Effect of warfarin on formation and growth of pre-neoplastic lesions in chemically induced colorectal cancer in the rat.

Anticoagulant drugs are known to have an effect on tumour growth. However, the mechanisms by which they act are poorly understood, and have therefore been investigated in this study. Wistar rats were given eight weekly subcutaneous injections of azoxymethane, at a dose of 10 mg kg-1 week-1. Following this they were randomized into two groups: a control group, which received no further treatment, and a warfarin treated group, which received warfarin at 'non-therapeutic' doses in their drinking water, for a further 8 weeks. Pairs of rats from each group were killed at 5-weekly intervals from 10 to 35 weeks after the first azoxymethane injection. At 40 weeks all remaining rats were killed. Samples of colonic mucosa from the descending colon and rectum were taken for scanning electron microscopy. The number of microadenomas per low power field was determined in both groups at each time interval. Tumour incidence and distribution were noted in animals killed at 40 weeks. The median number of microadenomas was significantly lower in warfarin treated animals than in controls at all time intervals. Tumour number was also significantly decreased by warfarin treatment (27 in azoxymethane treated animals, 10 in animals receiving azoxymethane and warfarin, P less than 0.05). The distribution of tumours along the colon was similar to that seen previously, following 12 weeks of azoxymethane. These effects occurred despite the non-concurrent administration of azoxymethane and warfarin.

Effect of deoxycholic acid on the tumour incidence, distribution, and receptor status of colorectal cancer in the rat model.

It has previously been observed that 25% of human colorectal cancers contain specific receptors to deoxycholic acid (DCA). In the present study, the effect of intrarectal instillation of DCA on tumour number, distribution, size, and DCA receptor status was measured in rats receiving the colorectal carcinogen, azoxymethane. Rats treated with azoxymethane and intrarectal DCA developed significantly more colorectal cancers than rats receiving azoxymethane and intrarectal saline (median 11.5, range 8-17 vs. median 6.0, range 3-9 tumours/rat, respectively, p less than 0.01). This reflected a significantly higher number of tumours in the distal colon of the DCA-treated group (median 8.0, range 5-10 tumours/rat) compared to the saline-treated group (p less than 0.01). In those rats receiving DCA and azoxymethane, 5 of 12 tumours tested were found to be DCA receptor-positive, compared with only 1 of 11 in the saline and azoxymethane group. These results confirm the belief that DCA acts as a tumour promoter, and suggest a possible role for DCA receptors.

Incidence and management of laser-associated oesophageal perforation.

The incidence of oesophageal perforation in 350 patients referred for laser treatment to palliate malignant dysphagia is reported. Perforation occurred in 6 per cent of patients or 2 per cent of treatment episodes. Perforation was usually due to oesophageal dilatation undertaken before laser treatment (23 of 25 perforations). Immediate recognition and the institution of an aggressive non-operative management protocol resulted in survival in 20 of 23 patients.

Prognostic factors and in vitro cytotoxic sensitivity in colorectal cancer.

The poor response rates to chemotherapy for colorectal cancer justify attempts to rationalize selection of patients for treatment, and the development of systems to evaluate new cytotoxic agents. Refinement of prognostic indices may identify colorectal cancer patients at a higher risk of recurrence who merit more aggressive treatment. We report our experience with the stem cell assay and pulse thymidine labelling in 43 primary colorectal cancers. Thirty-six tumours were evaluable, and clonogenic growth was obtained in 30 (83 per cent). In 24 tumours (67 per cent) growth was adequate for meaningful interpretation of a cytotoxic drug assay. Frequency of growth and colony forming efficiency did not correlate with histopathological grade, Dukes' stage or tumour cell kinetic indices. Thymidine labelling indices correlated with Dukes' stage (A and B versus C and D, P less than 0.01, Mann-Whitney U test). Cytotoxic assays with 5-fluorouracil and 5'-deoxy-5-fluorouridine were undertaken in 18 cases (14 primary carcinomas, 4 malignant ascites), of which 14 were evaluable and 3/14 (21.5 per cent) were chemosensitive in vitro. Both drugs were equally effective in vitro at clinically attainable plasma concentrations. This is in accordance with the response rates observed clinically with 5-FU chemotherapy in colorectal cancer.

Effect of warfarin on cell kinetics, epithelial morphology and tumour incidence in induced colorectal cancer in the rat.

The effect of low dose warfarin and high dose warfarin on epithelial cell kinetics (as determined by stathmokinetic techniques), and preneoplastic morphological changes was studied during azoxymethane induced carcinogenesis in the rat. Warfarin, at either low or high dose, had no effect on crypt cell production rate (CCPR) at any time interval whereas tumour incidence in both low dose warfarin and high dose warfarin groups was significantly reduced. Morphological changes were observed using scanning electron microscopy, which by conventional histology were shown to be adenoma precursors. In the control group the number of microadenomas increased with time after starting azoxymethane. In warfarin treated animals, the number of microadenomas also increased with time, but the actual incidence was reduced when compared with controls. These results suggest that the effects of warfarin on tumour development is unrelated to its anticoagulant effect, because increased dose did not result in greater tumour reduction. Furthermore, there was no overall change in CCPR when warfarin was administered. Warfarin may exert a specific effect, by preventing neoplastic change in cells which have undergone morphologically undetectable changes associated with early carcinogenesis.

Cell kinetics and in vitro clonogenicity of primary colorectal cancer: clinicopathological relationships and the implications for chemotherapy.

Cells with the capacity for clonogenic growth in vitro can be isolated from primary human colorectal carcinomas. In this study colonies were grown, composed of cells which expressed epithelial membrane antigen and CEA, confirming their neoplastic character. Adequate growth for assessing the cytotoxicity of drugs for use in clinical chemotherapy regimes was obtained from 64% of the specimens. Colony forming efficiency of the tumour cells was not related to clinical stage or pathological grade of the parent tumour. The S-Phase fraction of the tumour was established in vitro using pulse thymidine labelling. The thymidine labelling index for Dukes' stage A and B tumours was significantly higher (median 15.7%, range 10.1-23.6%) than for Dukes' stages C and D (median 11.7%, range 0.1-13.6%). Colony forming efficiency in vitro was independent of the thymidine labelling index of the tumour. These findings are discussed with reference to the known heterogeneity of colorectal adenocarcinomas.

Operative mortality rates among surgeons: comparison of POSSUM and p-POSSUM scoring systems in gastrointestinal surgery.

PURPOSE: The original Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity and the more recent Portsmouth predictor equation for mortality scoring systems were developed to provide risk-adjusted mortality rates in general surgery. The aim of this study was to compare crude and risk-adjusted operative mortality rates among four surgeons using the above scoring systems and assess their applicability for patients scored retrospectively. METHODS: A total of 505 consecutive patients undergoing major gastrointestinal surgery were analyzed; 65 percent underwent colorectal, 27.5 percent underwent upper gastrointestinal, and 7.5 percent underwent small-bowel surgery. The observed:predicted mortality ratios using the Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity and Portsmouth predictor equation for mortality scoring systems were calculated for each surgeon. RESULTS: The actual overall operative mortality rate was 11.1 percent (elective was 3.9 percent, and emergency was 25.1 percent). The Portsmouth predictor equation for mortality equation predicted a mortality rate of 11.3 percent (P = 0.51). However, the Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity scoring system was found to overpredict death by a factor of two: 21.5 percent (P < 0.001). Mortality rates among the four surgeons varied from 7.6 to 14.7 percent but depended on the proportion of elective vs. emergency surgery. The observed:predicted ratio for Portsmouth predictor equation for mortality was close to unity (0.905-1.067) for all surgeons, but it was 0.45 to 0.56 for Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity. CONCLUSION: The Portsmouth predictor equation for mortality equation seems to be a more accurate predictor of mortality in gastrointestinal surgery. It would seem to provide the best choice for analyzing operative mortality rates for individual surgeons, taking into account variation in case mix and fitness of patients even when scored retrospectively. This has important implications for the future assessment of surgeons' clinical standards and the assessment of quality of surgical care.

Combination chemotherapy with epirubicin, cisplatin and 5-fluorouracil for the palliation of advanced gastric and oesophageal adenocarcinoma.

The palliative efficacy of laser therapy with combination chemotherapy (cisplatin, epirubicin and continuous infusion of 5-fluorouracil) was assessed in 34 patients with inoperable gastro-oesophageal cancer. Comparison was made with a group of 30 patients treated previously by laser alone. Twenty patients responded to chemotherapy. There was a significant improvement in dysphagia, as measured by a decreased laser requirement to maintain satisfactory swallowing. In this non-randomized prospective phase II trial, palliation was attained and some responses were long-lasting (median duration of response 8.7 (range 2.3 to more than 29.2) months).