Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine — A 30 year study

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1469 CHROMOSOMAL INSTABILITY IS ASSOCIATED WITH TELO· MERE SHORTENING IN UC PATIENTS WITH DYSPLASIA OR CANCER. David A. Crispin, Shawna M. Dziadon, Rodger C. Haggitt, Peter S. Rabinovitch, Mary P. Bronner, Univ of Washington, Seattle, WA. Introduction: We have previously reported that chromosomal instability (CIN) is present through-out the colons of UC patients with dysplasia/ cancer, even in mucosa that is histologically negative. We have now determined that shortened telomere length is directly associated with CIN. We hypothesize that the CIN found in UC mucosa may be a product of a bridge-breakage-fusion mechanism that occurs secondary to sticky ends when telomeres become short. Methods:To directly test this hypothesis, we assayed controls (n=5) and histologically negative rectal biopsies from UC patients with dysplasia/cancer elsewhere (n= 13), for both CIN and telomere length. We used a quantitative histologic assay of telomere length based on in situ hybridization with telomere-specific protein nucleic acid (PNA) probes. In situ histologic evaluation allows us to compare telomere length in epithelial cells and stromal cells, using the latter as a control for the former. CIN is deterimined by flourescence in situ hybridization (FISH) analysis of epithelium from the other half of the same biopsy. Results: Chromosomal arm and centromere losses (but not gains) are statistically related to telomere shortening [R=0.73 (p= 0.0006) and R=0.75 (p=0.0004), respectively]. Conclusion: CIN and shortened telomeres are both present in non-dysplastic mucosa from UC patients who have dysplasia/cancer elsewhere. Moreover, the extent of telomere shortening is directly proportional to the level of CIN. We speculate that oxidative injury and cellular proliferation, associated with chronic inflammation in UC, may cause telomere shortening and this in turn may lead to chromosomal instability and neoplastic progression. 1470 DECISION ANALYSIS OF SURVEILLANCE FOR COLORECTAL CANCER IN ULCERATIVE COLITIS. Fabiola Delco, Amnon Sonnenberg, VA Med Ctr - II IF, Albuquerque, NM. Background and Aim: Patients with long-standing, extensive ulcerative colitis harbor an increased risk of developing colorectal cancer. The aim of the study is to assess the feasibility of surveillance colonoscopy in preventing death from colorectal cancer. Methods: In a hypothetical cohort of 1000 50-year old patients with chronic ulcerative colitis, the benefit of life years saved are weighted against the costs of bi-annual colonoscopy, proctocolectomy, and the terminal care of patients dying from colorectal cancer. Two separate Markov processes are modeled to compare the cost-benefit relationship in patients with or without surveillance. The cumulative lifetime probability of developing colorectal cancer serves as a threshold to determine which of the two management strategies is associated with a larger net benefit. Results: If the cumulative probability of colorectal cancer exceeds a threshold value of 27%, surveillance becomes more beneficial than no surveillance. This calculated threshold is only slightly lower than the expected true cumulative cancer rate of 30%. Varying the cost of colonoscopy between $200, $500 and $1,500 results in changes of the threshold value between 18%,21 % and 35%, respectively. Changes in the sensitivity by 10% have little influence on the threshold. As the sensitivity decreases from baseline 95% to 80%, the threshold rises to 36%. High mortality rates of colorectal cancer despite surveillance negate the benefit surveillance. For instance, an increase in mortality from baseline 13% to 26% raises the threshold to 35%. A reduction in health-related quality of life (HRQL) after proctocolectomy exerts the strongest influence on the threshold; a decrease of HRQL from baseline 95% to 85% increases the threshold from baseline 27% to 64%. If several of the assumptions built into the model are varied jointly, even small changes can lead to extreme threshold values. Conclusions: It is not possible to prove that frequent colonoscopies scheduled at regular intervals are an effective means to manage the increased risk of colorectal cancer associated with ulcerative colitis. 1471 LONG-TERM RISK OF MALIGNANCY AFTER TREATMENT OF INFLAMMATORY BOWEL DISEASE WITH AZATHIOPRINE· A 30 YEAR STUDY. Alan G. Fraser, Derek P. Jewell, Dept of Gastroenterology, Oxford, United Kingdom. Background: Data from renal transplant and rheumatoid arthritis patients suggests that there is an increased risk of malignancy after treatment with azathioprine. Whether this is true for inflammatory bowel disease patients remains uncertain. Methods: Clinical records from 2205 patients (855 Crohn's disease and 1350 ulcerative colitis attending the inflammatory bowel disease clinic at the John Radcliffe Hospital, Oxford were reviewed. Results: Azathioprine was given to 626 patients (1968-99). The mean duration of azathioprine use (total of all courses) was 26.5 months. The mean duration of follow-up from diagnosis was 13.7 years (8423 patientyears) and the mean duration of follow-up from start of azathioprine treatment was 6.9 years. Patients given azathioprine were more likely to have Crohn's disease than ulcerative colitis and patients with ulcerative colitis were more likely to have total colitis. The observed number of colorectal cancers (including patients with DALM and high-grade dyspla-

GASTROENTEROLOGY Vol. 118, No.4

sial for patients given azathioprine was 4/134 (3.0%) for total colitis and 3/165 (1.8%) for left-sided colitis. For patients not given azathioprine 18/294 (6.1%) and 10/333 (3.0%) had colorectal cancer (including dysplasia) for total colitis and left-sided colitis respectively. No cancers were observed in 411 patients with proctitis only. For Crohn' s disease, 7 patients had colorectal cancer; 3 had been given azathioprine. The risk of colorectal cancer was higher for male sex (p=0.OO4) and for ulcerative colitis (p=0.02), there was a trend for greater extent of colitis to be significant (total colitis> left-sided colitis, p=0.07) but azathioprine treatment was not significant (Cox regression analysis). The cumulative risk of colorectal cancer (including dysplasia) after 10, 20, 30 and 40 years of ulcerative colitis was 0.5%, 1.3%,2.4% and 7.6% respectively. For all other cancer diagnoses, 17/619 (2.7%) had been given azathioprine and 44/1586 (2.8%) had not been given azathioprine treatment (adjusted for 7 patients with cancer diagnosis before treatment given). Seven patients had lymphoma; 3 had been given azathioprine prior to cancer diagnosis; I had rheumatoid arthritis and ulcerative colitis). Conclusion: Azathioprine treatment does not increase the risk of colorectal cancer or other tumours for patients with Crohn's disease or ulcerative colitis. The risk of colorectal cancer is higher for male sex, for ulcerative colitis and increases with years of IBD diagnosis.

1472 IS THERE AN INCREASED RISK OF INTESTINAL AND EXTRAINTESTINAL CANCER IN PATIENTS WITH CROHN'S DIS· EASE? A POPULATION·BASED COHORT FOLLOWED FROM 1962 TO 1997. Tine Jess, Karen V. Winther, Pia Munkholm, Ebbe Langholz, Vibeke Binder, Dept of Gastroenterology, Herlev Univ Hosp, Copenhagen, Denmark. Background: Both small bowel cancer and colorectal cancer have been reported increased in patients with Crohn's disease (CD) in long term studies from referral centers. In a strictly regional cohort of patients with CD we previously published a significantly increased risk of small bowel cancer (2/0.04; RR 50; p=O.OOI) but no increase in colorectal cancer (2/1.8; RR l.l; NS). The median observation time was, however, only 8.5 years (range, 1-26). The cohort has been reassessed and the median observation period thereby prolonged to 17 years (range, 1-36). Aim: To estimate the risk of intestinal and extra intestinal cancer in patients with CD compared to the Danish background population. Material and Methods: The cohort comprises 374 patients with CD diagnosed in Copenhagen County within the period 1962-1987. The observation time of the cohort was extended until the 31st of December 1997. The patients were followed until end of the study, death or emigration, confirmed by the Danish Central Person Registry. Relative risk (RR) as observed/expected cancer occurrence (according to age and gender-matched numbers from the Danish National Cancer Registry) and lifetime cancer riSko_74 = l_e-C IR(o.74) were calculated. Results: 9 cancers of the gastrointestinal tract were found in 8 of the 374 patients. One gastric cancer, 4 cancers of the small intestine, 2 colonic and 2 rectal cancers. (One patient had two simultaneously occurring carcinomas in the ileocecal region). RR of small bowel cancer was 4/0.06 = 66.7 (p
1473 THE PREVALENCE OF COLORECTAL CANCER IS NOT IN· CREASED IN THE DECEASED GRANDPARENTS OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE. Keith Leiper, Peter L. McLaren, Jonathan M. Rhodes, Univ of Liverpool, Liverpool, United Kingdom. Background The relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) is complex. It is commonly assumed that the extent and duration of inflammation are the prime factors in increasing the risk of CRC in IBD. However, although the relative risk of CRC is increased with early age of onset of UC, the risk remains constant over time. Furthermore proctitis and proctosigmoiditis have a negligible increased CRC risk irrespective of disease activity and long term remission from IBD symptoms does not reduce the risk of CRe. We hypothesised that the risk of developing IBD and CRC could be coinherited factors rather than causally linked. If this hypothesis is correct there should be an increased prevalence of CRC in relatives of patients with IBD. Methods A self reported questionnaire was administered to outpatients with IBD. Questions included personal cancer history and cancer and IBD history in first and second degree relatives. Case note review was used to validate self reported IBD diagnosis and determine the extent of disease. Data was analysed by Fischer exact and chi-square tests. Results One hundred and fifty one patients returned questionnaires and had the diagnosis of IBD confirmed by case note review. Sixty eight had Crohn's disease (CD) and 83 ulcerative colitis (UC). Mean age (SD) were 45 (12) for UC and 43 (12) for CD. From a total of 540 relatives in the CD group and 692 relatives in