for the other 22 (91.7%) patients, obvious rectal inflammation was found at follow-up endoscopy. Of the 24 patients, 8 (33.3%) were initially misdiagnosed with infectious colitis. No diagnosis was changed to Crohn’s disease. The uses of corticosteroid or biologic agents, hospitalisation rate, and colectomy rates were not different between the rectal sparing UC group and typical UC group. CONCLUSIONSome patients with UC can reveal atypical patterns of disease distribution, such as rectal sparing in its initial stage; but despite this, the clinical course and prognosis may not differ from those of typical UC patients.

Clinical Phenotype and Disease Course of Inflammatory Bowel Disease: A Comparison Between Sporadic and Familial Cases

The role of genetic and environmental factors in inflammatory bowel disease's (IBD) clinical course is not fully clear. We aimed to assess the clinical phenotype, disease course, and prognosis of familial IBD in comparison with sporadic cases. We conducted a prospective national matched case-control study of registered IBD patients in the Iranian Registry of Crohn's and Colitis (IRCC) recruited from 2017 until 2020. Sporadic and familial IBD patients were matched based on age, sex, and disease duration. Data on demographics, past medical disease, family history of IBD, disease type, clinical phenotype, extraintestinal manifestations, IBD medications, IBD activity using the IBD-control-8 questionnaire and the Manitoba IBD index, emergency visits in the past 12 months, admissions in the past 3 months, history of colon cancer, IBD-related surgeries, and aggressive phenotype were gathered. Variable distributions were compared between sporadic and familial cases. Overall, 5231 patients with ulcerative colitis (UC, 18.3% familial) and 1438 patients with Crohn's disease (CD, 16.7% familial) were registered in the IRCC. Age at diagnosis was similar between familial and sporadic cases. After matching, 3523 UC patients and 908 CD patients were enrolled in the study. Extraintestinal manifestations, UC extent, CD location and behavior, anti-TNF use, disease activity, colon cancer, IBD-related surgeries and the aggressive phenotype were similar between these sporadic and familial cases. The prevalence of familial UC and CD cases in Iran was more similar to western countries, and family history did not show a predictive value for disease phenotype, course, and outcomes in our study.

Comparison of inflammatory bowel disease relapse after top-down or step-up therapy: a population-based cohort study.

The therapeutic effect of top-down therapy for inflammatory bowel disease (IBD) has not been fully evaluated in real-world clinical settings. We compared the effectiveness of top-down and step-up therapies for IBD. We retrospectively evaluated patients who were admitted with IBD (Crohn's disease [CD] or ulcerative colitis [UC]) between 2012 and 2019 using the nationwide Japan Diagnosis Procedure Combination database. Patients who received immunomodulators or biologic agents at the start of observation were assigned to the top-down group and those who did not were enrolled in the step-up group. Relapse was the primary outcome, a composite outcome defined as surgery, new steroid or immunomodulator use, hospitalization, a new biologic agent, or switching biologic agents. We analyzed 6715 patients (CD, N = 3643; UC, N = 3072). Relapse occurred in 1982 CD cases (54.4%). The cumulative CD relapse incidence was 32.9% at 1year and 61.3% at 5years in the top-down group and 30.7% at 1year and 58.6% at 5years in the step-up group. Relapse occurred in 2032 UC cases (47.8%). The cumulative relapse incidence was 33.5% at 1year and 50.0% at 5years in the top-down group and 35.2% at 1year and 51.6% at 5years in the step-up group. No clinical factors associated with relapse were identified in patients with CD or UC. Compared with step-up therapy, top-down therapy was not associated with a decreased relapse risk in a real-world population of patients with CD or UC.

Abstract 175: Pathway modeling to translate the 27-gene immuno-oncology algorithm into bladder cancer

Abstract Background The 27-gene immuno-oncology (IO) algorithm has demonstrated an association with immune checkpoint inhibitor (ICI) response in TNBC, NSCLC, and metastatic urothelial carcinoma (mUC). The algorithm can be run on data generated from either a qPCR assay or from analysis of whole transcriptome RNA-seq data. It integrates gene expression information from infiltrating inflammatory cells with signatures from surrounding stroma and tumor cells to classify cases into likely responder versus non-responders. We hypothesized that because the algorithm derives its biologic signature from the tumor immune microenvironment (TIME), the classification function and thresholds might translate to other solid tissue types based upon biologic separation of inflammatory phenotypes. Methods Using NSCLC and breast cancer datasets from TCGA, we identified 939 genes that comprise the Mesenchymal (M), Mesenchymal Stem-like (MSL), and Immunomodulatory (IM) gene expression patterns centered around a previously described 101-gene signature (Ring, 2016). We applied this 939 gene set to 433 bladder samples from TCGA (UC) and k-means clustered the genes based upon each of the three centroids. Clinical cases were also organized by k-means clustering (k=3). Pathway analysis was performed (GSEA—UCSD/Broad). We assessed classification of UC cases by looking at enrichment of inflammatory pathways into the IM cluster compared to mesenchymal pathways into the M or MSL clusters. The threshold for responder classification using the 27-gene IO algorithm previously established in TNBC was assessed by quantitating the fraction of cases enriched into the IM cluster (potential responders) as opposed to the M or MSL clusters (potential non-responders). Results The 939 genes centered around the 101-gene signature encoded twenty different physiologic pathways. Ten of these pathways included at least one of the genes from the 27-gene IO algorithm. Significant enrichment of inflammatory cell pathways was seen into the IM cluster as opposed to mesenchymal and reactive fibroblast pathways enriched into the M and MSL clusters. Pathways containing therapeutic targets designed to overcome resistance to ICIs were enriched in the MSL gene expression centroid. The 27-gene IO algorithm threshold applied to the TCGA samples classified 79% as responders in the IM cluster as opposed 16% in the M and MSL. Discussion These results support the hypothesis that gene expression signatures discerning TIME physiology associated with ICI response are tissue agnostic and relevant in multiple solid tissue types. The dramatic enrichment of responders into the IM cluster using previously established thresholds is consistent with appropriate biologic classification of the cases and supports utilizing the 27-gene IO algorithm and established threshold for association with ICI response in treated mUC cohorts. Citation Format: Robert S. Seitz, Tyler J. Nielsen, Brock L. Schweitzer, David R. Hout, Douglas T. Ross. Pathway modeling to translate the 27-gene immuno-oncology algorithm into bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 175.

P530 Proactive therapeutic drug monitoring of anti-TNF agents is associated with higher mucosal healing rates in Crohn’s disease

Abstract Background Reactive therapeutic drug monitoring (TDM) is routinely used in managing secondary loss of response to anti-TNF agents. Proactive TDM use has been associated with better clinical outcomes but its use in routine practice is still controversial. We aimed to investigate whether using proactive TDM strategy will result in higher mucosal healing and clinical remission rates. Methods After review of electronic case files, all patients that received anti-TNF treatment for active disease from 01.01.2017-01.02.2021. and responded to induction were included. Patients starting treatment for postoperative prophylaxis were excluded from the study. In the proactive group TDM was performed in week 14 and patients with subtherapeutic trough levels were dose optimized and underwent subsequent TDM measurments until the target trough level was reached. In the reactive group TDM was performed in the case of loss of response. Mucosal healing was defined as SES CD 3 for patients with CD and Mayo endoscopic score of £ 1 for UC patients. Clinical remission after 52 weeks was defined by the attending physician. Results A total of 161 IBD patients were included, 109 patients with CD and 52 patients with UC. There were 69 patients in the proactive group and 92 patients in the reactive group. No significant difference regarding age at diagnosis, age at treatment initiation, disease duration , prior immunomodulator use and time do endoscopy was observed between groups. A higher proportion of patients in the proactive group achieved mucosal healing but the difference between groups was not significant in the total cohort (proactive 52.4% vs reactive 42.2%; p=0.250). A significantly higher proportion of CD patients (n=109) in the proactive group achieved mucosal healing compared to the reactive group (56.8% vs 34.8%; p=0.039). No significant difference in mucosal healing rates between the groups was observed in UC cases. No significant difference in clinical remission rates was observed between the proactive and reactive group in the total cohort, CD and UC patients respectively. Conclusion Proactive TDM strategy is a valuable tool in managing CD patients resluting in higher rates of mucosal healing. Further studies are needed to define the optimal timepoints for proactive TDM.

A155 REAL-WORLD USE OF CORTIMENT IN ULCERATIVE COLITIS: A POPULATION-BASED STUDY

Abstract Background Ulcerative colitis (UC) is a relapsing and remitting disease with variable severity. BudesonideMMX (Cortiment®) was approved by Health Canada for the treatment of mild to moderate UC in July 2016. It offers the advantage of extensive first pass hepatic metabolism resulting in decreased systemic corticosteroid toxicity. Most public drug plans in Canada do not cover it, limiting its use to private insurance and self-pay. Aims To characterize the UC patients who use Cortiment® and explore prescribing patterns and short-term outcomes. Methods Population-based administrative data identified patients who were covered by the Alberta Health Care Insurance Plan and dispensed Cortiment® from August 1, 2016 to December 31, 2017. Analyses identified: age, sex, rural/urban status, Material [MDI] and Social Deprivation Indices [SDI], UC-related medications 6-months before and 10-weeks following Cortiment® dispensing, and disease exacerbation indicators (new dispense of corticosteroids, hospitalization with inflammatory bowel disease (IBD) as most responsible diagnosis, or IBD-related surgery). Results We identified 427 UC patients dispensed Cortiment®. The median age was 47 years (25th %: 35; 75th %: 59) and 57.4% were females. Most individuals (91.3%, n=390) resided in an urban setting, as compared to approximately 73% of all UC cases. Distribution of patients across SDI was consistent while the MDI had a higher proportion in the more well-off categories. 77.5% had a UC-related drug therapy in the 6 months prior to Cortiment® dispensing and 71.7% had a UC-related drug dispensed in the 10-weeks following. Approximately, 30% had a disease exacerbation indicators in the 10 weeks following dispensing: 24.8% new corticosteroid, 3.7% UC-related hospitalization, and <2.3% UC-related surgery. Conclusions Despite lack of public drug coverage, Cortiment® was dispensed across socioeconomic classes. The high dispensing within urban sites suggests that rural UC patients may have less access to Cortiment®. While a quarter of Cortiment® dispensings had a new concurrent dispensing of prednisone, <5% of these patients were admitted to hospital for a flare of UC. Funding Agencies Ferring Pharmaceuticals

Patient-centric care in bladder cancer: Virtual simulation to benefit clinical decision-making of oncologists.

492 Background: Immunotherapy (IO) utility in bladder cancer (UC) has expanded into multiple stages of disease. Employing IO optimally requires mastery of clinical trial data, patient eligibility criteria, and interpretation of biomarkers and determination of treatment sequencing. Given the nuanced therapeutic decision-making, education was developed in partnership between Medscape Oncology and Society for Immunotherapy of Cancer (SITC) to assist oncologists in improving their performance surrounding the management of patients with advanced UC. Methods: A virtual patient simulation (VPS) continuing medical education (CME)-certified activity depicting 2 advanced UC cases was made available to oncologist members of Medscape. The cases depicted 1) a patient with newly diagnosed metastatic UC with comorbidities and PDL1+ disease and 2) a patient with advanced UC progressing on platinum therapy with no actionable mutations. The VPS platform captures real-life decision making process of oncologists in an EHR-like format supported by an extensive database of diagnostic and treatment possibilities. Learners were able to interact with patients via video, order lab tests, assess patients, make diagnoses, and order treatments matching the scope and depth of actual practice. Tailored clinical guidance (CG) employing up-to-date evidence-based and faculty recommendations was provided after each decision point. Decisions were collected pre- and post-CG and analyzed using McNemar’s test to determine p-values. Data were collected from 4/28/20 to 7/13/20. Results: Analyses from oncologists (n = 51-66) found significant improvement in performance measured pre- to-post CG: Case 1: Ordering appropriate testing to determine patient eligibility for therapy (39% pre; 65% post; p < .001) Prescribing appropriate therapy based on patient- and disease-specific factors (38% pre; 77% post; p < .001) Providing appropriate counseling and follow-up for a patient receiving treatment (65% pre; 80% post; p < .01) Case 2: Ordering appropriate testing to determine patient eligibility for therapy (39% pre; 57% post; p < .01) Prescribing appropriate therapy based on patient- and disease-specific factors (25% pre; 41% post; p < .01) Providing appropriate counseling and follow-up for a patient receiving treatment (71% pre; 82% post; p < .05). Conclusions: This activity demonstrates the value of providing oncologists a simulation platform to practice and master clinical decision-making of the limitless possible diagnostic and therapeutic options in the management of advanced UC. Insights from rationales for each clinical decision point uncover continued gaps for oncologists on guideline recommendations, efficacy outcomes, or molecular implications. They also highlight barriers including limited experience or confidence with IO.

A NEW BACTERIAL TRANSFER THERAPY FOR IBD: ENDOSCOPIC BIFIDOBACTERIUM AND XYLOGLUCAN ADMINISTRATION

Abstract 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.

Depression in individuals who subsequently develop inflammatory bowel disease: a population-based nested case–control study

ObjectiveDepression is a potential risk factor for developing IBD. This association may be related to GI symptoms occurring before diagnosis. We aimed to determine whether depression, adjusted for pre-existing GI...

Solute carrier family 12 member 2 as a proteomic and histological biomarker of dysplasia and neoplasia in ulcerative colitis.

Ulcerative colitis (UC) patients have a greater risk of developing colorectal cancer through inflammation-dysplasia-carcinoma sequence of transformation. The histopathological diagnosis of dysplasia is therefore of critical clinical relevance, but dysplasia may be difficult to distinguish from inflammatory changes. A proteomic pilot study on 5 UC colorectal dysplastic patients highlighted proteins differentially distributed between paired dysplastic, inflammatory and normal tissues. The best candidate marker was selected and immunohistochemistry confirmation was performed on AOM/DSS mouse model lesions, 37 UC dysplasia, 14 UC cancers, 23 longstanding UC, 35 sporadic conventional adenomas, 57 sporadic serrated lesions and 82 sporadic colorectal cancers. Differential proteomics found 11 proteins significantly more abundant in dysplasia compared to inflammation, including Solute carrier family 12 member 2 (SLC12A2) which was confidently identified with 8 specific peptides and was below the limit of quantitation in both inflammatory and normal colon. SLC12A2 immunohistochemical analysis confirmed the discrimination of preneoplastic and neoplastic lesions from inflammatory lesions in mice, UC and in sporadic contexts. A specific SLC12A2 staining pattern termed "loss of gradient" reached 89% sensitivity, 95% specificity and 92% accuracy for UC-dysplasia diagnosis together with an inter-observer agreement of 95.24% (multirater κfree of 0.90; IC95%: 0.78 - 1.00). Such discrimination could not be obtained by Ki67 staining. This specific pattern was also associated with sporadic colorectal adenomas and cancers. We found a specific SLC12A2 immunohistochemical staining pattern in precancerous and cancerous colonic UC-lesions which could be helpful for diagnosing dysplasia and cancer in UC and non-UC patients.

Review Article: Prognostic Value of CK5/6 Expression in Urinary Bladder Carcinoma

Abstract Background: Bladder cancer in Egypt is the most prevalent malignancy among Egyptian males (16%), producing >7900 deaths annually, which is strikingly higher than most other parts of the world. The genesis and progression of urothelial bladder carcinoma (UBC) is known to involve alterations in several molecular pathways. Subtyping of bladder carcinoma patients based on the molecular alterations in their primary tumors may permit risk stratification and administration of more personalized therapies. Aim of Study: The aim of this study is to review the studies investigating the frequency of CK 5/6 expression and its value in the stratification of urothelial bladder carcinoma in English literature. Material and Methods: The data were retrieved from databases (PubMed, Medscape and Google scholar) and also material available on the Internet from 2001 till 2019. A structured systematic review was performed with the results tabulated. Results: The initial search presented 8 articles (2001- 2019). The frequency of CK 5/6 expression in UBC cases ranged between 19.7% and 62%. Positivity of CK 5/6 showed significant association with female gender, advanced tumor stage and pure SCC and UC with squamous differentiation. Positivity for CK 5/6 showed significant association with shorter overall survival in UC cases with squamous differen-tiation. CK5/6 expression alone was not associated with clinical outcome in any of the articles but showed significant association when combined with other markers. Conclusions: CK 5/6 as a basal marker could identify aggressive subtypes of urothelial carcinoma as those associated with squamous differentiation and advanced stage, however, it is not related to grading.

Evaluation of Role of Beta 2 Microglobulin and P- ANCA in the diagnosis of Ulcerative Colitis and Their Correlation to Disease Activity

Abstract Background Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract. Diagnosis of IBD has been based on a combination of clinical data, blood parameters, radiology and endoscopy. Activity in IBD is determined by direct and non-invasive laboratory markers. The ideal marker for IBD that is easy, specific and predictor of relapse of the disease has not yet been identified. The aim of this work is to evaluate the role of P-ANCA and Beta 2 microglobulin as new biomarkers in predictors of diagnosis and disease activity in patients with ulcerative colitis. Materials and Methods The current case control study was conducted in Tropical Department of Ain-Shams University Hospitals on 40 cases of ulcerative colitis which included twenty patients in activity and twenty patients in remission. 40 controls were consisting of twenty patients with irritable bowel syndrome and twenty healthy controls in the period from October 2016 to May 2018. Results Mean B2-M values were significantly higher in active ulcerative colitis (2.26± 0.55mg/L) than in healthy controls (1.43 ± 0.22 mg/L) and IBS (1.51 ± 0.23 mg/L). Also, mean B2-M values were significantly higher in active disease when compared to patients in remission. The difference between different disease severities according to endoscopic picture in terms of serum B2-M levels was statistically insignificant (P > 0.05).Also the difference between mild disease and inactive group was insignificant. Regarding the P-ANCA, most of active UC cases (80 %) have positive P-ANCA. While only 15 % of the inactive cases have positive P-ANCA and the difference between them is highly statistically significant (P = 0.000). Most of P-ANCA positive ulcerative colitis patients (52.6%) have moderate endoscopic activity and (21.1%) have severe endoscopic activity, while only (10.5%) have mild activity with high statistical significance (P = 0.001). Conclusion B2-M and P-ANCA may be a predictor of disease activity in UC

A65 VARIATION IN THE CARE OF CHILDREN WITH INFLAMMATORY BOWEL DISEASE: A CANGIEC POPULATION-BASED STUDY

Abstract Background Inflammatory bowel disease (IBD) is rising rapidly in Canadian children. These children require consistent high-quality specialized care to prevent long-term complications. Aims Evaluate variation in health services utilization and surgery rates across pediatric IBD centres in Ontario. Methods Incident cases of IBD <16y (1999–2010), identified from health administrative data using a validated algorithm, were assigned to pediatric IBD centres based on location of IBD hospitalization, endoscopy and outpatient care. Children receiving IBD-specific care outside pediatric centres were also grouped. Frailty models, median hazard ratios (MHR), and Kendall’s t described variation in IBD-related ED visits, hospitalizations, and surgery 6–60 months after diagnosis, adjusting for age, sex, rural/urban household, and income. Mean diagnostic lag (time from first health system contact for an IBD symptom to final IBD diagnosis) and proportion of children with IBD care by gastroenterologists (GIs) at each centre were evaluated as centre-level predictors of variation. Results Of 2584 IBD cases, 73.4% were treated in a pediatric IBD centre. Between-centre differences accounted for 0.18% (MHR 1.06) and 0.41% (MHR 1.09) of variation in hospitalizations and ED visits, respectively. Children treated at centres where a higher proportion of children were cared for by GIs were more likely to be hospitalized (HR 2.09, 95% CI 1.26–3.45). Children treated at centres with a longer mean diagnostic lag were also more likely to be hospitalized (HR 1.01, 95% CI 1.003–1.02). ED visits were not associated with the proportion of children cared for by gastroenterologists or diagnostic lag. Among 1529 CD cases, 14.1% required intestinal resection; 1.79% of variation in the risk of surgery resulted from between-centre differences (MHR 1.20). Surgery was less common among patients at centres where more children were cared for by GIs (HR 0.24, 95% CI 0.07–0.84) and with a longer mean diagnostic lag (HR 0.98, 95% CI 0.97–0.99). After adjusting for these, between-centre differences accounted for 0.005% (MHR 1.01) of variation in care. Minimal variation was observed among the 11.0% of 872 UC cases requiring colectomy, with 0.37% of variation due to between-centre differences (MOR 1.09). Colectomy risk was not associated with GI care or diagnostic lag. Conclusions Variation in ED visits, hospitalizations, and surgery among children with IBD is small; however, centre-level differences in GI specialist care use and time to diagnosis were associated with hospitalization and surgery. It is essential to understand between-centre differences to reduce variation and ensure high-quality care. Funding Agencies CCC

Unfavorable Cancer-specific Survival After Neoadjuvant Chemotherapy and Radical Cystectomy in Patients With Bladder Cancer and Squamous Cell Variant: A Multi-institutional Study.

Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs). We relied on a retrospective, multicenter database of 2858 patients with BCa who had undergone radical cystectomy with or without NAC from 1990 to 2017. Pure and mixed HVs were grouped into 6 categories: squamous cell carcinoma (SCC; n= 283; 45%), other subtypes (n= 95; 15%), micropapillary (n= 85; 14%), adenocarcinoma (n= 65; 10%), small cell (n= 54; 8.6%), and sarcomatous (n= 47; 7.6%). Kaplan-Meier and Cox regression analyses were used to examine cancer-specific survival (CSS) according to the HV, using pure UC as the reference. Logistic regression models were used to examine the odds of clinical-to-pathologic downstaging after NAC according to the HV. Overall, we identified 2229 cases of pure UC and 629 cases of BCa with HVs at radical cystectomy. Of the 450 NAC-treated patients, only those patients with SCC (n= 44; 9.8%) had had worse CSS (median CSS, 33 vs. 116 months; P< .001) and higher mortality rates (hazard ratio, 2.1; P= .03) compared with those with pure UC (n= 328; 72.9%). The results of the analyses were also confirmed when the pure and mixed cases were considered separately. After adjusting for NAC, only SCC showed a lower rate of clinical-to-pathologic downstaging (odds ratio, 0.4; P= .03) compared with UC. SCC was the HV exhibiting the lowest effect of NAC in terms of activity and CSS. Compared with pure UC, SCC seemed to be insensitive to traditional NAC regimens.

OP19 Perinatal factors do not affect paediatric inflammatory bowel disease risk: A Scottish Nationwide Cohort study using administrative health data 1981–2017

Abstract Background The incidence of paediatric-onset inflammatory bowel disease (PIBD) continues to rise, with genetic-environmental interactions expected to play a vital role. Given gestation and infancy are sensitive periods for environmental change, we aimed to determine whether a mode of delivery, gestational age or type of infant feeding contribute to the development of PIBD in a nationwide cohort of high-risk Scottish children using administrative health data research methodology. Methods All children born in Scotland 1981–2017 were identified within the Scottish Morbidity Record maternity inpatient dataset (SMR02). Data linkage was applied to determine mode of delivery, gestational age and type of infant feeding, with PIBD cases defined as any inpatient International Classification of Diseases (ICD) coding for Crohn’s disease (CD; 555/K50), ulcerative colitis (UC; 556/K51) or inflammatory bowel disease unclassified (IBDU; 558.9/K52.3) until age 16. Validation was performed within an entire Scottish health board (16% of the total population) via individual case-note verification. Hazard ratios (HRs) were calculated for each exposure using Cox proportional hazards models with the following potential confounding factors included as covariates: sex, maternal age, year of birth, postcode area and deprivation quintile. Dependent interactions were also explored between the three main exposures. Results A study population of 2 013 851 children were identified including 1721 PIBD cases. Individual validation was performed on all 298 (17%) PIBD-coded patients within NHS Lothian; 242/261 CD and UC cases were validated as true positive (positive predictive value 93%); all 37 IBDU cases were false positive with this ICD code excluded from all further analysis. Children delivered vaginally did not have an altered risk of developing PIBD compared with Caesarean section; adjusted HR 0.95 [95% CI 0.84–1.08] (p = 0.424). Children born prematurely did not have an altered risk of developing PIBD; 24–31 weeks gestation HR 0.97 [95% CI 0.56–1.68] (p = 0.922); 32–36 weeks gestation HR 0.96 (95% CI 0.76–1.20] (p = 0.699). Children not exclusively breast feeding at 6 weeks of age did not have an altered risk of developing PIBD; formula feeding HR 0.97 [95% CI 0.81–1.15] (p = 0.705); other/unknown feeding type HR 0.90 [95% CI 0.74–1.08] (p = 0.259). No two-way interactions were significant and none of the three exposures was significantly related to CD or UC in PIBD subtype analysis. Conclusion This robust, validated population-based study of over 2 million Scottish births utilising administrative health data confidently demonstrates no association between mode of delivery, gestational age, type of feeding and the development of PIBD.

Reduced expression of GATA3 predicts progression in non–muscle invasive urothelial carcinoma of the urinary bladder

ABSTRACTUrothelial carcinoma (UC) of the urinary bladder is the ninth most common cancer worldwide. The majority of these patients present with non–muscle invasive bladder cancer (NMIBC). GATA3 has recently emerged as one of the diagnostically helpful immunohistochemical markers for UC. The published literature, however, lacks comprehensive studies on the impact of GATA3 expression on the prognosis of UC patients. This study evaluated and statistically analyzed the immunohistochemical expressions of GATA3 and Ki67 in 50 Egyptian patients with NMIBC and correlated the markers’ expressions with clinicopathological variables and patients’ outcome. Ten control cases were included. The expressions of GATA3 and Ki67 were significantly downregulated and upregulated respectively in UC cases compared to the control group. GATA3 down-expression was significantly associated with high grade tumors and tumor progression with 72% prediction accuracy. Higher proliferative activity was significantly correlated with high grade, non-papillary growth pattern, and lamina propria invasion. The predictive performance of GATA3 and Ki67 in predicting malignancy and tumor grade was good. We concluded that GATA3 downregulation and increased proliferative activity might be implicated in UC tumorigenesis, loss of differentiation, and aggressiveness. Reduced GATA3 expression could predict progression in NMIBC with an accuracy of 72% and thus it constitutes a potentially promising novel prognostic marker in patients with urothelial carcinoma.

Environmental, Nutritional, and Socioeconomic Determinants of IBD Incidence: A Global Ecological Study.

The wide variation in inflammatory bowel disease [IBD] incidence across countries entails an opportunity to recognise global disease determinants and hypothesise preventive policies. We fitted multivariable models to identify putative environmental, nutritional, and socioeconomic determinants associated with the incidence of IBD (i.e. ulcerative colitis [UC] and Crohn's disease [CD]). We used the latest available country-specific incidence rates, and aggregate data for 20 determinants, from over 50 countries accounting for more than half of the global population. We presented the associations with exponentiated beta coefficients (exp[β]) indicating the relative increase of disease incidence per unit increase in the predictor variables. Country-specific incidence estimates demonstrate wide variability across the world, with a median of 4.8 new UC cases (interquartile range [IQR] 2.4-9.3), and 3.5 new CD cases [IQR 0.8-5.7] per 100 000 population per year. Latitude (exp[β] 1.05, 95% confidence interval [CI] 1.04‒1.06, per degree increase), prevalence of obesity [1.05, 1.02‒1.07, per 1% increase], and of tobacco smoking [0.97, 0.95‒0.99, per 1% increase] explained 71.5% of UC incidence variation across countries in the adjusted analysis. The model for CD included latitude [1.04, 1.02‒1.06], expenditure for health (1.03, 1.01‒1.05, per 100 purchasing power parity [PPP]/year per capita increase), and physical inactivity prevalence [1.03, 1.00‒1.06, per 1% increase], explaining 58.3% of incidence variation across countries. Besides expenditure for health, these associations were consistent in low/middle- and high-income countries. Our analysis highlights factors able to explain a substantial portion of incidence variation across countries. Further high-quality research is warranted to develop global strategies for IBD prevention.

Cancer Risk in Inflammatory Bowel Disease: A 6-Year Prospective Multicenter Nested Case–Control IG-IBD Study

In a 6-year, multicenter, prospective nested case-control study, we aimed to evaluate risk factors for incident cancer in inflammatory bowel disease (IBD), when considering clinical characteristics of IBD and immunomodulator use. The secondary end point was to provide characterization of incident cancer types. All incident cases of cancer occurring in IBD patients from December 2011-2017 were prospectively recorded in 16 Italian Group for the Study of Inflammatory Bowel Disease units. Each of the IBD patients with a new diagnosis of cancer was matched with 2 IBD patients without cancer, according to IBD phenotype (ulcerative colitis [UC] vs Crohn's disease [CD]), age (±5 years), sex. Risk factors were assessed by multivariate logistic regression analysis. Cancer occurred in 403 IBD patients: 204 CD (CD cases), 199 UC (UC cases). The study population included 1209 patients (403 IBD cases, 806 IBD controls). Cancer (n = 403) more frequently involved the digestive system (DS; 32%), followed by skin (14.9%), urinary tract (9.7%), lung (6.9%), genital tract (6.5%), breast (5.5%), thyroid (1.9%), lymphoma (2.7%, only in CD), adenocarcinoma of the small bowel (SBA; 3.9%, 15 CD, 1 pouch in UC), other cancers (15.9%). Among cancers of the DS, colorectal cancer (CRC) more frequently occurred in UC (29% vs 17%; P < 0.005), whereas SBA more frequently occurred in CD (13% vs 6.3% P = 0.039). In CD, perforating (B3) vs non-stricturing non-perforating (B1) behavior represented the only risk factor for any cancer (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.33-4.11). In CD, risk factors for extracolonic cancer (ECC) were a B3 vs B1 and a stricturing (B2) vs B1 behavior (OR, 2.95; 95% CI, 1.62-5.43; OR, 1.79; 95% CI, 1.09-2.98). In UC, risk factors for ECC and for overall cancer were abdominal surgery for UC (OR, 4.63; 95% CI, 2.62-8.42; OR, 3.34; 95% CI, 1.88-5.92) and extensive vs distal UC (OR, 1.73; 95% CI, 1.10-2.75; OR, 1.99; 95% CI, 1.16-3.47). Another risk factor for ECC was left-sided vs distal UC (OR, 1.68; 95% CI, 1.00-2.86). Inflammatory bowel disease duration was a risk factor for skin and urinary tract cancers. Perforating CD, extensive UC, and abdominal surgery for UC were identified as risk factors for overall incident cancer and for ECC. The clinical characteristics associated with severe IBD may increase cancer risk.

Abstract 5786: Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies

Abstract Prexigebersen (liposome-incorporated nuclease resistant antisense oligonucleotides specific for GRB2, L-GRB2) has proven highly effective in the treatment of leukemia, however its application in solid malignancies including gynecologic cancer has yet to be investigated. Given the biological significance of GRB2, we aim to assess the effect of prexigebersen in pre-clinical models. We tested the clinical significance of GRB2 using publicly available high-throughput data. We investigated the expression of GRB2 in a series of in vitro (Western Blotting) experiments in high-grade serous (HGSC) and uterine (UC) carcinoma models. We also tested in vivo (orthotopic mouse model) the biological effects of prexigebersen in HGSC models (OVCAR 5), first in a dose-defining experiment then in combination with standard dose paclitaxel. We first examined GRB2 using TCGA and GISTIC data and found alterations (amplifications, deletions and mutations) in 6% (33 of 594) of HGSC cases and 5% (25 of 547) of UC cases. Amplifications of GRB2 are associated with a decreased patient survival (p&amp;lt;0.01) in UC, suggesting it to be an attractive therapeutic target. GRB2 was expressed in most ovarian (HEYA8, OVCAR5, SKOV3, and OVCAR3) and uterine (MFE 319, Ishikawa and Hec1a) cancer cell lines tested. We performed a dose-defining in vivo experiment on an orthotopic mouse model of ovarian cancer (OVCAR 5). We found a maximum decrease in GRB2 expression at a dose of 15 mg/kg prexigebersen and a dose dependent decrease in tumor burden (p&amp;lt;0.05). We then performed an additional in vivo model in which prexigebersen was combined with standard dose paclitaxel. There was an eighty-six percent decrease in tumor burden (p&amp;lt;0.05), and multinodular burden (p&amp;lt;0.01) in the combination prexigebersen/paclitaxel group compared to control. Prexigebersen shows promising preclinical efficacy and may be a novel therapeutic strategy in gynecologic malignancies. Citation Format: Olivia D. Lara, Cristian Rodriquez-Aguayo, Emine Bayrakter, Paola Amero, Selanere Mangala, Chris LaFargue, Ana Tari-Ashizawa, Gabriel Lopez-Berestein, Anil Sood. Grabbing GRB2: The use of liposome-incorporated Grb2 antisense oligonucleotides as a novel therapy in gynecologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5786.