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Biomedical subjects

A Howell

Publications and source records attributed to A Howell.

At least 109 records · Page 6Linked to original sources
PubMed1997

Citrobacter freundii and fatal neutropenic enterocolitis following adjuvant chemotherapy for breast cancer.

Neutropenic enterocolitis is increasingly being recognized as a life-threatening complication of chemotherapy, mainly for haematological and lymphoproliferative malignancies. It is under-recognized clinically, with the diagnosis often being made on post-mortem examination. Although active medical management is generally preferred, surgical intervention may be indicated. We report a case of fatal neutropenic enterocolitis, secondary to Citrobacter freundii, following adjuvant chemotherapy for breast cancer. We also review the literature, examining the aetiology, diagnosis and management of this often fatal entity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Estrogen sensitivity of normal human breast tissue in vivo and implanted into athymic nude mice: analysis of the relationship between estrogen-induced proliferation and progesterone receptor expression.

High serum concentrations of estradiol (E2) equivalent to those observed in the luteal phase of the menstrual cycle stimulate both epithelial cell proliferation and progesterone receptor (PgR) expression in normal human breast tissue xenografted into athymic nude mice. We report here the results of further investigations designed to determine whether the induction of PgR expression and proliferation require different E2 concentrations and whether proliferating cells expressed the PgR. In untreated normal breast xenografts, the PgR was virtually undetectable and proliferation was at basal levels. Progesterone (Pg) treatment alone had no effect compared to no treatment. Treatment with E2 at follicular phase serum concentrations maximally increased PgR expression but was without effect on proliferation. However, treatment with E2 at luteal phase serum concentrations, alone or in combination with Pg, significantly increased both the PgR content and the proliferation of the breast epithelium. These experimentally derived data reflected the observations made on normal breast tissue at surgical biopsy where PgR content was similar in both halves of the menstrual cycle, whereas proliferation was significantly higher in the luteal phase. Finally, using double labelling techniques, it was demonstrated that proliferating epithelial cells rarely expressed PgR in normal breast tissue obtained at surgical biopsy. These results suggest that the threshold of E2 required to induce PgR expression in normal human breast epithelial cells is lower than that required to induce proliferation and that the majority of proliferating breast cells do not express the PgR.

Adult↗
PubMed1997

Type I insulin-like growth factor receptor gene expression in normal human breast tissue treated with oestrogen and progesterone.

The epithelial proliferation of normal human breast tissue xenografts implanted into athymic nude mice is significantly increased from basal levels by oestradiol (E2), but not progesterone (Pg) treatment at serum concentrations similar to those observed in the luteal phase of the human menstrual cycle. Type I IGF receptor (IGFR-I) mRNA and protein have been shown to be up-regulated by E2 in MCF-7 breast cancer cells in vitro in which IGF-I and E2 act synergistically to stimulate proliferation. We have investigated the expression of the IGFR-I mRNA in normal human breast xenografts treated with or without E2 or Pg alone and in combination. Northern analysis of 20 micrograms of RNA extracted from the breast xenograft samples showed no hybridization with 32P-labelled IGFR-I probe, although an 11-kb species of IGFR-I mRNA could be seen when 20 micrograms of RNA extracted from either MCF-7 breast cancer cells or human breast carcinomas was examined in this way. In order to analyse the expression of IGFR-I mRNA in breast xenografts, a quantitative reverse transcription-polymerase chain reaction (RT-PCR) was employed in which RNA loading, reverse transcription and PCR efficiencies were internally controlled. The data indicate that the IGFR-I mRNA is up-regulated by two to threefold compared with untreated levels by 7 and 14 days E2 treatment. In contrast, 7 or 14 days Pg treatment down-regulates the receptor mRNA to approximately half that of untreated levels, whereas combination E2 and Pg treatment produced a twofold increase in IGFR-I mRNA levels compared with untreated tissue. The results are consistent with the suggestion that E2 may act to stimulate proliferation indirectly via a paracrine mechanism involving IGFs in normal as well as malignant human breast epithelial cells.

Animals↗
PubMed1997

Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial.

PURPOSE: A multicenter phase II study to determine the activity and toxicity of Caelyx (Doxil; Sequus Pharmaceuticals Inc, Menlo Park, CA) in patients with metastatic breast cancer. PATIENTS AND METHODS: Seventy-one patients with stage IV breast cancer were treated with Caelyx at doses of 45 to 60 mg/m2 every 3 to 4 weeks for a maximum of six cycles. Twenty-eight patients had received prior chemotherapy with a nonanthracycline regimen. Fifty-two patients had disease at multiple sites. Hepatic and pulmonary disease were the predominant metastatic site in 50 patients. Response was assessable in 64 cases. RESULTS: Sixteen patients achieved a partial response and a complete response (overall response rate, 31%; (95% confidence interval, 20% to 43%). Twenty patients (31%) had stable disease on treatment. Neutropenia > or = grade 3 occurred in 10% of cycles (27% of patients) and mucositis > or = grade 3 in 10% of cycles (32% of patients). Significant alopecia was rare and routine prophylactic antiemetics were not required. At doses of 60 mg/m2 every 3 weeks, seven of 13 patients had > or = grade 3 skin toxicity; overall, this toxicity complicated 25% of treatment cycles. The incidence of > or = grade 3 skin toxicity was greatly reduced at doses of 45 mg/m2 every 4 weeks, occurring in five of 32 patients and affecting only 5% of 126 treatment cycles. CONCLUSION: Caelyx is an active agent in advanced breast cancer with a safety profile that differs markedly from nonliposomal doxorubicin. A regimen of 45 mg/m2 every 4 weeks was well tolerated in this cohort of women with advanced poor-prognosis breast cancer. The mild myelosuppression seen with this regimen would favor its use in combination chemotherapy.

Antibiotics, Antineoplastic↗
PubMed1997

Serum 1,25-dihydroxyvitamin D may be related inversely to disease activity in breast cancer patients with bone metastases.

1,25-dihydroxyvitamin D (1,25-(OH)2D) stimulates differentiation and controls proliferation in breast cancer cells. The role of endogenous 1,25-(OH)2D and its relation to PTH related protein (PTHrP) during the progression of breast cancer is not known; we therefore investigated these hormones in two studies. In a cross-sectional study of patients with breast cancer at different stages of disease, serum 1,25-(OH)2D levels (mean +/- SE) were highest in early disease (102 +/- 3.7 pmol/L), fell in normocalemic patients with bone metastases (52 +/- 5.3 pmol/L; P < 0.01), and were lowest in hypercalcemic patients (33 +/- 5.6 pmol/L; P < 0.001). PTHrP was detectable in the serum of only one normocalcemic patient with progressive metastases but was present in 11 of the 12 hypercalcemic patients, thus PTHrP did not stimulate 1,25-(OH)2D synthesis. In a 6-month longitudinal study of normocalcemic patients with bone metastases undergoing hormonal therapy, serum 1,25-(OH)2D concentrations fell in patients whose disease progressed (P = 0.0056), but remained constant in those who were stable or responded to treatment. These changes in 1,25-(OH)2D preceded clinical signs of progression and predicted disease response. In the progressive group, five of whom died during the study, 1,25-(OH)2D decreased between the initial and final samples, PTH fell significantly from 24.8 to 13.5 ng/L (P = 0.025), serum calcium rose from 2.27 to 2.39 mmol/L (P = 0.017), and the urinary calcium/creatinine ratio rose from 0.37 to 0.68 (P = 0.046). PTH and 1,25-(OH)2D were significantly correlated in the final samples from this group, Spearman's rank correlation = 0.80, P = 0.022. The results indicate that normocalcemia in these patients is maintained, at the expense of suppressing PTH and 1,25-(OH)2D, in the face of increased calcium released from lytic lesions in bone. Loss of the antiproliferative effects of 1,25-(OH)2D may then permit more rapid secondary growth of the tumor.

Bone Neoplasms↗
PubMed1997

Antiestrogens: future prospects.

Tamoxifen is currently the endocrine therapy of choice for early and advanced breast cancer. Attempts to improve the therapeutic efficacy have included altering the triphenylethylene ring structure of tamoxifen, forming new nonsteroidal ring structures or creating steroidal estradiol analogs with greater antiestrogenic activity. There are now six nonsteroidal compounds either on the market or in clinical development and one steroidal "pure" antiestrogen has entered clinical trials. A number of these agents show improved estrogen-receptor binding affinity, antiestrogenic activity, and/or antitumor activity compared with tamoxifen. Preclinical and clinical data on these compounds are discussed and compared with tamoxifen when possible.

Estrogen Antagonists↗
PubMed1997

ARIMIDEX: a potent and selective aromatase inhibitor for the treatment of advanced breast cancer.

Aromatase inhibitors have been available for a number of years and their ability to reduce circulating estradiol levels has been shown to produce clinical benefit in women with advanced breast cancer. Until recently, the only commercially available aromatase inhibitor was aminoglutethimide. Although aminoglutethimide has been shown to be efficacious in the treatment of advanced breast cancer, it does cause significant toxicity and requires the use of concomitant hydrocortisone therapy. Anastrozole is one of a new class of potent aromatase inhibitors able to suppress estradiol to the limit of detection of sensitive assays without suppressing adrenal steroidal synthesis. Two large clinical trials (n = 764) conducted in the U.S.A. and in Europe evaluated two doses of anastrozole, 1 and 10 mg a day, compared to megesterol acetate, 40 mg four times a day, in postmenopausal women who had progressed while on tamoxifen. Response rates and time to progression with anastrozole were similar to those of megesterol acetate. Objective responses (CR + PR) were 10.3%, 8.9% and 7.9% in the 1 and 10 mg of anastrozole and megesterol acetate treatment groups, respectively. Another 25.2%, 22.6% and 26.1% had stable disease for over 24 weeks on 1, 10 mg anastrozole and megesterol acetate, respectively. Anastrozole and megesterol acetate were well tolerated; however, more patients had significant weight gain on megesterol acetate than with anastrozole treatment. The weight gain seen with megesterol acetate continued to increase over time. Anastrozole has a better therapeutic index (fewer side-effects) and has recently been approved by the FDA and a number of other regulatory agencies around the world for the treatment of advanced breast cancer.

Anastrozole↗
PubMed1996

Tumour angiogenesis as a prognostic marker in infiltrating lobular carcinoma of the breast.

The importance of angiogenesis, assessed by tumour microvessel density, as a marker of survival was examined in 160 patients with infiltrating lobular carcinoma of the breast (ILC). The median follow-up was 5.1 years. Of these patients, 46 were node-negative, 59 were node-positive, and in 55 the pathological lymph node status was not known. Tumour sections were immunohistochemically stained with Factor VIII-related antibody. Microvessels were identified using previously recommended methodology and counted in three separate fields, selected from areas of highest vascularity, at x 200 magnification (field area = 0.785 mm2). Only the highest count was considered in the analysis. No association was found between microvessel density and age, menopausal status, tumour size, histological subtype, peritumoural vessel invasion, and lymph node involvement at presentation. There was no association between microvessel density and overall survival or relapse-free survival. These results suggest that microvessel density assessment, using currently recommended methods, is unlikely to be of prognostic value in ILC.

Adult↗
PubMed1996

Effects of short-term antiestrogen treatment of primary breast cancer on estrogen receptor mRNA and protein expression and on estrogen-regulated genes.

Effects of the pure antiestrogen ICI182780 and tamoxifen on ER-protein, ER-mRNA, and estrogen-regulated mRNA expression were analysed using matched pretreatment core-cut biopsies and post-treatment mastectomy samples from 43 ER positive human breast cancers. Sixteen controls received either no preoperative treatment (n = 9) (7 days) or placebo (n = 7) (median 21 days) prior to primary surgery. Nineteen patients received ICI182780 6 mg/day (n = 10) or 18 mg/day (n = 9) for 7 days. Eight patients were given preoperative tamoxifen (4 x 40 mg-day 1, 20 mg/day thereafter, median 21 days). ER-protein expression was assessed on pre and post treatment samples by immunocytochemistry. ER, pS2, pLIV1, and actin-mRNA expression was determined by northern analysis on post-treatment samples only. ER-mRNA levels were similar to controls following ICI182780 or tamoxifen treatment. However ER-protein levels were significantly suppressed by ICI182780, particularly at the higher dosage (p = 0.0013). Tamoxifen had no significant effect on ER-protein levels. The ER-mRNA and ER-protein contents of control tumors were linearly related (Spearman r = 0.719, p = 0.006). A similar relationship between pretreatment protein and post ICI182780 treatment mRNA levels was observed (r = 0.652, p = 0.005). However, comparison of post ICI182780 treatment protein and mRNA results shows a loss of linearity through a reduction in protein without concurrent loss of mRNA (r = 0.28, p = 0.257). pS2 mRNA hybridization was lower in ICI182780 treated samples than controls (Mann-Whitney p = 0.035) but was unaffected by tamoxifen. pLIV1 mRNA hybridization was uninfluenced by either treatment. Short term exposure of breast tumors to ICI182780 appears to produce a greater inhibition of estrogen-induced transcriptional events than tamoxifen. These effects appear to occur without a concurrent reduction in ER mRNA levels.

Antineoplastic Agents, Hormonal↗
PubMed1996

A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer.

The aim of this study was to compare the efficacy and tolerability of the new aromatase inhibitor 'ARIMIDEX' (anastrozole) with megestrol acetate in the treatment of advanced breast cancer in postmenopausal women. Anastrozole is a new potent and highly selective non-steroidal aromatase inhibitor. We conducted a prospective randomised trial comparing two doses of anastrozole (1 and 10 mg orally once daily) with megestrol acetate (40 mg orally four times daily) in postmenopausal patients with advanced breast cancer who progressed after prior tamoxifen therapy. All patients were analysed for efficacy as randomised (intention to treat) and for tolerability as per treatment received. Of the 378 patients who entered the study, 135 were randomised to anastrozole 1 mg, 118 to anastrozole 10 mg, and 125 patients to megestrol acetate. After a median follow-up of 192 days, response rate which included complete response, partial response and patients who had disease stabilisation for 6 months or more was 34% for anastrozole 1 mg, 33.9% for anastrozole 10 mg and 32.8% for megestrol acetate. There were no statistically significant differences between either dose of anastrozole and megestrol acetate in terms of objective response rate, time to objective progression of disease or time to treatment failure. The three treatments were generally well tolerated, but more patients on megestrol acetate reported weight gain, oedema and dyspnoea as adverse events while more patients on anastrozole reported gastro-intestinal disorders, usually in the form of mild transient nausea. Patients on anastrozole did not report higher incidences of oestrogen withdrawal symptoms. Anastrozole is an effective and well tolerated treatment for postmenopausal patients with advanced breast cancer. The higher 10 mg dose did not result in additional clinical benefit, but was well tolerated reflecting the good therapeutic margin with anastrozole. Based on this data, anastrozole 1 mg should be the recommended therapeutic dose.

Adult↗
PubMed1996

New endocrine therapies for breast cancer.

How do the new endocrine therapies stand up to the aims of modern endocrine therapy outlined in Table 1? We wish to see increased efficacy, decreased toxicity and improved general health in women taking a new agent. None of the new non-steroidal anti-oestrogens have shown unequivocal evidence of improved efficacy in the clinic to mirror their improved profiles over tamoxifen in preclinical studies. We know that toremifene is equivalent to tamoxifen, but we do not have any phase III data from the other four compounds in development. The specific steroidal antioestrogen, ICI 182,780, looks very promising, but is early in its developmental programme. The new aromatase inhibitors are likely to prove equal to tamoxifen or progestagens, but it is disappointing that improved oestrogen suppression has not led, to date, to improved efficacy. No comment can be made about adjuvant or preventative therapy for any of the new agents, although trials are planned for the new aromatase inhibitors in this clinical situation. Currently, the antiprogestins are disappointing and we will need to wait a considerable time for new agents in preclinical testing to reach the clinic. Many of the new agents are associated with decreased toxicity. It is likely that the NSAEs will be equitoxic with tamoxifen. The steroidal antioestrogen looks particularly non-toxic as do the new aromatase inhibitors, and thus we have an advance in terms of reduced toxicity. The effects of the new agents on the uterus, lipids and bone are in the early stages of testing. Raloxifene, ICI 182,780 and the new aromatase inhibitors are expected to have no proliferative effects on the endometrium, but only the new NSAEs are expected to have beneficial cardiovascular and skeletal effects. If the steroidal anti-oestrogens and new aromatase inhibitors become adjuvant therapies of choice, other agents to prevent osteoporosis and cardiovascular events may also have to be administered.

Animals↗
PubMed1996

Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer.

Aged↗