Earlier stages of colorectal cancer detected with immunochemical faecal occult blood tests.

BACKGROUND: The aim of colorectal cancer screening is to improve prognosis by the detection of early cancer and precursor stages. We compared the stage distribution of asymptomatic colorectal cancer patients detected by a positive immunochemical or guaiac-based faecal occult blood test (FOBT) with symptomatic colorectal cancer patients. METHODS: In a longitudinal cohort study tumour stages were assessed in 144 symptomatic (mean age 69.3 years, 56% male) and 41 asymptomatic colorectal cancer patients (mean age 64.9 years, 56% male) of which 11 were detected with guaiac FOBT s (G-FOBT, Hemoccult-II) and 30 with immunochemical FOBTs (I-FOBT, OCSensor). Stage distributions were used to calculate average stage specific predicted five-year survival rates and to analyse group differences with Wilcoxon log-rank test. RESULTS: Colorectal cancer was detected in significantly earlier stages in symptomatic compared with asymptomatic patients patients (p<0.0001). Average stage specific predicted five-year survival was 59.1% in symptomatic and 76.6% in asymptomatic patients. Compared with the symptomatic patients the stage distribution for colorectal cancer patients detected with Hemoccult-II was not significantly different(p=0.29), whereas colorectal cancer was detected at significantly earlier stages with the OCSensor (p<0.0001).Treatment could be confined to colonoscopy in 27% of the asymptomatic patients compared with 3% of the symptomatic patients (p<0.0001). Cancer distribution over the colon was comparable between symptomatic and asymptomatic patients (p=0.3). CONCLUSIONS: Compared with symptomatic patients,patients detected by FOBT and especially immunochemical FOBT , presented significantly more often at earlier stages suggesting increased survival. Additionally treatment could more often be confined to colonoscopy.

Role of bile acids in colorectal carcinogenesis.

Dietary factors are considered important environmental risk determinants for colorectal cancer development. Epidemiological studies have shown that a high fat (or meat) intake is associated positively and a high starch, fibre (non-starch polysaccharide), vegetable and fruit intake negatively with colorectal cancer incidence. One mechanism by which these effects are possibly exerted is through the metabolism of secondary bile acids. Secondary bile acids are formed after enzymatic deconjugation and dehydroxylation of primary bile acids in the large bowel by anaerobic bacteria. It has been shown that these compounds can have tumour-promoting capacities in animal experiments. In epidemiological studies, colonic cancer risk is related to the faecal bile acid concentration. In serum and bile of patients with colonic adenomas, more deoxycholic acid was detected than in healthy controls. Secondary bile acids are toxic to several cell systems at physiological concentrations. The exact mechanism by which these amphiphilic molecules exert their action is not well understood. It might act through membrane damage, intracellular mitochondrial action or genotoxic effects. So far the evidence that bile acids are involved in colonic carcinogenesis is largely circumstantial. It is, however, well accepted that environmental factors, such as dietary habits influence genetic susceptibility. Bile acids could play a promoting role in this process.

Effect of resistant starch on colonic fermentation, bile acid metabolism, and mucosal proliferation.

Resistant starch is by definition that part of starch that escapes digestion in the small bowel. Cecal fermentation of resistant starch into short-chain fatty acids will result subsequently in a decrease in pH. Thus, resistant starch may have the same effect on colonic luminal contents and mucosa as some fiber components. We studied the effects of adding 45 g native amylomaize (Hylon-VII) to a standardized diet in 14 healthy volunteers on fermentation and colonic mucosal proliferation. Hylon-VII is a high amylose maize starch, containing 62% resistant starch. During amylomaize consumption, breath hydrogen excretion rose 85% and fecal short chain fatty acid output increased 35% (P < 0.01). Excretion of primary bile acids increased and the soluble deoxycholic acid concentration decreased by 50% (P = 0.002). Subsequently, cytotoxicity of the aqueous phase of feces--as measured on a colon cancer cell line--decreased (P = 0.007). Colonic mucosal proliferation in rectal biopsies (proliferating cell nuclear antigen immunostaining) decreased from 6.7 to 5.4% (P = 0.05). We speculate that resistant starch consumption decreases colonic mucosal proliferation as a result of the decreased formation of cytotoxic secondary bile acids, which is possibly mediated through acidification of the large bowel by production of short-chain fatty acids.

Effect of resistant starch on breath-hydrogen and methane excretion in healthy volunteers.

Colonic fermentation of dietary carbohydrates and fiber might produce a protective effect against the development of large bowel cancer. Resistant starch, ie, starch that escapes small bowel digestion, is a candidate fermentable substrate that has been hitherto little studied. We supplemented 19 healthy volunteers with 15 g native amylomaize (Hylon-VII) three times a day, containing 28 g type II resistant starch, or with dextrins as a placebo for 7 d in a crossover design. Pre-experimentally, 11 subjects regularly produced breath methane and 8 did not. Resistant starch increased 24-h integrated excretion of breath hydrogen. The mean rise relative to placebo was 35% (P = 0.03) for all subjects and 60% for eight subjects not producing methane (P = 0.02). The 11 methane producers showed a 93% increase in breath-methane excretion on resistant starch (P = 0.03). Continued consumption of 28 g type II resistant starch/d is well tolerated and increases colonic fermentation in healthy volunteers.

A new method for the determination of the cytotoxicity of bile acids and aqueous phase of stool: the effect of calcium.

Soluble secondary bile acids in the colon are supposed to be cytotoxic for normal colonic cells, resulting in an increased compensatory proliferation of colonic crypt cells, which is associated with an increased risk for colonic cancer. We developed a sensitive method to determine cytotoxicity of bile acids in the HT-29 colon cancer cell line, using a tetrazolium-based colorimetric assay. Only in vital cells, tetrazolium-salts are converted into formazan, which can be measured easily. Chenodeoxycholic acid and deoxycholic acid (DCA) were cytotoxic in concentrations above 100 microM, which is in the physiological range for soluble DCA in faeces. Conjugation of bile acids diminished cytotoxicity 7-10 fold. In this concentration range, no effect of calcium or calcium phosphate was demonstrated, suggesting that the effect of calcium on colonic proliferation is not mediated by a precipitation of soluble bile acids in the large bowel. Finally, we could demonstrate a significant correlation between the cytotoxicity of the aqueous phase of faeces and the soluble DCA concentration.

Colorectal cancer in patients with X-linked agammaglobulinaemia.

Primary immunodeficiency disorders can predispose to certain malignancies but hitherto no such relation has been established for X-linked agammaglobulinaemia (XLA). We have diagnosed rapidly progressive colorectal cancer in 3 unrelated young adults with XLA. We could find no explanation for the tumours. Since the calculated incidence of rectosigmoid cancer is increased 30-fold in patients with XLA, we advise the screening of these individuals, and perhaps people with other agammaglobulinaemias, for colorectal cancer.

The role of carbohydrate fermentation in colon cancer prevention.

Diet is an important factor in the development of colonic cancer. Fibre has been shown to decrease this risk. Part of this protective effect is probably mediated by colonic fermentation. About 10% of starch in the normal diet escapes digestion and absorption in the small bowel, and is therefore called resistant starch. This is a considerably larger source of fermentable substrate than fibre in the diet and could thus contribute significantly to the prevention of this malignancy. Short chain fatty acids, produced during fermentation, reduce colonic pH, affecting the intraluminal concentration of the putative co-carcinogenic secondary bile acids by precipitation, and by inhibition of their enzymatic formation from primary bile acids. The role of secondary bile acids in promoting colonic carcinogenesis is probably mediated by their cytotoxic effect on colonic mucosa, leading to a compensatory increase in proliferation. A hyper-proliferative mucosa, having an enhanced sensitivity to mutagenic substances, is associated with an increased risk of colorectal cancer. Butyrate, one of the short chain fatty acids, could be significant, as it has anti-neoplastic properties in vitro and in vivo. We conclude that fermentation is probably the key factor in the protective effect of fibre on colon carcinogenesis. Furthermore, consumption of resistant starch seems to be another way of stimulating fermentation.

Current status of interferon alpha in the treatment of chronic hepatitis B.

Interferon alpha is the only available therapy for patients with chronic hepatitis B. With interferon alpha 3-15 MU thrice weekly or 5 MU daily during 3-6 months one-third of the patients achieve seroconversion of HBeAg and HBV-DNA together with normalization of aminotransferases and slight improvement of histology. Loss of HBsAg is reported in a minority of responders during treatment, but increases during follow-up. Patients with baseline alanine aminotransferase of at least twice the upper limit of normal and low HBV-DNA concentration achieve the best response rates. HIV-positive patients with low CD4 counts and Asians are poor responders. As side-effects influenza-like symptoms are experienced by almost all patients. Mild leukopenia, thrombocytopenia and decreased hairgrowth are frequently reported. Severe depression, depersonalization and psychosis are reported in a small number of patients but tend to be poorly recognized in some studies. The decision whether dose reduction is indicated seems strongly related to the opinion of the investigator. Although long-term effects on the occurrence of cirrhosis and the development of hepatocellular carcinoma are not available yet, the achieved results are promising.