Crohn's Disease Phenotypes and Associations With Comorbidities, Surgery Risk, Medications and Nonmedication Approaches: The MAGIC in IMAGINE Study.

BACKGROUND: We aimed to establish a cohort of persons with Crohn's disease (CD) enrolled from 14 Canadian centers to describe the contemporary presentation of CD in Canada. METHODS: All enrollees were at least 18 years old and underwent chart review for phenotype documentation by Montreal Classification at time of enrollment, comorbidities, inflammatory bowel disease (IBD) and other surgeries, and use IBD and other therapies. RESULTS: Of 2112 adults, 59% were female, and the mean age was 44.1 (+/-14.9SD) years. The phenotype distribution was B1 = 50.4%, B2 = 22.4%, B3 = 17.3%, and missing information = 9.9%. Perineal disease was present in 14.2%. Pertaining to disease location, 35.2% of patients had disease in L1, 16.8% in L2, 48% in L3, and 0.4% in L4. There was no difference in phenotype by gender, anxiety score, depression score. Disease duration was significantly different depending on disease behavior type (B1 = 12.2 ±â€…10.1; B2 = 19.4 ±â€…12.9; B3 = 18.9 ±â€…11.8, P < .0001). Isolated colonic disease was much less likely to be fibrostenotic or penetrating than inflammatory disease. Penetrating disease was more likely to be associated with ileocolonic location than other locations. Perineal disease was most commonly seen in persons with B3 disease behavior (24%) than other behaviors (11% B1; 20% B2 disease, P < .0001) and more likely to be seen in ileocolonic disease (L3;19%) vs L2 (17%) and L1 (11%; P < .0001). Surgery related to IBD occurred across each behavior types at the following rates: B1 = 23%, B2 = 64%, and B3 = 74%. Inflammatory bowel disease-related surgery rates by location of disease were L1 = 48%, L2 = 21%, and L3 = 51%. CONCLUSIONS: In exploring this large contemporary CD cohort we have determined that inflammatory disease is the main CD phenotype in Canada and that CD-related surgery remains very common.

Forecasting the Incidence and Prevalence of Inflammatory Bowel Disease: A Canadian Nationwide Analysis.

INTRODUCTION: Canada has a high burden of inflammatory bowel disease (IBD). Historical trends of IBD incidence and prevalence were analyzed to forecast the Canadian burden over the next decade. METHODS: Population-based surveillance cohorts in 8 provinces derived from health administrative data assessed the national incidence (2007-2014) and prevalence (2002-2014) of IBD. Autoregressive integrated moving average models were used to forecast incidence and prevalence, stratified by age, with 95% prediction intervals (PI), to 2035. The average annual percentage change (AAPC) with 95% confidence interval (CI) was calculated for the forecasted incidence and prevalence. RESULTS: The national incidence of IBD is estimated to be 29.9 per 100,000 (95% PI 28.3-31.5) in 2023. With a stable AAPC of 0.36% (95% CI -0.05 to 0.72), the incidence of IBD is forecasted to be 31.2 per 100,000 (95% PI 28.1-34.3) in 2035. The incidence in pediatric patients (younger than 18 years) is increasing (AAPC 1.27%; 95% CI 0.82-1.67), but it is stable in adults (AAPC 0.26%; 95% CI -0.42 to 0.82). The prevalence of IBD in Canada was 843 per 100,000 (95% PI 716-735) in 2023 and is expected to steadily climb (AAPC 2.43%; 95% CI 2.32-2.54) to 1,098 per 100,000 (95% PI 1,068-1,127) by 2035. The highest prevalence is in seniors with IBD (1,174 per 100,000 in 2023; AAPC 2.78%; 95% CI 2.75-2.81). DISCUSSION: Over the next decade, the Canadian health care systems will contend with the juxtaposition of rising incidence of pediatric IBD and a rising prevalence of overall IBD driven by the aging population.

Variation in the Care of Children with Inflammatory Bowel Disease Within and Across Canadian Provinces: A Multi-Province Population-Based Cohort Study.

Purpose: The incidence of childhood-onset inflammatory bowel disease (IBD) is rising. We described variation in health services utilization and need for surgery among children with IBD between six and 60 months following IBD diagnosis across Canadian pediatric centers and evaluated the associations between care provided at diagnosis at each center and the variation in these outcomes. Patients and Methods: Using population-based deterministically-linked health administrative data from four Canadian provinces (Alberta, Manitoba, Nova Scotia, Ontario) we identified children diagnosed with IBD <16 years of age using validated algorithms. Children were assigned to a pediatric center of care using a hierarchical approach based on where they received their initial care. Outcomes included IBD-related hospitalizations, emergency department (ED) visits, and IBD-related abdominal surgery occurring between 6 and sixty months after diagnosis. Mixed-effects meta-analysis was used to pool results and examine the association between center-level care provision and outcomes. Results: We identified 3784 incident cases of pediatric IBD, of whom 2937 (77.6%) were treated at pediatric centers. Almost a third (31.4%) of children had ≥1 IBD-related hospitalization and there were 0.66 hospitalizations per person during follow-up. More than half (55.8%) of children had ≥1 ED visit and there were 1.64 ED visits per person. Between-center heterogeneity was high for both outcomes; centers where more children visited the ED at diagnosis had more IBD-related hospitalizations and more ED visits during follow-up. Between-center heterogeneity was high for intestinal resection in Crohn's disease but not colectomy in ulcerative colitis. Conclusion: There is variation in health services utilization among children with IBD and risk of undergoing intestinal resection in those with Crohn's disease, but not colectomy among children with ulcerative colitis, across Canadian pediatric tertiary-care centers. Improvements in clinical care pathways are needed to ensure all children have equitable and timely access to high quality care.

Health Services Utilization and Specialist Care in Pediatric Inflammatory Bowel Disease: A Multiprovince Population-Based Cohort Study.

BACKGROUND: Patterns of health services utilization among children with inflammatory bowel disease (IBD) are important to understand as the number of children with IBD continues to increase. We compared health services utilization and surgery among children diagnosed <10 years of age (Paris classification: A1a) and between 10 and <16 years of age (A1b). METHODS: Incident cases of IBD diagnosed <16 years of age were identified using validated algorithms from deterministically linked health administrative data in 5 Canadian provinces (Alberta, Manitoba, Nova Scotia, Ontario, Quebec) to conduct a retrospective cohort study. We compared the frequency of IBD-specific outpatient visits, emergency department visits, and hospitalizations across age groups (A1a vs A1b [reference]) using negative binomial regression. The risk of surgery was compared across age groups using Cox proportional hazards models. Models were adjusted for sex, rural/urban residence location, and mean neighborhood income quintile. Province-specific estimates were pooled using random-effects meta-analysis. RESULTS: Among the 1165 (65.7% Crohn's) children with IBD included in our study, there were no age differences in the frequency of hospitalizations (rate ratio [RR], 0.88; 95% confidence interval [CI], 0.74-1.06) or outpatient visits (RR, 0.95; 95% CI, 0.78-1.16). A1a children had fewer emergency department visits (RR, 0.70; 95% CI, 0.50-0.97) and were less likely to require a Crohn's-related surgery (hazard ratio, 0.49; 95% CI, 0.26-0.92). The risk of colectomy was similar among children with ulcerative colitis in both age groups (hazard ratio, 0.71; 95% CI, 0.49-1.01). CONCLUSIONS: Patterns of health services utilization are generally similar when comparing children diagnosed across age groups.

Among 1165 children with inflammatory bowel disease, health services utilization was similar for children diagnosed <10 years of age and those diagnosed ≥10 years of age, except younger children had fewer emergency department visits and Crohn's disease­related surgeries.

Clinical Outcomes in a Large Canadian Centralized CLL Clinic Based on Treatment and Molecular Factors over a Decade.

FISH cytogenetics, TP53 sequencing, and IGHV mutational status are increasingly used as prognostic and predictive markers in chronic lymphocytic leukemia (CLL), particularly as components of the CLL International Prognostic Index (CLL-IPI) and in directing therapy with novel agents. However, testing outside of clinical trials is not routinely available in Canada. As a centralized CLL clinic at CancerCare Manitoba, we are the first Canadian province to evaluate clinical outcomes and survivorship over a long period of time, incorporating the impact of molecular testing and the CLL-IPI score. We performed a retrospective analysis on 1315 patients diagnosed between 1960 and 2018, followed over a 12-year period, where 411 patients had molecular testing and 233 patients had a known CLL-IPI score at the time of treatment. Overall, 40.3% (n = 530) of patients received treatment, and 47.5% (n = 252) of patients received multiple lines of therapy. High-risk FISH and CLL-IPI (4-10) were associated with higher mortality (HR 2.03, p = 0.001; HR 2.64, p = 0.002), consistent with other studies. Over time, there was an increase in the use of targeted agents in treated patients. The use of Bruton's tyrosine kinase inhibitors improved survival in patients with unmutated IGHV and/or TP53 aberrations (HR 2.20, p = 0.001). The major cause of death in patients who received treatment was treatment/disease-related (32%, n = 42) and secondary malignancies (57%, n = 53) in those who were treatment-naïve. Our data demonstrate the importance of molecular testing in determining survivorship in CLL and underpinning the likely immune differences in outcomes for those treated for CLL.

Proton Pump Inhibitor Use Before and After a Diagnosis of Inflammatory Bowel Disease.

BACKGROUND: Proton pump inhibitors (PPIs) have an impact on the gut microbiome. We investigated whether increased use of PPIs was associated with a diagnosis of inflammatory bowel disease (IBD). METHODS: The University of Manitoba IBD Epidemiology Database includes all Manitobans diagnosed with IBD between 1984 and 2018 with age-, sex-, and geography-matched control subjects and comprehensive prescription drug data from April 1995. Subjects were considered to be users if they received 2 PPI prescriptions. We assessed PPI prescriptions prediagnosis and for 3 years postdiagnosis of IBD. The absolute and relative rates were calculated and compared for PPI use pre- and post-IBD diagnosis. RESULTS: A total of 5920 subjects were diagnosed with IBD after April 1996. Rates of PPI use in control subjects increased gradually from 1.5% to 6.5% over 15 years. Persons with IBD had a higher rate of PPI use, peaking up to 17% within 1 year of IBD diagnosis with a rate ratio (RR) of 3.1 (95% confidence interval [CI], 2.9-3.3). Furthermore, persons with Crohn's disease (RR, 4.2; 95% CI, 3.7-4.6) were more likely to have been PPI users prediagnosis than persons with ulcerative colitis (RR, 2.4; 95% CI, 2.2-2.7). Important predictors of increased PPI use were older age, year of data collection, and Crohn's disease diagnosis. CONCLUSIONS: Persons with IBD have higher PPI use preceding their diagnosis. Possibly, the use of a PPI alters the gut microbiome, increasing the risk for IBD diagnosis; or persons with IBD have increased rates of dyspepsia, warranting PPI use; or some IBD symptoms are treated with PPIs whether warranted or not.

Proton pump inhibitor (PPI) use is increased in persons with IBD for up to years prior to their diagnosis, raising the possibility that their use increases the risk for inflammatory bowel disease (IBD), or alternatively, persons with IBD have more upper gastrointestinal complaints. Another possibility is that early IBD-related symptoms are being managed rightly or wrongly with PPI therapy. Further, there is an increased use of PPI therapy post­IBD diagnosis compared with matched control subjects. While the use of PPI therapy in persons with IBD may be appropriate, physicians need to rigorously review their use at all times, especially in persons with IBD, as in this population their use may be excessive and possibly detrimental.

A Canadian Provincial Screening Program for Lynch Syndrome.

INTRODUCTION: Manitoba implemented the first Canadian provincial program of reflex screening through mismatch repair immunohistochemistry (MMR-IHC) for all colorectal cancers diagnosed at age 70 years or younger in December 2017. We evaluated compliance to universal reflex testing and for referrals to Genetics for individuals with MMR-deficient tumors. METHODS: We searched the provincial pathology database with "adenocarcinoma" in the colorectal specimen pathology reports between March 2018 and December 2020. We cross-referenced with paper and electronic records in the Program of Genetics and Metabolism to determine whether patients with MMR-deficient tumors had been referred for Genetic assessment and what proportion of patients and first-degree relatives accepted an appointment and genetic testing. We performed logistic regression analysis to identify predictors of testing. RESULTS: We identified 3,146 colorectal adenocarcinoma specimens (biopsies and surgical resections) from 1,692 unique individuals (mean age 68.66 years, male 57%). Of those aged 70 years or younger (n = 936), 89.4% received MMR-IHC screening. Individual pathologists (categorized by the highest, average, and lowest screening rates) were the biggest predictors of MMR-IHC screening on multivariable analysis (highest vs lowest: odds ratio 17.5, 95% confidence interval 6.05-50.67). While only 53.4% (n = 31) of 58 screen-positive cases were referred by pathologists for genetic assessment, other clinicians referred an additional 22.4% (n = 13), resulting in 75.8% overall referral rate of screen-positive cases. Thirteen (1.4%) patients (1.1%, aged 70 years or younger) were confirmed to experience Lynch syndrome through germline testing, and 8 first-degree relatives (an average of 1.6 per patient) underwent cascade genetic testing. DISCUSSION: The first Canadian Lynch syndrome screening program has achieved high rates of reflex testing.

Risks of Melanoma and Nonmelanoma Skin Cancers Pre- and Post-Inflammatory Bowel Disease Diagnosis.

BACKGROUND: We compared risks of nonmelanoma skin cancers (NMSCs) and melanoma preceding and following a diagnosis of inflammatory bowel disease (IBD) and to evaluate the effect of thiopurines and anti-tumor necrosis factor α (anti-TNF-α) on skin cancer risk in IBD. METHODS: This was a retrospective, historical cohort study using the population-based University of Manitoba IBD Epidemiology Database (11 228 IBD cases and 104 725 matched controls) linked to the Manitoba Cancer Registry. Logistic and Cox regression analyses were performed to calculate skin cancer risks prior to and after IBD diagnosis. RESULTS: Persons with ulcerative colitis (UC) were more likely to have basal cell carcinoma (BCC) predating their UC diagnosis (odds ratio, 1.32; 95% confidence interval [CI], 1.08-1.60). Risks of squamous cell carcinoma (SCC), other NMSCs, or melanoma prior to IBD diagnosis were not significantly increased. Post-IBD diagnosis, risks of BCC (hazard ratio, 1.53; 95% CI, 1.37-1.70) and SCC (hazard ratio, 1.61; 95% CI, 1.29-2.01) were significantly increased across all IBD groups except for SCC in UC. There was no significant association between melanoma and IBD post-IBD diagnosis. The risks of BCC and melanoma were increased in thiopurine and anti-TNF users, and risk of SCC was increased in only thiopurine users. Nested cohort analysis of persons with IBD with censoring at both thiopurines and anti-TNF use confirmed a higher baseline risk of BCC and no effect on SCC, comparable to pre-IBD diagnosis findings. CONCLUSIONS: The risk of BCC preceding a diagnosis of UC is higher than in non-UC controls, compared with a generally increased risk of all NMSCs post-IBD diagnosis. Thiopurine and anti-TNF therapy increase the risks for skin cancers in persons with IBD after their diagnoses.

The risk of basal cell carcinoma preceding a diagnosis of ulcerative colitis is higher than in non­inflammatory bowel disease (IBD) controls, compared with a generally increased risk of all nonmelanoma skin cancers post­IBD diagnosis. There was no significant association between melanoma and IBD post­IBD diagnosis. Anti-tumor necrosis factor therapy increase the risks for melanoma and both anti-tumor necrosis factor and thiopurine therapies increase the risk for nonmelanoma skin cancers in persons with IBD after their diagnoses.

Aeroallergen-related Diseases Predate the Diagnosis of Inflammatory Bowel Disease.

OBJECTIVE: This study aimed to determine whether having a diagnosis of asthma or allergic rhinitis (AR) increased the risk of being diagnosed with inflammatory bowel disease (IBD) and whether there was increased incidence of these diseases after a diagnosis of IBD. DESIGN: This is a retrospective, historical cohort-based study. We used the administrative data of Manitoba Health and the population-based University of Manitoba IBD Epidemiology Database. We used numbers of prescriptions for drugs used to treat asthma and to treat AR to identify diagnoses of asthma and AR, respectively.We calculated relative risks (RRs) to assess incidence of IBD compared with matched controls after diagnoses of asthma and AR and hazard ratios to determine the incidence of asthma and AR after IBD diagnosis. RESULTS: Compared with controls, a diagnosis of asthma or AR preceding a diagnosis of IBD was increased in cases (RR, 1.62; 95% confidence interval [CI], 1.50-1.75; and RR, 2.10; 95% CI, 1.97-2.24) with a similar outcome by subtype of IBD (Crohn's disease vs ulcerative colitis) and by sex. On sensitivity analysis, diagnoses of asthma or AR were comparable when considering at least 5, 10, 15 or 20 drug prescriptions. Persons with IBD were more likely to develop asthma or AR than controls after being diagnosed with IBD (hazard ratio for asthma, 1.31, 95% CI, 1.18-1.45; and hazard ratio for AR, 2.62, 95% CI, 2.45-2.80). CONCLUSIONS: The association between asthma, AR, and IBD suggest the possibility that whatever triggers the onset of these atopic diseases may trigger the onset of IBD as well, and aeroallergens are plausible culprits.

This study demonstrates that a preexisting diagnosis of asthma or allergic rhinitis is associated with an increased risk of subsequently developing IBD. These data reinforce the importance of considering that gastrointestinal complaints in patients with asthma and allergic rhinitis may reflect a possible diagnosis of IBD. It also raises the possibility that aeroallergens may be environmental cause(s) of IBD.

Sleep Disturbances, Bowel Movement Kinetics, and Travel Interruption With Bowel Preparation: A Bowel CLEANsing National Initiative Substudy.

INTRODUCTION: We investigated sleep disturbances, bowel movement (BM) kinetics, and travel experience with different bowel preparation regimens in a substudy of patients enrolled in a randomized multicenter Canadian clinical trial. METHODS: Patients scheduled to have a colonoscopy between 7:30 am and 10:30 am (early morning) were randomized to (i) 4-L single-dose polyethylene glycol (PEG) given in the evening before, (ii) 2-L split-dose PEG (+bisacodyl 15 mg), or (iii) 4-L split-dose PEG. Patients scheduled to undergo a colonoscopy between 10:30 am and 4:30 pm (afternoon) were randomized to (iv) 2-L single-dose PEG (+bisacodyl 15 mg) in the morning, (v) 2-L split-dose PEG (+bisacodyl 15 mg), or (vi) 4-L split-dose PEG. Patients were asked to record information on BM kinetics, sleep, and travel to the endoscopy unit. Continuous and categorical variables were compared between groups using a Kruskal-Wallis test or χ 2 test, respectively. Intention-to-treat analyses were performed. RESULTS: Overall, 641 patients were included in this substudy. Patients undergoing early morning colonoscopies reported the most awakenings in the night when assigned to 4-L single-dose day-before PEG and the highest reduction in sleep hours when assigned to 4-L split-dose PEG. There were no significant between-group differences in urgent BMs, fecal incontinence episodes, or travel interruptions. Overall, 17% of those traveling for more than an hour had to stop for a BM during travel, with no significant difference between groups. DISCUSSION: Day-before and split-dose high-volume PEG regimens for colonoscopies scheduled before 10:30 am lead to the greatest sleep disturbance.

Rituximab Treatment of Primary Cutaneous Follicle Center Lymphoma: A Retrospective Review.

BACKGROUND: Primary cutaneous B-cell lymphoma (PCBCL) presents only in the skin at the time of diagnosis with no evidence of extracutaneous disease, and primary cutaneous follicle center lymphoma (PCFCL) is the most common subtype. There is currently a lack of prospective randomized control trials and large retrospective studies investigating the efficacy of different treatment options for PCFCL. This retrospective study was conducted to describe our local clinical experience and outcomes of patients treated with rituximab-containing regimens. OBJECTIVES: To describe our local clinical experience and treatment outcomes of patients treated with rituximab-containing regimens. METHODS: A retrospective study consisting of 25 PCFCL patients treated with different modalities. Patient records were reviewed and analyzed using a Kaplan-Meier estimation and SAS 9.4 software. RESULTS: After the initial treatment, all patients had CR except for 1 patient in the observation group. Further, 60% of patients in surgery, 20% in chemoimmunotherapy, 67% in rituximab monotherapy, 33% in steroid injection/systemic prednisone, and 33% in observation experienced a relapse. Although no significant difference was found between treatment groups due to the small sample size, time to relapse trends provides insight into treatment responses. Chemoimmunotherapy had the lowest relapse rate in the first 5 years post-treatment, whereas surgery had a higher tendency to relapse. CONCLUSIONS: Despite the potential for rituximab-containing chemoimmunotherapy to yield adverse effects, it is effective in achieving a prolonged clinical remission in patients with PCFCL. It remains a reasonable treatment option for diffuse, extensive, or treatment-resistant disease.

Improving Colonoscopy Bowel Preparation and Reducing Patient Anxiety Through Recently Developed Online Information Resource: A Cross-sectional Study.

Introduction: Invasive medical procedures such as colonoscopies can cause psychological distress and anxiety. Mycolonoscopy.ca is a multilanguage website that provides online written and video information (individual items reported in prior publications to be highly rated by patients) regarding preparation and what to expect before, during, and after colonoscopy. Information about how to access the website is included with all colonoscopy appointment materials in Winnipeg, Manitoba. We evaluated the use of mycolonoscopy.ca among patients undergoing colonoscopy and examined the association between visitation to the website and patient outcomes. Methods: A paper-based survey was distributed to patients attending their colonoscopy appointments between 11/2019 and 3/2020. Logistic regression analyses were performed to determine the factors associated with website visitation, procedural worry, and bowel preparation scores. Results: Five hundred and ninety-three surveys were distributed, of which 506 were completed. 17.4% of participants had visited the website before their colonoscopy. Visitors to mycolonoscopy.ca were more likely to consume a split-dose bowel preparation (63.9%) compared with non-visitors (52.5%) (P = 0.006). 31.3% of website visitors were very/extremely worried about their colonoscopy compared with 17.9% of non-visitors. 76.6% of individuals agreed/strongly agreed that visiting the website helped them prepare for their colonoscopy and 69.7% who visited the website agreed/strongly agreed that it helped to reduce their stress/anxiety for the procedure. In multivariable analyses, visitation to website was associated with higher adequate bowel preparation (OR:10.55; 95% CI:1.35 to 82.4). Conclusion: Use of an informative online platform such as mycolonoscopy.ca can help to improve patient education before colonoscopy, reduce worry surrounding the procedure, and improve bowel preparation.

Characteristics of colorectal cancer and use of colonoscopy before colorectal cancer diagnosis among individuals with inflammatory bowel disease: A population-based study.

INTRODUCTION: There are limited recent data on the characteristics of inflammatory bowel disease (IBD)-associated colorectal cancer (CRC) and the use of colonoscopy prior to CRC diagnosis among persons with IBD. We analyzed IBD-CRC characteristics, survival after IBD-CRC diagnosis and the use of colonoscopy prior to IBD-CRC diagnosis over time. METHODS: We identified individuals with and without IBD from the University of Manitoba IBD Epidemiology Database and CRC from linkage to the Manitoba Cancer Registry. We compared characteristics of IBD-CRC and sporadic-CRC using logistic regression and survival after CRC diagnosis using Cox regression analysis. We assessed rate and predictors of colonoscopy use 5 years to 6 months prior to IBD-CRC. RESULTS: 1,262 individuals with CRC were included (212 IBD-CRC). IBD was associated with an increased risk of death after CRC diagnosis in 2004-2011 (HR 1.89; 95% CI 1.25-2.88) but not in 2012-2017 (HR = 1.002; CI 0.50-2.03). In the 5 years to 6 months prior to IBD-CRC (1989-2018), 51% underwent colonoscopy, which was very similar to IBD without CRC and contrasted to 9% among sporadic CRCs. Exposure to colonoscopy pre IBD-CRC remained stable through the study period (1989-2002 OR = 1.25; CI 0.77-2.01; 2003-2011 OR = 1.21; CI 0.56-1.70; reference 2012-2018). Exposure to colonoscopy pre-IBD-CRC was not associated with improved post-CRC survival. CONCLUSION: The risk of death following CRC diagnosis is not impacted by a diagnosis of IBD in recent years. There is a very high proportion of post colonoscopy CRC among IBD-CRC, which has not changed over the years and needs detailed root-cause analysis and interventions.

Nuclear TIGAR mediates an epigenetic and metabolic autoregulatory loop via NRF2 in cancer therapeutic resistance.

Metabolic and epigenetic reprogramming play important roles in cancer therapeutic resistance. However, their interplays are poorly understood. We report here that elevated TIGAR (TP53-induced glycolysis and apoptosis regulator), an antioxidant and glucose metabolic regulator and a target of oncogenic histone methyltransferase NSD2 (nuclear receptor binding SET domain protein 2), is mainly localized in the nucleus of therapeutic resistant tumor cells where it stimulates NSD2 expression and elevates global H3K36me2 mark. Mechanistically, TIGAR directly interacts with the antioxidant master regulator NRF2 and facilitates chromatin recruitment of NRF2, H3K4me3 methylase MLL1 and elongating Pol-II to stimulate the expression of both new (NSD2) and established (NQO1/2, PRDX1 and GSTM4) targets of NRF2, independent of its enzymatic activity. Nuclear TIGAR confers cancer cell resistance to chemotherapy and hormonal therapy in vitro and in tumors through effective maintenance of redox homeostasis. In addition, nuclear accumulation of TIGAR is positively associated with NSD2 expression in clinical tumors and strongly correlated with poor survival. These findings define a nuclear TIGAR-mediated epigenetic autoregulatory loop in redox rebalance for tumor therapeutic resistance.

Metabolic Alterations in Sputum and Exhaled Breath Condensate of Early Stage Non-Small Cell Lung Cancer Patients After Surgical Resection: A Pilot Study.

Every year, close to two million people world-wide are diagnosed with and die of lung cancer. Most patients present with advanced-stage cancer with limited curative options and poor prognosis. Diagnosis of lung cancer at an early stage provides the best chance for a cure. Low- dose CT screening of the chest in the high-risk population is the current standard of care for early detection of lung cancer. However, CT screening is invasive due to radiation exposure and carries the risk of unnecessary biopsies in non-cancerous tumors. In this pilot study, we present metabolic alterations observed in sputum and breath condensate of the same population of early- stage non-small cell lung cancer (NSCLC) patients cancer before and after surgical resection (SR), which could serve as noninvasive diagnostic tool. Exhaled breath condensate (EBC) (n=35) and sputum (n=15) were collected from early-stage non-small cell lung cancer (NSCLC) patients before and after SR. Median number of days for EBC and sputum collection before and after SR were 7 and 42; and 7 and 36 respectively Nuclear magnetic resonance (NMR) and liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) were used to analyze the metabolic profile of the collected samples. A total of 26 metabolites with significant alteration post SR were identified, of which 14 (54%) were lipids and 12 constituted nine different chemical metabolite classes. Eighteen metabolites (69%) were significantly upregulated and 8 (31%) were downregulated. Median fold change for all the up- and downregulated metabolites (LC-QTOF-MS) were 10 and 8, respectively. Median fold change (MFC) in concentration of all the up- and downregulated metabolites (NMR) were 0.04 and 0.27, respectively. Furthermore, glucose (median fold change, 0.01, p=0.037), adenosine monophosphate (13 log fold, p=0.0037) and N1, N12- diacetylspermine (8 log fold p=0.011) sputum levels were significantly increased post-SR. These identified sputa and EBC indices of altered metabolism could serve as basis for further exploration of biomarkers for early detection of lung cancer, treatment response, and targets for drug discovery. Validation of these promising results by larger clinical studies is warranted.

Hospitalization With Clostridioides difficile in Pediatric Inflammatory Bowel Disease: a Population-Based Study.

OBJECTIVES: Several studies have demonstrated higher rates of Clostridioides difficile infection (CDI) in adults with inflammatory bowel disease (IBD). We conducted a population-based study comparing the risk of hospitalization with CDI in children with and without IBD. METHODS: Using health administrative data and validated algorithms, we identified all children (<16 years) diagnosed with IBD in 5 Canadian provinces, then age and sex matched to 5 children without IBD. Province-specific 5-year incidence rates of hospitalization with CDI were pooled and generalized linear mixed-effects models were used to estimate the crude incidence rate ratio (IRR) comparing (1) children with and without IBD and (2) children with Crohn disease and ulcerative colitis. Hazard ratios (HR) from Cox proportional hazards models adjusting for age, sex, rural/urban household, and income were pooled using fixed-effects models. RESULTS: The incidence rate of CDI identified during hospitalization was 49.06 [95% confidence interval (CI), 39.40-61.08] per 10,000 person-years (PY) in 3593 children with IBD compared to 0.39 (95% CI, 0.13-1.21) per 10,000 PY in 16,284 children without IBD (crude IRR, 133.4, 95% CI, 42.1-422.7; adjusted HR, 68.2, 95% CI, 24.4-190.4). CDI was identified less often in children with Crohn disease than ulcerative colitis (crude IRR, 0.51, 95% CI, 0.32-0.82; adjusted HR, 0.69, 95% CI, 0.46-1.05). CONCLUSIONS: Children with IBD have a markedly higher incidence of CDI identified during a hospitalization relative to children without IBD. Consequently, symptomatic children with IBD who are hospitalized should be screened for CDI.

Effect of clinical versus administrative data definitions on the epidemiology of C. difficile among hospitalized individuals with IBD: a population-based cohort study.

BACKGROUND: Hospitalization admissions and discharge databases (DAD) using the International Classification of Diseases (ICD) codes are often used to describe the epidemiology of Clostridioides difficile infections (CDI) among those with Inflammatory bowel disease (IBD), even though DAD CDI definition can miss many cases of CDI. There are no data comparing the assessment of the epidemiology of CDI among those with IBD by DAD versus laboratory diagnosis. We used a population-based dataset to determine the effect of using DAD versus laboratory CDI diagnosis on CDI assessment among those with IBD. METHODS: We linked the University of Manitoba IBD Epidemiology Database to the provincial CDI laboratory dataset for the years 2005-2014. Time trends of CDI were assessed using joinpoint analyses. We used stratified logistic regression analysis to assess factors associated with CDI among individuals with IBD. RESULTS: Time trends of CDI among hospitalized individuals with IBD were similar when using DAD or the laboratory CDI diagnosis. Prior hospital admission and antibiotic exposure were associated with CDI using either of the CDI definitions, 5-ASA use was associated with CDI using DAD but not laboratory diagnosis, whereas corticosteroid exposure was associated with laboratory-based CDI diagnosis. Using laboratory results as gold standard, DAD had a sensitivity and specificity of 75.4% and 99.6% for CDI among those with IBD. CONCLUSIONS: Using ICD codes in the DAD for CDI provides similar epidemiological time trend patterns as identifying CDI in the laboratory dataset. Hence, ICD codes are reliable to determine CDI epidemiology among hospitalized individuals with IBD.

Earlier Anti-TNF Initiation Leads to Long-term Lower Health Care Utilization in Crohn's Disease but Not in Ulcerative Colitis.

BACKGROUND & AIMS: The timing of initiating biologic therapy in persons with Crohn's disease (CD) and ulcerative colitis (UC) is an area of ongoing controversy. In particular, there is concern that delaying the initiation of biologic therapy may lead to more treatment-resistant disease, which can result in more complications and hospitalizations. METHODS: We used health administrative data from Manitoba, Canada to identify all persons with a new diagnosis of inflammatory bowel disease (IBD) between 2001 and 2018 who received tumor necrosis factor antagonists (anti-TNF) therapy and had at least 1 year of post anti-TNF initiation follow-up. We measured the rates of hospitalization, surgery, and outpatient visits, prior to and for up to 5 years following anti-TNF initiation. We compared the rates of these health care utilization outcomes between persons receiving anti-TNFs within 2 years following diagnosis and those receiving anti-TNFs more than 2 years following IBD diagnosis. We used inverse probability treatment weighting to adjust for baseline differences in risk between the 2 groups. RESULTS: Among 742 persons with CD, early anti-TNF initiators had fewer IBD-specific and overall hospitalizations over the 5 years following the start of therapy. Incidence of resective surgery was also lower in earlier anti-TNF initiators with CD if the first year following initiation was excluded from the analysis. In 318 cases of UC, there was no impact of the timing of anti-TNF therapy on the rates of hospitalization and surgery. CONCLUSIONS: Earlier administration of anti-TNF therapy is associated with reduced downstream health care resource utilization in CD, though these impacts are not evident in UC.

IBD Disability Index Is Associated With Both Direct and Indirect Costs of Inflammatory Bowel Disease.

INTRODUCTION: We aimed to determine both direct (medical) and indirect (lost wages) costs of IBD and the association between the degree of IBD-related disability and extent of IBD-related costs. METHODS: Persons age 18-65 from the population-based University of Manitoba IBD Research Registry completed a survey including the IBD Disability Index (IBDDI) and questions related to employment, missed work (absenteeism), and reduced productivity at work (presenteeism). Administrative health data including surgeries, hospitalizations, physician claims, and prescriptions were linked to the survey and assessed. To calculate annual wage loss, number of days of missed work was multiplied by the average wage in Manitoba for the given occupation per Statistics Canada. Costs were adjusted to 2016-17 Canadian dollars. Using descriptive and regression analysis, we explored the association between IBDDI and annual direct and indirect costs associated with IBD. RESULTS: Average annual medical costs rose from $1918 among those with IBDDI 0-4 to $9,993 among those with IBDDI 80-86. Average annual cost of lost work rose from $0 among those with IBDDI 0-4 to $30,101 among those with IBDDI 80-86. Using linear regression, each additional unit of IBDDI was associated with an increase of $77 in annual medical cost (95% CI, $52-102; P < .001) and an increase of $341 in annual cost of lost wages (95% CI, $288-395; P < .001). CONCLUSIONS: Costs related to IBD are significantly associated with the degree of IBD-related disability. Among the approximate 30% of the IBD population with IBDDI scores ≥40, the indirect costs of absenteeism and presenteeism accounts for ~75% of the total IBD-related costs.

Costs related to IBD (both direct and indirect) are significantly associated with the degree of IBD-related disability. Among the approximately 30% of the IBD population with IBDDI scores ≥40, the indirect costs of absenteeism and presenteeism accounts for ~75% of the total IBD-related costs.

Metabolic Changes in Early-Stage Non-Small Cell Lung Cancer Patients after Surgical Resection.

Metabolic alterations in malignant cells play a vital role in tumor initiation, proliferation, and metastasis. Biofluids from patients with non-small cell lung cancer (NSCLC) harbor metabolic biomarkers with potential clinical applications. In this study, we assessed the changes in the metabolic profile of patients with early-stage NSCLC using mass spectrometry and nuclear magnetic resonance spectroscopy before and after surgical resection. A single cohort of 35 patients provided a total of 29 and 32 pairs of urine and serum samples, respectively, pre-and post-surgery. We identified a profile of 48 metabolites that were significantly different pre- and post-surgery: 17 in urine and 31 in serum. A higher proportion of metabolites were upregulated than downregulated post-surgery (p < 0.01); however, the median fold change (FC) was higher for downregulated than upregulated metabolites (p < 0.05). Purines/pyrimidines and proteins had a larger dysregulation than other classes of metabolites (p < 0.05 for each class). Several of the dysregulated metabolites have been previously associated with cancer, including leucyl proline, asymmetric dimethylarginine, isopentenyladenine, fumaric acid (all downregulated post-surgery), as well as N6-methyladenosine and several deoxycholic acid moieties, which were upregulated post-surgery. This study establishes metabolomic analysis of biofluids as a path to non-invasive diagnostics, screening, and monitoring in NSCLC.