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Biomedical subjects

A Howell

Publications and source records attributed to A Howell.

At least 181 records · Page 10Linked to original sources
PubMed1988

Single dose versus daily intravenous aminohydroxypropylidene biphosphonate (APD) for the hypercalcaemia of malignancy.

Thirty patients with hypercalcaemia and known malignant disease were randomly allocated to receive 60 mg 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (APD) intravenously as a single dose or as consecutive daily doses of 30 mg (two days) or 15 mg (four days). The rate of infusion was the same for each regimen (7.5 mg/hour). Calcium concentrations fell in all patients and returned to normal in all but two. Relapse of hypercalcaemia occurred after a mean of 21 days in each group. Urinary calcium excretion fell in all groups and symptoms were greatly improved. After relapse patients were retreated with APD (30 mg as a single infusion) and normocalcaemia maintained by regular infusions at two to three week intervals. APD given as a single 60 mg infusion over eight hours together with rehydration is recommended as the initial management of the hypercalcaemia of malignancy, followed by 30 mg APD roughly every two to three weeks to maintain normal or near normal serum calcium concentrations.

Calcium↗
PubMed1988

The definition of the 'no change' category in patients treated with endocrine therapy and chemotherapy for advanced carcinoma of the breast.

In the criteria used for assessment of response to treatment for advanced breast cancer the definition of no change (NC) is clear; however, there is no indication of the duration of stabilization required for patients to qualify for this category of response. We have made the assumption that NC is a worthwhile category of response if the overall time to progression (TTP) and survival of this group is not significantly different from patients with partial remissions (PR). Two hundred and sixty-three evaluable patients treated with endocrine therapy and 302 evaluable chemotherapy-treated patients were studied and the TTP and survival curves for PR and periods of NC from 1 to 6 months compared. For the endocrine-treated patients the TTP and survival curves for NC became non-significantly different from the PR curves after 4 and 5 months respectively. For chemotherapy-treated patients the TTP curves became non-significantly different from PR at 4 months and for survival the period was 3 months. In order to define NC as a useful category of response and to eliminate the possibility that NC taken for a shorter period could simply represent a slowly progressive tumour, we suggest that the minimum period of disease stabilization be taken as 5 months for both endocrine- and chemotherapy-treated patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Cellular aspects of breast cancer: workshop report.

It has not been possible in this review to cover all the submitted posters nor indeed all the points discussed during the workshop session. It is hoped, however, that major points of interest have been presented and that areas where there is consensus and areas where controversy remains concerning the clinical value of particular investigations have been highlighted. It is also hoped that some new potential growth areas for investigation of tumour biology have been defined.

Animals↗
PubMed1988

The effect of age and menstrual cycle upon proliferative activity of the normal human breast.

The aim of this study was to determine the proliferative activity within the epithelial cells of the normal human breast in 122 patients (6 reduction mammoplasties and 116 fibroadenoma excisions) in relation to age and the phase of the menstrual cycle. Thirty three of the patients were on oral contraceptives and 33 were parous. Thin tissue slices were incubated with tritiated thymidine and processed for autoradiography. Other samples were fixed directly and prepared for histology. The labelling, mitotic and apoptotic indices (LI, MI and AI) were determined and all illustrated considerable variability. The labelling indices are significantly (P less than 0.05) influenced by both patient age and stage during the menstrual cycle and ranged from 0-11.5%. Maximum LI values were obtained on the 20.8th day of the cycle. A square root transformation of the data was used to reduce the skewness of the data to a more normal distribution. The square root of the LI declined by 0.22 per decade. The mitotic data showed similar significant (P less than 0.05) correlations against age and day of cycle with a peak on the 21.5th day of the cycle, a decline by 0.072 per decade and a range from 0-0.6%. The data for apoptotic cells were less clearly influenced by the stage of the menstrual cycle but showed a significant (P less than 0.5) decline with age. The AI in parous patients was significantly higher than that in non-parous patients. There was no significant effect of oral contraceptives on any of the parameters measured when age and stage of cycle were taken into account. The considerable variability in the data could not be fully accounted for by either technical factors, the age of the patients, or the day of the cycle. We conclude that proliferation is negatively related to age and is influenced by the menstrual cycle but that additional as yet unknown factors must account for a large part of the variability seen in the data.

Adolescent↗
PubMed1988

The relationship of body weight to response to endocrine therapy, steroid hormone receptors and survival of patients with advanced cancer of the breast.

High body weight is associated with increased production of oestrogens which may influence the clinical behaviour of breast cancer. We have examined the influence of body weight on the response to endocrine therapy, steroid hormone receptor content and survival in 227 women who either presented with or developed advanced cancer of the breast. One hundred and thirty-three (59%) patients presented with operable disease and 94 (41%) with locally advanced tumours. Two hundred (88%) were treated by tamoxifen and 27 (12%) by ovarian ablation. High body weight was correlated with advanced tumour stage (P = 0.002) and progesterone receptor (PR) positivity (P = 0.01), but not with the presence of oestrogen receptor (ER P = 0.21). The association between high body weight and PR positivity was particularly noticeable among ER positive tumours. There was no significant relationship between the nature of the response to therapy and weight (P = 0.57). There was no significant difference in survival from the start of endocrine therapy (P = 0.95), nor the time to progression of disease (P = 0.29) between patients above and below the median weight of 64 kg. Among the patients with operable disease, there was no difference in overall survival (P = 0.42), relapse free survival (P = 0.69), and survival from the start of endocrine therapy (P = 0.85) according to body weight.

Body Weight↗
PubMed1988

In situ hybridisation and S1 mapping show that the presence of infiltrating plasma cells is associated with poor prognosis in breast cancer.

In order to identify potential markers of prognosis in breast cancer, representative cDNA libraries were constructed using RNA isolated from primary breast tumour tissue associated with good and poor prognosis. Cross-screening of these libraries repeatedly identified cloned mRNA species associated with the immune system, in particular B-cells, in libraries derived from tumours of poor prognosis. We have used one of these a kappa IV light chain cDNA probe, in two complementary studies to investigate the relationship between immunoglobin gene expression and prognosis. The results obtained using a combination of S1 mapping, RNA blotting and in situ hybridisation demonstrate that the presence of plasma cells, as defined by infiltrating cells which express high levels of immunoglobulin kappa-chain mRNA, is associated with a poor prognosis.

Adult↗
PubMed1988

Ultrastructural observations on the basal lamina in the normal human breast.

The ultrastructure of the basal lamina of histologically normal human breast tissue was determined in 19 women undergoing operations for removal of a fibroadenoma or reduction mammoplasty. The day of the menstrual cycle was determined by hormone assay and direct questioning. Previously documented ultrastructural appearances were confirmed: in addition, three morphological variants were found. In all tissue examined, there was reduplication of basal lamina in some areas, which has been described previously as a pathological feature. Also, there was complex branching of the basal lamina into the periductular connective tissue. Some projections contained cytoplasmic processes and, in almost all, hemidesmosomes were seen. The third variant consisted of loops of basal lamina thrown up in folds into the collagenous stromal cuff. Reduplication of basal lamina was detected in breast tissue removed at all stages of the menstrual cycle, looping was not and could not be related to any particular phase of the menstrual cycle. However, complex branching was seen predominantly in the periovulatory and early luteal phase. We conclude that these appearances are normal variants of basal lamina. The appearance of branching basal lamina in the luteal phase suggests that this may be produced in response to endocrine stimulation.

Basement Membrane↗
PubMed1987

Fibroblasts from relatives of patients with hereditary breast cancer show fetal-like behaviour in vitro.

Fetal and normal adult skin fibroblasts show distinctive migratory behaviour when plated on three-dimensional collagen gels. Skin fibroblasts from 13 of 15 patients with hereditary breast cancer showed fetal-like behaviour compared with only 1 of 12 age-matched healthy controls (p less than 0.015; Wilcoxon signed-rank matched-pairs test). In addition, 10 of 15 first-degree relatives of patients with hereditary breast cancer showed a fetal-like fibroblast phenotype, compared with none of 7 surgical controls (p less than 0.009; chi 2 test). These results suggest that abnormalities expressed by skin fibroblasts may help identify people at increased risk of breast cancer developing.

Adult↗
PubMed1987

Endocrine therapy for advanced carcinoma of the breast: effect of tumor heterogeneity and site of biopsy on the predictive value of progesterone receptor estimations.

This study was carried out to assess the influence of site of biopsy and tumor heterogeneity upon the value of progesterone receptor (PR) measurements for prediction of response of patients with advanced carcinoma of the breast to tamoxifen or ovarian ablation. One hundred eighty-one assessable patients were studied. Sixty-nine % of responders and 31% of nonresponders were PR positive. The times to progression and survival were not significantly different for responders whether they were receptor positive or receptor negative. PR was measured on operable primary tumors (97), inoperable primary tumors (59), and secondary deposits (69). The proportion of responders who had PR-positive biopsies from these sites was 59%, 88%, and 61%, respectively, and the proportion of PR-positive nonresponders was 30%, 27%, and 42%, respectively. Ten to 12 separate PR measurements were made on seven tumors, and in four of them, there were PR-positive and PR-negative areas which could account for false positive and false negative results. We conclude that the optimum prediction of response was seen when the biopsy was performed on inoperable primary tumors. Errors in prediction of response at this site were, in part, explained by within-tumor heterogeneity of PR; the greater errors in prediction when measurements were made on operable primary tumors or on secondary deposits are presumed to be related to the additional effects of change in receptor status with time and between-tumor-site heterogeneity, respectively.

Biopsy↗
PubMed1987

Endocrine therapy for advanced carcinoma of the breast: relationship between the effect of tamoxifen upon concentrations of progesterone receptor and subsequent response to treatment.

In some cell lines and tumors of mammary origin, tamoxifen causes an increase of progesterone receptor (PR) as a result of its partial estrogen agonist activity. In this study we have assessed the effect of tamoxifen on PR in patients with advanced carcinoma of the breast in order to test if those with a rise in PR are more likely to respond to endocrine therapy. PR was measured before and a median of 13 days after treatment with tamoxifen in a group of 52 patients with either locally advanced (n = 28) or recurrent (n = 24) carcinoma of the breast. Controls were a group of patients with operable disease who had two biopsies with no intervening tamoxifen (n = 51) or with intervening tamoxifen (n = 58). In the test group PR was higher in the second biopsy than the first in 21 patients, and 19 of these responded to continued endocrine therapy (90%). In the remaining 31 patients PR was either lower in the second biopsy (n = 19) or was negative in both biopsies (n = 12), and 11 of the total of 31 patients (35%) responded to continued endocrine therapy. The prediction of response and time to progression was better when both biopsies were taken into account than either the first or the second alone. The prediction of survival was similar for the group selected by an increase in the second biopsy and the group with PR present in the second biopsy. The controls without tamoxifen showed a marked variation in the level of PR in the first and second biopsies, suggesting heterogeneity of PR across the tumors studied. However, the PR level was significantly higher in the second biopsy in the controls given tamoxifen and in the test group compared with those with no intervening treatment (p = 0.031). This study indicates that some effect of tamoxifen upon PR can be demonstrated in human mammary tumors in vivo and that, by taking a second biopsy for PR estimation during treatment with tamoxifen, a more precise indication of subsequent response is obtained. The value of a single estimation of PR before treatment on secondary deposits is limited, and if one biopsy only is performed, it is of greater predictive value if taken after a few days treatment with tamoxifen.

Aged↗
PubMed1987

Effects of salt loading on the fractional volume of atria-specific granules in Dahl salt-sensitive and salt-resistant rats.

The cardiac atria are known to play a role in blood volume homeostasis, secreting a peptide that induces a potent natriuresis and diuresis. This peptide is atrial natriuretic factor (ANF), and its primary site of storage is within atria-specific granules found in atrial cardiocytes. Since salt loading results in an increase in circulating levels of ANF, our aim was to determine if the atria-specific granule population in the cardiocytes of Dahl rats would decrease accordingly. To this end, the fractional volume of the atria-specific granules was determined by ultrastructural morphometric analysis in the Dahl salt model of hypertension. This analysis was performed on the right atria of Dahl Salt-resistant (DR) and salt-sensitive (DS) rats fed either a low-salt (0.4%) or high-salt (8%) diet for 12 weeks prior to sacrifice. DR and DS rats fed a low-salt diet had significantly reduced plasma sodium levels and osmolalities, and a significantly lower mean arterial blood pressure than did rats fed a high-salt diet. The fractional volume of atria-specific granules was significantly lower in salt-loaded DR (P less than 0.01) and DS (P less than 0.025) rats than in their respective low-salt controls. This significant decrease in atrial granules corresponds to the reported decrease in the storage of atrial ANF in salt-loaded rats, and provides a morphological verification of the biochemical studies. Moreover, these results, in combination with a growing body of physiological data, lend support to the hypothesized role of ANF in the regulation of water-electrolyte balance, which may play an important role in cardiovascular pathophysiological states related to hypertension.

Animals↗
PubMed1987

Clinical pharmacology of oral and intravenous 4-demethoxydaunorubicin.

The clinical pharmacology of 4-demethoxydaunorubicin (4-DMDNR) was studied in 28 patients with advanced breast cancer, using a sensitive reverse-phase HPLC technique. All patients had normal renal and hepatic function. The serum levels of 4-DMDNR after a single i.v. bolus injection followed a triple exponential decay curve (T 1/2 alpha = 9.6 min, T 1/2 beta = 3.2 h and T 1/2 gamma = 34.7 h) and conformed to a three-compartment model. Comparison of the area under the curve (AUC) and urinary excretion for the oral and i.v. routes suggests an oral bioavailability of approximately 24%. In patients treated with a schedule of weekly oral administration for periods of up to 12 months there was no significant alteration in either AUC or elimination half-life for the parent drug or its principal metabolite 13-OH4DMDNR. Moreover, there was no evidence of accumulation of the metabolite although measurable amounts were present 7 days after administration of 4-DMDNR.

Administration, Oral↗
PubMed1987

Infiltrating lobular carcinoma of the breast: response to endocrine therapy and survival.

The records of 480 patients who received systemic therapy for advanced breast cancer in the University Hospital of South Manchester from 1975 to 1983 were examined. There were 264 with infiltrating duct carcinomas (IDC) and 33 with infiltrating lobular carcinomas (ILC) for whom the response to endocrine therapy was known. There were 92 responses (35%) among the IDC patients and 9 (27%) among the ILC patients. Sixty-seven per cent of IDC patients tested had steroid hormone receptor positive tumours compared to 90% for ILC (P less than 0.001). Comparison of survival from diagnosis, disease free interval and survival from relapse showed no significant differences between the two groups. Thus despite almost all ILC patients having hormone receptor positive tumours their survival was similar to that of IDC patients. This appears to be due to a lower than expected response rate to endocrine therapy. This is a further indication of the different biological characteristics of these two histological sub-types of breast carcinoma.

Breast Neoplasms↗