Familial adenomatous polyposis: mental health, psychosocial functioning and reactions to genetic risk in adolescents.

Familial adenomatous polyposis (FAP) in a parent requires diagnostic follow-up and treatment from adolescence in possible gene carriers in order to prevent cancer development. A nationwide sample (n = 22) of adolescent FAP offspring including 85% of eligible individuals aged 11-20 years and their parents were interviewed with regard to adolescent mental health, psychosocial functioning, knowledge about FAP and genetic risk, and experiences with testing and surgery. Thirty-six percent of the FAP offspring fulfilled criteria for a psychiatric diagnosis. For adolescents older than 15 years, this was increased relative to a comparison group with Hirschprung's disease and a general population sample. Neither genetic testing nor FAP diagnosis in adolescent FAP-offspring differentiated significantly between those who fulfilled the criteria and those who did not for psychiatric diagnosis, while a global score of chronic family difficulties did. This may imply that experiencing parental illness more than inheriting FAP is a perceived stressor for adolescent FAP offspring.

Relationship between Fecal Content of Fatty Acids and Cyclooxygenase mRNA Expression and Fatty Acid Composition in Duodenal Biopsies, Serum Lipoproteins, and Dietary Fat in Colectomized Familial Adenomatous Polyposis Patients.

A few familial adenomatous polyposis studies have focused upon faecal sterols and bile acids but none has analysed the fecal content of fatty acids. We report here findings of an observational study on 29 colectomized familial adenomatous polyposis patients that describe the fecal content of fatty acids, and relate this to the proportions of fatty acids and levels of cyclooxygenase mRNA expression in duodenal biopsies, levels of serum lipoproteins, and diet. In the ileostomy group separately (n = 12), the fecal content of arachidonic acid was correlated negatively to the proportions of eicosapentaenoic acid and docosahexaenoic acid in duodenal biopsies. Total serum-cholesterol was negatively correlated to the fecal content of saturates and monounsaturates. The fecal palmitoleic acid/palmitic acid ratio was positively correlated to the levels of cyclooxygease-2 expression in duodenal biopsies.In the ileal-pouch-anal anastomosis group separately (n = 17), significant correlations were found between the fecal contents of oleic acid, linoleic acid, and alpha-linolenic acid, and the proportions of myristic acid, oleic acid and eicosaenoic acid in duodenal biopsies. Dietary monounsaturates were positively correlated to different fecal fatty acids. Future studies should focus on molecular mechanisms relevant to fatty acid metabolism, inflammation, and angiogenesis, in addition to nutrition.

Carbon dioxide insufflation in colonoscopy: safe and effective in sedated patients.

BACKGROUND AND STUDY AIMS: Several studies have shown that insufflation of carbon dioxide (CO2) instead of air during colonoscopy can reduce postprocedural pain. However, CO2 insufflation might also lead to CO2 retention in the human body. It was recently shown that this side effect does not occur in unsedated patients, but that sedation leads to impaired respiration. Sedated patients may therefore be more prone to CO2 retention. This randomized, double-blinded study was designed to investigate whether CO2 insufflation leads to CO2 retention in sedated patients. PATIENTS AND METHODS: A total of 103 consecutive patients undergoing colonoscopy were randomly assigned to the use of either CO2 or air insufflation. End-tidal carbon dioxide (ETCO2), a noninvasive parameter for arterial P CO2, was recorded before the examination, twice during it, and 10 min after it. Midazolam or pethidine, or both, were used for sedation. The patient's pain during the examination and 1, 3, 6, and 24 h afterwards was registered using a questionnaire. RESULTS: CO2 was used in 52 patients and air insufflation in 51. A total of 52 patients (51 %) received sedation. There were no differences in ETCO2 between the CO2 and air group. A slight increase in ETCO2 was observed in sedated patients, while there was no increase in unsedated patients. CO2 insufflation significantly reduced pain after the procedure at all time points. CONCLUSIONS: This study indicates that CO2 insufflation reduces pain and is safe to use in colonoscopy for sedated patients.

Duodenal adenomatosis in familial adenomatous polyposis.

BACKGROUND: The prevalence of duodenal carcinoma is much higher in familial adenomatous polyposis (FAP) than in the background population, and duodenal adenomatosis is found in most polyposis patients. AIMS: To describe the long term natural history of duodenal adenomatosis in FAP and evaluate if cancer prophylactic surveillance of the duodenum is indicated. METHODS: A prospective five nation study was carried out in the Nordic countries and the Netherlands. PATIENTS: A total of 368 patients were examined by gastroduodenoscopy at two year intervals during the period 1990-2001. RESULTS: At the first endoscopy, 238 (65%) patients had duodenal adenomas at a median age of 38 years. Median follow up was 7.6 years. The cumulative incidence of adenomatosis at age 70 years was 90% (95% confidence interval (CI) 79-100%), and of Spigelman stage IV 52% (95% CI 28-76%). The probability of an advanced Spigelman score increased during the study period (p<0.0001) due to an increasing number and size of adenomas. Two patients had asymptomatic duodenal carcinoma at their first endoscopy while four developed carcinoma during the study at a median age of 52 years (range 26-58). The cumulative incidence rate of cancer was 4.5% at age 57 years (95% CI 0.1-8.9%) and the risk was higher in patients with Spigelman stage IV at their first endoscopy than in those with stages 0-III (p<0.01). CONCLUSIONS: The natural course of duodenal adenomatosis has now been described in detail. The high incidence and increasing severity of duodenal adenomatosis with age justifies prophylactic examination, and a programme is presented for upper gastrointestinal endoscopic surveillance.

Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation.

BACKGROUND: Primary sclerosing cholangitis (PSC) confers a high risk of cholangiocarcinoma (CC) development. Since patients at risk of CC may be selected for early liver transplantation, it is a challenge to identify any predisposing factors. We compared the presentation and natural history of a large number of PSC patients with and without later CC development to identify features associated with risk of CC. METHODS: Clinical and laboratory data from presentation and follow-up were collected from 394 PSC patients from five European countries. The cohort included 48 (12.2%) patients with CC. RESULTS: CC was diagnosed within the first year after diagnosis of PSC in 24 (50%) cases and in 13 (27%) patients at intended liver transplantation. Jaundice, pruritus, abdominal pain and fatigue were significantly more frequent at diagnosis of PSC in the group that developed CC, but not after exclusion of cases diagnosed within the first year. Inflammatory bowel disease was diagnosed at least 1 year before PSC more often among patients with CC development than among those without (90% and 65%, respectively: P = 0.001). The duration of inflammatory bowel disease before diagnosis of PSC was significantly longer in patients who developed CC than in the remaining group (17.4 years and 9.0 years, respectively: P=0.009 in multivariate analysis). CONCLUSIONS: A high proportion of CC cases is diagnosed within the first year after diagnosis of PSC. A long history of inflammatory bowel disease is a risk factor for CC development.

Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis.

BACKGROUND: Patients with cholestatic liver function tests and histological features of primary sclerosing cholangitis (PSC) but a normal cholangiogram are considered to have small duct PSC. The natural history of this condition is unknown. METHODS: Thirty three patients with small duct PSC were identified among patients admitted for diagnostic workup of cholestatic liver function tests in one centre in the UK (Oxford) and one centre in Norway (Oslo). A total of 260 patients with large duct PSC were compared, and prognosis in terms of death, cholangiocarcinoma, biochemical features, histological features, and symptoms analysed. RESULTS: Mean age at diagnosis was 38 years and 39 years in small duct and large duct PSC, respectively. Mean follow up was 106 months in small duct and 105 months in large duct patients. Four patients originally considered to have small duct developed large duct PSC. Two of these underwent liver transplantation during follow up. Of the remainder who did not develop large duct PSC, two patients died during follow up: one of liver failure and the other of cardiac death unrelated to her liver disease. A total of 122 (47%) large duct patients either required liver transplantation (34 patients) or died (88 patients). Small duct patients had a significantly better survival compared with large duct patients. Among small duct patients, none developed cholangiocarcinoma compared with 28 of 260 (11%) large duct patients. CONCLUSIONS: Patients with small duct PSC seem to have a good prognosis in terms of survival and development of cholangiocarcinoma. Small duct PSC progresses to large duct PSC in a small proportion of patients.

Pyoderma gangrenosum associated with crohn disease: effect of TNF-alpha blockade with infliximab.

Eight patients with pyoderma gangrenosum associated with Crohn disease were treated with infliximab. All had active mucosal inflammation indicated by endoscopic examination. Within 1-4 months, infliximab treatment resulted in complete healing of the pyoderma gangrenosum in 3 cases (1 parastomal, 2 lower limb), partial healing in 3 (2 parastomal, 1 lower limb) and temporary improvement in 2. Adverse effects such as skin rash, pneumonia and diarrhoea were seen in three patients. Our results imply that infliximab has a therapeutic potential on skin manifestations associated with inflammatory bowel disease, even though successful treatment may require repeat courses of infliximab infusions.

Heterogeneity of intraepithelial lymphocytes in refractory sprue: potential implications of CD30 expression.

BACKGROUND: Refractory sprue is defined as primary or secondary failure to respond to a gluten free diet in patients with coeliac disease-like enteropathy and may signify cryptic or overt enteropathy associated T cell lymphoma. AIMS: To study in detail jejunal morphology and immunophenotypes in patients with refractory sprue in the search for features that might be useful to predict prognosis. PATIENTS: Seven patients are described, representing all such cases identified in our hospital over a 13 year period. METHODS: Biopsy and/or surgical resection specimens were examined by morphology, immunohistochemistry, including enzymatic and immunofluorescent detection, and molecular biology. RESULTS: All patients had phenotypically abnormal intraepithelial lymphocytes (IELs) that lacked CD8, T cell receptor alpha beta (or gamma delta), and/or expressed CD30 in addition to variable expression of the natural killer cell receptor CD94. A monoclonal T cell population was present in six cases, data from the seventh being inconclusive. Three patients had overt lymphoma with CD30+ tumour tissue intervening between intact mucosa that contained neoplastic IELs. Intriguingly, CD30+ IELs were observed both a long way away from, and in direct continuity with, the tumours in these patients. Such CD30+ cells were hardly detected in patients without tumours, two of which are in good health several years after the initial diagnosis. CONCLUSIONS: Our data suggest that abnormal IELs in patients with refractory sprue are phenotypically heterogeneous. CD30 expression by these cells may indicate a worse prognosis, including the occurrence of overt lymphoma.

Secondary amyloidosis in inflammatory bowel disease: a study of 18 patients admitted to Rikshospitalet University Hospital, Oslo, from 1962 to 1998.

BACKGROUND: Amyloidosis (A) is a well-known but rare complication to inflammatory bowel disease (IBD). We describe 18 patients with IBD and A, with special emphasis on clinicopathologic features and site relationships, comparing our results with previously reported cases in the world literature. METHODS: Patient records were collected from the files of the medical department at Rikshospitalet. Clinical data were compiled from records. RESULTS: Fifteen of the 18 patients had Crohn's disease (CD), 1 had ulcerative colitis (UC), one had UC preceding CD, and 1 had indeterminate colitis. There was a male preponderance of 13:5 = 2.6. Five of the patients had A at the time of diagnosis of IBD. Median time from diagnosis of IBD to A was 4 years, and A was diagnosed within 5 years after onset of IBD in 11 patients. Thirteen of the patients had suppurative complications; 12 had extraintestinal manifestations. Sixteen of the patients had been treated by bowel resection, 14 due to refractory IBD. Ten patients had been treated by renal transplantation. After 15 years of follow-up, the survival rate was 60%. CONCLUSIONS: Our findings strengthen the previous impression of an approximately 3-fold increased preponderance in males, with at least 10-fold increased frequency in CD compared with UC, and with a possible relationship to suppurative complications and extraintestinal manifestations, as well as an increased risk of having a bowel resection. The increased survival seems to be due to the introduction of renal transplantation.

M cell pockets of human Peyer's patches are specialized extensions of germinal centers.

M cells in follicle-associated epithelium of Peyer's patches (PP) mediate antigen entrance into the underlying lymphoid tissue. To investigate the functional potential of B cells in this unique microcompartment, the expression of co-stimulatory molecules necessary for B-T cell interaction was examined in histologically normal human PP by three-color immunohistochemistry. In the M cell areas, CD80 / CD86 expression was much more frequent on memory (sIgD(-)CD20(+)) B cells than on naive (sIgD(+)CD20(+)) B cells. M cell areas identified by such co-expression of CD20 and CD80 / CD86 were always spatially related to germinal centers (GC). Contrary to the GC B cell phenotype (sIgD(-)CD20(+)CD80 / 86(hi)CD10(+)Bcl-2(-)), however, M cell-associated B cells with a high level of CD80 / CD86 were CD20(lo)CD10(-)Bcl-2(+), and adjacent memory T cells (CD3(+)CD45R0(+)) often expressed CD40L (CD154). Autologous peripheral blood B-T cell cocultures with purified protein derivative as antigen showed that the sIgD(-)CD80 / CD86(hi)CD20(lo) phenotype could indeed be generated during cognate B-T interactions, concurrent with CD40L up-regulation on memory T cells. Thus, this M cell-associated phenotype might result from B-T cell interactions in the course of antigen presentation by memory B cells, with subsequent CD40 engagement by CD40L-expressing cognate memory T cells. We propose that this M cell-associated event contributes to memory B cell survival and diversification of intestinal immunity, representing a specialized limb of GC function.

[Genetic analysis in familial adenomatous polyposis]. / Genetiske analyser ved familiaer adenomatøs polypose.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder caused by germline mutations in the APC gene. FAP is characterised by a variable, but normally large number of colorectal adenomas and variations in extracolonic manifestations. These variations are associated with specific mutations of the APC gene. MATERIAL AND METHODS: Representatives from 70 Norwegian families are under molecular investigation. Analyses have so far been concentrated on the part of the APC gene associated with classic FAP. RESULTS: Germline mutations causing FAP have been identified in 36 of the 70 families examined. All mutations identified are confined to the first half of the gene and correlate to classic FAP. INTERPRETATION: Because of the mutation heterogeneity in FAP, the size of the APC gene and variations in phenotype, it is a laborious task to identify the causative mutations. Better approaches to the analysis of the whole APC have now been established and will result in a higher degree of mutation detection independent of phenotype. Family history and phenotype-genotype correlations are still important guidelines for efficient molecular genetic analysis of the APC gene. Genetic surveillance, personal and socio-economic benefits from presymptomatic and predictive testing of members of FAP families are discussed.

Glomerular and tubular renal functions after long-term medication of sulphasalazine, olsalazine, and mesalazine in patients with ulcerative colitis.

To date there are only few reports evaluating the potential nephrotoxic reactions of the new 5-aminosalicylic acid (5-ASA) preparations in patients with ulcerative colitis (UC). The aim of this study was to screen the tubular and glomerular functions in patients with UC in maintenance treatment with either 5-ASA azo-compounds (sulphasalazine and olsalazine) or mesalazine. Patients with UC in clinical remission treated with either sulphasalazine, olsalazine, or mesalazine for more than 1 year were included in an open, single-blind retrospective Norwegian multicenter study. Serum and urine creatinine, serum and urine beta2-microglobulin, urine N-acetyl-beta-glucoseamidase (NAG), urine alkaline phosphatase, urine microalbumin, urine alanine amino peptidase, and urine beta2-microglobulin were measured. Fifty-two females and 75 males (n = 127), ages 20-69, were evaluated. Thirty-six patients were treated with sulphasalazine (mean treatment time 10.1+/-6.6 years [mean +/- SD]), 32 patients were treated with olsalazine (2.3+/-1.4 years), and 59 patients with mesalazine (3.2+/-2.0 years). At inclusion, there were no significant differences in the serum or urine values between the groups. In 17 patients (1 patient [3%] in the sulphasalazine group, 4 patients [13%] in the olsalazine group, and 12 patients [20%] in the mesalazine group), at least one abnormal serum and/or urine value was detected. After 10 years of treatment, only one abnormal value was found among the 19 patients in the sulphasalazine group. The abnormal values observed in the other groups indicated minor glomerular or tubular renal damage. In conclusion, long term sulphasalazine treatment appears to be safe and free of nephrotoxic side effects, whereas minor glomerular and tubular impairment are observed in a few patients treated with olsalazine and mesalazine.

Villous, hypermucinous mucosa in long standing ulcerative colitis shows high frequency of K-ras mutations.

BACKGROUND: K-ras mutation is one of the first genetic alterations in classical colorectal carcinogenesis. AIMS: To investigate the role of K-ras mutations in carcinogenesis, in long standing ulcerative colitis. METHODS: A total of 161 microdissected and 100 DNA samples from 13 patients were analysed for K-ras codons 12 and 13 mutations by means of a combination of enriched polymerase chain reaction amplification and temporal temperature gradient electrophoresis. RESULTS: K-ras mutations were found in 21/161 (13%) microdissected samples in 7/13 large bowels (16 and five in codons 12 and 13, respectively), and in 10/100 (10%) mucosal DNA samples (six and four, respectively). One of four patients with six adenocarcinomas had a K-ras mutation in a carcinoma, as well as one of two patients with large dysplasia associated lesion or mass (DALM). Eight of 13 (61%) areas with villous architecture and large, distended goblet cells, had a K-ras mutation, which was significantly more frequent than in low grade dysplasia (one of 23, 4%) but did not reach significance versus high grade dysplasia (four of 14, 28.5%). K-ras mutations were found in one of 20 (5%) flat lesions indefinite for dysplasia, two of 14 (14%) in non-villous, hypermucinous mucosa, and in one of 57 flat areas negative for dysplasia. CONCLUSION: The highest K-ras mutation frequency was found in villous, hypermucinous mucosa. We suggest that this entity should be investigated further as a potential risk lesion for cancer development. It may represent a pathway directly from non-classical dysplasia to cancer, not previously described.

Germline and somatic mutations in exon 15 of the APC gene and K-ras mutations in duodenal adenomas in patients with familial adenomatous polyposis.

BACKGROUND: In sporadic colorectal adenomas mutations in the adenomatous polyposis gene (APC) are among the first gene aberrations to appear. In familial adenomatous polyposis (FAP) the patients already have a germline mutation in the APC gene. To investigate the natural history of duodenal adenomas in FAP patients, we examined germline and somatic mutations of the APC gene and K-ras mutations in these lesions. METHODS: Frozen sections from 54 duodenal polyps from 31 FAP patients were used to histologically verify the presence of adenomatous growth in the mucosa; the rest of each biopsy specimen was processed for DNA extraction. APC exon 15 was investigated with the protein truncation test (PTT), using four overlapping polymerase chain reaction (PCR) fragments, and samples showing an APC mutation were thereafter sequenced. The adenomas were examined for K-ras mutations by use of a combination of the 'enriched PCR method' and temporal temperature gradient electrophoresis. RESULTS: APC germline mutations in exon 15 were found in 19 of 31 (61%) patients, whereas somatic mutations were localized to 12 of 54 (22%) duodenal adenomas. In seven adenomas both the germline and the somatic mutations were found, whereas five small adenomas showed somatic mutations only. There was no tendency for more mutations to be detected in large and severely dysplastic adenomas compared with small and mildly dysplastic ones. K-ras mutations were found in four (7%) duodenal adenomas. CONCLUSIONS: The low rate of somatic APC and K-ras mutations in duodenal adenomas may indicate another neoplastic pathway than in FAP adenomas of the large bowel, or that a modifier gene is cosegregating with the disease.

HLA class II haplotypes in primary sclerosing cholangitis patients from five European populations.

The association of primary sclerosing cholangitis (PSC) to HLA class II genes was studied by comparing patients from five different European populations. Deduced HLA-DRB1, DQA1, DQB1 haplotypes of 256 PSC patients from England, Italy, Norway, Spain and Sweden were compared to those observed in 764 ethnically-matched controls. Increased frequencies of the DRB1*03, DQA1*0501, DQB1*02 (RR=3.0, P<0.00001) and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes (RR=2.4, P<0.0001) were observed in all five patient groups. A total of 16% of the PSC patients were homozygous for the DRB1*03, DQA1*0501, DQB1*02 haplotype compared to 1% of the controls (RR=20, P<0.0001). The DRB1*04, DQA1*03, DQB1*0302 haplotype was significantly reduced in frequency(RR=0.4, P<0.00001). Among Norwegian, Swedish and British patients that did not carry neither the DRB1*03, DQA1*0501, DQB1*02 nor the DRB1*13, DQA1*0103, DQB1*0603 haplotype, an increased frequency of the DRB1*15, DQA1*0102, DQB1*0602 haplotype was observed (RR=2.0, P<0.0001). Thus, PSC was found to be positively associated to three different HLA class II haplotypes (i.e. the DRB1*03, DQA1*0501, DQB1*02, the DRB1*15, DQA1*0102, DQB1*0602 and the DRB1*13, DQA1*0103, DQB1*0603 haplotypes) and negatively associated to one HLA class II haplotype (i.e. the DRB1*04, DQB1*0302 haplotype).

Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease.

BACKGROUND & AIMS: Celiac disease appears to be a T cell-mediated enteropathy induced by gluten in genetically predisposed individuals. Duodenal biopsy specimens from patients with celiac disease and histologically normal controls were investigated to see if cytokine expression is related to disease activity. METHODS: Cytokine messenger RNA (mRNA) expression was determined by quantitative reverse-transcription polymerase chain reaction and in situ expression by immunohistochemistry. RESULTS: In normal controls, mRNA levels were usually below the quantitative limit, even after in vitro gluten stimulation. By contrast, interferon (IFN)-gamma mRNA was increased more than 1000-fold in untreated disease. In vitro gluten stimulation of specimens from treated patients (gluten-free diet) increased IFN-gamma mRNA to the levels of untreated patients. In addition, increased mRNA levels for interleukin (IL)-2, IL-4, IL-6, and tumor necrosis factor alpha were found after such stimulation, whereas mRNA for IL-5, IL-10, and IL-12p40 was usually below the quantitative level. Biopsy specimens from untreated patients contained on average 10-fold more lamina propria cells positive for IFN-gamma than normal controls, whereas cells containing IL-4 were rare in both subject groups. CONCLUSIONS: The results show that mucosal gluten exposure in patients with celiac disease rapidly elicits high levels of IFN-gamma expression and lower levels of IL-2, IL-4, IL-6, and tumor necrosis factor alpha even in the virtual absence of IL-12.

Clinical course during the 1st year after diagnosis in ulcerative colitis and Crohn's disease. Results of a large, prospective population-based study in southeastern Norway, 1990-93.

BACKGROUND: The clinical course and prognosis in ulcerative colitis (UC) and Crohn's disease (CD) have been described in many studies, mostly retrospective. Such studies are hampered by problems such as inclusion over a long time period, proper definitions, incomplete case records, and outdated methods of diagnosis. In a prospective study we identified 846 patients with inflammatory bowel disease (IBD) over a 4-year period from 1990 to 1993. Uniform diagnostic and therapeutic strategies were used as a basis for later assessment of the short-term clinical course in different subgroups of UC and CD and analysis of potential risk factors for relapse or surgery. METHODS: At the time of follow-up, a mean of 16.2 months after diagnosis, 496 UC patients and 232 CD patients, altogether 98%, were available for evaluation. A colonoscopy was performed in 88% (410 of 465) of the UC patients attending a clinical examination and in 76% (164 of 216) of the CD patients. RESULTS: Eleven patients with UC and five patients with CD died during follow-up, four of complications related to IBD. The cumulative 1-year relapse rate in the remaining patients was 50% for UC and 47% for CD. Of the patients with relapses 11 % of the UC patients and 10% of the CD patients had a chronic relapsing course without any difference with regard to the various disease categories in UC or CD. An increased risk of relapse was found in patients less than 50 years old only in UC. In UC a higher risk for surgery was found in patients with extensive colitis compared with left-sided colitis (P = 0.011), and CD patients with small-bowel involvement had a higher risk of surgery than patients with disease confined to the colon (P = 0.021). There was no excess risk of relapse or surgery in smokers as compared with non-smokers or former smokers, nor did the risk of relapse vary with the level of cigarette consumption in either UC or CD patients. CONCLUSION: The high relapse rate of around 50% for both UC and CD calls for a review of the existing treatment. Further follow-up will be necessary to improve our ability to make clinical decisions relating to medical and surgical treatment options.

Inflammatory bowel disease: re-evaluation of the diagnosis in a prospective population based study in south eastern Norway.

BACKGROUND: The incidence figures for ulcerative colitis (UC) and Crohn's disease (CD) have been difficult to interpret, and geographical variations may be due to differences in classification criteria and study design. Few studies have based the incidence on prospective systematic follow up to confirm the initial diagnosis. METHODS: Between 1990 and 1993, in a prospective incidence study of inflammatory bowel disease (IBD) in south eastern Norway, 527 cases of UC, 228 cases of CD, 36 cases of indeterminate colitis (IND), and 55 cases of possible IBD were identified, yielding an annual incidence of 13.6, 5.9, 0.9, and 1.4 per 10(5) respectively. The diagnosis and all clinical data were reviewed by two gastroenterologists independently of each other. One to two years after diagnosis, all patients were offered a clinical follow up in which the initial diagnosis was assessed. RESULTS: Between the time of diagnosis and the follow up, 16 patients had died, four of complications related to IBD. Of the remaining 830 patients, 98% (814/830) were available for follow up, 93% (772/830) attended a clinical examination which included a colonoscopy in 77% (637/830), and the remainder had had a telephone interview, or reassessment based on hospital records, or both. Twenty seven patients were reclassified as not having IBD (3%), and 65 patients were characterised as possible IBD (8%). Of the patients initially classified as UC, 88% had their diagnosis confirmed, compared with 91% with an initial diagnosis of CD. In patients with indeterminate colitis, 33% were classified as definite UC and 17% as CD. This reclassification of patients yielded a corrected annual incidence of 12.8 for UC and 6.0 for CD. CONCLUSION: At follow up one to two years after the diagnosis of IBD, the initial incidence was only marginally altered. This is probably due to uniform inclusion criteria and careful diagnostic methods. The study also illustrates the importance of the re-evaluation of the initial diagnosis as close to 10%, both among patients with UC and CD, were reclassified at follow up.

Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes.

In mice, integrin alpha 4 beta 7 is the main receptor used by lymphocytes that home to the Peyer's patches, although L-selectin contributes to the initial interaction with high endothelial venules. Less is known about the expression and function of these adhesion molecules in humans. The distribution of L-selectin and alpha 4 beta 7 on various B- and T-cell subsets was examined in human Peyer's patches (n = 8) and appendix (n = 4), collectively called gut-associated lymphoid tissue. Multicolor immunophenotyping was performed on cryosections, and dispersed cells were examined by flow cytometry. In cryosections, CD45RA+ T cells around and within interfollicular high endothelial venules, as well as surface (s)IgD+ B lymphocytes in the follicle mantles, often expressed abundant L-selectin but only intermediate levels of alpha 4 beta 7. CD45RO+ T cells and sIgD- B cells expressed higher levels of alpha 4 beta 7 and were often located near putative efferent lymphatics; only a small fraction (< 20%) of such memory cells expressed L-selectin. By flow cytometry, considerably more T than B lymphocytes co-expressed L-selectin and alpha 4 beta 7 (40% versus 25% and 67% versus 39%, respectively). In samples with many L-selectin+ cells (> 30%), more of these lymphocytes co-expressed alpha 4 beta 7 than in samples with few L-selectin+ cells. Because L-selectin and alpha 4 beta 7 were co-expressed on lymphocytes located near high endothelial venules, and because such co-expression was relatively common when many L-selectin+ cells were present, both of these molecules might participate in homing to human gut-associated lymphoid tissue. Such homing is probably most pronounced for T lymphocytes that were found to express L-selectin and alpha 4 beta 7 more often than B lymphocytes. The selective and relatively high expression of alpha 4 beta 7 on memory cells located near efferent lymphatics indicated a different migratory capacity; after exit from gut-associated lymphoid tissue, such stimulated cells might home mainly to mucosal effector sites.

K-ras mutations and HLA-DR expression in large bowel adenomas.

A total of 72 sporadic colorectal adenomas in 56 patients were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene and for HLA-DR antigen expression related to clinicopathological variables. Forty K-ras mutations in 39 adenomas were found (54%): 31 (77%) in codon 12 and nine (23%) in codon 13. There was a strong relationship between the incidence of K-ras mutations and adenoma type, degree of dysplasia and sex. The highest frequency of K-ras mutations was seen in large adenomas of the villous type with high-grade dysplasia. Fourteen out of 15 adenomas obtained from 14 women above 65 years of age carried mutations. HLA-DR positivity was found in 38% of the adenomas, large tumours and those with high-grade dysplasia having the strongest staining. Coexpression of K-ras mutations and HLA-DR was found significantly more frequently in large and highly dysplastic adenomas, although two-way analysis of variance showing size and grade of dysplasia to be the most important variable. None of the adenomas with low-grade dysplasia showed both K-ras mutation and HLA-DR positivity (P = 0.004). K-ras mutation is recognised as an early event in colorectal carcinogenesis. The mutation might give rise to peptides that may be presented on the tumour cell surface by class II molecules, and thereby induce immune responses against neoplastic cells.