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  • The meaning, measurement and modification of hypoxia in the laboratory and the clinic.

    Hammond, E M; Asselin, Marie-Claude; Forster, D; O'Connor, James P B; Senra, J M; Williams, K J; The Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, UK. (2014-05)
    Hypoxia was identified as a microenvironmental component of solid tumours over 60 years ago and was immediately recognised as a potential barrier to therapy through the reliance of radiotherapy on oxygen to elicit maximal cytotoxicity. Over the last two decades both clinical and experimental studies have markedly enhanced our understanding of how hypoxia influences cellular behaviour and therapy response. Furthermore, they have confirmed early assumptions that low oxygenation status in tumours is an exploitable target in cancer therapy. Generally such approaches will be more beneficial to patients with hypoxic tumours, necessitating the use of biomarkers that reflect oxygenation status. Tissue biomarkers have shown utility in many studies. Further significant advances have been made in the non-invasive measurement of tumour hypoxia with positron emission tomography, magnetic resonance imaging and other imaging modalities. Here, we describe the complexities of defining and measuring tumour hypoxia and highlight the therapeutic approaches to combat it.
  • Quantifying heterogeneity in human tumours using MRI and PET.

    Asselin, Marie-Claude; O'Connor, James P B; Boellaard, R; Thacker, Neil A; Jackson, Alan; Wolfson Molecular Imaging Centre, University of Manchester, UK. (2012-03)
    Most tumours, even those of the same histological type and grade, demonstrate considerable biological heterogeneity. Variations in genomic subtype, growth factor expression and local microenvironmental factors can result in regional variations within individual tumours. For example, localised variations in tumour cell proliferation, cell death, metabolic activity and vascular structure will be accompanied by variations in oxygenation status, pH and drug delivery that may directly affect therapeutic response. Documenting and quantifying regional heterogeneity within the tumour requires histological or imaging techniques. There is increasing evidence that quantitative imaging biomarkers can be used in vivo to provide important, reproducible and repeatable estimates of tumoural heterogeneity. In this article we review the imaging methods available to provide appropriate biomarkers of tumour structure and function. We also discuss the significant technical issues involved in the quantitative estimation of heterogeneity and the range of descriptive metrics that can be derived. Finally, we have reviewed the existing clinical evidence that heterogeneity metrics provide additional useful information in drug discovery and development and in clinical practice.
  • Positron emission tomography imaging approaches for external beam radiation therapies: current status and future developments.

    Price, Patricia M; Green, Melanie M; Department of Academic Radiation Oncology, The University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, UK. pprice@imperial.ac.uk (2011-12)
    In an era in which it is possible to deliver radiation with high precision, there is a heightened need for enhanced imaging capabilities to improve tumour localisation for diagnostic, planning and delivery purposes. This is necessary to increase the accuracy and overall efficacy of all types of external beam radiotherapy (RT), including particle therapies. Positron emission tomography (PET) has the potential to fulfil this need by imaging fundamental aspects of tumour biology. The key areas in which PET may support the RT process include improving disease diagnosis and staging; assisting tumour volume delineation; defining tumour phenotype or biological tumour volume; assessment of treatment response; and in-beam monitoring of radiation dosimetry. The role of PET and its current developmental status in these key areas are overviewed in this review, highlighting the advantages and drawbacks.
  • The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397).

    Barnett, G C; De Meerleer, G; Gulliford, S L; Sydes, M R; Elliott, Rebecca M; Dearnaley, D P; University of Cambridge, Department of Oncology, Oncology Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK. (2011-11)
    A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate.
  • Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.

    Ho, Kean F; Marchant, Thomas E; Moore, Christopher J; Webster, Gareth J; Rowbottom, Carl G; Pennington, Hazel; Lee, Lip W; Yap, Beng K; Sykes, Andrew J; Slevin, Nicholas J; Academic Radiation Oncology, The Christie NHS Foundation Trust, Manchester, UK. hokeanfatt@hotmail.com (2012-03-01)
    Parotid-sparing head-and-neck intensity-modulated radiotherapy (IMRT) can reduce long-term xerostomia. However, patients frequently experience weight loss and tumor shrinkage during treatment. We evaluate the use of kilovoltage (kV) cone beam computed tomography (CBCT) for dose monitoring and examine if the dosimetric impact of such changes on the parotid and critical neural structures warrants replanning during treatment.
  • Biodistribution, pharmacokinetics and metabolism of interleukin-1 receptor antagonist (IL-1RA) using [¹⁸F]-IL1RA and PET imaging in rats.

    Cawthorne, Christopher; Prenant, C; Smigova, A; Julyan, Peter J; Maroy, R; Herholz, K; Rothwell, N; Boutin, H; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK. (2011-02)
    Positron emission tomography (PET) has the potential to improve our understanding of the preclinical pharmacokinetics and metabolism of therapeutic agents, and is easily translated to clinical studies in humans. However, studies involving proteins radiolabelled with clinically relevant PET isotopes are currently limited. Here we illustrate the potential of PET imaging in a preclinical study of the biodistribution and metabolism of ¹⁸F-labelled IL-1 receptor antagonist ([¹⁸F]IL-1RA) using a novel [¹⁸F]-radiolabelling technique.
  • Mitochondrial DNA mutations in head and neck cancer are infrequent and lack prognostic utility.

    Challen, C; Brown, H; Cai, C; Betts, Guy N J; Paterson, I; Sloan, P; West, Catharine M L; Birch-Machin, M; Robinson, M; Centre for Oral Health Research, School of Dental Sciences, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4BW, UK (2011)
  • Exon-array profiling unlocks clinically and biologically relevant gene signatures from formalin-fixed paraffin-embedded tumour samples.

    Hall, J S; Leong, Hui Sun; Armenoult, L S C; Newton, G E; Valentine, Helen R; Irlam, Joely J; Möller-Levet, Carla S; Sikand, Kanwal A; Pepper, Stuart D; Miller, Crispin J; West, Catharine M L; Translational Radiobiology Group, School of Cancer and Enabling Sciences, Manchester Academic Health Science Centre, The University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2011-03-15)
    Degradation and chemical modification of RNA in formalin-fixed paraffin-embedded (FFPE) samples hamper their use in expression profiling studies. This study aimed to show that useful information can be obtained by Exon-array profiling archival FFPE tumour samples.
  • The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis.

    Gee, H E; Buffa, F M; Camps, C; Ramachandran, A; Leek, R; Taylor, M; Patil, M; Sheldon, H; Betts, Guy N J; Homer, J; West, Catharine M L; Ragoussis, J; Harris, A L; Molecular Oncology Laboratories, Department of Oncology, University of Oxford, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK. (2011-03-29)
    To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer.
  • Radiation and the genome: from risks to opportunities for therapeutic exploitation.

    Robson, T; West, Catharine M L; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. T.Robson@qub.ac.uk (2010-08)
    On 1 December 2009, the Radiation and Cancer Biology Committee of the British Institute of Radiology (BIR) held a one-day conference on the theme of radiation and the genome. Talks covered genomic instability (its importance for radiation-induced carcinogenesis and potential for exploitation in the development of novel chemoradiotherapy combinations) and the prospects of exploiting knowledge of the genome to understand how individual genetic variation can impact on a patient's likelihood of developing toxicity following radiotherapy. The meeting also provided an overview of stem cell biology and its relevance for radiotherapy in terms of both tumour (somatic) and normal tissue (germline) sensitivity to radiation. Moreover, the possibility of manipulating stem cells to reduce radiation-induced normal tissue damage was considered.
  • Use of multiple biological markers in radiotherapy-treated head and neck cancer.

    Silva, Priyamal; Slevin, Nicholas J; Sloan, Philip; Valentine, Helen R; Ryder, W David J; Price, Patricia M; West, Catharine M L; Homer, Jarrod J; School of Cancer & Enabling Sciences, The University of Manchester, Manchester, UK. (2010-06)
    OBJECTIVE: Management of patients with head and neck squamous cell carcinoma is often based on clinical parameters, with little appreciation of the underlying tumour biology. Single biological marker studies fail to acknowledge the complexity of these tumours. Our aim was to define a profile of biological markers associated with outcome. DESIGN: This retrospective study involved consecutive patients with oropharyngeal squamous cell carcinoma treated with primary radiotherapy between 1996 and 2001. Pre-treatment biopsies were used to study the immunohistochemical expression of nine biological markers. Markers were chosen to reflect biologically relevant pathways. RESULTS: Following analysis of nine markers, a profile of two markers was derived (carbonic anhydrase 9 and major vault protein), the co-expression of which conferred a significantly poor probability of locoregional control. The prognostic effect of these biomarkers in combination was greater than their effect individually. CONCLUSION: Biomarker profiles can be established which highlight large differences in locoregional control. Identifying tumours that express both carbonic anhydrase 9 and major vault protein may facilitate patient selection for more aggressive treatment.
  • The hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) controls metastatic disease when used as an adjuvant to radiotherapy.

    Lunt, S; Cawthorne, Christopher; Ali, M; Telfer, B; Babur, M; Smigova, A; Julyan, Peter J; Price, Patricia M; Stratford, I; Bloomer, W; Papadopoulou, M; Williams, K; School of Pharmacy and Pharmaceutical Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. (2010-07-13)
    BACKGROUND: Metastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth. METHODS: The NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm(3)) were irradiated with 25 Gy (single fraction) to control primary growth. Equitoxic drug treatments (NLCQ-1 (10 mg kg(-1)) once daily; RB6145 (75 mg kg(-1)) and tirapazamine (13 mg kg(-1)) twice daily) were administered 3-6 days post-radiotherapy when hypoxic cells were evident in lung micrometastases. Mice were culled when 50% of controls exhibited detrimental signs of lung metastases. RESULTS: In total, 95% of control mice presented with lung disease. This was significantly reduced by NLCQ-1 (33%; P=0.0002) and RB6145 (60%; P=0.02). Semi-quantitative grading of lung disease revealed a significant improvement with all treatments, with NLCQ-1 proving most efficacious (median grades: control, 4; NLCQ, 0 (P<0.0001); RB6145, 1 (P<0.001), tirapazamine, 3 (P=0.007)). Positron emission tomography (PET) was evaluated as a non-invasive means of assessing metastatic development. Primary and metastatic KHT tumours showed robust uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG). Metastatic burden discernable by [(18)F]FDG PET correlated well with macroscopic and histological lung analysis. CONCLUSION: The hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.
  • Radiolabeling with fluorine-18 of a protein, interleukin-1 receptor antagonist.

    Prenant, C; Cawthorne, Christopher; Fairclough, M; Rothwell, N; Boutin, H; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK. cprenant@cyclopharma.fr (2010-09)
    IL-1RA is a naturally occurring antagonist of the pro-inflammatory cytokine interleukin-1 (IL-1) with high therapeutic promise, but its pharmacokinetic remains poorly documented. In this report, we describe the radiolabeling of recombinant human interleukin-1 receptor antagonist (rhIL-1RA) with fluorine-18 to allow pharmacokinetic studies by positron emission tomography (PET). rhIL-1RA was labeled randomly by reductive alkylation of free amino groups (the epsilon-amino group of lysine residues or amino-terminal residues) using [(18)F]fluoroacetaldehyde under mild reaction conditions. Radiosyntheses used a remotely controlled experimental rig within 100min and the radiochemical yield was in the range 7.1-24.2% (decay corrected, based on seventeen syntheses). We showed that the produced [(18)F]fluoroethyl-rhIL-1ra retained binding specificity by conducting an assay on rat brain sections, allowing its pharmakokinetic study using PET.
  • Radiotherapy in the management of unresectable locally advanced pancreatic cancer: a survey of the current UK practice of clinical oncologists.

    Saleem, Azeem; Jackson, A; Mukherjee, S; Stones, N; Crosby, T; Tait, D; Price, Patricia M; University of Manchester Academic Radiation Oncology, The Christie NHS Foundation Trust, Manchester, UK. azeem.saleem@manchester.ac.uk (2010-05)
    A survey was conducted by the Academic Clinical Oncology and Radiobiology Research Network (ACORRN) to evaluate current radiotherapy practice and to inform future research needs in patients with locally advanced pancreatic cancer. A clear need for a co-ordinated multicentre approach, given the limited number of patients who may qualify for such UK trials, was identified. Such trials should incorporate evidence-based treatment protocols and appropriate quality assurance procedures to ensure delivery of the highest standards of radiation-based therapy within, and without, clinical trials.
  • Antimigratory and antimetastatic effect of heparin-derived 4-18 unit oligosaccharides in a preclinical human melanoma metastasis model.

    Kenessey, István; Simon, Erika; Futosi, Krisztina; Bereczky, Bíborka; Kiss, Andrea; Erdödi, Ferenc; Gallagher, John T; Tímár, József; Tóvári, József; Department of Tumor Progression, National Institute of Oncology, Budapest, Hungary. (2009-12)
    Heparin and its derivatives have been shown to inhibit angiogenesis and metastasis formation. Accordingly, we investigated the effect of heparin fragments containing 4 to 22 monomers on human melanoma cell proliferation, migration and invasion in vitro as well as on the in vivo metastatic potential in a SCID mouse model. Only oligosaccharide dp18 had significant inhibitory effect on cell proliferation. In contrast, cell migration was inhibited by all oligosaccharides studied except dp8 and dp22. Anti-CD44v3 antibody stimulated cell migration and invasion, and this effect could be attenuated by oligosaccharides dp4 and dp18. These fragments also inhibited the catalytic activity of myosin light chain phosphatase as well. Moreover, oligosaccharides dp4 and dp18 reduced the number of lung colonies formed in SCID mice intravenously injected with human melanoma cells, while dp22 proved to be ineffective in this respect. These studies revealed that fragments of heparin have an antimigratory and antimetastatic potential. These fragments lack the haemostatic effect of heparin, suggesting that they are potential specific antimetastatic agents in anticancer therapy.
  • An efficient synthetic strategy for obtaining 4-methoxy carbon isotope labeled combretastatin A-4 phosphate and other Z-combretastatins.

    Pettit, George R; Minardi, Mathew D; Hogan, Fiona; Price, Patricia M; Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA. bpettit@asu.edu (2010-03-26)
    Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [(11)C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [(11)C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.
  • Point: why choose pulsed-dose-rate brachytherapy for treating gynecologic cancers?

    Davidson, Susan E; Hendry, Jolyon H; West, Catharine M L; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. Susan.Davidson@christie.nhs.uk (2010-08-09)
  • An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.

    Price, Gareth J; Sharrock, Phillip J; Marchant, Thomas E; Parkhurst, J M; Burton, D; Jain, Pooja; Price, Patricia M; Moore, Christopher J; North Western Medical Physics, The Christie NHS Foundation Trust, Manchester, UK. Gareth.Price@physics.cr.man.ac.uk (2009-11-07)
    Patient motion is an important factor affecting the quality of external beam radiotherapy in breast patients. We analyse the motion of a dense set of surface points on breast patients throughout their treatment schedule to assess the magnitude and stability of motion, in particular, with respect to breast volume. We use an optical sensor to measure the surface motion of 13 breast cancer patients. Patients were divided into two cohorts dependent upon breast volume. Measurements were made during radiotherapy treatment beam delivery for an average of 12 fractions per patient (total 158 datasets). The motion of each surface point is parameterized in terms of its period, amplitude and relative phase. Inter-comparison of the motion parameters across treatment schedules and between patients is made through the creation of corresponding regions on the breast surfaces. The motion period is spatially uniform and is similar in both patient groups (mean 4 s), with the small volume cohort exhibiting greater inter-fraction period variability. The mean motion amplitude is also similar in both groups with a range between 2 mm and 4 mm and an inter-fraction variability generally less than 1 mm. There is a phase lag of up to 0.4 s across the breast, led by the sternum. Breast patient motion is reasonably stable between and during treatment fractions, with the large volume cohort exhibiting greater repeatability than the small volume one.
  • Adding more content to screening: reactivation of FOXO as a therapeutic strategy.

    Zanella, Fabian; Carnero, Amancio; Experimental Therapeutics Programme, Spanish National Cancer Research Centre, Madrid, Spain. (2009-10)
    The discovery of novel targets that can be pharmacologically exploited to lead to a better disease outcome has long been an aim of biomedical research. At present, the technology and robotisation available have pushed the search for novel molecules to a high-throughput screening (HTS) context, making it possible to screen several hundreds of compounds or genes in a single day. High-content screenings (HCS) have added a refined complexity to the screening processes, as the information drawn from an image- based assay is more complete than the monoparametric readouts obtained in classical HTS assays. Here, we review the development of HCS platforms to identify molecules influencing FOXO nuclear relocation and activation as pharmacological targets, their applicability and the future directions of the screening field.

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