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Biomedical subjects

A Howell

Publications and source records attributed to A Howell.

At least 127 records · Page 7Linked to original sources
PubMed1992

Reduction in apoptosis relative to mitosis in histologically normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast.

The aims of this study in 227 premenopausal women were (a) to determine the mitotic index (MI), the thymidine labelling index (LI), and the apoptotic index (AI) within the epithelial cells of histologically 'normal' human breast biopsy material removed away from the site of either a fibroadenoma or a carcinoma; and (b) to relate differences in the kinetic indices of the 'normal' epithelium to the pathology in the same breast diagnosed as fibroadenoma alone (125 patients), fibroadenoma with accompanying mild fibrocystic change (79 patients), or carcinoma (23 patients). Ratios of the average indices (AI/MI, AI/LI, MI/LI) were also calculated to minimize uncertainties related to the total cell population counted, the denominator in the LI, MI, and AI. All indices and ratios of indices were corrected for age, averaged over the cycle, and expressed as log-transformed values for analysis. Significant (P less than 0.001) reductions in AI and in apoptosis relative to mitosis (reduced AI/MI) were found in 'normal' epithelium from breasts having fibrocystic change (AI = 0.17 +/- 0.02; AI/MI = 1.01 +/- 0.18) and carcinoma (AI = 0.19 +/- 0.04; AI/MI = 0.88 +/- 0.29), compared with breast with fibroadenoma alone (AI = 0.27 +/- 0.03; AI/MI = 1.29 +/- 0.39). In the absence of significant differences in MI and LI between the 'normal' tissue groups, this finding raises the possibility that reduced epithelial cell apoptosis might be causally associated with the development of fibrocystic change and with an increased risk of development of carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenofibroma↗
PubMed1992

Changes in the extracellular matrix of the normal human breast during the menstrual cycle.

The normal human mammary gland undergoes a well defined sequence of histological changes in both epithelial and stromal compartments during the menstrual cycle. Studies in vitro have suggested that the extracellular matrix surrounding the individual cells plays a central role in modulating a wide variety of cellular events, including proliferation, differentiation and gene expression. We therefore investigated the distribution of a number of extracellular matrix molecules in the normal breast during the menstrual cycle. By use of indirect immunofluorescence, with specific antibodies, we demonstrated that laminin, heparan sulphate proteoglycan, type IV collagen, type V collagen, chondroitin sulphate and fibronectin undergo changes in distribution during the menstrual cycle, whereas collagen types I, III, VI and VII remain unchanged. These changes were most marked in the basement membrane, sub-basement membrane zone and delimiting layer of fibroblasts surrounding the ductules where basement membrane markers such as laminin, heparan sulphate proteoglycan, and type IV and V collagens appear greatly reduced during the mid-cycle period (days 8 to 22). These results suggest that some extracellular matrix molecules may act as mediators in the hormonal control of the mammary gland, whereas others may have a predominantly structural role.

Adenofibroma↗
PubMed1992

Doxorubicin in advanced breast cancer: influence of schedule on response, survival and quality of life.

The influence of scheduling of doxorubicin on response, survival and quality of life was assessed in a randomised trial in patients with advanced breast cancer, none of whom had previously received cytotoxic chemotherapy for advanced disease. 28 patients received 75 mg/m2 doxorubicin every 3 weeks for four courses (arm 1) and 31 patients received 25 mg/m2 weekly for 12 courses (arm 2). Response rates and median time to progression were similar in the two arms and median survival was 8 months in both arms. However, amongst patients receiving treatment every 3 weeks, psychological distress measured using the Rotterdam symptom checklist fell significantly over the course; no such change was observed in those treated weekly. Physical symptoms related to cancer improved during treatment similarly for both groups.

Adult↗
PubMed1992

Normal human breast xenografts activate N-nitrosodimethylamine: identification of potential target cells for an environmental nitrosamine.

Normal human breast tissue maintained as xenografts in female Balb/c (nu/nu) athymic mice is capable of metabolising N-nitrosodimethylamine (NDMA) to active intermediates that will react with DNA. Administration of NDMA to mice with slow-release implants of 17 beta-oestradiol which provide human physiological (luteal phase) circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al., 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants. In mice with oestrogen implants, measurements of the amounts of the promutagenic lesion, O6-methyl-2'-deoxyguanosine formed in DNA clearly indicated a dose related increase in the extent of reaction. Detection of O6-methyl-2'-deoxyguanosine using immunohistochemical procedures revealed that the nuclei of cells of the glandular epithelium, supportive tissue and adipose tissue, in decreasing order of prevalence, were positively stained for the presence of this DNA lesion. Epithelial cells, which are the putative target cells for carcinogenesis in the breast, are therefore prone to promutagenic damage as a result of exposure to an environmental nitrosamine.

Animals↗
PubMed1992

Response after withdrawal of tamoxifen and progestogens in advanced breast cancer.

Tumor response after withdrawal of endocrine therapy for advanced breast cancer with estrogens and androgens is well described. There have been few reports of withdrawal responses (WRs) after cessation of treatment with the newer antiestrogens and progestogens. We assessed WR in women after cessation of adjuvant therapy at first relapse, and after progression on first, second or third line endocrine therapy for advanced disease. One of seven patients (14%) responded after cessation of tamoxifen adjuvant therapy at relapse. Sixty-five of 72 patients were evaluable for WR after cessation of tamoxifen as first line therapy for advanced disease. There were five partial responses (8%) and 14 (22%) 'no change' with a median duration of WR of 10 months (range 3-40 months). WR were seen mainly in soft tissue disease but there were two responses in lung and two in bone. Four of 21 (19%) patients had a WR after cessation of norethisterone acetate (3) and tamoxifen (1), all used as second line therapy. WR are therefore demonstrable after cessation of tamoxifen and norethisterone acetate with durations of response similar to those found with additive therapy. Assessment of WR may represent a way of prolonging the overall response duration in patients with relatively indolent metastatic breast cancer, particularly in soft tissues.

Adult↗
PubMed1992

Infusion rate and pharmacokinetics of intravenous pamidronate in the treatment of tumour-induced hypercalcaemia.

We report the results of two consecutive randomized studies in the treatment of malignant hypercalcaemia with intravenous pamidronate. Overall normocalcaemia was achieved in greater than 90% of patients and a single infusion of 60 mg pamidronate given over 2 hours was as effective in restoring normocalcaemia as infusions given over 4, 8 or 24 hours. Similarly duration of normocalcemia after treatment with pamidronate and the control of the symptoms of hypercalcaemia were independent of infusion rate. Study of the pharmacokinetics of pamidronate in the treatment of hypercalcaemia show this drug to have a very high clearance due to calcified tissue retention and renal excretion. The initial half life of the drug in plasma is very short and most of the drug is cleared before distribution equilibrium is achieved. Short infusions of pamidronate are as safe and effective as infusions given over a longer time and are therefore to be preferred because of their greater convenience.

Adult↗
PubMed1992

West Midlands Oncology Association trial of adjuvant chemotherapy in node-negative breast cancer.

Between 1976 and 1984, 574 patients with operable breast cancer and histologically negative axillary lymph nodes were randomly assigned after mastectomy to receive either no further treatment or chemotherapy with oral LMF (fluorouracil, 500 mg, methotrexate, 25 mg, and chlorambucil, 10 mg, on day 1; fluorouracil, 500 mg, and chlorambucil, 10 mg, on day 2). There is no overall survival or relapse-free survival benefit at a median follow-up of 10 years and 8 years, respectively. There are significantly more local relapses in the control group (P less than .01), but an excess of distant relapses in the treated group is not statistically significant (P = .24). A positive treatment effect in small tumors (relapse-free survival, odds ratio = 0.55, P = .01) and a negative effect in progesterone receptor-positive tumors (survival, odds ratios = 2.04, P = .04) is probably ascribable to chance. Analysis of various prognostic factors shows that tumor size and histological grade have a clear effect on both relapse-free interval and survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Oral contraceptive (OCP) use increases proliferation and decreases oestrogen receptor content of epithelial cells in the normal human breast.

The effect of ingestion of oral contraceptives (OCP) on cell proliferation and oestrogen (ER) and progesterone receptor (PR) expression of the epithelial cells of the normal human breast was compared with findings in controls not taking OCPs. Histologically normal breast tissue was removed during operation for fibroadenoma or reduction mammoplasty in 216 women whose mean age was 28.1 +/- 8.5 years (+/- SD range 14-53 years). During natural cycles the mean proportion of cells expressing ER was 3.94 +/- 3.71 (% mean +/- SD, range 0-20.8, n = 51), while of those expressing PR it was 12.1 +/- 7.1% (range 3.0-36.1, n = 47). There was a significant decline in ER during the menstrual cycle [p = 0.001 by multiple linear regression (MLR)], but there was no significant change in the proportion which expressed PR. The mean proportion of proliferating cells (LI) was 2.50 +/- 2.42 (range 0-11.5, n = 147). There was a significant increase of LI during the cycle (p = less than 0.001, MLR) and a significant inverse relationship between LI and ER (r = -0.29, p less than 0.01). Use of the OCP significantly reduced the number of cells which expressed ER and increased the LI earlier in the cycle. No effect of OCP use on the number of PR+ cells was detectable. We conclude that significant changes in the proportions of ER+ and proliferating cells occur during natural menstrual cycles. These changes are perturbed by ingestion of OCPs, so that there is greater suppression of ER and a longer period of high proliferation during the menstrual cycle. These results may explain the relationship between OCP use and the possible risk of breast cancer.

Adolescent↗
PubMed1991

Migration stimulating activity in serum of breast cancer patients.

An assay to measure the ability to stimulate migration of fibroblasts into collagen gel was carried out on serum from treated and untreated breast cancer patients and from healthy controls. Migration stimulating activity was found in the serum of 10 (83%) of 12 untreated breast cancer patients immediately before surgical resection of the primary tumour and in 9 (75%) of them 4 days after resection; in 13 (93%) of 14 patients 1-13 years after tumour resection who had received adjuvant treatment; and in 2 (10%) of 20 healthy women matched for age. The migration stimulating activity in cancer patients' serum was indistinguishable from the migration stimulating factor produced in vitro by fetal and cancer patient skin fibroblasts in its behaviour in various biochemical fractionation procedures. The presence of this activity in the serum of treated breast cancer patients clearly distinguishes it from other oncofetal proteins, which all seem to be produced by tumours.

Adult↗
PubMed1991

Heterogeneity amongst fibroblasts in the production of migration stimulating factor (MSF): implications for cancer pathogenesis.

Fetal skin fibroblasts migrate into 3D collagen gels to a significantly greater extent than do adult cells. This enhanced motility of fetal fibroblasts appears to result from the production of a "migration stimulating factor" (MSF) which is not made by their normal adult counterparts. Adult skin fibroblasts retain responsiveness to MSF and cells exposed to this factor achieve the elevated levels of migration characteristic of fetal cells. MSF has been purified to homogeneity, has an apparent molecular mass of 70 kD and has been further characterized in terms of a number of biochemical parameters. Studies concerned with the mechanism of action of MSF indicate that it stimulates the production of a high molecular weight class of hyaluronic acid (HA). Concurrent exposure of cells to Streptomyces hyaluronidase blocks the stimulation of adult fibroblast migration by MSF. In a related series of experiments, we have shown that TGF-beta inhibits the effects of MSF on both cell migration and HA production. Taken together, these data suggest that the stimulation of fibroblast migration by MSF is dependent upon (and may directly result from) a primary induction of HA synthesis. We have previously reported that skin fibroblasts obtained from patients with sporadic and familial breast cancer, as well as the unaffected first-degree relatives of familial breast cancer patients, commonly display a fetal-like migratory phenotype. Subsequent work has indicated that (a) these fetal-like cells also produce MSF, and (b) detectable levels of MSF are present in the serum of sporadic breast cancer patients both prior to and following surgical resection of the primary tumor mass. On the basis of these and related observations, we have put forward an hypothesis suggesting that the disruption in normal epithelial-mesenchymal interactions caused by the persistent production of MSF by fibroblasts in the adult may contribute directly to the pathogenesis of an epithelial cancer. The demonstration of aberrant fibroblasts in sporadic cancer patients (both in our own and independent studies) is not consistent with the "germ-line genetic lesion" model commonly invoked to account for the presence of such cells in patients with hereditary cancer syndromes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Prospective assessment of the role of five tumour markers in breast cancer.

Retrospective analysis previously identified significant elevation of five tumour markers, carcinoembryonic antigen (CEA), ferritin, orosomucoid. C-reactive protein and erythrocyte sedimentation rate (ESR), in patients with systemic breast cancer and showed that changes in each of these markers individually correlated significantly with therapeutic response. In this study we have prospectively tested these findings. None of the five markers was significantly elevated in primary breast cancer compared to normal control or benign breast disease groups. They therefore appear to have no role either in screening or in the differential diagnosis of breast cancer. There was a significant elevation of all five markers in patients with systemic breast cancer (P less than 0.0001: analysis of variance) but sequential changes in CEA and ESR only correlated significantly with the UICC-assessed response. Prospective confirmation of the correlation between changes in serum CEA and ESR provides the basis for using these markers in the assessment of response to therapy in patients with systemic breast cancer.

Adult↗
PubMed1991

The clearance and bioavailability of pamidronate in patients with breast cancer and bone metastases.

The pharmacokinetics and bioavailability of pamidronate were assessed in patients with breast cancer, 6 subjects received the drug intravenously and 7 orally. The initial plasma half-life of pamidronate was short (42 +/- 27 min) and the apparent total plasma clearance was high (471 +/- 298 ml/min). The renal clearance (74 +/- 34 ml/min) was similar to the creatinine clearance (66 +/- 19 ml/min). Most of the renal elimination occurred during and immediately post a 4 h infusion of the drug (23.2 +/- 7.9% in 24 h). The non-renal clearance was ascribed to uptake by bone and deep tissue compartments. Little additional drug appeared in the urine after 24 h. The mean bioavailability was estimated using a parallel study design to be 0.3% for a 300 mg oral dose.

Administration, Oral↗
PubMed1991

Viridans streptococcal bacteraemia in patients with haematological and solid malignancies.

Thirty-three episodes of septicaemia caused by viridans streptococci are reported in 32 adults under treatment for malignant diseases. The underlying diseases were acute leukaemia (17), lymphoma (4), myeloma (1), small cell carcinoma of the bronchus (6), carcinoma of the breast (2) and carcinoma of the stomach (2). Important predisposing factors included severe neutropenia and oral mucositis due to intensive chemotherapeutic regimens. There was a poor response to standard empirical antibiotics and a mortality of 12%. A role for prophylactic penicillin in high risk groups is suggested.

Adolescent↗
PubMed1991

Parathyroid hormone-related protein(50-69) and response to pamidronate therapy for tumour-induced hypercalcaemia.

A region-specific radioimmunoassay has been employed to measure levels of immunoreactive parathyroid hormone-related protein(50-69) (iPTHrP(50-69)) in patients with tumour-induced hypercalcaemia (TIH). This assay is based on an antiserum raised against synthetic human PTHrP(50-69). The assay showed no cross-reactivity with human or bovine parathyroid hormone(1-84). The effect of a single dose (60 mg) of pamidronate was studied in 25 consecutive patients with TIH. All were rehydrated prior to treatment. All but 2 patients (8%) became normocalcaemic after treatment; both of these had very high levels of iPTHrP(50-69). Time to achieve normocalcaemia, as an index of relative resistance to pamidronate, correlated positively with pretreatment level of iPTHrP(50-69). Absence of radiological evidence of bone metastases also predicted relative resistance to pamidronate. In this study, iPTHrP(50-69)-induced osteoclastic bone resorption was a more important mechanism in the causation of TIH than PTHrP-induced renal reabsorption of calcium as assessed by the renal thresholds for calcium and phosphate.

Adult↗
PubMed1991

Psychiatric morbidity in patients with advanced cancer of the breast: prevalence measured by two self-rating questionnaires.

Two hundred and twenty-two women with advanced cancer of the breast were asked to complete two previously validated self-assessment questionnaires (Hospital Anxiety and Depression Scale (HADS) and the Rotterdam Symptom Checklist (RSCL) in order to determine the prevalence and persistence of affective disorders in this group of patients. Fifty-six (27%) of 211 women who completed the HADS and 33 (22%) of 204 who completed the RSCL rated as probable cases of an anxiety state and/or depressive illness. One hundred and fifty-five patients completed the questionnaires again 1-3 months later. Twenty-one (13%) were persistently anxious or depressed as judged by the HADS compared with 14 (10%) on the RSCL. When both questionnaires were considered together, approximately one third of patients had scores suggestive of an affective disorder and in one third of these it was persistent. Only 30 patients (43% of cases) were detected as 'cases' by both questionnaires and this finding warrants further investigation.

Anxiety Disorders↗
PubMed1991

Screening for psychiatric morbidity in patients with advanced breast cancer: validation of two self-report questionnaires.

Eighty-one patients with advanced breast cancer completed the Hospital Anxiety and Depression Scale (HADS) and Rotterdam Symptom Checklist (RSCL) to determine how well these questionnaires identified patients suffering from an anxiety state or depressive illness, compared with an independent interview by a psychiatrist who used the Clinical Interview Schedule. A threshold score was defined for each questionnaire which gave the optimal sensitivity and specificity. Seventy-five per cent of patients were correctly identified as suffering from an affective disorder by both the Rotterdam Symptom Checklist and by the Hospital Anxiety and Depression Scale. Twenty-one per cent of 'normal' patients were misclassified by the Rotterdam Checklist and 26% by the Hospital Anxiety and Depression Scale. When the HADs anxiety and depression subscales were analysed separately, the performance of the anxiety items was superior to that of the depression items. Both questionnaires were found to have good predictive value and could be used in patients with advanced cancer to help screen out those with an affective disorder.

Anxiety Disorders↗