The Academic Department of Radiation Oncology is a joint initiative between the University of Manchester and the Christie Hospital NHS Trust, based at the Christie site.The objective of ADRO is to innovate technological advances in radiotherapy and molecular imaging for translation into clinical practice. ADRO is a multidisciplinary group which draws on expertise in physical sciences, imaging, radiobiology and clinical management. This collection contains items published from 2008 onwards

Recent Submissions

  • 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. (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. (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. (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. (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. (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.
  • 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. (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. (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. (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.
  • Optimization of the injected activity in dynamic 3D PET: a generalized approach using patient-specific NECs as demonstrated by a series of 15O-H2O scans.

    Walker, Mathew D; Matthews, Julian C; Asselin, Marie-Claude; Saleem, Azeem; Dickinson, Clare; Charnley, Natalie; Julyan, Peter J; Price, Patricia M; Jones, Terry; School of Cancer and Imaging Sciences, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom. (2009-01-30)
  • Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors.

    O'Connor, James P B; Naish, Josephine H; Parker, Geoff J M; Waterton, John C; Watson, Yvonne; Jayson, Gordon C; Buonaccorsi, Giovanni A; Cheung, Susan; Buckley, David L; McGrath, Deirdre M; West, Catharine M L; Davidson, Susan E; Roberts, Caleb; Mills, Samantha J; Mitchell, Claire L; Hope, Lynn; Ton, N Chan; Jackson, Alan; Imaging Science and Biomedical Engineering, University of Manchester, Manchester, United Kingdom. james.o' (2009-11-15)
    PURPOSE: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS: DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.
  • Assessment of bladder motion for clinical radiotherapy practice using cine-magnetic resonance imaging.

    McBain, Catherine A; Khoo, Vincent S; Buckley, David L; Sykes, Jonathan S; Green, Melanie M; Cowan, Richard A; Hutchinson, Charles E; Moore, Christopher J; Price, Patricia M; Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester, United Kingdom. (2009-11-01)
    PURPOSE: Organ motion is recognized as the principal source of inaccuracy in bladder radiotherapy (RT), but there is currently little information on intrafraction bladder motion. METHODS AND MATERIALS: We used cine-magnetic resonance imaging (cine-MRI) to study bladder motion relevant to intrafraction RT delivery. On two occasions, a 28 minute cine-MRI sequence was acquired from 10 bladder cancer patients and 5 control participants immediately after bladder emptying, after abstinence from drinking for the preceding hour. From the resulting cine sequences, bladder motion was subjectively assessed. To quantify bladder motion, the bladder was contoured in imaging volume sets at 0, 14, and 28 min to measure changes to bladder volumes, wall displacements, and center of gravity (COG) over time. RESULTS: The dominant source of bladder motion during imaging was bladder filling (up to 101% volume increase); rectal and small bowel movements were transient, with minimal impact. Bladder volume changes were similar for all participants. However for bladder cancer patients, wall displacements were larger (up to 58 mm), less symmetrical, and more variable compared with nondiseased control bladders. CONCLUSIONS: Significant and individualized intrafraction bladder wall displacements may occur during bladder RT delivery. This important source of inaccuracy should be incorporated into treatment planning and verification.
  • Strong association of the HLA-DP6 supertype with childhood leukaemia is due to a single allele, DPB1*0601.

    Taylor, G M; Hussain, A; Verhage, V; Thompson, P D; Fergusson, W D; Watkins, Gillian R; Lightfoot, T; Harrison, Christine J; Birch, Jillian M; Cancer Immunogenetics Group, School of Cancer and Imaging Sciences, University of Manchester, St Mary's Hospital, Manchester, UK. (2009-05)
    We previously reported that susceptibility to childhood B cell precursor ALL (BCP ALL) is associated with HLA-DPB1 alleles having glutamic acid (E) rather than lysine (K) in the P4 antigenic peptide-binding pocket. Clustering approximately 90% of DPB1 alleles into DPB69E (DP2, 6, 8) and DPB69K (DP1, 3, 4) supertypes revealed that DP2 and DP8 are associated with BCP ALL, but DP6 is also associated with non-BCP leukaemia. Here, we report that only one of seven alleles with the DP6 supertype (DPB1(*)0601) is associated with childhood leukaemia (leukaemia vs controls: odds ratio, 95% confidence interval [OR, CI]: 4.6, 2.0-10.4; corrected P=0.019), but not with childhood solid tumours or lymphomas. DPB1(*)0601 is also significantly associated with leukaemia subtypes, including BCP ALL, Pro-B ALL, T-ALL and AML. DPB1(*)0601 is significantly over-transmitted (76.9%) from parents to children with BCP ALL (OR; CI: 4.7; 1.01-22.2). Sequencing the coding region of DPB1(*)0601 revealed an exon 1-4 haplotype [T-DEAV-KIL-RVI] shared with DPB1(*)0301 and 0901, but no evidence of germline mutations in childhood leukaemia. These results suggest that the DPbeta0601 molecule may be functionally involved in childhood leukaemia. Analysis of peptide binding and T-cell activation by DPbeta0601-peptide complexes should help determine its role in childhood leukaemia causation.

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