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Biomedical subjects

J R Hardy

Publications and source records attributed to J R Hardy.

At least 19 recordsLinked to original sources
PubMed1991

Phase II study of the amsacrine analogue CI-921 (NSC 343499) in non-small cell lung cancer.

CI-921 (NSC 343499; 9-[[2-methoxy-4-[(methylsulphonyl)amino]phenyl]amino] -N,5-dimethyl- 4-acridinecarboxamide) is a topoisomerase II poison with high experimental antitumour activity. It was administered by 15 min infusion to 16 evaluable patients with non-small cell lung cancer (NSCLC) (7 with no prior treatment, 9 patients in relapse following surgery/radiotherapy) at a dose (648 mg/m2 divided over 3 days, repeated every 3 weeks) determined by phase I trial. Patients had a median performance status of 1 (WHO), and median age of 61 years. The histology comprised squamous carcinoma (11), adenocarcinoma (1), mixed histology (2), bronchio-alveolar carcinoma (1) and large cell undifferentiated carcinoma (1). Neutropenia grade greater than or equal to 3 was seen in 15 patients, infections with recovery in 3, and grand mal seizures in 1 patient. Grade less than or equal to 2 nausea and vomiting occurred in 66% courses and phlebitis in the infusion arm in 37%. 1 patient with squamous cell carcinoma achieved a partial response lasting 5 months. Further testing in this and other tumour types using multiple daily schedules is warranted.

Adult↗
PubMed1991

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer.

This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m-2 (day 1), mitozantrone 7-8 mg m-2 (day 1 and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The overall response rate (complete and partial) was 53% (95% Confidence Limits (CL): 43-62%) for 3M and 49% (CL; 39-58%) for VAC. The response according to sites of metastases was the same for both treatment groups. Symptomatic toxicity including alopecia, neuropathy, vomiting (P less than 0.001) and nausea (P less than 0.01) were significantly less for 3M. Myelosuppression including leucopenia (P less than 0.001) and thrombocytopenia (P less than 0.001) was significantly greater with 3M at day 21, although there was no difference in nadir counts in patients at special risk of myelosuppression and there was no evidence of an increase in infective or bleeding complications. There was no significant difference in the duration of response to 3M (10 months, CL 6-15) and VAC (11 months, CL 7-12), nor in survival (3M, 8 months, CL 6-12; VAC, 10 months, CL 8-12). These results indicate that 3M is as effective as, but has significantly less symptomatic toxicity than, an anthracycline containing regimen for the treatment of advanced breast cancer.

Adult↗
PubMed1990

Combination of tamoxifen, aminoglutethimide, danazol and medroxyprogesterone acetate in advanced breast cancer.

Seventy-four post-menopausal women with metastatic breast cancer were treated with a combination hormonal regimen consisting of tamoxifen, aminoglutethimide danazol and medroxyprogesterone acetate (POND). 72% of the patients had received no previous treatment. The overall response rate (complete and partial remission) was 43.5% with a median response duration of 19 months and a median survival of 27 months. The most common sites of response were in regional nodes and local chest wall disease. The major side-effects were those expected from the individual agents: nausea, lethargy, rash and oedema.

Aged↗
PubMed1990

How many tests are required in the diagnosis of palpable breast abnormalities?

Palpable breast nodules in 143 patients attending our primary diagnosis breast clinics were assessed by clinical examination, needle cytology, mammography, ultrasonography and magnetic resonance imaging (MRI). The diagnostic accuracy of all test combinations was compared with the final diagnosis of malignant or benign disease. Two-test combinations increased the sensitivity of diagnosis over that of the individual tests to between 93% and 100% except for MRI/mammography and MRI/cytology. The combinations of three or more tests increased the sensitivity further, but at the expense of an increased false-positive rate. MRI does not appear to have an important role in the primary diagnosis of breast cancer. Mammography is necessary because of the possibility of occult or multifocal disease. Clinical examination was associated with a high false-positive rate. The combination of cytology and ultrasound was best at correctly diagnosing malignancy, but in this series only 42% of patients underwent ultrasound examination. The role of breast ultrasound together with needle aspiration cytology for the diagnosis of malignancy in palpable breast nodules deserves further evaluation.

Adult↗
PubMed1990

Magnetic resonance imaging in the detection of skeletal metastases in patients with breast cancer.

Eighty-four patients with breast cancer at high risk of bone metastases were investigated with magnetic resonance imaging (MRI) of the thoracolumbar spine. Of 58 patients with normal limited skeletal surveys (LSS) and bone scans (BS), 4 (7%) had MR images compatible with malignant infiltration. Fourteen patients had abnormal bone scans with normal or non-diagnostic plain films; 7 of these patients (50%) had MR images compatible with malignant infiltration. Twelve patients had single or multiple wedge collapses of uncertain aetiology on plain film; MR demonstrated metastatic disease as the cause of wedge collapse in 7 (58%). MRI may define a group of patients with extra-osseous relapse who have occult metastatic disease. Although the detection rate in patients with primary breast cancer is low (4/45), MRI is of value in determining the cause of wedge collapse in postmenopausal women with breast cancer and may elucidate the cause of an abnormal bone scan with normal or non-diagnostic plain films.

Bone Neoplasms↗
PubMed1989

The effect of cimetidine, phenobarbitone and buthionine sulphoximine on the disposition of N-5-dimethyl-9-[(2-methoxy-4-methyl-sulphonylamino)phenylamino]- 4-acridinecarboxamide (CI-921) in the rabbit.

N-5-dimethyl-9-[(2-methoxy-4-methylsulphonyl-amino)phenylamino]-4- acridinecarboxamide (CI-921) is an amsacrine analogue currently undergoing phase II clinical trials as an antitumor drug. Significant alterations in the plasma clearance (CL) of amsacrine have been demonstrated in rabbits after pretreatment with cimetidine (CT), phenobarbitone (PB) and buthionine sulphoximine (BSO). In the present study, the influence of these agents on the disposition of CI-921 was investigated in rabbits. After a short infusion of CI-921 (12.7 mumol/kg), blood (8 x 3 ml) was collected up to 12 h and the total plasma concentration of CI-921 determined by HPLC. Model-independent pharmacokinetic parameters were compared by Student's paired t-test. CT pretreatment significantly (P = 0.011) increased the AUC (mean, 21%; range, 3%-43%) and significantly (P = 0.019) decreased the CL (mean, 17%; range, 4%-30%). The induction effect of PB pretreatment was not confirmed with CI-921. No significant reduction in AUC or increase in CL was apparent. BSO pretreatment caused a small but significant (P = 0.049) increase in AUC (mean, 20.5%; range, 4%-59%) but had no effect on CL. Although more modest changes in kinetic parameters were observed with CI-921 than with amsacrine, these results suggested the involvement of the hepatic mixed-function oxidase system but not PB-inducible cytochrome P-450 isozymes in the elimination of CI-921 in the rabbit. As with amsacrine, a reduction in hepatic glutathione (GSH) concentrations in the body also appeared to have a modest effect on the disposition of CI-921.

Amsacrine↗
PubMed1989

Chemoprevention of breast cancer.

The hypothesis that oestrogen is an important promoter of human breast cancer raises the possibility that endocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a double-blind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10-15 year follow up in order to detect a 25% prevention effect.

Adult↗
PubMed1989

Cerebral metastases in patients with ovarian cancer treated with chemotherapy.

Cerebral metastases are considered an uncommon complication of ovarian carcinoma. In a series of 52 patients treated with platinum, Adriamycin, and cyclophosphamide combination chemotherapy, 6 patients developed cerebral metastases, an incidence (11.6%) higher than that reported by others. The median age of the patients with cerebral metastases was similar to that of patients without this complication. Cerebral metastases occurred as site of first relapse in three of six patients. Only one patient had extraperitoneal disease prior to chemotherapy and four of the six patients had attained a complete response following chemotherapy. Cerebral relapse occurred at 0, 21, 27, 30, 34, and 36 months from original diagnosis of ovarian carcinoma and 0, 9, 11, 19, 25 and 29 months following first treatment with combination chemotherapy. The median survival was 33 months from diagnosis and 28.5 months from first treatment with chemotherapy. This compares with a median survival from diagnosis for the entire series of 30 months (28 months from first treatment). The result of treatment of established metastases was poor. Survival from diagnosis of cerebral metastases was 2, 2, 3, 6, 10, and 41 + months. If other series confirm these findings consideration may need to be given to prophylactic central nervous system radiotherapy for patients achieving complete remission after systemic chemotherapy.

Adult↗
PubMed1989

Magnetic resonance imaging of spinal amyloid.

This report describes a patient with a history of breast carcinoma who presented with back pain and multiple collapsed vertebrae. Magnetic resonance imaging (MRI) demonstrated a diffuse bone marrow abnormality, more in keeping with an infiltrative process than with metastases. A bone biopsy confirmed the suspected diagnosis of vertebral involvement by amyloid.

Amyloidosis↗