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Acetate-induced colitis promotes dimethylhydrazine-induced colonic tumors in rats
April 2000
the UC group colorectal cancer was reported in 2.8% and 2.7% of relatives respectively. Because of the uncertainty of the lifetime risk of CRC in young relatives, analysis of the prevalence of CRC in deceased grandparents was undertaken. Pooled data from both IBD groups showed a 3.2% prevalence of colorectal cancer in grandparents who had died (4.0% CD and 2.5% UC). This is consistent with the general population lifetime risk of CRC of 3% (ONS Cancer Statistics 1991). Discussion These data suggest that there is no increased prevalence of colorectal cancer in relatives of patients with inflammatory bowel disease. 1474 CANCER INCIDENCE AMONG PATffiNTS WITH INFLAMMA· TORY BOWEL DISEASE. A POPULATION BASED STUDY. Seppo E. Niemela, Jarno Valtonen, Eero I. Pukkala, Dept of Internal Medicine, Oulu Univ Hosp, Oulu, Finland; Finnish Cancer Registry, Helsinki, Finland. Patients with inflammatory bowel disease (lBD)have been shown to have an increased risk of colorectal cancer. Most of the studies are from the referral centres and there is a lack of comprehensive large scale population based studies. Aims: To describe the cancer risk pattern in Finnish IBD patients. Methods: IBD was included in the special refund category of the Finnish Social Insurance Institution (FSII) since 1986, and thus all medically treated Finnish IBD patients have been included in the register of the FSII. Cancer registration in Finland is virtually complete. A cohort of 8442 male and 7179 female patients with IBD 1986 onwards was identified from the Finnish Cancer Registry for subsequent cancer incidence up to 1997. Results: There were 542 cases of cancer in IBD patients, the expected number based on national rates being 439 (standardized incidence ratio (SIR) 1.2, 95%confidence interval 1.1-1.3). There was a statistically significant excess of cancers of the colon (SIR 2.8, 2.2-3.6), rectum (SIR 2.3, 1.7-3.2), and in male patients cancers of the liver (3.3, 1.7-5.7) and pancreas (2.0 1.2-3.2). The incidence of the lung cancer was significantly decreased (SIR 0.7, 0.5-0.9). The SIR for colorectal cancers exceeded 10 in ages 30-44 years. Conclusions: This large scale population based study confirmed the earlier results of the increased risk of colorectal cancers in IBD patients. The increased risk for liver and pancreatic cancers may reflect the coexistence of hepatobiliary and pancreatic disorders with IBD. 1475 ACETATE·INDUCED COLITIS PROMOTES DIMETHYLHYDR· AZINE·INDUCED COLONIC TUMORS IN RATS. Masaru Shinozaki, Toshiaki Watanabe, Hirokazu Nagawa, the Univ of Tokyo, Tokyo, Japan. [Background and aim] Although patients with chronic ulcerative colitis have a significantly increased risk of colorectal cancer development in comparison with the background population, the role of ulcerative colitis in the development of colorectal cancer remains unknown. Carcinogenesis is thought to consist of a combination of initiation, promotion, and progression. To clarify whether colitis promotes tumor development or not, we investigated the influence of repeated acetate enema-induced colitis on lesions induced by a single injection of 1,2-dimethylhydrazine (DMH). [Animals and methods] A dose of 200 mg/kg body weight DMH was administered to male Wistar rats, which were randomly allocated to two groups: colitis group and control group. Four weeks later, 6 ml/kg body weight 5% acetic acid (colitis group) or 0.9% saline (control group) was administered intrarectally through an 8-cm silicone catheter and continued once a week for 12 weeks. The animals were killed after 27 weeks of DMH injection. The number, size and location of macroscopic lesions and microscopic lesions detected with a stereomicroscope (aberrant crypt foci, ACF) were compared. Macroscopic tumors of 3 mm or more in diameter were evaluated histologically. Bromodeoxyuridine staining was performed to evaluate proliferave activity. Results: An increased number of macroscopic tumors was detected in the colitis group in comparison with control rats (4.18 vs. 0.89: p
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1476 CLINICAL USEFULNESS OF 1·8U EXPRESSION AND MICRO· SATELLITE INSTABILITY IN THE INFLAMED MUCOSA FOR THE PREDICTION OF COLONIC NEOPLASM IN ULCERATIVE COLITIS. Toshiyuki Tahara, Tadakazu Hisamatsu, Kazuhiro Kashiwagi, Toshihiko Ezaki, Haruhiko Ogata, Yasushi Iwao, Hiromasa Ishii, Takanori Kanai, Mamoru Watanabe, Toshifumi Hibi, Sch of Med, Keio Univ, Tokyo, Japan; Keio Cancer Ctr, Tokyo, Japan; Sch of Medicine, Keio Univ, Keio Cancer Ctr, Tokyo, Japan. Background: We have demonstrated that interferon inducible gene family 1-8U plays a significant role in the progression of ulcerative colitis (UC)associated colonic neoplasm (Cancer Res., in press, 1999). To establish an effective surveillance program for colonic neoplasm in UC with molecular biological technique, we assessed 1-8U expression and microsatellite alteration in the chronic inflamed and neoplastic colonic mucosa. Methods: I) We isolated 1-8U from UC-associated colonic neoplasm mucosa by mRNA differential display polymerase chain reaction (PCR). 1-8U expression in the colonic mucosa was assessed by Northern blot analysis or RT-PCR. 2) To detect microsatellite instability (MSI) in the colonic mucosa, extracted DNA was amplified by PCR with an appropriate pair of biotinylated primers for five rnicrosatellite loci. Results: I) 1-8U was expressed in all 5 patients with UC-associated colonic cancer and dysplasia. 2) 1-8U was significantly expressed in the inflamed UC mucosa without colonic neoplasm, but not in normal colon mucosa. 3) 1-8U expression in the inflamed colonic mucosa did not correlate with duration of the disease. 4) Eight of 12 UC-associated colonic cancer lesions (75%) and six of 12 UC-associated dysplastic lesions (50%) revealed high-level MSI (MSI-H) phenotypes. 5) Fifteen of 59 lesions (25%) in the inflamed UC mucosa without colonic neoplasm also revealed MSI-H. 6) There was no correlation between MSI-H phenotypes and duration of the disease. 7) Interestingly, all 4 cases showing MSI·H phenotypes in final diagnosis of UC-associated colonic cancer or dysplasia had already revealed MSI, 2 to 12 years before the final diagnosis at the stage of chronic colitis. Conclusions: Analysis of 1-8U expression and rnicrosatellite alteration in the inflamed colonic mucosa at surveillance colonoscopy is useful in identifying UC patients at high risk for neoplastic progression. 1477 COLORECTAL CANCER RISK IN ULCERATIVE COLITIS: FOL· LOW·UP OF A POPULATION·BASED COHORT IN COPENHA· GEN COUNTY, DENMARK, 1962 TO 1997. Karen V. Winther, Tine Jess, Ebbe Langholz, Pia Munkholm, Vibeke Binder, Dept of Gastroenterology, Herlev Univ Hosp, Copenhagen, Denmark. Background and Aims: Patients with ulcerative colitis carry increased risk of colorectal cancer. However, in a previous study of a population-based cohort of 1161 patients with ulcerative colitis diagnosed in Copenhagen County between 1962 and 1987, no increased colorectal cancer risk was observed after a median follow-up time of 12 years. The same cohort was followed-up again until the end of 1997 in order to reexamine colorectal cancer incidence and risk. The observation period was thereby prolonged another ten years to a total of 36 years, median 19 years. Methods: Patients were traced in the Danish Central Person Registry and the National Cancer and Cause-of-Death Registers. In cases of colorectal cancer individual hospital records and pathology descriptions were collected. Observed colorectal cancer incidence rates were compared with expected rates in the Danish population constructed from 1995 figures, supplied by the Danish National Board of Health and individually calculated person-years at risk. Observed versus expected cancer occurrence was presented as relative risk (RR) and compared using the :I test. The lifetime risk of colorectal cancer was calculated based on the cumulative incidence rate (CIR) as RiSko.74 = l_e·C1R . Results: By the end of 1997, a total of 14 patients had developed colorectal cancer. The expected number in a matching background population was 14.4, RR = 0.97 (NS). Five women and 9 men had developed colorectal cancer compared to expected 7.3 (RR = 0.68, NS), and 7.1 (RR = 1.27, NS) respectively. The median age at ulcerative colitis diagnosis, for those who developed cancer, was 44.5 years, (range 12-77) and the median disease duration before cancer was 12 years, (range 0-31 years). The calculated cumulative colorectal cancer incidence was 2.3% after 36 years compared to 2.5% expected. The calculated lifetime risk (0-74 years) for colorectal cancer was 2.3% compared to 3.75% in the Danish background population. Conclusion: In this population-based cohort of patients with ulcerative colitis, treated and followed from diagnosis with regular clinical control in gastroenterological departments, the previously reported absence of an increased colorectal cancer risk is now further confirmed after extension of the observation period by another ten years.
the UC group colorectal cancer was reported in 2.8% and 2.7% of relatives respectively. Because of the uncertainty of the lifetime risk of CRC in young relatives, analysis of the prevalence of CRC in deceased grandparents was undertaken. Pooled data from both IBD groups showed a 3.2% prevalence of colorectal cancer in grandparents who had died (4.0% CD and 2.5% UC). This is consistent with the general population lifetime risk of CRC of 3% (ONS Cancer Statistics 1991). Discussion These data suggest that there is no increased prevalence of colorectal cancer in relatives of patients with inflammatory bowel disease. 1474 CANCER INCIDENCE AMONG PATffiNTS WITH INFLAMMA· TORY BOWEL DISEASE. A POPULATION BASED STUDY. Seppo E. Niemela, Jarno Valtonen, Eero I. Pukkala, Dept of Internal Medicine, Oulu Univ Hosp, Oulu, Finland; Finnish Cancer Registry, Helsinki, Finland. Patients with inflammatory bowel disease (lBD)have been shown to have an increased risk of colorectal cancer. Most of the studies are from the referral centres and there is a lack of comprehensive large scale population based studies. Aims: To describe the cancer risk pattern in Finnish IBD patients. Methods: IBD was included in the special refund category of the Finnish Social Insurance Institution (FSII) since 1986, and thus all medically treated Finnish IBD patients have been included in the register of the FSII. Cancer registration in Finland is virtually complete. A cohort of 8442 male and 7179 female patients with IBD 1986 onwards was identified from the Finnish Cancer Registry for subsequent cancer incidence up to 1997. Results: There were 542 cases of cancer in IBD patients, the expected number based on national rates being 439 (standardized incidence ratio (SIR) 1.2, 95%confidence interval 1.1-1.3). There was a statistically significant excess of cancers of the colon (SIR 2.8, 2.2-3.6), rectum (SIR 2.3, 1.7-3.2), and in male patients cancers of the liver (3.3, 1.7-5.7) and pancreas (2.0 1.2-3.2). The incidence of the lung cancer was significantly decreased (SIR 0.7, 0.5-0.9). The SIR for colorectal cancers exceeded 10 in ages 30-44 years. Conclusions: This large scale population based study confirmed the earlier results of the increased risk of colorectal cancers in IBD patients. The increased risk for liver and pancreatic cancers may reflect the coexistence of hepatobiliary and pancreatic disorders with IBD. 1475 ACETATE·INDUCED COLITIS PROMOTES DIMETHYLHYDR· AZINE·INDUCED COLONIC TUMORS IN RATS. Masaru Shinozaki, Toshiaki Watanabe, Hirokazu Nagawa, the Univ of Tokyo, Tokyo, Japan. [Background and aim] Although patients with chronic ulcerative colitis have a significantly increased risk of colorectal cancer development in comparison with the background population, the role of ulcerative colitis in the development of colorectal cancer remains unknown. Carcinogenesis is thought to consist of a combination of initiation, promotion, and progression. To clarify whether colitis promotes tumor development or not, we investigated the influence of repeated acetate enema-induced colitis on lesions induced by a single injection of 1,2-dimethylhydrazine (DMH). [Animals and methods] A dose of 200 mg/kg body weight DMH was administered to male Wistar rats, which were randomly allocated to two groups: colitis group and control group. Four weeks later, 6 ml/kg body weight 5% acetic acid (colitis group) or 0.9% saline (control group) was administered intrarectally through an 8-cm silicone catheter and continued once a week for 12 weeks. The animals were killed after 27 weeks of DMH injection. The number, size and location of macroscopic lesions and microscopic lesions detected with a stereomicroscope (aberrant crypt foci, ACF) were compared. Macroscopic tumors of 3 mm or more in diameter were evaluated histologically. Bromodeoxyuridine staining was performed to evaluate proliferave activity. Results: An increased number of macroscopic tumors was detected in the colitis group in comparison with control rats (4.18 vs. 0.89: p
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1476 CLINICAL USEFULNESS OF 1·8U EXPRESSION AND MICRO· SATELLITE INSTABILITY IN THE INFLAMED MUCOSA FOR THE PREDICTION OF COLONIC NEOPLASM IN ULCERATIVE COLITIS. Toshiyuki Tahara, Tadakazu Hisamatsu, Kazuhiro Kashiwagi, Toshihiko Ezaki, Haruhiko Ogata, Yasushi Iwao, Hiromasa Ishii, Takanori Kanai, Mamoru Watanabe, Toshifumi Hibi, Sch of Med, Keio Univ, Tokyo, Japan; Keio Cancer Ctr, Tokyo, Japan; Sch of Medicine, Keio Univ, Keio Cancer Ctr, Tokyo, Japan. Background: We have demonstrated that interferon inducible gene family 1-8U plays a significant role in the progression of ulcerative colitis (UC)associated colonic neoplasm (Cancer Res., in press, 1999). To establish an effective surveillance program for colonic neoplasm in UC with molecular biological technique, we assessed 1-8U expression and microsatellite alteration in the chronic inflamed and neoplastic colonic mucosa. Methods: I) We isolated 1-8U from UC-associated colonic neoplasm mucosa by mRNA differential display polymerase chain reaction (PCR). 1-8U expression in the colonic mucosa was assessed by Northern blot analysis or RT-PCR. 2) To detect microsatellite instability (MSI) in the colonic mucosa, extracted DNA was amplified by PCR with an appropriate pair of biotinylated primers for five rnicrosatellite loci. Results: I) 1-8U was expressed in all 5 patients with UC-associated colonic cancer and dysplasia. 2) 1-8U was significantly expressed in the inflamed UC mucosa without colonic neoplasm, but not in normal colon mucosa. 3) 1-8U expression in the inflamed colonic mucosa did not correlate with duration of the disease. 4) Eight of 12 UC-associated colonic cancer lesions (75%) and six of 12 UC-associated dysplastic lesions (50%) revealed high-level MSI (MSI-H) phenotypes. 5) Fifteen of 59 lesions (25%) in the inflamed UC mucosa without colonic neoplasm also revealed MSI-H. 6) There was no correlation between MSI-H phenotypes and duration of the disease. 7) Interestingly, all 4 cases showing MSI·H phenotypes in final diagnosis of UC-associated colonic cancer or dysplasia had already revealed MSI, 2 to 12 years before the final diagnosis at the stage of chronic colitis. Conclusions: Analysis of 1-8U expression and rnicrosatellite alteration in the inflamed colonic mucosa at surveillance colonoscopy is useful in identifying UC patients at high risk for neoplastic progression. 1477 COLORECTAL CANCER RISK IN ULCERATIVE COLITIS: FOL· LOW·UP OF A POPULATION·BASED COHORT IN COPENHA· GEN COUNTY, DENMARK, 1962 TO 1997. Karen V. Winther, Tine Jess, Ebbe Langholz, Pia Munkholm, Vibeke Binder, Dept of Gastroenterology, Herlev Univ Hosp, Copenhagen, Denmark. Background and Aims: Patients with ulcerative colitis carry increased risk of colorectal cancer. However, in a previous study of a population-based cohort of 1161 patients with ulcerative colitis diagnosed in Copenhagen County between 1962 and 1987, no increased colorectal cancer risk was observed after a median follow-up time of 12 years. The same cohort was followed-up again until the end of 1997 in order to reexamine colorectal cancer incidence and risk. The observation period was thereby prolonged another ten years to a total of 36 years, median 19 years. Methods: Patients were traced in the Danish Central Person Registry and the National Cancer and Cause-of-Death Registers. In cases of colorectal cancer individual hospital records and pathology descriptions were collected. Observed colorectal cancer incidence rates were compared with expected rates in the Danish population constructed from 1995 figures, supplied by the Danish National Board of Health and individually calculated person-years at risk. Observed versus expected cancer occurrence was presented as relative risk (RR) and compared using the :I test. The lifetime risk of colorectal cancer was calculated based on the cumulative incidence rate (CIR) as RiSko.74 = l_e·C1R . Results: By the end of 1997, a total of 14 patients had developed colorectal cancer. The expected number in a matching background population was 14.4, RR = 0.97 (NS). Five women and 9 men had developed colorectal cancer compared to expected 7.3 (RR = 0.68, NS), and 7.1 (RR = 1.27, NS) respectively. The median age at ulcerative colitis diagnosis, for those who developed cancer, was 44.5 years, (range 12-77) and the median disease duration before cancer was 12 years, (range 0-31 years). The calculated cumulative colorectal cancer incidence was 2.3% after 36 years compared to 2.5% expected. The calculated lifetime risk (0-74 years) for colorectal cancer was 2.3% compared to 3.75% in the Danish background population. Conclusion: In this population-based cohort of patients with ulcerative colitis, treated and followed from diagnosis with regular clinical control in gastroenterological departments, the previously reported absence of an increased colorectal cancer risk is now further confirmed after extension of the observation period by another ten years.