Family history as a risk factor for colorectal cancer in inflammatory bowel disease.

BACKGROUND & AIMS: Familial colorectal cancer (CRC) is a risk factor for CRC in healthy individuals and, as indicated by case-control studies, possibly in ulcerative colitis. Little is known about the cancer risk in familial inflammatory bowel disease (IBD). We assessed the significance of familial CRC, or IBD, on the risk for CRC in patients with IBD. METHODS: Population-based cohort study of 19,876 individuals with ulcerative colitis or Crohn's disease born between 1941 and 1995. Registry-based follow-up and assessment of familial CRC, and IBD. Risk of CRC assessed as incidence proportion ("absolute risk," IP) and relative risk (RR). RESULTS: Familial CRC was associated with a more than 2-fold risk of CRC (adjusted RR = 2.5, 95% confidence interval 1.4-4.4) and an increase in the IP of CRC at 54 years of age from 3.8% to 6.9%. Patients with a first-degree relative diagnosed with CRC before 50 years of age had a higher RR (9.2, 95% confidence interval 3.7-23) and the highest IP (29%). No association with familial IBD was observed. CONCLUSIONS: Information on family history of CRC may be a simple way to identify individuals with IBD at elevated risk of developing CRC.

Colorectal cancer rates among first-degree relatives of patients with inflammatory bowel disease: a population-based cohort study.

BACKGROUND: Inflammatory bowel disease (IBD) and colorectal cancer might share a common cause and, therefore, relatives of patients with IBD could be at increased risk of this malignant disease. We aimed to assess cancer rates among first-degree relatives of patients with IBD to try to determine whether an association between the two diseases exists. METHODS: In a population-based study, we identified 114,102 first-degree relatives by registry linkage and followed them up for cancer occurrence. We used standardised incidence ratio (SIR) of cancer as relative risk. FINDINGS: 560 colorectal cancers were identified among relatives. First-degree relatives of patients with Crohn's disease or ulcerative colitis were not at increased risk of cancer (SIR 0.90, 95% CI 0.82-0.97). The relative risk was 0.96 (0.87-1.06, n=379) for colon cancer and 0.78 (0.68-0.91, 181) for rectal cancer. The SIRs were not affected by age, relation to patient, or type or extent of IBD in the patient. Relatives of patients with both IBD and colorectal cancer had an 80% increased risk of colorectal cancer. INTERPRETATION: Our results do not endorse a common cause of IBD and colorectal cancer. The slightly decreased relative risk for colorectal cancer among relatives could indicate the proportion of all colorectal cancer cases attributable to IBD.

[Learning among medical students. Teachers' commitment a decisive factor]. / Inlärning hos läkarstuderande. Lärarnas engagemang en avgörande faktor.

During their medical education, students take many courses in a variety of scientific subjects. This is most noticeable during the 5th term, when 6 subjects are taught in parallel during a 10 week period. This makes the process of learning very important. Using a modified written questionnaire we asked for students' opinions on factors important for learning. For crucial parameters such as coherence in knowledge and study motivation the students considered teachers' interest in students' learning to be the critical factor.

Allopurinol in addition to 5-aminosalicylic acid based drugs for the maintenance treatment of ulcerative colitis.

BACKGROUND: To investigate the value of combined treatment with allopurinol and 5-aminosalicylic (5-ASA) based drugs as maintenance treatment for ulcerative colitis (UC). METHODS: 199 patients with UC in remission but with active disease during the preceding 3 years were included. Allopurinol 100 mg twice daily or placebo was added to the 5-ASA based maintenance treatment. Clinical and endoscopic follow up was performed after 1, 6 and 12 months. RESULTS: Intention-to-treat analysis after 6 and 12 months showed similar results in both groups. A log-rank test showed that 77% in the allopurinol compared to 59% in the placebo group were still in remission after 6 months (P=0.0083) and 62% and 53% after 12 months, respectively (P=0.0936). This was mainly due to a higher than expected number of relapses during the first 3 months in the placebo group. After the first 3 months, the rate of relapse in each group was similar. CONCLUSIONS: It appears possible that allopurinol in combination with 5-ASA is better than 5-ASA alone for a 6-month, but not a 12-month period. This has to be verified in further dose-ranging studies.

Increased risk of cancer in ulcerative colitis: a population-based cohort study.

OBJECTIVE: There is an increased risk of colorectal cancer among patients with ulcerative colitis (UC). However, the overall and site specific cancer risks in these patients have been investigated to a limited extent. To study the association between UC and cancer, a population-based study of 1547 patients with UC in Stockholm diagnosed between 1955 and 1984 was carried out. METHODS: The patients were followed in both the National Cancer Register and the National Cause of Death Register until 1989. For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the UC disease cohort. RESULTS: A total of 121 malignancies occurred among 97 individuals as compared with 89.8 expected (standardized morbidity ratio [SMR] = 1.4; 95% confidence interval (CI), 1.1-1.6). Overall, an excess number of colorectal cancers (SMR, 4.1; 95% CI, 2.7-5.8), and hepatobiliary cancers in men (SMR = 6.0; 95% CI, 2.8-11.1) associated with primary sclerosing cholangitis, was observed. The risk of pulmonary cancer was decreased (SMR = 0.3; 95% CI, 0.1-0.9). In all, 91 extracolonic malignancies were observed, compared with the 82.3 expected (SMR = 1.11; 95% CI, 0.9-1.3). CONCLUSIONS: In UC patients, the overall cancer incidence is increased mainly because of an increased incidence of colorectal and hepatobiliary cancer. This increase is partly counterbalanced by a decreased risk of pulmonary cancer compared with that in the general population.

Sialyl-Tn antigen as a marker of colon cancer risk in ulcerative colitis: relation to dysplasia and DNA aneuploidy.

BACKGROUND & AIMS: Expression of the mucin-associated carbohydrate antigen sialyl-Tn (STn) and DNA aneuploidy has each been shown to correlate with malignant transformation in patients with sporadic colon cancer and in those with ulcerative colitis (UC). This study aimed to determine how STn expression topographically and temporally relates to aneuploidy and neoplasia in patients with long-standing UC. METHODS: Twenty-six patients enrolled in a cancer surveillance program were studied, and 1691 mucosal specimens from repeated colonoscopies and colectomies were assessed in a standardized, prospective fashion for the presence of dysplasia, aneuploidy, and STn antigen. RESULTS: STn was expressed in 47% of specimens from 6 patients who underwent colectomy for dysplasia and 7% of specimens from 6 well-matched patients who underwent surgery for medical intractability. Seven other patients who never developed dysplasia or aneuploidy expressed STn in 6% of biopsy specimens. STn expression was independent of aneuploidy in colons both with and without dysplasia. Of 5 patients with aneuploidy but without dysplasia, 4 expressed STn earlier than aneuploidy. CONCLUSIONS: In UC, STn antigen and DNA aneuploidy are independent markers of neoplastic transformation. Determination of STn expression may complement dysplasia and aneuploidy for identification of risk for colonic neoplasia in UC.

Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study.

BACKGROUND: Colonoscopic surveillance is a standard procedure in many patients with long standing, extensive ulcerative colitis (UC), in order to avoid death from colorectal cancer. No conclusive proof of its benefits has been presented however. AIMS: To evaluate the association between colonoscopic surveillance and colorectal cancer mortality in patients with UC. PATIENTS: A population based, nested case control study comprising 142 patients with a definite UC diagnosis, derived from a study population of 4664 patients with UC, was conducted. METHODS: Colonoscopic surveillance in all patients with UC who had died from colorectal cancer after 1975 was compared with that in controls matched for age, sex, extent, and duration of the disease. Information on colonoscopic surveillance was obtained from the medical records. RESULTS: Two of 40 patients with UC and 18 of 102 controls had undergone at least one surveillance colonoscopy (relative risk (RR) 0.29, 95% confidence interval 0.06 to 1.31). Twelve controls but only one patient with UC had undergone two or more surveillance colonoscopies (RR 0.22, 95% confidence interval 0.03 to 1.74), indicating a protective dose response relation. CONCLUSION: Colonoscopic surveillance may be associated with a decreased risk of death from colorectal cancer in patients with long standing UC.

Crohn's disease and cancer: a population-based cohort study.

BACKGROUND/AIMS: To study the association between Crohn's disease and cancer, we performed a population-based study of 1251 subjects with Crohn's disease diagnosed in Stockholm from 1955 to 1984 and followed in both the National Cancer Register and the National Cause-of-Death Register until 1989. METHODS: For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the Crohn's disease cohort. RESULTS: Overall, 69 malignancies occurred among 67 individuals as compared with 59.80 expected malignancies (standardized morbidity ratio [SMR] = 1.15; 95% confidence interval, 0.90-1.46). An excess number of cancers of the upper gastrointestinal tract (SMR, 3.05; 95% confidence interval, 1.67-5.11) was observed, mainly because of an increased number of cancers of the small intestine (SMR, 15.64; 95% confidence interval, 4.26-40.06). An increased occurrence of urinary bladder cancer was also observed (SMR, 2.68; 95% confidence interval, 1.08-5.53). CONCLUSIONS: The occurrence of colorectal cancer was not increased.

DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia.

Fifty-nine patients with longstanding, total ulcerative colitis were followed up in a prospective colonoscopic surveillance program. Biopsy specimens were sampled from predetermined locations of the colon and rectum at regular intervals. All specimens were assessed for histological dysplasia and, by flow cytometry, for detection of DNA aneuploidy during 8 years of follow-up. Special emphasis was made to correlate the findings of DNA aneuploidy with findings of dysplasia at colonoscopy or, in case proctocolectomy was performed, in the surgical specimen. Fifteen patients (25.4%) had DNA aneuploidy detected at least once during the follow-up. Eight of 10 patients with repeated findings had consistent ploidy level of the aneuploid peaks from one examination to another. Ten patients had multiple peaks. DNA aneuploidy tended to become more widespread in the bowel during the follow-up but persisted in the same part(s) of the colon and rectum. DNA aneuploidy occurred before development of definite dysplasia in 6 patients, simultaneously with development of dysplasia in 6 patients, and after the development of dysplasia in 1 patient only. In 2 patients, single aneuploid peaks were detected once but could not be found again at subsequent examinations. Dysplasia correlated closely topographically to DNA aneuploidy, but the latter finding was more common without concomitant dysplasia. Only in 1 patient, and at one examination, definite dysplasia was recorded without findings of DNA aneuploidy. Detection of DNA aneuploidy in patients with ulcerative colitis is persistent and reproducible and closely correlated to dysplasia. Widespread changes indicate that the entire colorectal mucosa is at increased risk of malignant transformation. Changes in nuclear DNA content appear to be an earlier phenomenon than dysplasia in the malignant transformation of the colorectal mucosa in ulcerative colitis, and the use of flow cytometry in surveillance programs may be of value for selection of patients at high risk of developing colorectal carcinoma.

Carcinoma and DNA aneuploidy in Crohn's colitis--a histological and flow cytometric study.

Twenty four patients with longstanding colonic Crohn's disease were examined prospectively with colonoscopy and multiple biopsy sampling in order to detect histological dysplasia or abnormal aneuploid DNA content, or both. Biopsy specimens were taken from 10 predetermined locations in the colon and rectum. No patient had definite dysplasia but three displayed DNA aneuploidy (12.5%), and one of these subsequently developed a carcinoma (Dukes' C at operation) in the ascending colon. No concomitant dysplasia was detected but the carcinoma as well as other parts of the mucosa were DNA aneuploid. It is concluded that dysplasia is rare in patients with Crohn's colitis, but findings of DNA aneuploidy warrant vigilance in follow up as this may indicate impending carcinoma. Further prospective studies are needed before the predictive value of DNA aneuploidy can be determined and before general recommendations of colonoscopic surveillance, as in longstanding ulcerative colitis, can be made.

Mucosal dysplasia and DNA content in ulcerative colitis patients with ileorectal anastomosis. Follow-up study in a defined patient group.

In a follow-up study of an epidemiologically defined patient group comprising 1,274 patients with ulcerative colitis diagnosed in Stockholm County during 1955-1979, 55 patients had undergone colectomy with ileorectal anastomosis (IRA). Nine of these were found to have Crohn's disease after histopathologic review of the colectomy specimens. Of the 46 patients with ulcerative colitis remaining for evaluation, two died postoperatively. Twenty-five patients were subsequently reoperated with rectal excision owing to intractable inflammatory activity (n = 22, one postoperative death) or owing to dysplasia (n = 3). Of 19 patients with their IRA still intact at time of follow-up, 15 patients (median disease duration 23 years) had a flexible sigmoidoscopy with multiple biopsies performed. The average length of the remaining rectum and sigmoid colon was 26 cm. No patient had findings of dysplasia, carcinoma, or DNA aneuploidy. None of the four remaining patients had developed dysplasia or carcinoma at the time of the latest regular rigid sigmoidoscopy. The risk of malignant transformation in this selected group of patients with ulcerative colitis operated upon with colectomy and IRA derived from an epidemiologically defined population seems to be low.

Colonoscopic surveillance in long-standing total ulcerative colitis--a 15-year follow-up study.

In a 15-year surveillance program composed of 72 patients with total ulcerative colitis, 12 patients developed definite dysplasia. At endoscopy, low-grade dysplasia was detected in seven patients, high-grade in four, and a carcinoma (Dukes' stage A at operation) in one. One of the patients with high-grade dysplasia and macroscopical lesions at colonoscopy had a carcinoma (Dukes' A) detected at operation. A sequential development of dysplasia was found in seven patients. The cumulative risk of developing at least low-grade dysplasia was 14% after 25 years of disease duration. Using flow cytometric analyses, abnormal, aneuploid DNA content was detected in biopsies of 12 of 59 patients (20.3%); this correlated significantly with low-grade and high-grade dysplasia. Aneuploidy preceded dysplasia in two patients and was also detected in two dysplasia-free patients. The long-term use of colonoscopic surveillance in ulcerative colitis is a reliable way to select patients, in whom dysplasia is developing, for prophylactic surgery. Additionally, flow cytometric DNA analyses may help in the selection. The risk of missing a carcinoma until it becomes incurable appears to be low.

Prognosis in ulcerative colitis.

In unselected patient populations with ulcerative colitis the overall prognosis is good and has improved over the years. There is still an appreciable excess mortality, however, particularly during the first years after diagnosis and it tends to increase with duration of disease. Patients with severe attacks, total colitis, and high age at diagnosis are particularly at risk. The disease runs an inactive or intermittent course in the majority of patients, although up to one fifth of the patients have a progress of the original extent of the colitis. Worldwide, there has been a time trend of decreased mortality possibly affecting younger patients in particular. Complications of the acute attack with or without surgery, liver disease, and colon cancer account for the major part of the colitis-related deaths whereas the mortality pattern in other respects does not differ significantly from that of the general population. The colon cancer incidence seems lower than previously reported but still accounts for approximately one tenth of all deaths. If this figure can be improved with cancer surveillance and prophylactic colectomy seems probable but remains to be shown. Pregnancy, if planned, should be encouraged when the patient is in remission although the disease or its standard treatment does not seem to dangerously affect the patient, fetus, or the newborn infant. Surgical and medical treatment probably accounts for most of the improvement in prognosis seen over the years. The postoperative mortality has been reduced, especially in series where new surgical procedures have been used. A high frequency of major postoperative complications still remains a challenge for improvement. The medical intensive treatment of the acute attack has contributed to the improved prognosis. If compliance is good, the sulfasalazine prophylaxis may be one of the explanations to the change into a milder disease pattern that has been observed recently. Finally, and most important, a majority of patients sustain a normal life with full working capacity. Those who have surgery adapt well, particularly when a continence-saving procedure is used. The sexual function follows the improvement although the patient's need for support and counseling should not be underestimated.

Surgical treatment of ulcerative colitis in Stockholm County, 1955 to 1984.

Time trends in surgical treatment of ulcerative colitis in Stockholm County over the 30-year period 1955 to 1984 were investigated. Four hundred eighty-six patients (263 men and 223 women) were submitted to colectomy with or without proctectomy. In elective cases, proctocolectomy was the procedure of choice until the 1980s, when subtotal colectomy became more common. In acute cases subtotal colectomy was the procedure of choice during the entire period. Major complications developed in 162 patients (33 percent) and 103 (21 percent) underwent another operation. The frequency of major complications increased, with the urgency of intervention being 25 percent in elective cases and 46 percent in acute cases (P less than .001). The postoperative mortality was 1.7 percent in 301 elective cases and 9.2 percent in 185 acute cases (P less than .001). The overall postoperative mortality was 4.5 percent and fell from 13 percent during 1960 to 1964 to 2.0 percent during 1980 to 1984 (P less than .01). In acute cases, the mortality during the same two periods fell from 36 to 3.0 percent (P less than .001). The postoperative mortality for proctocolectomy (2.7 percent) was significantly lower (P less than .01) than for subtotal colectomy (9.0 percent). Seventy-four percent of the patients treated by subtotal colectomy were acute cases, however, with a mortality of 11 percent and only 30 percent of the proctocolectomy cases were acute cases, with a mortality of 6.5 percent.

Ulcerative colitis and colon cancer: the role of surveillance.

Colon cancer is a well known complication of ulcerative colitis. Various methods have been discussed to reduce its risk. Since the introduction of the concept epithelial dysplasia and fiberoptic colonoscopy surveillance programmes have been launched based on these methods. The incidence of colon cancer in ulcerative colitis is moderately increased but constitutes only a fraction of all colon cancers diagnosed. Among these patients colon cancer almost exclusively affects those with extensive colitis. Duration of disease in these cases usually exceeds eight to ten years. The true benefit of a cancer surveillance programme will probably never be the subject of controlled prospective studies and is therefore difficult to evaluate. The concept of dysplasia is the major instrument for selecting patients for prophylactic colectomy. Development from normal mucosa to high grades of dysplasia shows individual variations from one to several years justifying annual colonoscopies in high risk patients. Strict criteria for dysplasia and independent evaluations from several pathologists should compensate for the subjective nature of dysplasia interpretation. The need for more objective markers such as DNA-flow cytometry is clearly needed. The role of DNA flow cytometry in surveillance, however, needs to be determined. The cost benefit aspects of such surveillance programmes have to be balanced against the total resources of a gastroenterology unit.

Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres.

A retrospective cohort of 823 patients with ulcerative colitis who resided at the time of diagnosis in one of three defined geographical areas (West Midlands region, Oxford region, England and Stockholm County, Sweden) was assembled. The patients were first seen at named hospitals in these areas and the diagnosis of ulcerative colitis established within five years of onset of symptoms between 1945-1965. All patients were 15 years of age or more at onset of disease and were followed for a minimum of 17 years and a maximum of 38 years. Ninety seven per cent completeness of follow up was achieved. Examining the colorectal cancer risk in the series relative to the risk in the general population by standardised morbidity ratios, there was an eight fold increased risk of cancer in the series as a whole. Dividing the series by extent of colitis, extensive colitis patients showed a 19 fold increase in risk. A four fold increased risk was shown in the remainder of the series (left sided colitis, proctitis and extent unknown). Life table analyses in extensive colitis gave cumulative risks of 7.2% (CI 3.6-10.8) at 20 years from onset of disease and 16.5% (CI 9.0-24.0) at 30 years from onset. No significant effect of age at onset, sex or referral centre could be detected. Examination of the data by interval from onset to cancer and by actual age at development of cancer suggests that patients who develop colorectal cancer will do so in a distribution around 50 years of age independent of duration of disease in adult onset ulcerative colitis (greater than 15 years at onset of disease). An inverse relationship was shown between age at onset of disease and interval from onset of disease to cancer. Further age specific rates for cancer increased up to 50 years and decreased thereafter. These results suggest that extensive colitis patients have a genetic predisposition to colorectal cancer and that longstanding inflammation is not of primary importance in the initiation/promotion of cancer in this disease.

The risk of colorectal cancer in ulcerative colitis. An epidemiologic study.

Patients with a definite diagnosis of ulcerative colitis in Stockholm County during the 35-year period 1945-79 were identified and followed up with regard to the development of cancer of the colon. We found 25 patients who had developed 31 cancers. In 24 of 25 cases this occurred in patients with total colitis. The cumulative risk of developing cancer for patients with total colitis at follow-up study was calculated by means of life-table methods. It was 13% at 25 years (SD +/- 4.2%) among patients diagnosed in 1945-79, compared with the 1.9% expected in a population matched for age and sex. Among patients diagnosed in 1955-79 the risk was approximately 5% at 20 years (SD +/- 3.0%), compared with 1.4% for the background population. The cancer risk for all patients with colitis was higher but not significantly higher than that of the general population. The outcome of patients who developed cancer was dependent on histologic staging (Dukes's) at surgery but not on age at cancer diagnosis.