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Biomedical subjects

R E Coleman

Publications and source records attributed to R E Coleman.

At least 19 recordsLinked to original sources
PubMed2006

Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro.

Breast cancer patients often receive both paclitaxel and zoledronic acid as part of their treatment, and these drugs are reported to have synergistic effects on the induction of apoptosis of breast cancer cells in vitro. We have found that the synergistic interaction is drug sequence dependent, with maximal levels of apoptosis achieved when cells are treated with paclitaxel followed by zoledronic acid, as opposed to the reverse sequence or simultaneous treatment. The synergistic interaction persists at clinically relevant concentrations and incubation periods. We report that the sequential treatment is associated with cell cycle changes and depends on breast cancer cell characteristics, with hormone independence, mutated p53 status and presence of BRCA1 gene being associated with higher levels of apoptosis. Finally, we have found that the synergistic induction of apoptosis is via zoledronic acid-mediated inhibition of the mevalonate pathway.

Antineoplastic Agents, Phytogenic↗
PubMed2006

A randomised phase II study of two different schedules of pegylated liposomal doxorubicin in metastatic breast cancer (EORTC-10993).

One hundred and sixteen women with measurable metastatic breast cancer participated in a randomised phase II study of single agent liposomal pegylated doxorubicin (Caelyx) given either as a 60 mg/m2 every 6 weeks (ARM A) or 50 mg/m2 every 4 weeks (ARM B) schedule. Patients were over 65 years of age or, if younger, had refused or been unsuitable for standard anthracyclines. The aims of the study were to evaluate toxicity and dose delivery with the two schedules and obtain further information on the response rate of liposomal pegylated doxorubicin as a single agent in anthracycline nai ve advanced breast cancer. Twenty-six patients had received prior adjuvant chemotherapy (including an anthracycline in 10). Sixteen had received non-anthracycline-based first-line chemotherapy for advanced disease. One hundred and eleven patients were evaluable for toxicity and 106 for response. The delivered dose intensity (DI) was 9.8 mg/m2 (95% CI, 7.2-10.4) with 37 (69%) achieving a DI of >90% on ARM A and 11.9 mg/m2 (95% CI, 7.5-12.8) with 37 (65%) achieving a DI of >90% on ARM B. The adverse event profiles of the two schedules were distinctly different. Mucositis was more common with the every 6 weeks regimen (35% CTC grade 3/4 in ARM A, 14% in ARM B) but palmar plantar erythrodysesthesia (PPE) was more frequent with the every 4 weeks regimen (2% CTC grade 3/4 in ARM A, 16% in ARM B). Confirmed objective partial responses by RECIST criteria were seen with both schedules; 15/51 (29%) on ARM A and 17/56 (31%) on ARM B. Liposomal pegylated doxorubicin showed significant activity in advanced breast cancer with a generally favourable side-effect profile. The high frequency of stomatitis seen with 6 weekly treatment makes this the less preferred of the two schedules tested.

Adult↗
PubMed2006

Current management of treatment-induced bone loss in women with breast cancer treated in the United Kingdom.

New therapeutic options in breast cancer have improved survival but consequently increase the relevance of late complications. Ovarian suppression/ablation and aromatase inhibitors (AI) in the adjuvant setting have improved outcome, but have clinically important adverse effects on bone health. However, investigation and management of cancer treatment-induced bone loss (CTIBL) is poorly defined with no national guidance. In 2004, a questionnaire was sent to over 500 breast surgeons and oncologists who treat breast cancer within the United Kingdom. The questionnaire evaluated access to bone densitometry and specialist expertise as well as attitudes to investigation of CTIBL and anticipated changes in the use of AI for postmenopausal early breast cancer. A total of 354 completed questionnaires were received, 47 from clinicians not currently treating breast cancer. Of the 307 evaluable questionnaires, 164 (53%) were from breast surgeons, 112 (36%) from clinical oncologists and 31 (10%) from medical oncologists. Although most respondents recognised that CTIBL was the responsibility of the treating breast team, investigations for CTIBL are limited even though most had adequate access to bone densitometry; 98 (32%) had not requested a DXA scan in the last 6 months and 224 (73%) had requested fewer than five scans. In all, 235 (76%) were not routinely investigating patients on AI for bone loss. A total of 277 (90%) felt that their practice would benefit from national guidelines to manage these patients, and the majority (59%) had little or no confidence in interpreting DXA results and advising on treatment. This questionnaire has highlighted clear deficiencies in management of CTIBL in early breast cancer. The development of national guidelines for the management of these patients and educational initiatives for breast teams are urgently required.

Aged↗
PubMed2006

From genetic abnormality to metastases: murine models of breast cancer and their use in the development of anticancer therapies.

Numerous mouse models of mammary cancer have been developed that mimic selective aspects of human disease. The use of these models has enabled preclinical chemotherapeutic, chemoprevention, and genetic therapy studies in vivo, the testing of gene delivery systems, and the identification of tumour and metastasis suppressor and inducer genes. This review has discussed the most abundantly used murine models of mammary cancer including: spontaneous tumours, chemically induced tumours, orthotopic and syngeneic tumour transplantation, injected tumours, and genetically engineered mice with a predisposition to neoplasia. Each model has been discussed with regards to its merits and limitations for investigating the genetic and phenotypic alterations involved in the human disease as well as its potential usefulness for the development of new treatment strategies. To date no single mouse model is available with the ability to replicate the entire disease process, however, existing models continue to provide invaluable insights into breast cancer induction and progression that would be impossible to obtain using in vitro models alone.

Animals↗
PubMed2006

Magnesium depletion in patients receiving cisplatin-based chemotherapy.

AIMS: To assess the incidence of hypomagnesaemia, the influence of different cisplatin dosages on the degree of hypomagnesaemia and the effect of routine magnesium supplementation on magnesium levels. MATERIALS AND METHODS: Magnesium levels for 214 consecutive patients receiving cisplatin-based chemotherapy were studied. Twenty different chemotherapy regimens were prescribed. Doses ranged from 7 to 51 mg/m(2)/week. The interval between cycles ranged from 1 to 4 weeks. The number of evaluable cycles ranged from one to eight. Patients receiving bleomycin, etoposide and cisplatin (BEP) chemotherapy routinely received 60 mmol magnesium per cycle; patients receiving cisplatin, vincristine, methotrexate, bleomycin - dactinomycin, cyclophosphamide, etoposide (POMB-ACE) chemotherapy routinely received 20 mmol magnesium per cycle. For all other chemotherapy regimens, magnesium was not routinely prescribed. RESULTS: Baseline magnesium levels were available for 195 patients, 92% were within the normal range. The average level was 0.82 mmol/l. There was a statistically significant decrease in magnesium levels from baseline to the lowest magnesium level (mean = 0.68 mmol/l, standard deviation = 0.13) (P < 0.0005). The incidence of hypomagnesaemia (serum magnesium < 0.7 mmol/l) at any point during chemotherapy was 43%. Multiple regression analysis showed a significant association between dose, frequency, and number of cycles given, and the degree of hypomagnesaemia (P = 0.001, P = 0.03 and P < 0.0005, respectively). Routine magnesium supplementation significantly reduced the degree of hypomagnesaemia if sufficient amounts of magnesium are given: 60 mmol magnesium per cycle for a regimen containing 33 mg/m(2)/week cisplatin is sufficient; 20 mmol magnesium per cycle for a regimen containing 40 mg/m(2)/week cisplatin is insufficient. CONCLUSIONS: It is recommended that magnesium levels should be measured routinely in all patients receiving cisplatin and that all cisplatin-based chemotherapy regimens should be supplemented routinely with sufficient doses of magnesium (40-80 mmol magnesium per cycle depending on the regimen).

Aged↗
PubMed2006

Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours.

BACKGROUND: Osteoprotegerin (OPG) is involved in the regulation of bone turnover through binding to the receptor activator of nuclear factor kappaB ligand (RANKL), and has also been reported to be a potential survival factor for several different cell types. The survival effects are mediated through inhibition of the activity of tumour necrosis factor related apoptosis inducing ligand (TRAIL). Both breast and prostate cancer cells produce sufficient amounts of OPG to be protected against the effects of TRAIL in vitro. AIMS: To investigate the spatial expression of OPG, RANKL, and TRAIL in non-neoplastic breast tissue and breast cancer, and its relation with oestrogen receptor (ER) expression. METHODS: Forty breast cancers (20 ER+, 20 ER-) and five non-neoplastic breast tissue samples were stained with antibodies against OPG, RANKL, and TRAIL. RESULTS: OPG was not expressed in non-neoplastic breast tissue except when colocalised with altered columnar epithelium. RANKL was expressed at the apical surface of luminal epithelial cells and TRAIL was expressed in myoepithelial cells. All three proteins were expressed in some breast cancers but showed no significant association with tumour type. OPG expression showed a significant positive correlation with ER expression (p = 0.011). CONCLUSIONS: This is the first published study of the spatial expression of OPG, RANKL, and TRAIL in breast tissue and breast cancer. The localisation of each protein was specific and they were not colocalised. This specificity may provide a useful marker of functional differentiation in breast cancer; for example, TRAIL expression as a marker of myoepithelial differentiation.

Apoptosis Regulatory Proteins↗
PubMed2005

Bisphosphonates in breast cancer.

Breast cancer is the leading type of cancer among women, and bone metastases are common in patients with breast cancer, affecting more than half of all patients with advanced disease. Bisphosphonates are the current standard of care for preventing skeletal complications associated with bone metastases. Clinical trials investigating the benefit of bisphosphonate therapy have used a composite end point defined as a skeletal-related event (SRE) or bone event, which typically includes pathologic fracture, spinal cord compression, radiation or surgery to bone, and hypercalcaemia of malignancy. Bisphosphonates significantly reduced the incidence of these events. Zoledronic acid, pamidronate, clodronate and ibandronate have demonstrated efficacy compared with placebo. Zoledronic acid has also been compared with another active bisphosphonate (i.e. pamidronate) and shown by multiple event analysis to be significantly more effective at reducing the risk of SREs. Bisphosphonates effectively reduce and prevent skeletal complications in patients with bone metastases from breast cancer. Preclinical data suggest that bisphosphonates have antitumour effects. Bisphosphonates may also be of use in the adjuvant setting.

Administration, Oral↗
PubMed2005

Salvage, dose intense and high-dose chemotherapy for the treatment of poor prognosis or recurrent germ cell tumours.

Most patients with metastatic testicular cancer are cured with cisplatin-based chemotherapy regimens. However, about 20-30% of patients with poor-risk germ cell tumours either fail to respond adequately or relapse after initial complete response. In an attempt to improve the treatment results, several phase II studies of high-dose chemotherapy (HDCT) and haematopoeitic stem cell support were performed initially in refractory or heavily pre-treated patients with germ cell tumours (GCT). Long-term disease-free survival (DFS) has been reported in nearly 13% (range 0-35%) of the patients in this group. Subsequently, HDCT trials have been conducted in first relapse; long-term DFS has been seen in 45% of the patients in these trials (range 21-67%). HDCT has also been evaluated in the first-line treatment of poor-risk GCTs; long-term DFS was achieved in 52% of the patients in this group (range 36-84%). Despite these encouraging results, a French randomised trial has failed to demonstrate any advantage of HDCT in the first-line treatment of poor-risk GCTs and thus the place of HDCT in routine practice remains uncertain. A number of randomised trials of HDCT are currently ongoing in the United States and Europe to better define the role of HDCT in this disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Reduced dose capecitabine is an effective and well-tolerated treatment in patients with metastatic breast cancer.

Fifty-seven patients with metastatic breast cancer have been treated with reduced dose capecitabine 1g/m2 twice daily for 14 days repeated every 3 weeks after failure of a number of chemotherapy regimens or hormonal treatment. The overall objective response rate was 28% with 2% complete response rate and 26% partial response. Twenty nine percent objective response rate was achieved in 17 patients pretreated with anthracyclines and taxanes. The median duration of response and survival were 8.5 and 9 months, respectively. One and two year overall survival probabilities were 37% and 20%, respectively. The most common treatment-related adverse events (all grades) were hand-foot syndrome (HFS) (32%), nausea (21%) and diarrhoea (19%). Dose limiting toxicities, especially HFS were rare. Within the limits of phase II trial, this reduced dose of capecitabine appears as effective for advanced breast cancer as full dose capecitabine with a lower incidence of toxicity.

Adult↗
PubMed2004

Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomised phase III study.

A randomised phase III trial was conducted to assess the role of interferon-alpha (INFalpha) 2a as maintenance therapy following surgery and/or chemotherapy in patients with epithelial ovarian carcinoma. Patients were randomised following initial surgery/chemotherapy to interferon-alpha 2a as 4.5 mega-units subcutaneously 3 days per week or to no further treatment. A total of 300 patients were randomised within the study between February 1990 and July 1997. No benefit for interferon maintenance was seen in terms of either overall or clinical event-free survival. We conclude that INF-alpha is not effective as a maintenance therapy in the management of women with ovarian cancer. The need for novel therapeutics or strategies to prevent the almost inevitable relapse of patients despite increasingly effective surgery and chemotherapy remains.

Adult↗
PubMed2004

A cancer research (UK) randomized phase II study of idoxifene in patients with locally advanced/metastatic breast cancer resistant to tamoxifen.

Idoxifene is a novel selective oestrogen receptor modulator (SERM) which had greater binding affinity for the oestrogen receptor (ER) and reduced agonist activity compared with tamoxifen in preclinical studies. In a randomized phase II trial in 56 postmenopausal patients with progressive locally advanced/metastatic breast cancer we assessed whether idoxifene showed evidence of activity compared with an increased 40 mg/day dose of tamoxifen in patients who had previously demonstrated resistance to the standard 20 mg/day dose of tamoxifen. Of 47 patients eligible for response (25 idoxifene, 22 tamoxifen), two partial responses and two disease stabilizations (SD) for >6 months were seen with idoxifene (overall clinical benefit rate 16%, 95% CI 4.5-36.1%). The median duration of clinical benefit was 9.8 months. In contrast, no objective responses were seen with the increased 40 mg/day dose of tamoxifen, although two patients had SD for 7 and 14 months (clinical benefit rate 9%, 95% CI 1.1-29.2%). Idoxifene was well tolerated and the reported possible drug-related toxicities were similar in frequency to those with tamoxifen (hot flushes 13% vs 15%, mild nausea 20% vs 15%). Endocrine and lipid analysis in both groups showed a similar significant fall in serum follicle-stimulating hormone and luteinizing hormone after 4 weeks, together with a significant rise in sex hormone binding globulin levels and 11% reduction in serum cholesterol levels. In conclusion, while idoxifene was associated with only modest evidence of clinical activity in patients with tamoxifen-resistant breast cancer, its toxicity profile and effects on endocrine/lipid parameters were similar to those of tamoxifen.

Adult↗
PubMed2004

Aromatase inhibitors in the adjuvant setting: bringing the gold to a standard?

The death rate from breast cancer is falling rapidly in most developed countries due, at least in part, to the use of adjuvant endocrine therapy in women with endocrine responsive disease. In post-menopausal women tamoxifen has been the gold standard for nearly 20 years. More recently the aromatase inhibitors (AI) have become established in the management of advanced breast cancer and are being evaluated in the adjuvant setting in trials that include tens of thousands of women. Recently, data have emerged that provide increasingly strong evidence supporting the use of AI in the adjuvant setting. Anastrozole as initial adjuvant endocrine treatment has shown superiority over tamoxifen in terms of disease free survival, and impressive reductions in the risk of recurrence have been demonstrated in trials evaluating the switch from tamoxifen to an AI, either letrozole after 5 or exemestane after 2-3 years of tamoxifen respectively. The data from these recent publications, and the potential impact on routine care of women with post-menopausal breast cancer is discussed.

Aged↗
PubMed2004

Baseline health-related quality-of-life data as prognostic factors in a phase III multicentre study of women with metastatic breast cancer.

The potential value of baseline health-related quality-of-life (HRQOL) and clinical factors in predicting prognosis was examined using data from an international randomised phase III trial which compared doxorubicin and paclitaxel with doxorubicin and cylophosphamide as first line chemotherapy in 275 women with metastatic breast cancer. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the related breast module (QLQ-BR23) were used to assess baseline HRQOL data. The Cox proportional-hazards regression model was used for both univariate and multivariate analyses of survival. In the univariate analyses, performance status (P<0.001) and number of sites involved (P=0.001) were the most important clinical prognostic factors. The HRQOL variables at baseline most strongly associated with longer survival were better appetite, physical and role functioning, as well as less fatigue (P<0.001). The final multivariate model retained performance status (P<0.001) and appetite loss (P=0.005) as the variables best predicting survival. Substantial loss of appetite was the only independent HRQOL factor predicting poor survival and was strongly correlated (/r/>0.5) with fatigue, role and physical functioning. In addition to known clinical factors, appetite loss appears to be a significant prognostic factor for survival in women with metastatic breast cancer. However, the mechanism underlying this association remains to be precisely defined in future studies.

Adult↗
PubMed2004

The role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease.

OBJECTIVE: To evaluate the role of second (and third) uterine evacuation in the management of persistent gestational trophoblastic disease (GTD). METHODS: This was an observational study of all cases registered over a 10-year period at the Trophoblastic Disease Centre at Weston Park Hospital, Sheffield. Five hundred and forty-four of 4050 women registered during 1991-2000 underwent a second uterine evacuation following a presumptive diagnosis of persistent GTD. The reason for evacuation, hCG level prior to the procedure, histological appearances of evacuated products and the clinical outcome (in terms of the need for chemotherapy) were determined. RESULTS: After a second uterine evacuation 368 patients (68%) completed the follow-up programme without further evidence of persistent disease or need for chemotherapy. If the diagnosis of persistent GTD was confirmed solely on the basis of elevated hCG levels then 171 of 282 (60%) patients did not require chemotherapy. Chemotherapy was more likely where there was histological evidence of persistent trophoblastic disease and where the urinary hCG was >1500 IU/L at the time of the repeat evacuation. Twenty-eight of 60 patients (46%) undergoing a third evacuation required chemotherapy. CONCLUSION: Second uterine evacuation can be a useful therapeutic option for patients with presumed persistent trophoblastic disease not mandating immediate chemotherapy, particularly where the hCG level is <1500 IU/L. Patients with documented persistent trophoblastic disease on histological examination of the second evacuation sample are more likely to require chemotherapy. Third evacuation is not now recommended.

Adolescent↗
PubMed2004

The management and survival of patients with advanced germ-cell tumours: improving outcome in intermediate and poor prognosis patients.

AIMS: The survival of germ-cell tumours (GCT) was transformed after the introduction of cisplatin-based therapy. Previous trials have indicated BEP (bleomycin, etoposide and cisplatin) as the optimum treatment, although some centres including our own advocate the use of the alternating regimen POMB-ACE (cisplatin, vincristine, methotrexate, bleomycin and dactinomycin, cyclophosphamide and etoposide) for men with intermediate or poor prognosis disease. We analysed the survival and management of GCT patients treated at a specialist cancer centre in relation to internationally recognised prognostic groupings. MATERIALS AND METHODS: We retrieved patient information using the Trent Testicular Tumour Registry and supplemented it with information from patient notes. This included all patients with Royal Marsden Hospital Stage II, III and IV disease and patients with stage I disease at diagnosis with raised markers or subsequent relapse. We compared the efficacy and toxicity of the BEP and POMB-ACE chemotherapy regimens, and assessed relapse-free and overall survival. RESULTS: We identified 178 non-seminomatous germ cell tumours (NSGCT) and 71 seminoma patients. Overall survival was similar to the International Germ Cell Cancer Collaborative Group (IGCCCG) classification for the good (95% vs 92%) and intermediate groups (82% vs 80%). The outcome for the poor prognosis group was better than expected in our series (57% vs 48%). There was a higher proportion of both immediate and late side-effects with POMB-ACE. CONCLUSION: Survival and disease progression rates at this single institution were at least as good as reported by the IGCCCG and somewhat better for the poor-prognosis group. This may reflect use of the POMB-ACE chemotherapy regimen as opposed to standard BEP regimen. However, a randomised comparison of BEP and POMB-ACE would be required to validate this.

Adolescent↗
PubMed2004

Osteoprotegerin (OPG) produced by bone marrow stromal cells protects breast cancer cells from TRAIL-induced apoptosis.

Advanced breast cancer is often associated with metastatic bone disease, causing a number of serious complications for the patients such as hypercalceamia, pain, nerve compression and fractures. The formation of bone metastases depends on complex interactions between tumour cells and the cells of the bone microenvironment, but the precise molecular mechanisms involved in the development of tumour-induced bone disease have not been identified. We have investigated the ability of bone marrow stromal cells (BMSC) isolated from breast cancer patients to generate osteoprotegerin (OPG), a molecule involved both in bone turnover and cell survival. The potential survival effects of OPG are mediated through binding to a member of the TNF super family, TNF-related Apoptosis Inducing Ligand (TRAIL), preventing association between TRAIL and its death-inducing receptors present on a number of tumour cell types. In the present report we show that bone marrow stromal cells isolated from breast cancer patients produce OPG when grown in culture. The levels of OPG present in BMSC conditioned medium is sufficient to protect breast cancer cells from undergoing TRAIL induced apoptosis. Our data suggest that bone-derived OPG may increase survival of breast cancer cells that reach the bone microenvironment as part of the metastatic process.

Apoptosis↗
PubMed2004

The detection of circulating breast cancer cells in blood.

At present, sampling of the lymph nodes or bone marrow for the detection of regions of metastatic disease in patients with breast cancer can only be undertaken at the time of initial diagnosis and surgery. However, the sampling of these tissues and the methods used are inaccurate, time consuming, and cannot be used for easy routine screening to determine disease recurrence and response to treatment. Because of the problems encountered with current methods and tissues sampled at the time of breast cancer diagnosis, this review discusses the urgent requirement for and potential development of a quick, simple, and accurate diagnostic test utilising the haematogenous system, a source of circulating tumour cells in patients with breast cancer, and highly sensitive molecular biological techniques, such as reverse transcription polymerase chain reaction. In addition, this review also highlights potential problems that may be encountered and should be avoided when devising such a test.

Biomarkers, Tumor↗