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Inherited and acquired risk factors in colonic neoplasia and modulation by chemopreventive interventions.

The progressively abnormal development of epithelial cells prior to tumor development leads to widely differing chemopreventive approaches. The diversity of these approaches has resulted in different assays to measure the activities of the agents. To apply these assays to preclinical studies, we have developed rodent models in which different stages of evolution of colonic neoplasia are expressed. In one model mice carrying a truncated Apc allele with a nonsense mutation in exon 15 have been generated by gene targeting and embryonic stem cell technology (Apc 1638 mice). These mice develop multiple gastrointestinal lesions including adenomas and carcinomas, focal areas of high grade dysplasia (FAD) and polypoid hyperplasias with FADS. The incidence of inherited colonic neoplasms has now been modulated by a chemopreventive regimen. Colonic lesions significantly increased in Apc 1638 mice on a Western-style diet, compared to Apc 1638 mice on AIN-76A diet which has lower fat content and higher calcium and vitamin D. These studies have also been carried out in normal mice, and have demonstrated without any chemical carcinogen that a Western-style diet induced colonic tumorigenesis. Modulation of cell proliferation has also been induced by Western-style diets in other organs including mammary gland, pancreas and prostate. These findings are leading to the development of new preclinical models for evaluating the efficacy of many classes of chemopreventive agents.

Animals↗

L-CAM expression in normal, premalignant, and malignant colon mucosa.

L-CAM is a cell adhesion molecule which is expressed at the intercellular borders of most epithelial cells. L-CAM has been demonstrated to act as an invasion suppressor in carcinoma cell lines. In order to determine whether or not L-CAM expression might distinguish between invasive and non-invasive or metastatic and non-metastatic colon neoplasms, we studied L-CAM expression in normal colon mucosa, colon adenomas with various degrees of dysplasia, and colon carcinomas by immunohistochemistry, using the 6F9 monoclonal anti-L-CAM antibody. Normal mucosa showed evenly distributed distinct L-CAM immunoreactivity along intercellular borders. In adenomas and carcinomas, a similar though weaker expression was observed. This pattern showed a tendency to decrease in parallel with decreasing differentiation. However, no correlation was found with Dukes stage or area within the tumour. In some carcinomas, L-CAM was expressed at the luminal surface of the cells. In others, L-CAM expression was not found. These results suggest that L-CAM expression is disregulated or lost as an early event in the development of colon neoplasia and indicate that L-CAM expression does not correlate with invasive or metastatic potential.

Adenoma↗

Adenocarcinoid tumor of the colon arising in preexisting ulcerative colitis.

Patients with ulcerative colitis are at increased risk of developing adenocarcinoma of the colon. The authors describe a patient whose colonic neoplasm demonstrated histologic characteristics of both an adenocarcinoma and a carcinoid tumor and which was pathologically identical to a appendiceal adenocarcinoid. Because individual tumor cells stained positively for both mucin and argentaffin granules, the histologic picture is unique among the malignancies seen in patients with ulcerative colitis and cannot be explained as a composite of two independent neoplasms that have grown together. Since the tumor discussed seems to have originated from a single cell line, the theory that carcinoids develop from neural crest cells which have migrated to embryonic gut endoderm must be regarded with considerable doubt.

Adenocarcinoma↗

Bacteremia with Streptococcus bovis and Streptococcus salivarius: clinical correlates of more accurate identification of isolates.

Two biotypes of Streptococcus bovis can be identified by laboratory testing and can be distinguished from the phenotypically similar organism Streptococcus salivarius. We assessed the clinical relevance of careful identification of these organisms in 68 patients with streptococcal bacteremia caused by these similar species. S. bovis was more likely to be clinically significant when isolated from blood (89%) than was S. salivarius (23%). There was a striking association between S. bovis I bacteremia and underlying endocarditis (94%) compared with that of S. bovis II bacteremia (18%). Bacteremia with S. bovis I was also highly correlated with an underlying colonic neoplasm (71% of patients overall, 100% of those with thorough colonic examinations) compared with bacteremia due to S. bovis II or S. salivarius (17% overall, 25% of patients with thorough colonic examinations). We conclude that careful identification of streptococcal bacteremic isolates as S. bovis biotype I provides clinically important information and should be more widely applied.

Adolescent↗

Screening colonoscopy in Chinese and Western patients: a comparative study.

OBJECTIVES: The aim of this study was to compare findings on screening colonoscopy in a Chinese cohort versus a concurrent Western cohort. METHODS: Asymptomatic adults aged 40 years or older concurrently underwent screening colonoscopy in two hospitals, one in Taiwan and the other in Seattle. The prevalence and distribution of colonic neoplasia and advanced neoplasia (defined as an adenoma >or=10 mm or with villous, high-grade dysplastic, or malignant features) were compared between the two groups. RESULTS: The Taiwan cohort was composed of 1,456 subjects. Colonic neoplasms were found in 214 (14.7%), advanced neoplasms in 58 (4%), and colon cancers in 4 subjects (0.3%). The Seattle cohort was composed of 3,403 subjects. Neoplasms were found in 705 (20.7%), advanced neoplasms in 166 (4.9%), and cancers in 11 subjects (0.3%). Age and male sex were risk factors for neoplasia in both groups. The adjusted risk ratio was 1.30 (95% confidence interval: 1.08-1.57) in Western versus Chinese patients. However, the prevalence of advanced neoplasms was not statistically different between the two cohorts. The Chinese cohort had a higher proportion of distal neoplasia (66.4%vs 52.6%; p= 0.0004). The sensitivity of a sigmoidoscopic screening strategy for detecting advanced neoplasia was higher in Chinese (79.3%) than in Western patients (67.5%). CONCLUSIONS: Compared to Westerners, Chinese patients have a slightly lower prevalence of colon neoplasia (but not advanced neoplasia), more distal distribution of neoplasia, and higher likelihood of concomitant proximal advanced neoplasia and distal neoplasia. Colonoscopy is safe, well-tolerated, and a viable screening option in Chinese patients, but its advantage over sigmoidoscopy as a screening tool may be smaller.

Adult↗

Population genetics of colonic cancer.

BACKGROUND: There are several well known but rare syndromes of inherited colonic cancer. Genetic epidemiologic studies also have demonstrated that relatives of individuals with colonic cancer in general exhibit an excess risk for this malignancy. METHODS: This report reviews the literature pertinent to genetic and familial risk for colonic cancer with emphasis on the recent work that suggests that inherited susceptibility to colonic neoplasms is common. RESULTS: The adenomatous polyposis syndromes are rare inherited colonic cancer conditions caused by a mutant gene which recently has been characterized. Hereditary nonpolyposis colorectal cancer is likewise inherited and may account for up to 5% of cases. The molecular genetics of this disease remain to be clarified. The majority of colonic cancer cases are considered sporadic but are known to often cluster in families. Recent work suggests that inherited susceptibility may be the basis of this familial occurrence. Screening strategies based on inherited and familial risk are suggested. CONCLUSIONS: Knowledge of the familial and inherited risk for colonic cancer is leading to a better understanding of this disease and is suggesting more directed preventive strategies.

Adenomatous Polyposis Coli↗

Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma.

The bcl-2 proto-oncogene encodes a Mr 25,000 protein that has been shown to prevent apoptosis or programmed cell death. The bcl-2 protein is detectable in basal cells of normal colonic epithelium, and an altered topographic distribution of this protein is found in colonic neoplasms. However, the clinical significance of abnormal bcl-2 expression in colon carcinomas remains unknown. We examined the prognostic value of the bcl-2 protein in TNM stage II colon carcinomas and its relationship to DNA ploidy, cell proliferation indices, p53 expression, and clinicopathological features. We analyzed 119 resected and otherwise untreated, paraffin-embedded stage II colon carcinomas for bcl-2 and p53 protein expression using immunohistochemistry. DNA ploidy and proliferative index (% S-phase + % G2-M) were determined by flow cytometry, and tumor grade and vascular microinvasion were assessed on histological sections. Cytoplasmic expression of the bcl-2 protein was detected in 72 (66%) of 110 carcinomas, and a high level of expression was significantly correlated with diploid DNA content (P = 0.02) and low proliferative activity (P = 0.005). bcl-2 was not associated with nuclear p53 expression. In a univariate analysis, a higher fraction of bcl-2-positive tumor cells was associated with better relapse-free survival (P = 0.02) and overall survival (P = 0.05) rates. Moreover, a high level of bcl-2 expression was an independent predictor of better relapse-free survival (P = 0.04), but not overall survival (P = 0.14), after adjustment for other variables, including proliferative index, DNA ploidy, and race. In conclusion, bcl-2 overexpression is associated with favorable prognostic features and may predict clinical outcome in stage II colon carcinomas.

Adult↗

Limitations in the CT diagnosis of acute diverticulitis: comparison of CT, contrast enema, and pathologic findings in 16 patients.

Pitfalls in CT diagnosis of acute diverticulitis were investigated in 16 patients with the disease who had misleading or equivocal CT features. The CT appearance was correlated with contrast enemas (13 cases) and with surgical assessment and pathologic evaluation of resected specimens (12 cases). Limitations in the CT diagnosis were related to (1) marked thickening of the colonic wall, between 1 and 3 cm in cross section simulating colonic neoplasm (all patients); (2) inability to visualize small amounts of fibropurulent exudate in the absence of pericolic inflammatory changes (eight patients); (3) failure to detect discrete intramural abscess (five patients). Resected surgical specimens available in 12 cases proved that colonic wall thickening was caused by muscular hypertrophy and various degrees of submucosal inflammation, edema, fibrosis, or focal organized inflammatory tissue. Contrast enema was useful in 10 out of 13 patients by excluding carcinoma of the colon and confirming the diagnosis of acute diverticulitis.

Acute Disease↗