Academic Unit of Clinical Oncology

Sheffield, United Kingdom

Academic Unit of Clinical Oncology

Sheffield, United Kingdom
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PubMed | Amgen Inc., Poznan University of Medical Sciences, Sunnybrook and Womens College Health science Center, University Paris - Sud and 5 more.
Type: Clinical Trial, Phase III | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2015

In a phase III trial in patients with castration-resistant prostate cancer (CRPC) and bone metastases, denosumab was superior to zoledronic acid in reducing skeletal-related events (SREs; radiation to bone, pathologic fracture, surgery to bone, or spinal cord compression). This study reassessed the efficacy of denosumab using symptomatic skeletal events (SSEs) as a prespecified exploratory end point.Patients with CRPC, no previous bisphosphonate exposure, and radiographic evidence of bone metastasis were randomized to subcutaneous denosumab 120 mg plus i.v. placebo every 4 weeks (Q4W), or i.v. zoledronic acid 4 mg plus subcutaneous placebo Q4W during the blinded treatment phase. SSEs were defined as radiation to bone, symptomatic pathologic fracture, surgery to bone, or symptomatic spinal cord compression. The relationship between SSE or SRE and time to moderate/severe pain was assessed using the Brief Pain Inventory Short Form.Treatment with denosumab significantly reduced the risk of developing first SSE [HR, 0.78; 95% confidence interval (CI) 0.66-0.93; P = 0.005] and first and subsequent SSEs (rate ratio, 0.78; 95% CI 0.65-0.92; P = 0.004) compared with zoledronic acid. The treatment differences in the number of patients with SSEs or SREs were similar (n = 48 and n = 45, respectively). Among patients with no/mild pain at baseline, both SSEs and SREs were associated with moderate/severe pain development (P < 0.0001). Fewer patients had skeletal complications, particularly fractures, when defined as SSE versus SRE.In patients with CRPC and bone metastases, denosumab reduced the risk of skeletal complications versus zoledronic acid regardless of whether the end point was defined as SSE or SRE.


Smith M.R.,Massachusetts General Hospital | Coleman R.E.,Academic Unit of Clinical Oncology | Klotz L.,Sunnybrook and Womens College Health science Center | Pittman K.,The Queen Elizabeth Hospital | And 8 more authors.
Annals of Oncology | Year: 2015

In this analysis of a phase III trial in patients with castration-resistant prostate cancer and bone metastases, treatment with denosumab reduced the risk of skeletal complications vs zoledronic acid regardless of whether the end point was defined as SSE or SRE. Both SSEs and SREs were associated with development of moderate/severe pain among patients with no/mild pain at baseline. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.


Coleman R.,Academic Unit of Clinical Oncology | De Boer R.,Royal Melbourne and Western Hospitals | Eidtmann H.,Universitats Frauenklinik Kiel | Llombart A.,Institute Oncologica | And 12 more authors.
Annals of Oncology | Year: 2013

Background: Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk. Patients and methods: Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points. Results: At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334). Conclusions: Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No: NCT00171340. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Ottewell P.D.,Academic Unit of Clinical Oncology | Wang N.,University of Sheffield | Meek J.,Academic Unit of Clinical Oncology | Fowles C.A.,University of Sheffield | And 3 more authors.
Endocrine-Related Cancer | Year: 2014

Up to 90% of patients with castrate-resistant prostate cancer develop bone metastases, and the majority of these men have received androgen deprivation therapy known to cause bone loss. Whether this treatment-induced change to the bone microenvironment affects disseminated tumour cells, potentially stimulating development of bone metastasis, remains to be determined. The objective of this study was to use an in vivo model mimicking androgen ablation to establish the effects of this intervention on disseminated prostate cancer cells in bone. We mimicked the effects of androgen deprivation on bone metastasis by castrating 12-week-old BALB/c nude mice that had disseminated, hormone-insensitive PC3 prostate cancer cells present in the long bones. Castration caused increased bone resorption and loss of bone volume, compared with sham operation. In addition, castration triggered growth of disseminated PC3 cells to form bone metastasis in 70% of animals. In contrast, only 10% of sham-operated animals had detectable long bone tumours. Weekly administration of 100 μg/kg zoledronic acid (ZOL) prevented castration-induced tumour growth in bone and increased bone volume, but did not eliminate the disseminated tumour cells. ZOL had no effect on tumour growth in the sham-operated animals, despite causing a significant increase in bone volume. This is the first demonstration that, in a model of prostate cancer bone metastasis, mimicking androgen ablation results in growth of disseminated tumour cells in bone through osteoclast-mediated mechanisms. We provide the first biological evidence supporting the administration of ZOL to prostate cancer patients at the time of androgen ablation to prevent subsequent relapse in bone. © 2014 Society for Endocrinology


Foan S.J.,Academic Unit of Clinical Oncology | Jackson A.M.,Academic Unit of Clinical Oncology | Spendlove I.,Academic Unit of Clinical Oncology | Aickelin U.,University of Nottingham
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2011

It is widely accepted that the immune system undergoes age-related changes correlating with increased disease in the elderly. T cell subsets have been implicated. The aim of this work is firstly to implement and validate a simulation of T regulatory cell (Treg) dynamics throughout the lifetime, based on a model by Baltcheva. We show that our initial simulation produces an inversion between precursor and mature Tregs at around 20 years of age, though the output differs significantly from the original laboratory dataset. Secondly, this report discusses development of the model to incorporate new data from a cross-sectional study of healthy blood donors addressing balance between Treg s and Th 17 cells with novel markers for Treg. The potential for simulation to add insight into immune aging is discussed. © 2011 Springer-Verlag.


Jackson A.M.,Academic Unit of Clinical Oncology | Mulcahy L.A.,Academic Unit of Clinical Oncology | Porte J.,University of Nottingham | Franks H.A.,Academic Unit of Clinical Oncology | And 5 more authors.
European Cytokine Network | Year: 2010

Mitogen-activated protein kinases (MAPK) are targets for the immune-modulation of dendritic cells (DC). However, our knowledge of their role in the regulation of IL-12-family cytokines is limited. This study investigated the roles of p38, JNK, p44/42 and PI3K pathways in IL-12/23/27 production by human DC, and their impact on naïve T H-responses. We first identified TOP and UBC as robust DC housekeeping genes. Peak transcription of p35 and p40 occurred by 12h, p19 and p28 by 8h and EBI3 by 12-24h. Using selective antagonists, we showed that p38 was a positive regulator of IL-12, 23 and 27, JNK positively regulated IL-12 and IL-27, and inhibition of MEK1/2 had no marked effect. In contrast, the PI3K pathway markedly attenuated IL-23 responses and, to a lesser extent, IL-12, but not IL-27. To identify the role of these soluble factors, we co-stimulated naïve CD4+ T-cells in the presence of DC supernatant. The presence of mature DC supernatant induced not only strong IFN responses, but also IL-10 and IL-17A. Inhibition of p38 ablated T H1 , and IL-10 and IL-17A responses, whilst modestly enhancing IL-5 secretion. In contrast, inhibition of MEK1/2 abolished IL-17A production, whilst leaving other responses unaffected, whereas inhibition of JNK or PI3K had no discernable effect. In summary, we describe the expression of IL-12-family cytokines from DC and propose a modified model for their regulation. This study further clarifies the potential for therapeutic modulation through these mediators.


PubMed | Academic Unit of Clinical Oncology
Type: Clinical Trial | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2013

Aromatase inhibitors are the preferred adjuvant endocrine therapy for the majority of postmenopausal women with hormone-responsive early breast cancer. Although generally more effective than tamoxifen, aromatase inhibitor therapy is associated with increased bone loss and fracture risk.Postmenopausal women receiving adjuvant letrozole (2.5 mg/day for 5 years; N = 1065) were randomly assigned to immediate zoledronic acid (zoledronate) 4 mg every 6 months for 5 years, or delayed zoledronate (initiated for fracture or on-study bone mineral density [BMD] decrease). The primary end point was the change in lumbar spine BMD at 12 months. Lumbar spine and total hip BMD at subsequent follow-up, disease-free survival (DFS), and overall survival were assessed as secondary end points.At 60 months (final analysis), the mean change in lumbar spine BMD was +4.3% with immediate zoledronate and -5.4% with delayed intervention (P < 0.0001). Immediate zoledronate reduced the risk of DFS events by 34% (hazard ratio [HR] = 0.66; P = 0.0375) with fewer local (0.9% versus 2.3%) and distant (5.5% versus 7.7%) recurrences versus delayed zoledronate. In the delayed group, delayed initiation of zoledronate substantially improved DFS versus no zoledronate (HR = 0.46; P = 0.0334).Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.

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