Biomedical subjects
T Cooke
Publications and source records attributed to T Cooke.
Lipoprotein [Lp(a)] and peripheral vascular disease.
Lipoprotein(a) [Lp(a)], which combines structural elements of the lipid and fibrinolytic systems, is a major independent risk factor for the development of coronary heart disease. Eighty-four consecutive patients with peripheral vascular disease (of whom 42 had concomitant ischaemic heart disease) and 43 healthy controls were enrolled in a case-control study. We found that the mean Lp(a) concentration in male patients with peripheral vascular disease (PVD) was almost threefold higher than that of controls, while in female patients the Lp(a) concentration was more than twice that of controls. This marked difference was borne out in patients with and without concomitant ischaemic heart disease (IHD). A multivariate logistic regression analysis indicated that Lp(a) is independently associated with PVD when adjusted for age and sex (odds ratio per 100 mg l-1 increase in Lp(a) = 1.35; P < 0.01). A similar association is observed for patients with concomitant IHD (odds ratio per 100 mg l-1 increase in Lp(a) = 1.65; P < 0.01).
The long term prognostic significance of c-erbB-2 in primary breast cancer.
The expression of the c-erbB-2 oncogene has been evaluated using an immunohistochemical technique with the 21N polyclonal antibody in paraffin embedded tissue from 465 patients treated between the years 1975-1981 for Stage I and II breast cancer. One hundred and four (22%) patients exhibited positive staining. This was not associated with any other variables. Expression of the oncogene was associated with significantly poorer survival which was independent of other tumour variables.
The long term prognostic significance of oestrogen receptor analysis in early carcinoma of the breast.
The long term prognostic significance of oestrogen receptors was assessed in a prospective study of 767 patients presenting between the years 1975 and 1981 with stage 1 and 2 breast cancer treated by mastectomy with either full axillary dissection or nodal sampling. Oestrogen receptor binding was determined by a dextran coated charcoal method and median follow up was 11 years. Oestrogen receptors were present in 396 (54%) of tumours. Absence of oestrogen receptors was associated with tumours of high histological grade, but there was no relationship between nodal status or tumour size. Oestrogen receptor status did not predict survival for the group as a whole or when stratified by nodal status. In multivariate analysis both nodal status and tumour size were powerful independent prognostic factors, but oestrogen receptors failed to achieve statistical significance.
The effects of intracolonic EGF on mucosal growth and experimental carcinogenesis.
Although intra-luminal epidermal growth factor (EGF) may stimulate cell proliferation in the upper gastrointestinal tract, its role in the large bowel has not been established. We have therefore studied the effect of intra-rectal EGF administration on both normal growth and carcinogenesis in the rat colon. Colonic cancer was induced in rats with azoxymethane (10 mg kg-1 week-1 for 12 weeks s.c.) and controls dosed with saline. In each group, animals were randomised to receive EGF (12 nM, 0.8 nM or saline control) in 0.5 ml saline via a rectal tube daily for 24 weeks. At this time, crypt cell production rates (CCPRs) were determined at two sites in the colon: one of maximal and another of minimal exposure to EGF (5 cm and 10 cm from the anal margin respectively). No effects of EGF were seen at 10 cm. The lower dose of EGF gave CCPRs that mirrored the control values. The higher dose of EGF in the animals not treated with azoxymethane stimulated mucosal growth. Azoxymethane increased in CCPR, but this was suppressed by the high dose of EGF. These results suggest that (1) luminal EGF and azoxymethane independently increase the colonic CCPR and their combined effect is not synergistic but antagonistic; (2) EGF may have a role in normal epithelial growth, but does not potentiate colonic carcinogenesis in this model.
Contamination of operating room personnel during total arthroplasty.
The authors prospectively evaluated the degree of contamination to the operating room team during 60 consecutive total joint arthroplasties. Each member of the team was required to wear a hood, mask, protective eyewear, and shoecovers. At the conclusion of each procedure, all members were assessed in terms of degree and location of contamination. One hundred percent of the surgeons and first assistants were exposed. The face and eyewear were noted to be the area of greatest contamination. The authors found orthopedic surgeons to be at significant risk of contamination with blood and body fluids during total joint arthroplasty.
Birthweight specific trends in cerebral palsy.
A register of infants with cerebral palsy born to mothers resident in the Mersey region from 1967-84 has been maintained using various sources of information. A total of 1056 patients are registered of whom 331 (31%) have hemiplegia or mixed hemiplegia, 236 (22%) have diplegias or mixed diplegia, and 369 (35%) have quadriplegia or mixed quadriplegia. The remainder have dyskinetic or dystonic forms except for seven, who are unclassified. There has been no significant change in the prevalence of cerebral palsy among infants of normal birth weight (greater than 2500 g). Among low birthweight infants (less than or equal to 2500 g) there has been a significant increase in prevalence of all the main clinical types. This increase started later among the very low birthweight infants (less than or equal to 1500 g) than among those weighing 1501-2500 g. These changes in prevalence could be the result of either improved survival of prenatally impaired infants because of improvements in medical care, or a reflection of failure to maintain optimal conditions at or around the time of birth.
Management of screen detected ductal carcinoma in situ of the female breast.
Thirty eight ductal carcinomas in situ of the female breast detected during the first 7 years of screening by the Guildford Breast Screening Unit have been treated by one surgeon. Twenty-eight cases were treated conservatively and ten by mastectomy. In the group treated conservatively there have been five local recurrences: four as ductal carcinoma in situ and one as node negative microinvasive carcinoma. There were no clinical or pathological features that predicted local recurrence, which was detected only by follow-up mammography. Based on these early results, an initially conservative approach to screen detected ductal carcinoma in situ is advocated.
Prognostic value of nucleolar organizer regions and ploidy values in advanced colorectal cancer.
The prognostic value of nucleolar organizer regions and ploidy status in patients with Dukes' C colorectal cancer was determined. In addition, nucleolar organizer regions and ploidy status were compared with the established prognostic indices age, sex, tumour location and degree of histological differentiation. Fifty-one patients (27 men, 24 women) aged 35-81 years (median 64.8 years) were studied. Five years after presentation, 16 patients were alive and well. Survivors had significantly lower nucleolar organizer region counts (median value and range) in primary tumours 12 (8-15) and lymph node metastases 11 (8-15) than non-survivors 17 (14-25) and 18 (13-25) respectively (P less than 0.05). Fewer survivors had aneuploid tumours than non-survivors: four survivors compared with 17 non-survivors. In a regression analysis model, nucleolar organizer regions were the most important individual variable for predicting survival (chi2 = 15, P less than 0.01) while ploidy values (chi2 = 6, P less than 0.2) were equivalent to histological differentiation.
The use of tumour markers in clinical practice.
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Proliferation patterns and aneuploidy in adenomatous polyps of the colon.
The frequency of aneuploidy and the proliferative activity of 57 colorectal adenomatous polyps was investigated by static cytophotometry and compared with 43 adenocarcinomas and 60 samples of normal mucosa. Twenty per cent of the adenomas contained aneuploid cells compared with 63 per cent of the adenocarcinomas. Except in the case of villous adenomas, there was a general increase in the proliferative activity of the diploid adenomas with increasing degrees of dysplasia. All of the adenomas showed an increase in proliferation compared with normal mucosa. There was a positive correlation between the size of the diploid adenomas and proliferative activity (P less than 0.001).
Experimental colonic carcinogenesis: changes in faecal bile acids after promotion of intestinal tumours by small bowel resection in the rat.
Small bowel resection promotes the development of colonic tumours in azoxymethane treated rats. As high faecal bile acid concentrations are associated with colonic cancer and may be altered by resection, we have studied changes in faecal bile acid concentrations during promotion of colonic carcinogenesis by increasing small bowel resection. Twenty rats in each group underwent either jejunal transection or 20%, 50%, or 80% proximal small bowel resection. Tumours were induced with azoxymethane 10 mg/kg by 12 weekly subcutaneous injections, and faecal bile acid concentrations were measured at six and 16 weeks. Colonic tumour number rose from 0.6 per rat in the transection group to 1.6 per rat in the 50% resection group (p less than 0.01) but were not significantly different to transection values at 0.8 per rat in the 80% resection group. Total daily faecal bile acid excretion and bile acid concentrations fell with increasing resection from 14.2 (1.6) mg/rat/day and 5.8 (0.7) mg/g dry faeces respectively in the transection group to 6.5 (0.5) mg/rat/day and 2.9 (0.2) mg/g respectively in the 80% resection group (p less than 0.001). The greatest reduction was seen in the concentration of deoxycholic acid which has been particularly associated with the aetiology of colonic cancer. The promotion of colonic tumours following small bowel resection in carcinogen treated rats is unlikely to be mediated by changes in faecal bile acid concentration or composition.
Alteration in colonic epithelial cell DNA associated with intestinal neoplasia: selection of high risk patients.
The proliferative activity of the colonic crypts of patients who are at high risk of developing colonic tumours has been assessed. Cells from the upper parts of the colonic crypts were collected at colonoscopy, and were stained for DNA by the Feulgen technique. Using a microdensitometer the DNA content of the cells was measured and a proliferative index calculated. Patients with single neoplasms had a proliferative index similar to controls although individual patients with hyperplastic mucosa could be identified. Patients with multiple neoplasms had an elevated proliferative index. These results may form the basis of a screening programme for colonic tumours.
Predictive power of progesterone receptor status in early breast carcinoma.
Progesterone receptor status (PgR) and oestrogen receptor status (ER) were examined in 332 women with stage I-II breast carcinoma treated at a single centre either by simple mastectomy with (n = 283) or without (n = 6) axillary clearance, or by segmental mastectomy with (n = 18) or without (n = 25) axillary clearance and radiotherapy; median follow-up time was 40 (range 10-60) months. Neither the concentration nor the presence of PgR related to either disease-free interval or survival. However both the presence and the concentration of ER were found to be associated with a longer disease-free interval amongst patients with stage II tumours (P less than 0.01). From this study it appears that progesterone receptor status does not predict outcome in early breast carcinoma.
Importance of cellular DNA content in pre-malignant breast disease and pre-invasive carcinoma of the female breast.
The risk of malignant change in pre-invasive breast disease such as proliferative atypia (PA) or the risk of invasive carcinoma arising from ductal carcinoma in situ (DCIS) remains uncertain in individual women because of the absence of any prognostic criteria. In order to clarify this, the cellular DNA content (ploidy) of 51 screen-detected lesions has been investigated. Cellular DNA measurements were made by static cytometry following Feulgen staining of disaggregated tissue sections and the resulting histograms classified as either diploid or aneuploid. Thirteen cases of PA and twelve of DCIS were compared with twenty-six biopsies showing DCIS with adjacent invasive carcinoma (DCIS + Ca). In the latter group, ploidy of the invasive carcinoma was compared with the associated DCIS in 16 cases. Aneuploid cells were found in approximately 30 per cent of PA and DCIS lesions but in 23 of 26 cases of DCIS + Ca. Of 16 assessable cases of co-existing DCIS and micro-invasive carcinoma both were aneuploid in 11, both diploid in 1, and in 4 cases the DCIS was aneuploid whereas the invasive carcinoma was diploid. These results suggest that aneuploidy may be of value in predicting the most biologically aggressive of these pre-invasive lesions.
Kinetic changes in experimental colonic urinary diversion.
An experimental model of colonic urinary diversion was performed on male Wistar rats to see if faeces, urine or a faeces and urine mixture produces tumours. Cell kinetic techniques, including the crypt cell production rate, and cellular DNA measurement were used to examine the effect of urine and of faeces on the colonic mucosa. Urinary diversion into the colon significantly increased colonic crypt activity. Tumours were found at the anastomosis when urine and faeces were mixed at 4 months, and at 6 months with urine alone.
Effect of a long-acting analogue of somatostatin, SMS 201-995, on the development of intestinal tumours in azoxymethane-treated rats.
The effect of daily parenteral administration of a long-acting analogue of somatostatin (SMS 201-995) on the development of intestinal tumours and the rate of crypt cell proliferation in azoxymethane-treated rats has been studied. SMS 201-995 had no significant effect on the number of colonic tumours induced. In the duodenum, SMS 201-995 administration was associated with a change in the number of tumours from 1.4/rat in saline-treated animals to 2.4/rat in animals treated for the last third of the study and 2.8/rat in animals treated with SMS for the entire duration of the study (P less than 0.02). SMS had no significant effect on the rate of cell proliferation in the duodenum, ileum or colon. The inhibition of release of gastrointestinal trophic hormones by this analogue of somatostatin thus does not appear to reduce the number of tumours in the intestine of azoxymethane-treated rats.