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Biomedical subjects

A Howell

Publications and source records attributed to A Howell.

At least 199 records · Page 11Linked to original sources
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↗
PubMed1986

Molecular expression of epitopes recognized by monoclonal antibodies HMFG-1 and HMFG-2 in human breast cancers: diversity, variability and relationship to prognostic factors.

Epitopes recognised by the monoclonal antibodies HMFG-1 and HMFG-2 are found on glycoprotein components in human breast cancers. This study used immunoblotting techniques to ascertain their molecular diversity, assess their relationship to known prognostic factors, and investigate their expression in sequential samples of breast tumours from individual patients. Both epitopes were expressed on components of a wide variety of molecular weights (HMFG-1, 130 to 450kDa; HMFG-2, 90 to 450kDa). The HMFG-2 epitope was expressed more frequently on components of less than 200kDa (p less than 0.0001). Progesterone receptors (PR), small tumour size and low histological grade correlated significantly with HMFG components greater than or equal to 300kDa. Higher staining intensity was associated with increased likelihood of PR positivity. Paired sequential samples were taken, with a median interval of 8 days, from 38 patients, 23 of whom were administered tamoxifen. In the majority of tumours profiles of expression of components carrying the epitopes were identical in both samples (HMFG-1, 30/38; HMFG-2, 22/38). Overall the results suggested that there was no consistent relationship between the differences observed and tamoxifen administration. We conclude that expression of the HMFG-1 and HMFG-2 epitopes is relatively constant in most tumours, but variable (and possibly subject to modulation) in others, and that their expression, particularly on high molecular weight components, is related to factors associated with good prognosis (PR, small size, low grade), and may be of independent prognostic value.

Antibodies, Monoclonal↗
PubMed1986

Occurrence of a fetal fibroblast phenotype in familial breast cancer.

We have previously shown that fetal and adult human skin fibroblasts display distinctive migratory phenotypes when cultured on 3-dimensional collagen gels in vitro. In the present study, we have used this information to assess the migratory behavior of fibroblasts obtained from patients with either benign or malignant breast disease, and correlated this with the presence of a family history of breast cancer. We have observed that fibroblasts from 17/34 patients with no previous family history of breast cancer displayed fetal-type behavior in our assay system; in contrast, fibroblasts from 15/16 patients with a positive family history of breast cancer behaved abnormally. This apparently increased probability of expressing a fetal-type migratory phenotype in the patients with a family history is statistically significant (p less than 0.008). Skin fibroblasts obtained from 2 healthy and unaffected first-degree relatives (one male and one female) of patients with a family history of breast cancer also exhibited a fetal-type migratory phenotype.

Breast Diseases↗
PubMed1986

A new hormonal therapy for prostatic cancer: long-term clinical and hormonal response.

Twenty-four patients with advanced prostatic cancer were treated with daily injections of the LHRH analogue ICI 118630 (Zoladex) for up to 2 1/2 years. Successful long-term suppression of LH (luteinising hormone) and testosterone was observed without any escape of testosterone. Immunoreactive LH concentrations rose significantly following the daily injection of LHRH analogue but there was no corresponding rise in testosterone concentrations, suggesting altered bioactivity of the LH. A long-term clinical response was obtained in 10 patients (41.6%) and the median duration of response in these patients was 25 months. Eight of the 10 had well to moderately differentiated tumours. The actuarial median survival of all patients was 22 months.

Aged↗
PubMed1986

Testosterone and gonadotrophin profiles in patients on daily or monthly LHRH analogue ICI 118630 (Zoladex) compared with orchiectomy.

Diurnal profiles of circulating gonadotrophins and testosterone have been measured in patients with prostatic carcinoma on long-term treatment with the LHRH agonist analogue ICI 118630, which was administered either by subcutaneous daily injection or monthly injection of the depot preparation. These have been compared with profiles in patients who had undergone orchiectomy. Daily injection of the analogue induced a significant rise in the level of LH but this was not associated with a significant rise in circulating testosterone. There was no diurnal variation of LH or testosterone concentration in patients receiving the depot preparation and this did not differ in patients who were "mid-cycle" compared with those who were "end-cycle". The depot preparation did, however, induce significantly lower circulating levels of testosterone than did daily injection of the analogue and the levels were comparable with those achieved after orchiectomy.

Aged↗
PubMed1986

A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer.

We randomized 122 premenopausal women to receive tamoxifen or to undergo a surgical oophorectomy. Of 54 evaluable women treated with tamoxifen, 24% had an objective response, as compared with 21% of 53 women having an oophorectomy. The median duration of response for tamoxifen (20 months) was longer than that for surgical oophorectomy (7 months), but this did not achieve statistical significance (P = .056). Overall median survival was 15 months for 58 patients receiving tamoxifen and 25 months for 53 patients undergoing oophorectomy (P = .18). Toxicity was greater in those undergoing oophorectomy, though both treatments were well tolerated. In those premenopausal women for whom hormonal therapy is indicated, tamoxifen is a suitable alternative to surgical oophorectomy.

Adult↗
PubMed1986

Intralobular stromal fibroblasts in the resting human mammary gland: ultrastructural properties and intercellular relationships.

The intralobular stroma of the resting human mammary gland was studied by thin-sectioning transmission electron microscopy on tissue obtained from reduction mammoplasty or adjacent to fibroadenomas. The arrangement of delimiting fibroblasts around the epithelium and their possession of contacts as shown by earlier studies were confirmed. Observations on other ultrastructural aspects show these cells to have abundant rough endoplasmic reticulum, a well developed Golgi apparatus and vesicles considered to contain collagen-precursor, and conflict with earlier data. The fine structure of those fibroblasts without close epithelial proximity has been described for the first time and was similar to that of delimiting fibroblasts. Other features applicable to both categories of fibroblast included: variation in overall staining intensity, structures resembling hemi-desmosomes, simple junctions, and close juxtapositions of cell surfaces forming 'contacts' with other fibroblasts as well as with mononuclear cells (lymphocytes, plasma cells, mast cells, macrophages). These cell contacts have not been documented previously. Contacts were structurally undifferentiated, forming spaces 20-50 nm wide which were occluded by lanthanum nitrate. Intralobular stromal cells were therefore organised into a kind of reticulum. The possible functions of this network are discussed. The concept of the epithelial-stromal junction is re-assessed in the light of these observations.

Adolescent↗
PubMed1985

Stereospecificity of 2-methylpiperidine binding to a nicotinic up-regulatory site in the rat brain P2 preparation.

(+/-)-2-Methylpiperidine has a high degree of specificity in enhancing the binding of (-)-[3H]nicotine in the rat brain P2 preparation. (-)- and (+)-2-Methylpiperidine have been resolved. The (+) but not the (-) isomer increased the binding of (-)-[3H]nicotine. The two isomers were equally effective in inhibiting the binding of (-)-[3H]nicotine in high concentrations. These data provide additional support for a stereospecific nicotinic up-regulatory site.

Animals↗