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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
PubMed1994

Effects of 4-hydroxytamoxifen and a novel pure antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro.

We have investigated the effects on breast cancer cell growth of 4-hydroxytamoxifen (4OHT), a conventional antioestrogen with agonist activity, and 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulphinyl)nonyl]oestra- 1,3,5,(10)- triene-3,17 beta-diol (ICI 182780), a novel, pure antioestrogen, using established human breast cancer cell lines and cancer cells obtained directly from breast cancer patients with malignant pleural effusions who had relapsed on tamoxifen. The effects of the two agents were assessed using the Courtenay-Mills clonogenic assay, which measures the growth of single cancer cells as colonies suspended in soft agar. The standard assay was modified by the use of defined serum- and phenol red-free growth medium. The growth of oestrogen receptor (ER)-positive MCF-7 cells in the assay was oestrogen responsive. Both antioestrogens inhibited the stimulatory effects of 1 nM oestradiol, but ICI 182780 caused significantly greater inhibition than 4OHT at 0.1-1.0 microM concentrations. In the absence of oestradiol, 4OHT but not ICI 182780 caused significant stimulation of colony formation at low (0.01-1.00 nM) concentrations. Neither antioestrogen had any effects on colony formation by the ER-negative Hs578T cell line. Successful colony formation was obtained in primary cultures from six out of eight malignant effusions. Colony formation was significantly stimulated by 0.1 nM oestradiol in four cases and by 10 nM 40HT in two cases. In contrast, ICI 182780 exhibited no intrinsic stimulatory activity and significantly inhibited both oestradiol- and 4OHT-stimulated cell growth. We conclude that the agonist activity of 4OHT and other conventional antioestrogens may cause treatment failure in some patients by stimulating breast cancer cell growth. The new, pure antioestrogen ICI 182780 is a more potent oestrogen antagonist than 4OHT and exhibits no growth-stimulatory activity. This agent may therefore offer therapeutic advantages over conventional antioestrogens in patients with advanced breast cancer and may be effective after conventional agents have failed.

Adult↗
PubMed1994

A controlled trial of adjuvant tamoxifen, with or without prednisolone, in post-menopausal women with operable breast cancer.

A randomised clinical trial has been conducted to compare adjuvant tamoxifen, 20 mg daily, with tamoxifen and prednisolone, 7.5 mg daily, in post-menopausal women with operable breast cancer. There were 254 evaluable patients, of whom 128 were given tamoxifen alone and 126 received tamoxifen and prednisolone. After a median follow-up of 48 months there was no significant difference in relapse-free or overall survival of the two groups. Furthermore, with survival slightly favouring tamoxifen, confidence intervals on the hazard ratio established that a difference in favour of tamoxifen plus prednisolone of even 5% at 5 years was very unlikely (P < 0.02). Thus, despite the relatively small number of patients in this trial, the data clearly establish that prednisolone is not of value as an additional adjuvant agent.

Aged↗
PubMed1994

The impact of genetic counselling on risk perception in women with a family history of breast cancer.

Women with a family history of breast cancer generally self-refer because they have a feeling that their risk is high. However, they have, in general, only a hazy notion of the population risk of breast cancer and their own risk in relation to this. It is probable that they are helped by genetic counselling and, if at substantial risk, by annual mammography. However, the psychological impact of assigning true risk and the value of mammography need to be evaluated. We have assessed risk perception by questionnaire in 517 new referrals to a family history clinic and 200 women returning to the clinic at least 1 year after counselling. Correct assignment of population lifetime risk of breast cancer was 16% in the uninformed precounsel group and 33% in the post-counsel group, likewise personal risk was correct in 11% and 41% respectively. Post-counsel women were significantly more likely to retain information if they were sent a post-clinic letter or if they assessed their personal risk as too high initially.

Adult↗
PubMed1994

Suramin for breast and prostate cancer: a pilot study of intermittent short infusions without adaptive control.

BACKGROUND: Suramin has shown promising activity against prostate and breast cancer but is severely neurotoxic. Complex adaptive pharmacokinetics have previously been used to adjust doses. We have undertaken a pilot study to assess the feasibility of administering suramin to outpatients with advanced cancer, using simple peak and trough monitoring. PATIENTS AND METHODS: Nine patients with cancer refractory to conventional therapy were studied, eight with breast cancer and one with prostate cancer. Two received continuous infusions of suramin 350 mg/m2/day through an indwelling central venous catheter. Both sustained axillary vein thromboses. Subsequent patients received suramin 500 mg/m2 as a one hour intravenous infusion thrice weekly until a trough serum level of 200 micrograms/ml was achieved. Treatment was repeated at 8 week intervals. Serum suramin levels were checked before and after each dose. RESULTS: Suramin treatment was well tolerated. Despite peak serum levels of up to 506 micrograms/ml, no serious toxicity was seen. No tumour responses were seen. CONCLUSIONS: We conclude that suramin can be safely and conveniently administered to outpatients by intermittent infusion without using complex adaptive dosing strategies. Suramin merits further study in less heavily pretreated breast cancer patients.

Adult↗
PubMed1994

Parathyroid hormone and parathyroid hormone-related protein in the investigation of hypercalcaemia in two hospital populations.

BACKGROUND AND OBJECTIVE: Parathyroid hormone-related protein (PTHrP) produced by cancers has a central role as a humoral mediator of hypercalcaemia in patients with malignancy. Since the prevalences of hypercalcaemia of malignancy and parathyroid disease reflect the population studied, hypercalcaemic patients from a district general hospital (DGH) and an oncology centre (OC) were studied in order to assess the diagnostic role of assays for serum PTH and plasma PTHrP in different clinical settings. DESIGN: A prospective study of consecutive patients presenting with their first episode of hypercalcaemia during an 18-month period. PATIENTS: A total of 123 patients (DGH, n = 69; OC, n = 54) had corrected serum calcium concentrations > 2.65 mmol/l. MEASUREMENTS: PTH, PTHrP, calcium and albumin were measured together with urine calcium and creatinine, enabling fractional calcium excretion to be assessed. Urine cyclic adenosine monophosphate was also measured. RESULTS: Hypercalcaemia was attributed to malignancy alone in 72 patients (DGH, n = 20; OC, n = 52), benign causes in 42 (DGH, n = 42) and parathyroid disease coexisting with malignancy in 9 (DGH, n = 7; OC, n = 2). Plasma PTHrP levels were increased in 59/72 (82%) patients with hypercalcaemia due to malignancy. Measurements of both analytes contributed to a change in the final diagnosis in 12 patients (10%). Thus serum PTH was increased in seven patients with parathyroid disease coexisting with malignancy, and plasma PTHrP was increased in five patients with previous undiagnosed malignancy. Median survival for patients with parathyroid disease and coexisting malignancy was 13 months compared with 3 months for those with hypercalcaemia due to malignancy alone (P < 0.02). CONCLUSIONS: Since hypercalcaemia was attributable to parathyroid disease in 10% of all patients with malignancy we advise measurement of serum PTH at the initial presentation of hypercalcaemia in all patients, while plasma PTHrP may be useful to identify those patients in whom malignancy may not be clinically apparent, or coexist with primary hyperparathyroidism.

Calcium↗
PubMed1993

Expression of activated gelatinase in human invasive breast carcinoma.

The expression of both 92- and 72-kDa gelatinases has been studied in 20 samples of human breast carcinoma by the technique of gelatin zymography. This technique allowed the relative amount of each gelatinase to be determined in small samples of tissue (< 10 mg). More importantly, active and latent forms of the two gelatinases were resolved. Two samples (10-20 mg) were cut from each piece of tumour in order to monitor the variability of gelatinase distribution within that section of tumour. The 72-kDa latent progelatinase was present in 15 of the 20 tumours, with trace amounts in two others. The 62-kDa activated form of this gelatinase was detected in all 15 of the tumours in which the latent form was present. The 92-kDa latent progelatinase was present in 11 of the 20 tumours, with trace amounts in four others. However, the 82-kDa activated form of this gelatinase was only clearly detected in two tumours, although three others showed the presence of trace amounts. The ratio of active to latent forms of the 72-kDa gelatinase ranged from 0.9 to 3.6. There were no marked correlations between gelatinase expression and established staging and prognostic markers. Analysis of three samples of fibroadenoma revealed only very low levels of gelatinase expression. On the basis of these results, activation of the 72-kDa progelatinase appears to be a more common event in invasive breast carcinoma than activation of the 92-kDa progelatinase. However, neither proteinase showed a correlation with metastatic progression, as measured by lymph node involvement.

Biomarkers, Tumor↗
PubMed1993

Serum immunoreactive and bioactive lactogenic hormones in advanced breast cancer patients treated with bromocriptine and octreotide.

6 patients with advanced breast cancer who had failed first and second line endocrine therapies received bromocriptine (1.25-2.5 mg twice daily per os) and octreotide (Sandostatin) via a continuous subcutaneous infusion (200-400 micrograms/24 h) until disease progression. Pre-treatment 24-h profiles of serum lactogenic hormones and their response to standard provocative tests were established and repeated at 2 weeks, and 3 and 6 months (or at tumour progression). Immunoreactive prolactin (ir-PRL), growth hormone (ir-GH) and insulin-like growth factor I (IGF-I) were measured by radioimmunoassay and bioactive lactogenic hormone levels (BLH) were estimated using the Nb2 rat lymphoma cell bioassay. Before treatment all patients showed episodic secretion of ir-PRL, ir-GH and BLH and provocative stimuli resulted in a peak of ir-GH and BLH maximal between 60 and 90 min after injection but no change in ir-PRL. After 2 weeks of treatment, ir-PRL levels were reduced to below the limit of detection in all 6 patients. Peaks of ir-GH and BLH were still apparent, although much reduced. Immunoreactive PRL continued to be profoundly suppressed in 3 of the 4 patients who remained on treatment for 3 to 6 months. Small pulses of ir-GH were still detectable in these patients with which BLH was, again, well correlated. After 2 weeks of treatment, serum IGF-I levels were reduced by 9-54% of the pretreatment values and generally remained suppressed throughout treatment. Clinically, 4 patients did not show disease progression for periods of up to 6 months and side-effects were minimal.

Aged↗
PubMed1993

Assessment of tumour vascularity as a prognostic factor in lymph node negative invasive breast cancer.

The association between tumour vascularity and relapse was examined in 93 patients with lymph node negative (LNN) invasive breast cancer. Factor VIII-related antibody was used to stain the microvessels. Vascularity was defined by the number of vessels per field counted in the area of highest vascular density at 100 x magnification. These vascular counts were divided into three groups of vascular density (group I: < 67, group 2: 68-100, group 3: > 101 vessels/field). Cross-tabulation analysis revealed a significant relationship between vascular density and tumour grade (P = 0.027). No association was found between vascularity and tumour size, tumour type, age or menopausal status. Survival analysis showed no association between vascularity and relapse-free (P = 0.92) or overall survival (P = 0.99). Significant associations between tumour grade and relapse-free (P = 0.0048) and overall survival (P = 0.0064) and between tumour size at the cut off of 15 mm diameter and relapse-free (P = 0.0097) and overall survival (P = 0.0271) were found. When grade was taken into account the effect of tumour size became non-significant (P = 0.059). Our results suggest that assessment of vascularity is not an independent prognostic factor in LNN invasive breast cancer.

Adult↗
PubMed1993

Effect of tamoxifen on Ki67 labelling index in human breast tumours and its relationship to oestrogen and progesterone receptor status.

This study aimed to investigate the effect of tamoxifen on breast tumour levels of oestrogen and progesterone receptor (ER and PR) and proliferation as defined by the Ki67 antibody. A group of primary breast cancer patients was randomised to receive either tamoxifen (n = 59) or placebo (n = 44) treatment in the interval between clinic and surgery (median 21 days). Frozen sections of breast tumour biopsies obtained before and after treatment were stained immunocytochemically to obtain the percentage of nuclei containing ER and PR, and a Ki67 labelling index (LI). Tamoxifen-treated patients had a median Ki67 LI of 5.6% in the first biopsy falling to 3.0% in the second biopsy (P < 0.001 by Wilcoxon's matched pairs test), whereas placebo-treated patients had a median Ki67 LI of 5.4% in the first biopsy and 5.75% in the second (no significant difference). No significant differences were observed when the median %ER or %PR staining before and after treatment were compared. The Ki67 LI tended to increase with increasing histological grade and was greater in tumours that were ER - ve compared to those that were ER + ve (> 5% nuclei stained), median 7.8% and 4.3% respectively (P = 0.011 by Mann-Whitney U-test). However, the decline in tumour Ki67 LI following anti-oestrogen treatment failed to correlate with ER and PR status or to predict recurrence over a short follow-up period. To our knowledge, this is the first time that tamoxifen treatment has been shown to reduce the Ki67 LI in human breast tumours in vivo. These data indicate that staining with the Ki67 antibody may be useful in monitoring response to anti-oestrogen therapy.

Adult↗
PubMed1993

Perception of risk in women with a family history of breast cancer.

We present the findings of a pilot study to assess the perception of risk in 155 women with a family history of breast cancer by questionnaire. Only 11% of women were able to identify the correct population risk and more than half were unable to assess their own lifetime risk within 50% of the clinicians' estimate. Although it is probable that women are helped by genetic counselling and if at substantial risk, annual mammography, the psychological impact of assigning true risk and the value of mammography need to be evaluated.

Adult↗
PubMed1993

High dose, dose-intensive chemotherapy with doxorubicin and cyclophosphamide for the treatment of advanced breast cancer.

UNLABELLED: Eighteen patients with advanced breast cancer were commenced on treatment with high dose doxorubicin (100 mg m-2) or doxorubicin (100 mg m-2) and cyclophosphamide (500 mg m-2) at 2 weekly intervals. Three cycles of treatment were planned. rG-CSF was given subcutaneously for 10 days, starting 24 h after each cycle of chemotherapy. Sixteen out of 18 patients responded (89%) of whom six (33%) achieved a complete remission. Twelve (67%) completed the three planned cycles, four (22%) received two cycles and two (11%) received one cycle only. The median time to progression was 5 1/2 months and the median survival was 18 1/2 months. Neutropenia occurred after 89% of courses and 65% of courses were accompanied by a significant (WHO grade III or IV) infection. The duration of neutropenia was short (mean 5.4 days) and mean time to absolute neutrophil count recovery (ANC > 1,000 x 10(6) litre) from the start of treatment was 11 days. Moderate to severe epithelial toxicity (WHO grade 3 or 4) accompanied 43% of courses and was dose limiting. CONCLUSION: High dose, dose intensive chemotherapy has an excellent initial therapeutic effect in advanced breast cancer but does not prolong duration of remission or overall survival beyond that of standard treatment. Although subcutaneous rG-CSF curtailed the expected duration of neutropenia substantially, the overall incidence of neutropenia and of infections requiring intravenous antibiotics was high. Furthermore, almost half of the courses were complicated by moderate to severe oral mucositis and/or mild to moderate palmar and plantar inflammation. The lack of survival benefit and excess toxicity seriously limits the wider application of this regime. It should not be used in place of standard dose palliative chemotherapy for metastatic breast cancer.

Adult↗
PubMed1993

A linkage study in seven breast cancer families.

Seven breast cancer families are examined for evidence of linkage to a site in the region of 17q12-q21, by using five markers. The families constitute a subset of a larger series of familial breast cancer; the seven families were selected because constitutional DNA was available on informative members, either from clinical samples or extracted from paraffin blocks. Two-point lod scores are reported. The maximum lod score, 0.8824, is obtained with marker NM23 at theta = 0. This is clearly not significant in itself; however, when taken in context with evidence from existing reports, it provides support for linkage to this region.

Adult↗
PubMed1992

Prognostic relevance of serum hyaluronan levels in patients with breast cancer.

The serum hyaluronan (HA) level of 238 women with breast cancer was measured by means of a specific radiometric assay. The results show no significant increase in serum HA when compared to levels in 120 control sera. A number of prognostic factors were evaluated including stage of disease, lymph-node involvement, tumour size, histology and presence of oestrogen and progesterone receptors in the tumour. No correlation was found with serum HA concentration and we conclude that serum HA level is of no prognostic significance in breast cancer.

Adult↗