Zoann Nugent

Rate and Predictors of Early / Missed Colorectal Cancers After Colonoscopy in Manitoba: A Population-Based Study

OBJECTIVES:Many of the colorectal cancers (CRCs) diagnosed within 3 years after a colonoscopy are likely because of lesions missed on the initial colonoscopy. In this population-based study, we investigated the rate and predictors of CRCs diagnosed within 3 years of a colonoscopy.METHODS:We identified individuals 50–80 years of age diagnosed with CRC between 1992 and 2008 from the provincewide Manitoba Cancer Registry. Performance of colonoscopy and history of co-morbidities was determined by linkage to the provincial universal health care insurance providers physician billing claims and hospital discharges databases. CRCs diagnosed within 6 months of a colonoscopy were categorized as detected CRCs and those 6–36 months after a colonoscopy as early/missed CRCs. Logistic regression analysis was performed to identify the patient, endoscopist, colonoscopy, and CRC factors associated with early/missed CRCs.RESULTS:Of the 4,883 CRCs included in the study, 388 (7.9%) were early/missed CRCs, with a range of 4.5% of rectum/rectosigmoid cancers in men to 14.4% of transverse colon/splenic flexure cancers in women. Independent risk factors associated with early/missed CRCs included prior colonoscopy, performance of index colonoscopy by family physicians, recent year of CRC diagnosis, and proximal site of CRC.CONCLUSIONS:This study suggests that approximately 1 in 13 CRCs may be an early/missed CRC, diagnosed after an index colonoscopy in usual clinical practice. Women are more likely to have early/missed CRC. It is unclear if this relates to differences in procedure difficulty, bowel preparation issues, or tumor biology between men and women.

Predictors of colorectal cancer after negative colonoscopy: a population-based study.

OBJECTIVES:A higher proportion of colorectal neoplasia among women occurs in the proximal colon, which might be more frequently missed by colonoscopy. There are no data on predictors of developing colorectal cancer (CRC) after a negative colonoscopy in usual clinical practice. We evaluated gender differences and predictors of CRC occurring after a negative colonoscopy.METHODS:All individuals 40 years or older with negative colonoscopy were identified from Manitobas provincial physicians’ billing claims database. Individuals with less than 5 years of coverage by the provincial health plan, earlier CRC, inflammatory bowel disease, resective colorectal surgery, or lower gastrointestinal endoscopy were excluded. CRC risk after negative colonoscopy was compared to that in the general population by standardized incidence ratios. Cox regression analysis was performed to determine the independent predictors of CRC occurring after negative colonoscopy.RESULTS:A total of 45,985 individuals (18,606 men; 27,379 women) were followed up for 229,090 person-years. After a negative colonoscopy, men had a 40–50% lower risk of CRC diagnosis through most of the follow-up time. Risk among women was similar to that of women in the general population in the first 3 years and then was 40–50% lower. Older subject age and performance of index colonoscopy by non-gastroenterologists were independent predictors for early/missed CRC (cancers occurring within 3 years of negative colonoscopy).CONCLUSIONS:Women may have a higher rate of missed/early CRCs after negative colonoscopy. Predictors of missed/early CRCs after negative colonoscopy include older age and performance of index colonoscopy by a non-gastroenterologist.

The Epidemiology of Colectomy in Ulcerative Colitis: Results From a Population-Based Cohort

OBJECTIVES:Previous studies have reported colectomy rates of over 50% in ulcerative colitis (UC), although changes in management may have influenced the rates of colectomy in the modern era. We sought to determine the incidence of colectomy in UC and identify risk factors associated with early colectomy (EC) and late colectomy (LC).METHODS:We used the University of Manitoba Inflammatory Bowel Disease Epidemiology Database, a population-based data set including UC patients with up to 25 years of post diagnosis follow-up. We tracked the occurrence of total colectomy in all patients with known UC, subdivided into EC (≤90 days from diagnosis date) and LC (>90 days from diagnosis). Survival curves were created and stratified by age, sex, era of diagnosis, and inpatient/hospital diagnosis. Cox proportional hazards modeling was used to determine which risk factors were predictive of either EC or LC.RESULTS:Among 3,752 patients with UC, 367 underwent colectomy. The 5-, 10- and 20-year actuarial risk of requiring colectomy was 7.5%, 10.4%, and 14.8%, respectively. Male sex (hazard ratio (HR): 63, 95% confidence interval (CI): 1.58–4.36) and being initially diagnosed during a hospitalization (HR: 12.46, 95% CI: 7.40–21.0) were predictive of EC after adjustment for confounders. In-hospital diagnosis was predictive of LC, whereas being diagnosed more recently was protective against LC (HR: 0.96, 95% CI: 0.93–0.98).CONCLUSIONS:The cumulative incidence of colectomy in UC is lower than previously reported, and appears to be decreasing further among more recently diagnosed cohorts of patients. Male sex and hospitalization at the time of diagnosis are major risk factors for EC and LC.

Outcomes of patients with Crohn's disease improved from 1988 to 2008 and were associated with increased specialist care.

BACKGROUND & AIMS We investigated factors that affect long-term outcomes in Crohns disease (CD). METHODS We performed a retrospective study of 3403 patients with CD, diagnosed between 1988 and 2008 in Manitoba, Canada. Subjects were assigned to cohorts based on diagnosis year: cohort I (before 1996), cohort II (1996-2000), or cohort III (2001 and after). We compared risks for surgery and hospitalization among the cohorts and assessed use of immunomodulators and specialists. RESULTS The 5-year risks of first surgery were 30%, 22%, and 18% for cohorts I, II, and III, respectively. The adjusted hazard ratios for first surgery in cohorts II and III, compared with cohort I, were 0.72 (95% confidence interval [CI], 0.62-0.84) and 0.57 (95% CI, 0.48-0.68), respectively. The adjusted hazard ratio for cohort III, compared with cohort II, was 0.79 (95% CI, 0.65-0.97). There was a higher prevalence of visits to a gastroenterologist within the first year of diagnosis among cohorts II and III (cohort I, 53%; cohort II, 72%; and cohort III, 88%; P<.0001), which was associated with a reduced need for surgery (hazard ratio, 0.83; 95% CI, 0.71-0.98) and contributed to differences in surgery rates among the cohorts. The association between early gastroenterology care and lower risk for surgery was most evident 2 years after diagnosis (hazard ratio, 0.66; 95% CI, 0.53-0.82). Use of immunomodulators within the first year of diagnosis was higher in cohort III than in cohort II (20% vs 11%; P<.0001). CONCLUSIONS Risk of surgery decreased among patients with CD diagnosed after, compared with before, 1996, and was associated with specialist care. Specialist care within 1 year of diagnosis might improve outcomes in CD.

5-Aminosalicylate Is Not Chemoprophylactic for Colorectal Cancer in IBD: A Population Based Study

OBJECTIVES:We aimed to determine if use of 5-aminosalicylates (5-ASA) was associated with a reduced risk of colorectal cancer (CRC) in people with inflammatory bowel disease (IBD).METHODS:We used the population-based University of Manitoba IBD Epidemiology Database that tracks all health-care visits from 1984 to 2008 of all Manitobans with IBD and all prescription medication use since 1995. In 2008, there were 8,744 subjects with IBD (ulcerative colitis 4,325, Crohns disease 4,419, females 4,851, males 3,893). In study I, we assessed the incidence of CRC among 5-ASA users (≥1 year, ≥5 years of cumulative use) compared with nonusers. In study II, we assessed a cohort of those with CRC (n=101) diagnosed in 1995–2008, matched to a control cohort by age, sex, disease duration, and disease diagnosis without CRC (n=303), and logistic analysis was undertaken.RESULTS:For study I, the hazard ratio for CRC among 5-ASA users was 1.04 (95% confidence interval (CI) 0.67–1.62, P=0.87) at ≥1 year of use and 2.01 (95% CI 1.04–3.9, P=0.038) at ≥5 years of use with no difference when assessing by diagnosis. Males, but not females, using 5-ASA for ≥5 years had an increased risk of CRC. In study II, CRC cases had similar use of any 5-ASA compared with controls for ≥1 year of use (1.02, 95% CI 0.60–1.74) or ≥5 years (1.96, 95% CI 0.84–4.55), and a similar mean number of 5-ASA prescriptions at 10 vs. 11 (P=0.8) and a similar mean number of dose days at 330 vs. 410 (P=0.69).CONCLUSIONS:Our results support the majority of studies to date that 5-ASA is not chemoprophylactic in IBD for CRC.

Increased Risk of Nonmelanoma Skin Cancers Among Individuals With Inflammatory Bowel Disease

BACKGROUND & AIMS There are limited data on the risk of nonmelanoma skin cancer (NMSC) among individuals with inflammatory bowel disease (IBD), including those with or without exposure to immunosuppressant medications. METHODS Individuals with IBD (n = 9618) were identified from the University of Manitoba IBD Epidemiology Database and matched with randomly selected controls (n = 91,378) based on age, sex, and postal area of residence on the date of IBD diagnosis (index date). Groups were followed up from the index date until a diagnosis of any invasive cancer (including NMSC), death, migration from the province, or the end of the study (December 31, 2009), whichever came first. Cox regression analysis was performed to calculate the relative risk of NMSC among the individuals with IBD, adjusting for frequency of ambulatory care visits and socioeconomic status. RESULTS Of the individuals followed, 1696 were diagnosed with basal cell skin cancer (BCC) and 341 were diagnosed with squamous cell skin cancer (SCC). Individuals with IBD had an increased risk for BCC, compared with controls (hazard ratio, 1.20; 95% confidence interval [CI], 1.03-1.40). Among patients with IBD, use of thiopurines increased the risk of SCC (hazard ratio, 5.40; 95% CI, 2.00-14.56), compared with controls. Use of thiopurines also was associated with SCC in a case-control, nested analysis of individuals with IBD (odds ratio, 20.52; 95% CI, 2.42-173.81). CONCLUSIONS The risk of BCC could be increased among individuals with IBD. Use of thiopurines increases the risk of SCC among individuals with IBD.

Risk of Cervical Abnormalities in Women With Inflammatory Bowel Disease: A Population-Based Nested Case-Control Study

BACKGROUND & AIMS We evaluated the risk of cervical abnormalities in women with inflammatory bowel disease (IBD) in a population-based, nested, case-control study. METHODS Cases with abnormal Papanicolaou (Pap) smears or cervical biopsies were matched with up to 3 controls (normal Pap smears) by year of birth, year of first health care coverage, and number of Pap smears in the preceding 5 years. A diagnosis of IBD before the index date was identified from the University of Manitoba IBD Epidemiology Database. Exposures to immunosuppressant drugs and corticosteroids were determined from the provincial drug prescription database. Analyses were adjusted for socioeconomic status and exposure to oral contraceptives and nonsteroidal anti-inflammatory drugs. RESULTS 19,692 women with cervical cytologic and/or histologic abnormalities were matched with 57,898 controls with normal Pap smears. There was no association between cervical abnormalities and ulcerative colitis (odds ratio [OR], 1.03; 95% confidence interval [CI], 0.77-1.38). The increase in risk in women with Crohns disease was limited to those exposed to 10 or more prescriptions of oral contraceptives (OR, 1.66; 95% CI, 1.08-2.54). The combined exposure to corticosteroids and immunosuppressants was associated with increased risk of cervical abnormalities (OR, 1.41; 95% CI, 1.09-1.81). There was no interaction between the effect of IBD and corticosteroids and/or immunosuppressants. CONCLUSIONS These findings do not support an association between IBD itself and the risk of developing cervical abnormalities. An increased risk in patients given a combination of corticosteroids and immunosuppressants should be considered in managing women with IBD.

Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study.

OBJECTIVES:There is anecdotal evidence that isotretinoin use is associated with development of colitis. We aimed at determining whether there is an association between isotretinoin use and development of inflammatory bowel disease (IBD).METHODS:The population-based University of Manitoba IBD Epidemiology Database and a control group matched by age, sex, and geographical residence were linked to the provincial prescription drug registry, a registry that was initiated in 1995. The number of users and duration of isotretinoin use were identified in both IBD cases and controls.RESULTS:We found that 1.2% of IBD cases used isotretinoin before IBD diagnosis, which was statistically similar to controls (1.1% users). This was also similar to the number of IBD patients who used isotretinoin after a diagnosis of IBD (1.1%). There was no difference between isotretinoin use before Crohns disease compared with its use before ulcerative colitis.CONCLUSIONS:Patients with IBD were no more likely to have used isotretinoin before diagnosis than were sex-, age-, and geography-matched controls. Although there may be anecdotes of isotretinoin causing acute colitis, our data suggest that isotretinoin is not likely to cause chronic IBD.

Risk of Second Primary Cancer and Death Following a Diagnosis of Nonmelanoma Skin Cancer

Cancer-free patients diagnosed with a first primary nonmelanoma skin cancer (NMSC) offer an opportunity for studying the risk of a second primary cancer without the confounding effect of systemic treatment. The objective of the study was to estimate the risk of second primary cancer in people with a history of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) and the risk of dying in cancer patients with a NMSC history. BCC and SCC cases diagnosed between 1956 and 2000 in Manitoba, Canada were followed-up for second primaries (other than NMSC). Standardized incidence and mortality ratios (SIR and SMR) were calculated. Men [SIR, 1.06; 95% confidence interval (95% CI), 1.02-1.10] and women (SIR, 1.07; 95% CI, 1.02-1.12) with a BCC history as well as men (SIR, 1.15; 95% CI, 1.08-1.22) with a SCC history were at greater risk of a second primary cancer. Overall, the increased risk was observed only in the first 4 years following a NMSC, although it remained increased for specific cancer sites. The risk remained higher in all age groups up to 75 years of age. People with a history of BCC (males: SMR, 1.09; 95% CI, 1.04-1.14; females: SMR, 1.24; 95% CI, 1.16-1.32) or SCC (males: SMR, 1.18; 95% CI, 1.09-1.27; females: SMR, 1.55; 95% CI, 1.35-1.79) had a greater risk of death following their second primaries. Even if NMSC patients are at greater risk of a second cancer, it is not recommended to follow them up beyond the generally accepted periodic examination of the skin.

A phosphorylation code for oestrogen receptor-α predicts clinical outcome to endocrine therapy in breast cancer

To determine the relationship of the multiple sites of oestrogen receptor alpha (ERalpha) phosphorylation to clinical outcome after tamoxifen therapy, sections from tissue microarrays representing over 300 ER+ breast cancers from patients who were treated with surgery+radiation and then tamoxifen were used for immunohistochemical determination of total ERalpha, p-S104/106-ERalpha, p-S118-ERalpha, p-S167-ERalpha, p-S282-ERalpha, p-S294-ERalpha, p-T311-ERalpha and p-S559-ERalpha. Relationships of phosphorylated ERalpha to overall and relapse-free survival (RFS; breast cancer death or recurrence) were tested using single (univariate) and multiple (multivariate) predictor statistical models. Large tumour size, node positivity, high grade, progesterone receptor (PR) negative status and low levels of p-S282-ERalpha were significantly associated with reduced overall survival (OS). Along with tumour size and node status, a novel phosphorylation score (P(7) score > or = 3), taking into account all seven p-ERalpha sites, was significantly associated with reduced OS in univariate and multivariate analyses (hazard ratio (HR)=2.24, 95% confidence interval (CI) 1.15-4.34, n=335; P=0.018). Along with tumour size, node status, grade and PR status, a high P(7) score (> or = 3) was significantly associated with reduced RFS in univariate and multivariate analyses (HR=1.71, 95% CI 1.03-2.86, n=332; P=0.039). Since ERalpha is the site at which integration of diverse signals occurs to regulate breast cancer growth and survival, the ERalpha phosphorylation score may be a surrogate marker of the balance between oestrogen-dependent and crosstalk-dependent receptor activity, and is potentially a prognostic marker of clinical outcome in a tamoxifen-treated population of patients.