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Background: Distinguishing hereditary non-polyposis colorectal cancer (HNPCC) from non-hereditary colorectal cancer (CRC) can increase the life expectancy of HNPCC patients and their close relatives. Aim: To determine the effectiveness, efficiency, and feasibility of a new strategy for the detection of HNPCC, using simple criteria for microsatellite instability (MSI) analysis of newly detected tumours that can be applied by pathologists. Criteria for MSI analysis are: (1) CRC before age 50 years; (2) second CRC; (3) CRC and HNPCC associated cancer; or (4) adenoma before age 40 years. Methods: The efficacy and cost effectiveness of the new strategy was evaluated against current practice. Decision analytic models were constructed to estimate the number of extra HNPCC mutation carriers and the costs of this strategy. The incremental costs and gain in life expectancy for a HNPCC mutation carrier were evaluated by Markov modelling. Feasibility was explored in five hospitals. Results: Using the new strategy, 2.2 times more HNPCC patients can be identified among a CRC population compared with current practice. This new strategy was found to be cost effective with an expected cost effectiveness ratio of J3801 per life year gained. When including the group of siblings and children, the cost effectiveness ratio became J2184 per life year gained. Sensitivity analysis showed these findings to be robust. Conclusions: MSI testing in a selection of newly diagnosed CRC patients was shown to be cost effective and a feasible method to identify patients at risk for HNPCC who are not recognised by family history.

Present guidelines to identify hereditary non-polyposis colorectal cancer (HNPCC) families are criticized for limitations in accuracy. The Amsterdam criteria I and II (AC I and AC II) are used to predict a germline mutation in one of the mismatch repair genes. In families not fulfilling the AC I and AC II criteria, individual indications to test cancer specimens for microsatellite instability (MSI) are guided by the Bethesda Guidelines (BG). Germline mutation testing is then performed in patients who conform to the BG and show MSI. We investigated the sensitivity and specificity of AC I, AC II, and BG. A meta-analysis of studies on the value of the AC I and AC II criteria for predicting germline mutation, as well as a meta-analysis of BG for the detection of MSI was performed. For the AC I, sensitivity varied from 54 to 91% and specificity varied from 62 to 84%. For the AC II, the pooled sensitivity was 78% and specificity ranged between 46 and 68%. Post-test probabilities of a positive test result were 0.61 and 0.46 for the AC I and AC II, respectively. Post-test probabilities of a negative test result were 0.17 and 0.21 for the AC I and AC II, respectively. For the BG, the pooled sensitivity was 89% and pooled specificity was 53%. Post-test probability of a positive test result was 41%, and post-test probability of a negative test result was 9%. The sensitivity and specificity of the Amsterdam criteria for predicting a germline mutation that causes HNPCC is not sufficient. The BG are useful for the detection of MSI in a group of patients suspected of having familial colorectal cancer (CRC), but sensitivity is very low in the total group of newly diagnosed CRC patients. Therefore, a new strategy is needed for the identification of HNPCC.

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Summary A series of 24 paired samples of colorectal carcinoma and the respective normal colorectal mucosa were analysed for Epidermal Growth Factor Receptor (EGFR) content by means of a standardised ligand binding assay.We, for the first time, found that EGFR levels are statistically significantly higher in normal colorectal mucosa biopsy samples than they are in colorectal carcinoma biopsy samples, the median EGFR levels being 77.5fmolmg-' of membrane protein (range 35-239), against 46fmolmg-' of membrane protein (range 22-81), respectively, P<0.001. In addition, we found that there are significant regional differences in EGFR expression in the normal human colon mucosa. The EGFR levels were significantly higher in samples from the proximal part of the colon than they were in samples from the distal part, the median EGFR levels being 124fmolmg-' of membrane protein (range 70-239) vs 55fmolmg-' membrane protein (range 35-156), P<0.05. The EGFR levels of the colorectal carcinoma samples did not show any regional variation.

Preoperative serum levels of the tumor markers CA 50, CA 19‐9, CA 19‐9 TruQuant, CA 72‐4, CA 195, carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) were measured in 94 patients with well‐staged adenocarcinoma of the stomach and in 15 patients with benign gastric diseases. In all patients with carcinoma, a laparotomy was done. The serum levels were correlated with the stage of disease, the location of the primary tumor, and the resectability and grade of differentiation. The marker CA 50 was the best, with an overall positivity of 59.5%. For CA 19‐9, this figure was 34%; for CA 19‐9 TruQuant, 22%; for CA 72‐4, 34%; for CA 195, 29%; for CEA, 33%; and for TPA, 50%. The best combination of two markers was CA 50 and TPA; this combination gave a positivity of 81%. There was no evident correlation with stage of disease and the percentage of positive serum levels or the median serum levels. The marker CA 50 gave the widest range of elevated serum levels between the cutoff level and the 90th percentile (54%). Patients with carcinoma of the cardia had higher preoperative serum levels than those with a tumor in other parts of the stomach. There was no correlation with the respectability of the tumor and the preoperative serum level. Patients with an undifferentiated tumors did not have significantly lower serum levels than those with more differentiated tumors. Currently, preoperative determination of serum tumor marker levels in patients with gastric carcinoma has no significance in clinical practice.

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