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This study is based on all patients with ulcerative colitis from a defined catchment area in Northern Sweden in a still ongoing colonoscopy surveillance programme, which started in 1977. From this material we selected tissue from eight groups of patients consisting of normal control biopsies (5), inactive colitis (10), active colitis (10), findings of low-grade dysplasia (10), high-grade dysplasia (6), aneuploidy (without dysplasia and with subsequent dysplasia) (10), and ulcerative colitis-associated cancers (5). The samples were evaluated according to immunohistochemical expression of CK7 and CK20. Colonic mucosa from normal controls and inactive colitis was found to be completely negative for CK7. In 9 out of 10 patients with active colitis, CK7 was sparsely expressed in a patchy manner and connected with active epithelial inflammatory areas. 7 out of 10 patients with low-grade dysplasia and 3 out of 6 with high-grade dysplasia were positive for CK7. Samples with aneuploidy without dysplasia were completely negative, while 2 out of 6 showing subsequent dysplasia were positive. Of the five cancers, two were positive for CK7. CK20 was expressed in nearly all samples but relatively more in the lower part of the crypts in neoplasia-associated lesions. Our results indicate a possible relationship between expression of CK7 and CK20 and neoplastic development of colorectal mucosa in patients with ulcerative colitis. Further studies are needed to elucidate whether these findings have clinical significance.

Patients with ulcerative colitis (UC) are at an increased risk of developing colorectal cancer (CRC). The aim of this study was to investigate the outcome for the patients who underwent limited resection of the colon and/or rectum instead of panproctocolectomy (PPC), with special attention to those with neoplastic changes.Since 1977, all known patients with UC from our catchment area have been included in our surveillance programme. A total of 210 patients with UC have been followed up with regular colonoscopies and biopsies. Indications for surgery were severe therapy-resistant disease (TRD), high-grade dysplasia (HGD), CRC or repeated findings of low-grade dysplasia (LGD). Patient compliance was excellent.Fifty-one patients were operated on. In 29 of these patients, PPC was performed initially. At the end-point of the study, additionally seven patients had been radically operated on and three more patients planned to undergo such an operation. Accordingly, 22 patients had their first operation performed as a resection of either a part of or the whole colon or rectum. In this group, there were four patients diagnosed with CRC and three with dysplasia-associated lesion or mass (DALM). One of them died 6 months after surgery because of disseminated CRC, whereas the other patients were alive at the end-point of the study. One of these seven patients with CRC or DALM had at end-point been radically operated on and two patients were awaiting such a procedure (in two patients because of LGD and in one patient because of TRD). Six of the patients who had a colorectal resection performed on the indication of TRD were radically operated later on, five of them because of relapsed TRD and one patient because of LGD in the remaining rectal mucosa. Twenty-one patients gained a mean of 9.4 years with presumably better bowel function, from undergoing a limited resection instead of PPC. None of the patients who underwent a colonic and/or rectal resection died because of CRC or metachronous cancer in their remaining colon or rectum.The results of this study indicate that a limited resection of the colon and/or rectum in patients with UC, which requires surgical intervention increases the time with presumably better bowel function and may therefore be an alternative to PPC without increased risk of dying from CRC. This is dependent on the flexibility of the medical service and patient compliance.

In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (or = 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels.

We have established a new experimental model of human clear cell sarcoma, UM-CCSI, using serial subcutaneous transplantation of intact tumour tissue in nude mice. The heterotransplanted nude mouse tumours retained characteristic morphological features of the primary clear cell sarcoma. Immunohistochemical analysis showed the retained expression patterns of S-100 protein, melanoma-associated antigen HMB-45 and vimentin in the xenografts as compared to the primary tumour. DNA index showed low variations both between the xenografts in the same passage and between the serial passages. Cytogenetic analysis of the primary tumour and the xenografts showed the unbalanced translocation der(6)t(6; I 2)(p23;q13). Based on the combined genetic data a reasonable interpretation of our findings is that there was a complex chromosomal rearrangement resulting in a cytogenetically cryptic EWS-ATFI fusion gene. Analysis of cell kinetics using in vivo incorporation of iododeoxyuridine and flow cytometry showed generally short potential doubling time (T-pot) of the xenografts. Volume doubling time showed low variations without correlation with T-pot. The retained phenotypic and genotypic characteristics of the primary tumour and the morphological and structural stability over time makes the model suitable for studies on the tumour biology and treatment of clear cell sarcoma. (C) 2002 Wiley-Liss, Inc.

Hereditary non-polyposis colorectal cancer, HNPCC, is an autosomal dominant condition predisposing to cancers of primarily the colorectum and the endometrium. The aim of our study was to identify persons at a high risk of hereditary colorectal cancer and to estimate their risk of colon and other HNPCC-associated tumours. Family histories of cancer were obtained on 89 persons with double primary (DP) cancers of the colon and the endometrium. The cancer risks in their 649 first-degree-relatives (FDR) were analysed. The microsatellite instability (MSI) status of the tumour of the proband was also analysed and the cancer risks were estimated in relation to MSI status and age at diagnosis in the proband (over or under 50 years). The overall standardised incidence ratio (SIR) was 1.69 (95% CI; 1.39-2.03). In the =50-year-old cohort the SIR was 2.67 (95% CI; 2.08-3.38). Colon, rectal and uterus cancer exhibited significantly increased risks. This risk was further increased in the =50-year-old MSI positive families. Several =50-year-old MSI negative HNPCC-like families with increased risks were also identified. In conclusion a FDR to a person with a DP cancer of the colorectum or the colon/endometrium have a significantly increased risk of having a colorectal or other HNPCC-associated cancers if the proband is diagnosed with one of the cancers before age 50. These families are candidates for genetic counselling and colorectal screening programmes. Mutations in mismatch repair genes can explain some of the increased risk in these families, but mutations in MSI negative families are probably due to other colon cancer susceptibility genes not yet described.

Background. In squamous cell carcinoma of the head and neck (SCCHN), overexpression of the p53 protein has been found in 34-80% of the tumors studied. No data are available regarding p53 expression versus tumor cell proliferation and prognosis for this tumor type. Methods. p53 protein levels were studied by immunohistochemical staining of 33 primary SCCHN using 3 antibodies (D07, PAb 1801, and CM1) that react with different epitopes of the p53 protein. The cellular expression of p53 was compared with in vivo incorporation of the thymidine analog iododeoxyuridine (IdUrd) and expression of proliferating cell nuclear antigen (PCNA). Results. Twenty-one tumors (64%) had a positive nuclear staining for p53 with the monoclonal antibody D07, which reacts with a denaturation-resistant epitope in wild-type and mutant p53. PAb 1801 and CM1 reacted with 19 and 20 tumors, respectively, all of which were D07-positive. No correlation was found between incorporation of IdUrd and p53 expression or between PCNA and p53 expression. The data indicate that intracellular accumulation of the p53 protein was related to tumor stage and localization of the tumor. No indication of a clinical or prognostic significance of p53 expression in SCCHN was found. Conclusions. No association between p53 deregulation and tumor cell proliferation was found.

Genomic alterations in renal cell carcinoma were investigated by DNA fingerprinting using the simple repetitive oligonucleotide probe (CAC)5. Nine of ten tumors showed somatic changes in the fingerprint pattern compared with constitutional DNA. The most consistent changes were deletions and/or decrease in intensity of a band. When using two or three samples from different parts within the tumor, up to three different cell clones could be detected. These results indicate that DNA fingerprinting analysis can be a useful technique for the study of genomic alterations and tumor heterogeneity in renal cell carcinoma. © 1993 Wiley-Liss, Inc.

The mucins contained in goblet cells of the descending colon of rats were histochemically labelled by Alcian blue pH 2.5 and quantified in an image analyzer (Cortex Controller) in 55 Sprague-Dawley rats. After transportation to the stress laboratory, 25 rats were compelled to swim for two consecutive hours/day either only once (five rats), for one week (five rats), two weeks (five rats), four weeks (five rats) or eight weeks (five rats). Twenty-five additional rats were only transported to the stress laboratory (i.e. ‘sham-handled’) controls, either once (five rats), one week (five rats), two weeks (five rats), four weeks (five rats) or eight weeks (five rats). The remaining five rats were ‘untransported’ resting rats (i.e. day 0). The results were expressed in per cent of Alcian blue stain cells/total mucosa analyse. When various time intervals were compared with those of day 0 (i.e. horizontal study) it was found that two hours and one, two weeks swimming resulted in a significantly decreased percentage of mucin-containing cells (p < 0.001). Contrariwise, a significantly increased mucous-cell population was found after eight weeks swimming. ‘Shamhandled’ rats had at two and eight weeks a significantly increased (p < 0.001) percentage of mucous-producing cells. Swimming and ‘sham-handled’ controls were compared at each time interval (i.e. vertical study). The results indicated that swimming rats had a significantly lower (p < 0.001) percentage of mucin-containing cells than transported rats had at day 1 and at one, two and eight weeks. It is concluded that during the first two weeks of daily physical stress, the mucin-cell population of the descending colon of the rat is reduced. This is followed by a hyperproduction of mucin-containing cells. A similar hyperproduction was found at 8 weeks in control rats, suggesting that the mucin-cell population may be altered even in the absence of physical stress. The possibility that protracted transportation acted as a psychical stress in our control rats should be considered.

Frequency of gallstones, concentration of bile acids and cholesterol in bile, concentration of cholesterol in serum, and structure of the small intestinal mucosa were analyzed in male Syrian Golden hamsters fed a stone provoking fibre-free diet with or without supplementation of brewer's spent grain (BSG), a concentrated barley fibre source from the by-product of brewing. A significantly lower frequency of gallstones was found in the animals with 10% BSG dietary supplementation. Addition of 30% BSG after an initial 6-week period with a fibre-free, stone provoking diet seemed to dissolve previously formed gallstones. Total bile acid concentration was higher in bile from animals given a diet supplemented with 10% BSG. In addition, the cholesterol concentration in both serum and bile was lower in the 30% BSG supplemented group. Structurally, a 10% BSG supplementation decreased ileal epithelium height whereas a high supplementation (30%) of BSG induced a decrease in epithelial height both of jejunal and ileal mucosa. The results show that BSG has significant effects on the metabolism of bile acids and cholesterol as well as on the morphology of the small intestinal mucosa.

DNA content was successfully determined by flow cytometry in 196 tissue samples from 25 renal cell carcinomas. Twelve tumors (48%) were homogeneously diploid/near-diploid, whereas 11 tumors were aneuploid and 2 tumors were polyploid. Cell clones with different DNA content were found in 11 tumors demonstrating a considerable heterogeneity in the non-diploid tumors; 9 of these 11 heterogeneous tumors contained both aneuploid and diploid cell clones. Tumor samples morphologically classified as grade 1 and 2 were 98% diploid and grade 4 samples were 78% aneuploid. No correlation between DNA distribution and morphologic grade was found for grade 3 tumor samples. Tumor proliferation rate, as determined by the fraction of cells in S-phase, was significantly higher in aneuploid samples compared to normal kidney tissue samples and diploid tumor samples.

Tumor DNA content was analysed in 26 patients with metastatic renal cell carcinoma. The primary tumors were homogenously diploid in ten patients (38%). In 16 patients (62%) an aneuploid DNA content was found in at least one of eight tumor samples analyzed. Patients with diploid tumors survived significantly longer (P less than 0.001) than patients with aneuploid primary tumors (median 32.5 and 6 months, respectively). The DNA content of the metastases seems to give additional prognostic information. The results indicate that DNA content is a useful prognostic predictor in renal cell carcinoma. Patients with homogenously diploid tumors might be treated aggressively with nephrectomy and excision of apparent metastases, particularly solitary, since these patients seem to have a chance for prolonged survival time. Aneuploidy in metastases, solitary and multiple, indicates that nephrectomy is not meaningful.