Gray Institute for Radiation Oncology and Biology

Oxford, United Kingdom

Gray Institute for Radiation Oncology and Biology

Oxford, United Kingdom
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Patterson D.M.,Mount Vernon Hospital | Zweifel M.,Mount Vernon Hospital | Middleton M.R.,Oxford Radcliffe Hospitals | Folkes L.K.,Gray Institute for Radiation Oncology and Biology | And 8 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. Experimental Design: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. Results: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m 2, then expanded cohorts to 15.4 mg/m 2 in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drugrelated dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m 2 or higher. Conclusions: The maximum tolerated dose was 8.5 mg/m 2 but escalation to 14 mg/m 2 was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m 2 and maximum tumor perfusion reductions were seen at doses of 11 mg/m 2 or higher, the recommended phase II dose is from 11 to 14 mg/m 2. ©2012 AACR.

Mandeville H.C.,Mount Vernon Cancer Center | Ng Q.S.,National Cancer Center | Daley F.M.,Gray Institute for Radiation Oncology and Biology | Barber P.R.,Gray Institute for Radiation Oncology and Biology | And 9 more authors.
Radiology | Year: 2012

Purpose: To assess the relationship between helical dynamic contrast material-enhanced (DCE) computed tomographic (CT) parameters and immunohistochemical markers of hypoxia in patients with operable non-small cell lung cancer (NSCLC). Materials and Methods: After institutional review board approval was obtained, 20 prospective patients who were suspected of having NSCLC underwent whole-tumor DCE CT with kinetic modeling (Patlak analysis) 24 hours before scheduled surgery. Flow-extraction product (in milliliters per 100 milliliters per minute) and blood volume (in milliliters per 100 milliliters) were derived. After surgery, matched whole-tumor sections were stained for exogenous and endogenous markers of hypoxia (pimonidazole infused intravenously 24 hours before surgery, immediately after DCE CT; glucose transporter protein). Correlation between DCE CT parameters and immunohistochemical markers was assessed by using the Spearman rank correlation. DCE CT parameters and immunohistochemical markers were also compared according to pathologic subtype, grade, stage, and nodal status by using the Mann-Whitney test. P values less than .05 indicated a statistically significant difference. Result: Fourteen patients with confirmed primary NSCLC underwent resection. There were negative correlations between blood volume and pimonidazole staining (r = -0.48, P = .004), and between flow-extraction product and glucose transporter protein expression (r = -0.50, P = .002). Flow-extraction product was significantly higher in adenocarcinomas than in squamous cell tumors (17.73 vs 11.46; P = .043). Glucose transporter protein expression was significantly lower for adenocarcinomas than for squamous tumors (14.07 vs 33.03; P ≤ .001) and in node negative than in node positive tumors (15.63 vs 23.85; P = .005). Conclusion: Blood volume and flow-extraction product derived at DCE CT correlated negatively with pimonidazole and glucose transporter protein expression, indicating the potential of these CT parameters as imaging biomarkers of hypoxia. © RSNA, 2012.

McLaughlin P.,Cork University Hospital | McLaughlin P.,University College Cork | Jones B.,Gray Institute for Radiation Oncology and Biology | Jones B.,Oxford Martin Particle Therapy Cancer Research Institute | And 2 more authors.
British Journal of Radiology | Year: 2012

On 11 March 2011, the Richter scale 0.9-magnitude Tokohu earthquake and tsunami struck the northeast coast of Japan, resulting in widespread injury and loss of life. Compounding this tragic loss of life, a series of equipment and structural failures at the Fukushima Dai-ichi nuclear power plant (FDNP) resulted in the release of many volatile radioisotopes into the atmosphere. In this update, we detail currently available evidence about the nature of immediate radioactive exposure to FDNP workers and the general population. We contrast the nature of the radioactive exposure at FDNP with that which occurred at the Chernobyl power plant 25 years previously. Prediction of the exact health effects related to the FDNP release is difficult at present and this disaster provides the scientific communitywith a challenge to help those involved and to continue research that will improve our understanding of the potential complications of radionuclide fallout. © 2012 The British Institute of Radiology.

Bentzen S.M.,University of Wisconsin - Madison | Dorr W.,Medical University of Vienna | Gahbauer R.,Ohio State University | Howell R.W.,New Jersey Medical School | And 6 more authors.
Radiotherapy and Oncology | Year: 2012

The International Commission on Radiation Units and Measurements (ICRU) Report Committee on "Bioeffect Modeling and Biologically Equivalent Dose Concepts in Radiation Therapy" is currently developing a comprehensive and consistent framework for radiobiological effect modeling based on the equieffective dose, EQDXα/β, a concept encompassing BED and EQD2 as special cases. © 2012 Elsevier Ireland Ltd. All rights reserved.

Gwynne S.,Singleton Hospital | Gwynne S.,Velindre Cancer Center | Spezi E.,Velindre Cancer Center | Sebag-Montefiore D.,University of Leeds | And 4 more authors.
British Journal of Radiology | Year: 2013

As the complexity of radiotherapy (RT) trials increases, issues surrounding target volume delineation will become more important. Some form of outlining assessment prior to trial entry is increasingly being mandated in UK RT trials. This document produced by the Outlining and Imaging Subgroup (OISG) of the National Cancer Research Institute will address methods to reduce interobserver variation in clinical trials and how to conduct an assessment of outlining through a pre-accrual benchmark case. We review currently available methods of describing the variation and identify areas where further work is needed. The OISG would encourage ongoing discussion with chief investigators in order to provide advice on individual aspects of benchmark case assessment for current and future trials. © 2013 The Authors.

Franks K.N.,St James's Hospital | Kancherla K.,St James's Hospital | Kancherla K.,Broomfield Hospital | Sethugavalar B.,St James's Hospital | And 4 more authors.
Journal of Urology | Year: 2011

Purpose: We studied the outcomes in patients with node positive penile cancer who received radiotherapy to inguinal and pelvic nodes. Although half of node positive cases are cured by lymphadenectomy, little data are available on the potential further benefits and toxicities of postoperative radiotherapy. Materials and Methods: We retrospectively audited the clinical notes and electronic records of 23 patients referred to a specialist center from 2002 to 2008 who received radiotherapy to the inguinal/pelvic nodes as adjuvant treatment after lymphadenectomy (14), or as high grade palliation for extensive/fixed nodes (8) or extensive local tumor (1). The primary outcome measure was overall survival. Secondary end points were locoregional recurrence-free survival and toxicity. Results: All 13 deaths were due to penile cancer. Patients with adjuvant therapy had better overall survival (66% vs 11%, p <0.001) and locoregional relapse-free survival (56% vs 22%, p = 0.03) than those with high grade palliation. Six of 14 adjuvant cases and 7 of 9 with high grade palliation relapsed locoregionally. Of patients with adjuvant therapy and extracapsular spread 1 of 6 with N1, 1 of 4 with N2 and 3 of 4 with N3 disease relapsed (p = 0.31). No life threatening toxicity was observed. It was difficult to determine the relative contributions of radiotherapy and surgery to leg/scrotal lymphedema. The study was limited by its small size, which reflects the rarity of this tumor. Conclusions: Adjuvant radiotherapy appears to have a role after inguinal lymphadenectomy, particularly in patients with extracapsular nodal spread, in whom historically survival rates have been poor. Our findings warrant further investigation in larger series of patients. © 2011 American Urological Association Education and Research, Inc.

Kotsopoulos J.,Womens College Research Institute | Kotsopoulos J.,University of Toronto | Chen Z.,University of Toronto | Vallis K.A.,Gray Institute For Radiation Oncology and Biology | And 6 more authors.
Cancer Causes and Control | Year: 2010

Selenium is an important cofactor of various antioxidant enzymes and has been shown to enhance DNA repair in normal human fibroblasts. Oral selenium supplementation has also been shown to decrease the number of chromosome breaks in BRCA1 mutation carriers. Because the predisposition to cancer among BRCA1 mutation carriers may be linked to high rates of DNA damage and chromosome breakage, we evaluated the association between toenail selenium concentrations and three measures of DNA repair capacity (the single-cell alkaline gel electrophoresis (comet) assay, the micronucleus test, and the enumeration of γ-H2AX nuclear foci) in female BRCA1 mutation carriers and in non-carriers. Toenail selenium levels were inversely associated with levels of chromosomal damage following exposure to gamma-irradiation, as assessed by the micronucleus test. This association was limited to women with a BRCA1 mutation (p = 0.03). Toenail selenium was not a significant predictor of DNA repair capacity, as quantified by either the comet assay or the number of γ-H2AX foci, in carriers or in non-carriers. These results provide evidence for a possible protective effect of selenium against BRCA1-associated breast cancers. © Springer Science+Business Media B.V. 2010.

Shrestha A.,University of Oxford | Hamilton G.,Gray Institute for Radiation Oncology and Biology | O'Neill E.,Gray Institute for Radiation Oncology and Biology | Knapp S.,University of Oxford | Elkins J.M.,University of Oxford
Protein Expression and Purification | Year: 2012

Bacterial over-expression of kinases is often associated with high levels of auto-phosphorylation resulting in heterogeneous recombinant protein preparations or sometimes in insoluble protein. Here we present expression systems for nine kinases in Escherichia coli and, for the most heavily phosphorylated, the characterisation of factors affecting auto-phosphorylation. Experiments showed that the level of auto-phosphorylation was proportional to the rate of expression. Comparison of phosphorylation states following in vitro phosphorylation with phosphorylation states following expression in E. coli showed that the non-physiological 'hyper-phosphorylation' was occurring at sites that would require local unfolding to be accessible to a kinase active site. In contrast, auto-phosphorylation on unphosphorylated kinases that had been expressed in bacteria overexpressing λ-phosphatase was only observed on distinct exposed sites. Remarkably, the Ser/Thr kinase PLK4 auto-phosphorylated on a tyrosine residue (Tyr177) located in the activation segment. The results give support to a mechanism in which auto-phosphorylation occurs before or during protein folding. In addition, the expression systems and protocols presented will be a valuable resource to the research community. © 2011 Elsevier Inc. All rights reserved.

Brunner T.B.,Gray Institute for Radiation Oncology and Biology | Kunz-Schughart L.A.,TU Dresden | Grosse-Gehling P.,TU Dresden | Baumann M.,TU Dresden
Seminars in Radiation Oncology | Year: 2012

Cancer stem cell research is one of the most thriving and competitive areas in oncology research because it has the potential to dramatically affect clinical outcomes. Led by progress in hematology, cancer stem cell research has now provided evidence to play an important role for solid cancers as well. Because radiotherapy is only second to surgery in terms of its curative potency, it is very important for radiation oncologists to learn whether progress in cancer stem cell biology can enable them to exploit this knowledge to help cure more patients suffering from cancer. The present article gives an overview about the challenges of the cancer stem cell concept and highlights some important phenomena that are under intense investigation, such as phenotypic plasticity of stemness and impact and dynamics of microenvironmental niches. We discuss the potential and limitations of current experimental and theragnostic tools and end up with an agenda for future research as outlook for translational possibilities in the clinic. © 2012 Elsevier Inc.

Kiltie A.E.,Gray Institute for Radiation Oncology and Biology
Current Opinion in Genetics and Development | Year: 2010

Bladder cancer is the 5th commonest cancer and two major risk factors are smoking and occupational chemical exposure. There is also evidence of a genetic component to its aetiology. Candidate gene studies have mostly focused on genes involved in adduct metabolism and DNA repair, including a recent consortium-based meta-analysis. Recently, two genome-wide association studies in bladder cancer have been published and a third is awaited with interest. These first two studies have identified three SNPs of genome-wide significance, two located within the 8q24 'gene desert'. These SNPs are positioned near or within loci of genes potentially implicated in cancer predisposition, namely MYC, TP63 and PSCA, although the functional significance of this is as yet unclear. © 2010 Elsevier Ltd.

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