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Biomedical subjects

J Mackay

Publications and source records attributed to J Mackay.

At least 55 records · Page 3Linked to original sources
PubMed1998

The use of videotaped information in cancer genetic counselling: a randomized evaluation study.

A video of introductory information about inherited susceptibility to breast cancer was made in consultation with clinicians in four Scottish cancer family clinics. One hundred and twenty-eight women, newly referred for breast cancer risk counselling were randomized to receive the video before (n = 66) or after (n = 62) counselling. Data were collected before randomization at clinic and by postal follow-up at 1 month. The Video Before group had shorter consultations with the breast surgeon (mean = 11.8 min+/-5.4 vs 14.6+/-7.2 for the Video After group). There was no difference between the groups in the accuracy of their risk estimate after counselling, although the Video Before group scored higher for self-reported (Z= 3.65, d.f. = 1, P < 0.01) and objectively assessed understanding (Z= 2.91, d.f. = 1, P < 0.01). At 1 month follow-up, the Video Before group were less likely to underestimate their risk estimate (38% vs 18%; chi2 = 4.62, d.f. = 1, P< 0.05), but there was then no difference between the groups in subjective or objective understanding. Use of the video was not associated with increased distress (GHQ, Spielberger State Anxiety) and was associated with greater satisfaction with the information given at the clinic. This study supports the value of videotape as a method of giving information to prepare women for breast cancer risk counselling. Observations of misunderstandings and distress emphasize the video should be seen as an aid to, not a substitute, for communications at the clinic.

Adult↗
PubMed1998

Screening for breast and ovarian cancer: the relevance of family history.

The recent identification of two breast and ovarian cancer susceptibility genes--BRCA1 and BRCA2--has received a lot of publicity. Public and professional expectations of the availability and utility of genetic testing have been raised and the importance of a family history of breast cancer overemphasized. In this chapter, we examine the significance of a family history of breast or ovarian cancer in determining individual risk. A strategy for management is proposed, based on stratifying women with such a history into three different categories of risk for breast cancer: high, moderate and low. Some of the more controversial aspects of screening for breast and ovarian cancer are reviewed, including the issue of management of women who are at increased risk of these cancers by virtue of a family history, genetic predisposition, or both. There is a need for further research to clarify the most appropriate management of those at moderate risk of developing these cancers. A management strategy for women at high risk is proposed. We believe that adoption of this strategy will strengthen consistent information giving from primary to tertiary care.

Breast Neoplasms↗
PubMed1997

BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland.

A restriction site-generating polymerase chain reaction (RG-PCR) assay was developed to detect the BRCA1 5382insC mutation that has been reported in multiple, apparently unrelated breast/ovarian carcinoma families. The assay has been used to screen tumour DNA from 250 breast cancer patients (aged 19-86 years) and from 80 ovarian cancer patients (aged 25-90 years) in a local population of patients with no known family history. Altogether, 0/80 (0%) ovarian and 1/250 (0.4%) breast tumour DNAs were found to have the 5382insC mutation. The sole positive case was a 26-year-old woman (BC185) with no known family history. One of the reasons for carrying out this analysis was that the 5382insC mutation had previously been shown to segregate with the disease in a very large Scottish 'West Lothian' kindred having breast/ovarian carcinoma. To investigate whether this apparently isolated case and the known family might be related, haplotypes for the markers D17S855, D17S1322, D17S1323 and D17S1327 were analysed. The mutant haplotype in the large kindred was identical to that reported in all other 5382insC mutation families for all markers with the exception of D17S1327. This implies that there has been a recombination event at the telomeric end of common ancestral haplotype in this family. Since the isolated case we identified carries the 'complete' common haplotype, it is unlikely that she is closely related to the West Lothian family.

Adult↗
PubMed1997

Industrial Genotoxicology Group collaborative trial to investigate cell cycle parameters in human lymphocyte cytogenetics studies.

Human lymphocyte cultures have been used for many years for assessing the in vitro clastogenic potential of test substances. In these assays the harvest time should be based on the cell cycle time in order to ensure that cells are sampled at an appropriate time for the detection of clastogenic effects. The sources of variation in the cell cycle time in routine cytogenetic assays have not been well studied. Consequently 13 laboratories, all members of the Industrial Genotoxicology Group, participated in a collaborative study to measure the variation in cell cycle time in cultured human peripheral blood lymphocytes under various conditions. The study was performed in two phases, spaced 6 months apart. The average generation time (AGT) was measured by the incorporation of bromodeoxyuridine. Very similar AGTs were found in the presence and absence of S9 mix. The mean AGT (mean of four donors) in each laboratory varied from 11.2 to 17.1 h, indicating there is significant variability in cell cycle times of human peripheral blood lymphocytes between laboratories. There was greater variation between laboratories than within laboratories. A comparison of AGT values at 72 h performed in experiments at least 6 months apart indicated good reproducibility in most laboratories. The study indicates that a 24 h post-treatment harvest may result in the analysis of very few first division cells unless very significant cell cycle delay is induced by the test substance. It was also found that a post-harvest time equivalent to 1.5 cell cycles will result in an approximately equal mixture of first and second division cells and therefore should by suitable for assessing both the induction of chromosome aberrations and polyploidy.

Animals↗
PubMed1997

Pre-operative radiotherapy and chemotherapy for non-resectable rectal cancer.

BACKGROUND: The treatment results of combined pre-operative radiotherapy and chemotherapy followed by surgery for patients with initially non-resectable primary rectal cancer were reviewed. METHODS: Thirteen patients with locally advanced non-resectable rectal cancer were treated with pre-operative irradiation consisting of 50.4-54 Gy plus concomitant 5-fluorouracil (5-FU) delivered during the 1st and 5th weeks of radiotherapy. RESULTS: Following pre-operative therapy, the resectability rate was 91%, with all but one patient undergoing complete resection. The pathologic complete response rate was 10%. The overall peri-operative and postoperative complication rate was 0.8 complications per patient. There was no postoperative mortality. CONCLUSIONS: This early experience indicates that high resectability rates are achievable with pre-operative radiotherapy and chemotherapy for non-resectable rectal cancer while maintaining acceptable postoperative morbidity.

Aged↗
PubMed1996

Definition and refinement of a region of loss of heterozygosity at 11q23.3-q24.3 in epithelial ovarian cancer associated with poor prognosis.

Previous cytogenetic and loss of heterozygosity (LOH) data suggest that disruption of chromosome 11q23-qter occurs frequently in epithelial ovarian cancer and is associated with an adverse clinicopathological phenotype. Ten polymorphic microsatellite repeat loci were analyzed by PCR from the 11q22-q25 region between D11S35 and D11S968 in 40 ovarian tumors (including 31 epithelial ovarian cancers). Two distinct regions of loss were detected, suggesting possible sites for genes involved in epithelial ovarian neoplasia: a large centromeric region between D11S35 and D11S933 (11q22-q23.3) and a telomeric 8.5-Mb region lying between D11S934 and D11S1320 (11q23.3-24.3) not previously defined. LOH of the latter region but not the former one was significantly associated with poor survival, despite all tumors in this study having LOH somewhere on chromosome 11. This analysis provides a starting point for positional cloning.

Carcinoma↗
PubMed1996

Weekly doxorubicin and continuous infusional 5-fluorouracil for advanced breast cancer.

Drug scheduling alterations can improve the therapeutic index of both 5-fluorouracil and anthracyclines. We investigated a regimen of weekly doxorubicin and continuous infusional 5-fluorouracil (AcF) in loco-regionally recurrent and metastatic breast cancer. The aims of this phase II study were to use low-dose weekly anthracyclines in a patient group where liver metastases are a frequent problem, to optimise scheduling of 5-fluorouracil using continuous infusion and to conserve alkylating agent use for late intensification in responding patients. Fifty-six patients received 5-fluorouracil 200 mg m-2 day-1 and doxorubicin 20-30 mg m-2 week-1 for at least 6 weeks. Sixty-two percent were chemonaive. Patients were evaluated for dose intensity, response, toxicity and survival. Of the assessable patients, 76% achieved UICC response criteria (20% complete response, 56% partial response). WHO grade 3+ toxicities were: alopecia, 98%; mucositis, 62%; neutropenia, 22%; and grade 3 palmar-plantar syndrome, 24%. Median survival was 13 months, with visceral metastasis conferring a significantly worse outcome (P = 0.03). Grade 3+ mucositis was more frequent with planned doxorubicin dose intensity > or = 25 mg m-2 week-1 (P = 0.04). AcF is highly active in breast cancer with acceptable toxicities and can be used before alkylating agent-based high-dose therapy.

Adult↗
PubMed1996

Extended harvest times are not necessary for the detection of in vitro clastogens in regulatory cytogenetics studies.

The choice of harvest time in in vitro cytogenetics assays is a critical factor in determining the sensitivity of the assay for detecting clastogenic potential. As yet there is no harmonization of regulatory requirements in this aspect. It has been suggested that the use of extended harvest times can improve the sensitivity of detecting some chemicals which either induce cell cycle delay or produce lesions which induce chromosome aberrations at divisions subsequent to the first post-treatment mitosis. The incidence of such chemicals encountered in the routine testing of chemicals for regulatory submissions is not known. Therefore a large database of 550 chemicals tested in nine laboratories using standard regulatory protocols, including a late harvest time, was assessed for the incidence of chemicals uniquely positive only at a delayed harvest time. The number of such chemicals was very low ( < 0.2%) and the chromosome damage induced by these chemicals may not result from direct genotoxic mechanisms. Based on these data it is recommended that there is no need to include an extended harvest time in in vitro cytogenetics assays except where it might help to resolve an equivocal result.

Animals↗
PubMed1996

Pharmacokinetics, metabolism and tumour disposition of 8-chloroadenosine 3',5'-monophosphate in breast cancer patients and xenograft bearing mice.

BACKGROUND: 8-Chloroadenosine 3',5'-monophosphate (8-Cl-cAMP) is undergoing phase I clinical trials as an anticancer drug. However, there is debate as to whether it is a prodrug for its 8-Cl-adenosine metabolite. DESIGN: Pharmacokinetics, metabolism and tumour disposition studies have been performed in 7 breast cancer patients receiving continuous infusion (28 day) 8-Cl-cAMP (0.54 or 1.08 mg/kg/day) and tumour biopsies were obtained before and on the last day of infusion. Parallel studies were performed in nude mice bearing the HT29 human colon cancer xenograft after continuous infusion (7 day) of active drug doses (50 or 100 mg/kg/day). RESULTS: Steady state plasma levels (Css) of 8-Cl-cAMP in patients ranged from 0.15-0.72 microM but 8-Cl-adenosine was not detected in plasma. In contrast, 8-Cl-cAMP was not detectable in 3 tumour biopsies but 8-Cl-adenosine was present in 2 samples at high concentrations (1.33 and 2.02 microM). In mice, Css of 8-Cl-cAMP ranged from 3.2-4.6 microM and 8-Cl adenosine was present in plasma only at the higher dose (100 mg/kg/day, peak concentration of 2.3 microM). In the HT29 xenograft, 8-Cl-cAMP levels were considerably lower than in plasma (0.37-1.22 microM) while 8-Cl-adenosine was present at 5.3-21.0 microM and 8-Cl-AMP was found at 11.3-35.7 microM. CONCLUSIONS: The fate of 8-Cl-cAMP in human tumours is characterised by extensive metabolism to products which are not generally observed in plasma. These data raise the possibility that 8-Cl-cAMP is a prodrug for a product of its metabolism in human tumours.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1996

A pilot study of infusional CMF (CMF-inf): active and well tolerated in breast cancer. The Edinburgh Breast Group.

BACKGROUND: We have previously shown that 5-fluorouracil (5-FU) given by continuous infusion is well tolerated and active in the treatment of breast cancer [1, 2]. We found that given infusional 5-FU could produce responses in patients whose disease was resistant to bolus 5-FU and speculated that it could be combined safely with methotrexate/cyclophosphamide in a manner analogous to i.v. CMF bolus. Using a modification of the i.v. CMF regimen, comprising a standard dosage of bolus cyclophosphamide at 750 mg/m2 and bolus methotrexate at 50 mg/m2 given every 3 weeks we altered the continuously infused 5-FU schedule to 200 mg/m2/24 hours and treated 28 patients of whom 23 had had previous chemotherapy (18 containing anthracycline, 4 bolus CMF and 19 infusional 5-FU alone or in combination with other drugs) and 4 post menopausal patients with locally advanced breast cancer. RESULTS: Fourteen responded (2 CR, 12 PR) out of 27 evaluable patients with onset of response between 3 and 9 weeks. Toxicity was relatively mild in the 28 evaluable patients and did not require cessation of treatment, with one exception (vomiting leading to dehydration at home and moderate transient uraemia). The main toxicities seen were WHO grade 3 neutropenia in 13/28 patients and grade 2 mucositis in 2 further patients. Grade 2 palmar/planter syndrome was reported in 4/28 patients and grade 2 or 3 nausea/vomiting was reported in 7/28 patients. CONCLUSION: This well tolerated regimen is clearly active in patients with heavily pretreated breast cancer and should be tested against intravenous or classical CMF in a randomised trial.

Adult↗