Fetal-like fibroblasts: their production of migration-stimulating factor and role in tumor progression.
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Amino Acid Sequence↗
Biomedical subjects
A Howell
Publications and source records attributed to A Howell.
Tropisetron compared with a metoclopramide-based regimen in the prevention of chemotherapy-induced nausea and vomiting.
This randomised, open, parallel group study compared the antiemetic efficacy and tolerability of tropisetron with metoclopramide plus lorazepam in 102 patients receiving a first course of non-cisplatin-containing chemotherapy. Control of acute vomiting by tropisetron was significantly superior to that of the metoclopramide regimen, with total control (no vomiting) in 45% of 51 patients in the tropisetron group compared with 22% of 51 patients in the metoclopramide group (P = 0.013); total and partial control (< 5 vomits) occurred in 67 and 47% of patients, respectively (P = 0.044). The incidences of acute nausea and of delayed nausea and emesis were similar in the two treatment groups. Both tropisetron and metoclopramide were well tolerated; no adverse effects were attributed to tropisetron administration with the exception of headache. One patient in the metoclopramide group reported confusion and tremor thought to be related to the antiemetic therapy. Tropisetron is an effective and well-tolerated agent in the prevention of chemotherapy-induced vomiting. The control of acute nausea was similar in the two treatment groups, but tropisetron was superior to a metoclopramide-based regimen in the control of acute vomiting.
Acute Disease↗
Cancer experience in the relatives of an unselected series of breast cancer patients.
First- and second-degree relatives of an unselected series of 402 breast cancer patients have been studied for their cancer experience. In the first-degree relatives an excess of all cancers is seen [overall relative risk (RR) = 1.28, P = 0.002; males RR = 1.26, P = 0.047; females RR = 1.30, P = 0.022). There is a marked excess of sarcoma (RR = 4.26, P = 0.0064); females are at high risk of breast cancer (RR = 2.68, P < 0.0001) and males have an excess of carcinoma of the lip, oral cavity and pharynx (RR = 4.22, P = 0.0032). Second-degree relatives have a non-significant excess of all cancers (RR = 1.14, P = 0.14); females have a borderline excess of breast cancer (RR = 1.53, P = 0.08) and an excess of carcinoma of the kidney (RR = 7.46, P = 0.0012) and males have an excess of carcinoma of the trachea and lung (RR = 1.50, P = 0.032). No excess of prostate or ovarian carcinoma was seen. Relatives are at slightly higher risk if the index patient is diagnosed between the ages of 40 and 49 (first-degree RR = 1.64, P = 0.007; second-degree RR = 1.43, P = 0.02). The excess of cancers, including breast cancers, is not limited to a few high-risk families, but appears to be spread across many. These observations may be accounted for by shared environmental factors within families or a common predisposing gene with low penetrance.
Adolescent↗
Response to intravenous bisphosphonate therapy in hypercalcaemic patients with and without bone metastases: the role of parathyroid hormone-related protein.
Plasma parathyroid hormone related-protein (PTHrP) may inhibit the calcium-lowering effect of bisphosphonate therapy. In this prospective study we examined the relationship between plasma PTHrP levels, renal tubular markers of calcium reabsorption, and the effectiveness of intravenous bisphosphonate therapy (IVBPT) in lowering serum calcium in patients with hypercalcaemia of malignancy (HM), with and without bone metastases. Thirty-five symptomatic hypercalcaemic patients (17 without and 18 with bone metastases) were treated with IVBPT (pamidronate 30-60 mg or BM21.0955 2-6 mg). Normocalcaemia was achieved in 24/35 (71%) patients with a mean fall in serum calcium of 0.85 mmol l-1 (range 0.11-1.93, P < 0.001). In the 35 patients studied, serum calcium levels reached a nadir between days 3 and 7, and this was accompanied by a small but significant reduction in plasma PTHrP levels (median reduction 0.77 pmol l-1, P = 0.007). Patients who responded to bisphosphonate therapy by becoming normocalcaemic had significantly lower basal plasma PTHrP levels, mean 4.06 vs 8.2 pmol l-1 (P < 0.04). A significant reduction in urinary calcium excretion was seen (mean 106 mumol l-1, P < 0.02) in patients with bone metastases, and urinary cAMP (mean 170 mmol l-1, P < 0.01) fell in all patients. Patients without demonstrable bone metastases had significantly higher plasma PTHrP levels (P < 0.002), required more doses of IVBPT, and had a poorer reduction in serum calcium compared with patients with bone metastases, only one of whom required more than one dose. We conclude that circulating PTHrP has an important role in increasing renal tubular reabsorption of calcium in HM, thus reducing the effectiveness of bisphosphonate therapy, particularly in patients with humoral HM and no bone metastases.
Bone Neoplasms↗
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↗
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↗
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↗
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↗
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↗
Rapid haematological recovery after high-dose consolidation chemotherapy with peripheral blood progenitor cells (PBPC) as sole source of support collected at a single apheresis.
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Adult↗
Timing of peripheral blood progenitor cell (PBPC) collections during recovery from chemotherapy supported by haematopoietic growth factor.
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Antineoplastic Combined Chemotherapy Protocols↗
Haemopoietic cells mobilised into the circulation by lenograstim as alternative to bone marrow for allogeneic transplants.
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Bone Transplantation↗
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↗
The potential for proteinase inhibition in cancer treatment.
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Endopeptidases↗
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↗
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↗
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↗
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↗