Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis.

Fifty sporadic colorectal carcinomas diagnosed in 1991 were analysed for microsatellite instability at four loci. Five of 50 (10 per cent) tumours showed replication errors (RERs) at two or more loci and were classed as RER-positive (RER+). A further five showed RERs at one locus only. A significant association (Fisher exact test) was found between RER+ tumours and location in the proximal colon, exophytic shape, size >5 cm, histological margin, lymphoid reaction, and near-diploid DNA content. There was no significant difference for age, sex, grade, mucin production, p53 protein overexpression or Duke's stage. There was no significant difference in survival as measured over a 60-month follow-up period. The findings, though limited by the small case numbers involved, show an association between RER positivity in sporadic colorectal tumours and certain clinico-pathological features. They do not suggest a better clinical outcome for sporadic RER+ tumours.

Activated protein C resistance, thrombophilia, and inflammatory bowel disease.

Thromboembolic events frequently complicate the clinical course of patients with inflammatory bowel disease (IBD). Hereditary thrombophilia may contribute to this tendency. Resistance to activated protein C is the most recently described thrombophilic state and may account for up to 40% of patients with thrombophilia. Thirty-seven patients with IBD were studied (mean age 44 years, range 18-82 years). Three patients had a history of thrombotic episodes. The 37 controls included 23 men and 17 women (mean age 48 years, range 16-89 years). Disease activity was assessed using the Harvey Bradshaw index for patients with Crohn's disease and the Truelove and Witts grading system for patients with ulcerative colitis. Levels of fibrinogen, antithrombin III (ATIII), protein C, protein S, activated protein C resistance (APCR), and the presence of a lupus anticoagulant (LA) were determined. Median ATIII levels in patients with IBD were significantly lower than controls (98% vs 106%, P = 0.007), while fibrinogen was elevated (4.2 vs 3.3 g/liter, P = 0.026) despite quiescent disease activity. LA was detected in 7/37 patients in the IBD group compared to 0/37 controls. (chi2 = 5.68, P = 0.017). No significant difference was observed in levels of inherited thrombophilic factors and in particular APCR between IBD patients and controls. In conclusion, the presence of inherited thrombophilic defects, in particular APCR, is uncommon in patients with IBD and does not merit routine screening.

Nitrofurantoin-induced hepatotoxicity mediated by CD8+ T cells.

Nitrofurantoin is a synthetic nitrofuran commonly used for the treatment and prophylaxis of urinary tract infections. We describe the case of a 75-yr-old woman who was taking nitrofurantoin as prophylaxis against recurrent urinary tract infections, and who subsequently developed pulmonary and hepatic toxicity. We postulate that a breakdown product of the drug or the drug itself complexed to an endogenous peptide is presented by the class I HLA antigen on the hepatocyte cell membrane, inducing cytotoxic T cell activation and subsequently, hepatocyte death.

Hyposplenism and gluten-sensitive enteropathy. Natural history, incidence, and relationship to diet and small bowel morphology.

Splenic function was quantitatively assessed using "pitted" erythrocyte counts in 177 patients with gluten-sensitive enteropathy. Hyposplenism was found to be a common, but not inevitable, complication of gluten-sensitive enteropathy that fluctuated with disease activity. Splenic function improved after withdrawal of gluten from the diet and a close relationship was demonstrated between hyposplenism and the morphology of the small intestine. The severity of the hyposplenism increased with advancing age and prolongation of exposure to dietary gluten. Splenic function did not vary with the HLA-A, -B, and -DR antigens, but, due to the presence of HLA-B8 and -DR3 in the vast majority of patients, a role for this haplotype in the causation of the hyposplenism cannot be excluded.

'Pitted' erythrocytes: impaired formation in splenectomized subjects with congenital spherocytosis.

'Pitted' erythrocyte counts are widely used in the quantitative assessment of functional hyposplenism and in the prediction of recurrence of splenic function in splenectomized subjects. Both of these functions require counts from electively splenectomized controls for comparison. The 'pitted' erythrocyte counts in patients splenectomized for congenital spherocytosis are lower than those found in subjects whose spleens were removed electively for other reasons. This appears to be due to the specific membrane defect which impairs the formation of the vacuoles which are responsible for the appearance of 'pitted' erythrocytes under the interference-phase microscope.

HLA type of patients with coeliac disease and malignancy in the west of Ireland.

HLA, A, B, and DR typing was done on seven of 10 patients with lymphoma, and six patients with carcinoma, all of whom had a flat small intestinal mucosa. Sixty-nine per cent (nine of 13) had HLA B8 and 71% (five of seven) had DR3. The corresponding levels for the local coeliac population are 76% and 84% respectively and the local non-coeliac population 43% and 44%. Two of the patients with lymphoma had a child with coeliac disease. The histological type of the lymphoma was malignant histiocytosis of the intestine in seven, histiocytic lymphoma in two, and was not classifiable in one. The similarity of the HLA type suggests that the flat mucosa in both groups is due to coeliac disease.

Glycoprotein synthesis and secretion in human colon cancers and normal colonic mucosa.

Glycoprotein synthesis and secretion were measured in short-term organ culture of normal and neoplastic colonic mucosa from 11 patients undergoing colectomy for colon cancer. Mucosal explants were incubated for up to 24 hr with [3H]glucosamine, which was incorporated into both explant and secreted glycoproteins. Structural and functional viability was documented by morphological studies that showed excellent preservation of architectural detail and biochemical studies that documented a steady increase in glycoprotein synthesis during 24-hr incubation. The major difference between normal and neoplastic mucosa was a 35% decrease (p less than 0.02) in the incorporation of [3H]glucosamine into tumor explants, as compared to the amount incorporated into normal explants from the same patient. The rate of secretion of radiolabeled glycoproteins into the medium did not differ significantly. Separation of explants into particulate and cytosol fractions showed that the overall decreases in glycoprotein synthesis in tumor explants was primarily due to a marked reduction in particulate glycoprotein synthesis in the cancer tissue.