DNA markers predicting benefit from adjuvant fluorouracil in patients with colon cancer: a molecular study.

BACKGROUND: Present clinical algorithms assign adjuvant chemotherapy according to prognosis, but clinical decision-making would be greatly improved if reliable predictive markers were available to identify which subsets of patients benefit most from treatment. We examined molecular markers in preserved tissue from patients with Dukes' B or C colon cancer randomised to receive, or not, adjuvant fluorouracil, and assessed each marker's prognostic and predictive value. METHODS: Formalin-fixed paraffin-embedded paired normal and tumour samples were obtained from 393 patients with colon cancer from the UK AXIS trial of postoperative portal vein infusion fluorouracil versus control. We measured loss of heterozygosity (LOH) and microsatellite instability at four loci: P53 (17p13), D18S61 (18q22.3), D18S851 (18q21.1), and DP1 (5q21). The prognostic value of each marker was assessed with the log-rank test, and the predictive value by comparison of treatment hazard ratios with the chi(2) test for heterogeneity (CSH). FINDINGS: In 228 (58%) patients informative for LOH at D18S61, this marker was significantly predictive: benefit from fluorouracil was significantly greater in patients retaining heterozygosity than in those with LOH (CSH p=0.02). Conversely, LOH at D18S61 was a significant prognostic marker of improved outcome in untreated patients. 314 (80%) patients were informative for LOH at at least one of the three 17p and 18q sites, of whom half retained heterozygosity at one or more site. The effect of chemotherapy in these patients was striking (hazard ratio 0.45, 95% CI 0.28-0.73), whereas chemotherapy had no effect in patients with no retained heterozygosity (0.91; 0.56-1.48), CSH p=0.039. INTERPRETATION: Retention of heterozygosity at one or more 17p or 18q sites was associated with the ability to benefit from adjuvant fluorouracil. These results support the principle of developing molecular markers as predictive factors in treatment decisions.

Expression of the 17-1A antigen in gastric and gastro-oesophageal junction adenocarcinomas: a potential immunotherapeutic target?

BACKGROUND: A murine monoclonal antibody against the 17-1A epithelial antigen has been shown to be a useful adjuvant therapy in colorectal cancer. Its clinical use could be extended to patients with upper gastrointestinal adenocarcinoma. AIM: To determine the distribution of the antigen in gastric and oesophageal adenocarcinoma. METHODS: The activity of two monoclonal antibodies active against 17-1A epithelial antigen was studied in gastric and gastro-oesophageal junction adenocarcinomas: fresh frozen tissue from both the carcinoma and adjacent mucosa was stained using immunocytochemistry with a murine monoclonal antibody (17-1A edrecolomab, Glaxo Wellcome); paraffin embedded tissue was stained using the humanised monoclonal antibody 3622W94 (Glaxo Wellcome). RESULTS: 29 of 33 cancers (88%) stained with the murine antibody and 39 of 40 (98%) with the humanised antibody. The degree of staining was greater in well differentiated and moderately differentiated tumours. There was no staining of the normal background gastric or oesophageal mucosa, but areas of intestinal metaplasia stained intensely. The humanised monoclonal 3622W94 antibody produced more intense staining than the murine antibody. CONCLUSIONS: The high incidence of expression of the 17-1A antigen in patients with gastric and gastro-oesophageal junction adenocarcinomas suggests a potential role for these antibodies as an adjuvant treatment for these common cancers.

Nonvalvular myocardial involvement in metastatic carcinoid disease.

A patient with the unusual post mortem finding of myocardial metastatic carcinoid tumour without classical valvular or endocardial carcinoid disease is described. This rare occurrence may represent an aggressive type of carcinoid tumour, with metastatic disease occurring before the development of classical fibrous valvular and endocardial pathology.

Standardisation of a self-report questionnaire for use in evaluating cognitive, affective and behavioural side-effects of anti-epileptic drug treatments.

The development and standardisation of an inventory for measuring anti-epileptic drug effects on cognition and affect is described. The Side Effect and Life Satisfaction inventory (SEALS) was derived from symptoms and side-effects reported by a patient population. It was administered to 45 patients on two occasions and test-retest reliability was demonstrated. It was administered to 923 patients with epilepsy. An underlying factor structure was produced by principal components analysis, consisting of five sub-scales which were stable when data from males and females were analysed separately or together. Validity was evaluated by comparing inventory scores of patients undergoing a number of treatment trials to show that the inventory was sensitive to treatment differences when other variables were controlled. Patients taking two or more anti-epileptic drugs had poorer SEALS scores than those taking a single drug. Patients taking vigabatrin and one other AED had poorer scores than those taking lamotrigine (LTG) and one other AED. A comparison of changes from baseline to week 4 of a double blind comparison of carbamazepine (CBZ) and LTG showed significantly greater improvement in SEALS scores for patients taking LTG, and significantly poorer scores in those patients taking CBZ who dropped out of the study, than in those who continued. It is concluded that SEALS is a valid and reliable tool for use in anti-epileptic drug trials.

Effects of chlordiazepoxide and sodium valproate in two tests of spatial behaviour.

The effects of chlordiazepoxide (CDP) and sodium valproate (VPA) were studied in rats trained to asymptotic performance on two tests of spatial behaviour, the 8-arm radial maze and the 8-choice arena. The task in the 8-arm maze was to locate a single food pellet at the end of each arm. Both CDP and VPA caused an increase in errors, an increase in performance time, and the utilization of a non-spatial response strategy. The task in the 8-choice arena was to locate a single water bottle from an octagonal array of eight otherwise empty bottles. For one group the goal bottle remained in the same place from trial to trial; for a second group the position of the goal bottle was cued by a black card over the nozzle; for the third group the goal bottle was uncued and moved randomly from trial to trial. VPA had no effect on performance, but CDP impaired performance in all three groups. These patterns of effects suggest that VPA may specifically disrupt working memory, but that the impairment of spatial performance by CDP probably results from a non-specific perceptual or attentional deficit.