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Biomedical subjects

A Howell

Publications and source records attributed to A Howell.

At least 217 records · Page 12Linked to original sources
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↗
PubMed1987

A phase II study of oral weekly 4-demethoxydaunorubicin in advanced breast cancer.

Thirty-eight patients with advanced breast cancer were treated with oral 4-demethoxydaunorubicin in a continuous weekly schedule at a dose of 15 mg/m2/week. Subjective toxicity consisted of mild nausea (grade 1) in 52% with more severe GI side effects (grade 2) in 15%. Three patients developed grade 1 alopecia and there were no episodes of cardiac failure. Significant neutropenia (grade 2/3) only occurred in patients with marrow involvement or widespread bone disease. There was one CR and 5 PRs, an overall response rate of 15.7% (95% confidence limits 6-31%). In addition 6 patients had disease stabilization for at least 6 months. Fourteen patients progressing on 4-demethoxydaunorubicin have received adriamycin 60 mg/m2 21 days. There have been 5 PRs in this group indicating possible non-cross-resistance between these two agents.

Adult↗
PubMed1987

DNA analysis by flow cytometry, response to endocrine treatment and prognosis in advanced carcinoma of the breast.

The relationship between DNA content of mammary cancer and subsequent response to endocrine therapy was studied in 136 patients with advanced disease. All were treated with tamoxifen or ovarian ablation as first-line systemic therapy after relapse and were evaluable for response according to UICC criteria. DNA characterisation by flow cytometry was used on formalin fixed paraffin-embedded samples of tumour. Tumours were grouped according to DNA index into diploid (n = 52, 38%), 'tetraploid' (n = 46, 34%) and 'other DNA-aneuploid' (n = 38, 28%). The highest proportion of oestrogen receptor positive tumours (ER + ve) was found in the 'tetraploid' tumours (38/46, 85%, Chi-square = 8.53, P less than 0.02), and response rates, (SD + PR + CR), were 26/52 (50%), 34/46 (74%), and 15/38 (39%) respectively (Chi-square = 10.88, P less than 0.005). Patients with diploid or 'tetraploid' tumours survived longer and stayed in remission longer than those with 'other DNA-aneuploid' tumours. We suggest that 'tetraploid' or 'near tetraploid' human mammary tumours may comprise a distinct group of endocrine responsive tumours within the overall group of aneuploid tumours. The conventional interpretation of DNA histograms, grouping into diploid and aneuploid, may be masking important features of some tumour groups.

Adult↗
PubMed1987

Effect of tamoxifen upon cell DNA analysis by flow cytometry in primary carcinoma of the breast.

The effect of tamoxifen upon cellular DNA ploidy in carcinoma of the breast was assessed by flow cytometry (FCM), in a prospective group of 77 patients with primary operable disease. Each had a needle biopsy at the outpatient visit for diagnosis and FCM analysis, and definitive surgery was performed a median of 8 days later. Forty received tamoxifen during this period - 40 mg qds loading dose for 24 h, followed by 20 mg daily until the day of operation: 37 patients received no therapy. The DNA histogram from the needle biopsy was compared with that obtained from the resected tumour for each individual. There was little change between the pair of histograms from tumours from the untreated patients. In those who had received tamoxifen the most consistent effect was a marked reduction in the magnitude of the 'tetraploid' peak in tetraploid or near-tetraploid tumours with DNA indices 1.8-2.0. There was little change in diploid or 'other DNA-aneuploid' tumours. In tetraploid tumours (DNA index of 2.0) the percentage of nuclei in the diploid S phase was significantly related to the percentage of nuclei in the diploid G2 + M/tetraploid G1 peak (P less than 0.003, unpaired t test). These data suggest that an effect of tamoxifen can be demonstrated by FCM upon tumours exhibiting a tetraploid or near-tetraploid DNA content. It is possible that tetraploid or near-tetraploid human mammary tumours may be a distinct group of endocrine responsive tumours within the overall group of aneuploid tumours, and that the majority are probably derived from the diploid population rather than being a true aneuploid population.

Adult↗
PubMed1987

cis-platinum and ovarian carcinoma. In vitro chemosensitivity of cultured tumour cells from patients receiving high dose cis-platinum as first line treatment.

A study on the in vitro sensitivity of tumour cells from patients with ovarian cancer has been carried out in parallel with a clinical study designed to evaluate the role of high-dose cis-platinum (CIS) as first-line chemotherapy. A total of 50 samples from 102 patients have been successfully cultured and screened for in vitro chemosensitivity to 7 drugs, including CIS. The malignant nature of cells growing in culture was confirmed using a combination of karyology, morphology and immunohistochemical staining with HMFG2. Tumours were graded as sensitive (less than 40% of control 3H-leucine incorporation), intermediate (41-60% of control) or resistant (greater than 61% of control) to CIS. Correlation of in vitro sensitivity to cis-platinum with clinical response to cis-platinum assessed using CT scan and second-look laparotomy, showed positive correlation in 9/11 (89%) patients (8 = S/S; 1 = R/R); positive correlation between in vitro sensitivity to phosphoramide mustard and clinical response was also found in 4/6 patients receiving cyclophosphamide (3 = S/S; 1 = R/R). All patients with sensitive tumours showed a clinical response to cis-platinum. Comparison of cis-platinum sensitivity with sensitivity to phosphoramide mustard and melphalan showed that some tumours were sensitive only to cis-platinum; resistance to cis-platinum and sensitivity to phosphoramide mustard/melphalan was an infrequent occurrence. Some tumours which were resistant to cis-platinum showed sensitivity to adriamycin and bleomycin, particularly those from untreated patients. Sensitivity to 5-fluorouracil and resistance to cis-platinum was found in approximately equal proportions of tumours in both the treated and untreated groups.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Hypothesis: persistent expression of fetal phenotypic characteristics by fibroblasts is associated with an increased susceptibility to neoplastic disease.

Published data from our own and other laboratories have indicated that fibroblasts obtained from patients with different types of epithelial cancers commonly display aberrant (i.e. fetal-like or transformed) phenotypic characteristics. Previous interpretations of these results have tended to regard the study of fibroblasts as a convenient means to demonstrate genetic abnormalities also expressed in the target epithelial cell population and did not ascribe a particular causative role to fibroblast abnormalities in the genesis of neoplastic lesions. In this communication we present an alternative, but not mutually exclusive, hypothesis suggesting that aberrations expressed solely by fibroblasts may lead to the development of an epithelial tumour by virtue of a dysfunction in normal epithelial-mesenchymal interactions.

Disease Susceptibility↗
PubMed1986

Mechanism of action of adjuvant chemotherapy in early breast cancer.

The relation between tumour oestrogen and progesterone receptor status, menstrual status, relapse-free survival, and overall survival was analysed in 411 patients with early breast cancer randomised to receive either postoperative adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) or no additional treatment (control). Prolongation of time to recurrence and survival was seen predominantly in premenopausal patients; these effects were seen only with tumours positive for steroid receptors, particularly progesterone. Chemotherapy led to permanent amenorrhoea in 61% of premenopausal patients. The therapeutic effects of chemotherapy were seen only when CMF induced permanent amenorrhoea in premenopausal patients. These findings support the hypothesis that the effect of adjuvant chemotherapy in early breast cancer may be mediated by ovarian suppression.

Adult↗