• 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; et al. (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.
    • Real-time optical measurement of the dynamic body surface for use in guided radiotherapy.

      Price, Gareth J; Parkhurst, J M; Sharrock, Phillip J; Moore, Christopher J; Developing Technologies, Christie Medical Physics and Engineering, The Christie NHS Foundation Trust, Manchester, UK. Gareth.Price@physics.cr.man.ac.uk (2012-01-21)
      Optical measurements are increasingly used in radiotherapy. In this paper we present, in detail, the design and implementation of a multi-channel optical system optimized for fast, high spatial resolution, dynamic body surface measurement in guided therapy. We include all algorithmic modifications and calibration procedures required to create a robust, practical system for clinical use. Comprehensive static and dynamic phantom validation measurements in the radiotherapy treatment room show: conformance with simultaneously measured cone beam CT data to within 1 mm over 62% ± 8% of the surface and 2 mm over 90% ± 3%; agreement with the measured radius of a precision geometrical phantom to within 1 mm; and true real-time performance with image capture through to surface display at 23 Hz. An example patient dataset is additionally included, indicating similar performance in the clinic.
    • Addition of novel degenerate electrical waveform stimulation with photodynamic therapy significantly enhances its cytotoxic effect in keloid fibroblasts: first report of a potential combination therapy.

      Sebastian, A; Allan, Ernest; Allan, Donald; Colthurst, J; Bayat, A; Plastic & Reconstructive Surgery Research, School of Translational Medicine, Manchester Interdisciplinary Biocentre (MIB), The University of Manchester, UK. (2011-12)
      We recently reported use of photodynamic therapy (PDT) for treating keloid disease (KD). However, in view of high recurrence rates post any treatment modality, adjuvant therapies should be considered. Additionally, we previously demonstrated the effect of a novel electrical waveform, the degenerate wave (DW) on differential gene expression in keloid fibroblasts.
    • Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers.

      Harrington, K J; Billingham, L J; Brunner, T B; Burnet, N G; Chan, C S; Hoskin, P; Mackay, Ranald I; Maughan, T S; Macdougall, J; McKenna, W G; et al. (2011-08-23)
    • Brain inflammation is induced by co-morbidities and risk factors for stroke.

      Drake, C; Boutin, H; Jones, M S; Denes, A; McColl, B W; Selvarajah, J R; Hulme, S; Georgiou, R F; Hinz, R; Gerhard, A; et al. (2011-08)
      Chronic systemic inflammatory conditions, such as atherosclerosis, diabetes and obesity are associated with increased risk of stroke, which suggests that systemic inflammation may contribute to the development of stroke in humans. The hypothesis that systemic inflammation may induce brain pathology can be tested in animals, and this was the key objective of the present study. First, we assessed inflammatory changes in the brain in rodent models of chronic, systemic inflammation. PET imaging revealed increased microglia activation in the brain of JCR-LA (corpulent) rats, which develop atherosclerosis and obesity, compared to the control lean strain. Immunostaining against Iba1 confirmed reactive microgliosis in these animals. An atherogenic diet in apolipoprotein E knock-out (ApoE(-/-)) mice induced microglial activation in the brain parenchyma within 8 weeks and increased expression of vascular adhesion molecules. Focal lipid deposition and neuroinflammation in periventricular and cortical areas and profound recruitment of activated myeloid phagocytes, T cells and granulocytes into the choroid plexus were also observed. In a small, preliminary study, patients at risk of stroke (multiple risk factors for stroke, with chronically elevated C-reactive protein, but negative MRI for brain pathology) exhibited increased inflammation in the brain, as indicated by PET imaging. These findings show that brain inflammation occurs in animals, and tentatively in humans, harbouring risk factors for stroke associated with elevated systemic inflammation. Thus a "primed" inflammatory environment in the brain may exist in individuals at risk of stroke and this can be adequately recapitulated in appropriate co-morbid animal models.
    • The use of a realistic VMAT delivery emulator to optimize dynamic machine parameters for improved treatment efficiency.

      Boylan, Christopher J; Rowbottom, Carl G; Mackay, Ranald I; North Western Medical Physics, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. (2011-07-07)
      The delivery of volumetric modulated arc therapy (VMAT) requires the simultaneous movement of the linear accelerator gantry, multi-leaf collimators and jaws while the dose rate is varied. In this study, a VMAT delivery emulator was developed to accurately predict the characteristics of a given treatment plan, incorporating realistic parameters for gantry inertia and the variation in leaf speed with respect to gravity. The emulator was used to assess the impact of dynamic machine parameters on the delivery efficiency, using a set of prostate and head and neck VMAT plans. Initially, assuming a VMAT system with fixed dose rate bins, the allowable leaf and jaw speeds were increased and a significant improvement in treatment time and average dose rate was observed. The software was then adapted to simulate a VMAT system with continuously varying dose rate, and the increase in delivery efficiency was quantified, along with the impact of an increased leaf and jaw speed. Finally, a set of optimal dynamic machine parameters was derived assuming an idealized scenario in which the treatment is delivered in a single arc at constant maximum gantry speed.
    • Perfusion Estimated with Rapid Dynamic Contrast-Enhanced Magnetic Resonance Imaging Correlates Inversely with Vascular Endothelial Growth Factor Expression and Pimonidazole Staining in Head-and-Neck Cancer: A Pilot Study.

      Donaldson, Stephanie B; Betts, Guy N J; Bonington, Suzanne C; Homer, Jarrod J; Slevin, Nicholas J; Kershaw, Lucy E; Valentine, Helen R; West, Catharine M L; Buckley, David L; School of Cancer and Enabling Sciences, University of Manchester, Manchester, United Kindom; North Western Medical Physics, The Christie, Manchester, United Kingdom. (2011-05-04)
      PURPOSE: To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples taken during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined. RESULTS: Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining (r = -0.79, p = 0.03) and VEGF expression (r = -0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia (r = -0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF (r = 0.82, p = 0.02). CONCLUSIONS: Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression.
    • A national dosimetric audit of IMRT.

      Budgell, Geoff J; Berresford, Joe; Trainer, Michael; Bradshaw, Ellie; Sharpe, Peter; Williams, Peter C; North Western Medical Physics, The Christie NHS Foundation Trust, Manchester, UK. (2011-05)
      A dosimetric audit of IMRT has been carried out within the UK between June 2009 and March 2010 in order to provide an independent check of safe implementation and to identify problems in the modelling and delivery of IMRT.
    • 4D cone beam CT phase sorting using high frequency optical surface measurement during image guided radiotherapy.

      Price, Gareth J; Marchant, Thomas E; Parkhurst, James M; Sharrock, Phillip J; Whitfield, Gillian A; Moore, Christopher J; The Christie Hospital NHS Foundation Trust, Manchester (2011-03-16)
    • Bias in iterative reconstruction of low-statistics PET data: benefits of a resolution model.

      Walker, M D; Asselin, M-C; Julyan, Peter J; Feldmann, M; Talbot, P S; Jones, T; Matthews, J C; School of Cancer and Enabling Sciences, Wolfson Molecular Imaging Centre, MAHSC, The University of Manchester, Manchester, UK. (2011-02-21)
      Iterative image reconstruction methods such as ordered-subset expectation maximization (OSEM) are widely used in PET. Reconstructions via OSEM are however reported to be biased for low-count data. We investigated this and considered the impact for dynamic PET. Patient listmode data were acquired in [(11)C]DASB and [(15)O]H(2)O scans on the HRRT brain PET scanner. These data were subsampled to create many independent, low-count replicates. The data were reconstructed and the images from low-count data were compared to the high-count originals (from the same reconstruction method). This comparison enabled low-statistics bias to be calculated for the given reconstruction, as a function of the noise-equivalent counts (NEC). Two iterative reconstruction methods were tested, one with and one without an image-based resolution model (RM). Significant bias was observed when reconstructing data of low statistical quality, for both subsampled human and simulated data. For human data, this bias was substantially reduced by including a RM. For [(11)C]DASB the low-statistics bias in the caudate head at 1.7 M NEC (approx. 30 s) was -5.5% and -13% with and without RM, respectively. We predicted biases in the binding potential of -4% and -10%. For quantification of cerebral blood flow for the whole-brain grey- or white-matter, using [(15)O]H(2)O and the PET autoradiographic method, a low-statistics bias of <2.5% and <4% was predicted for reconstruction with and without the RM. The use of a resolution model reduces low-statistics bias and can hence be beneficial for quantitative dynamic PET.
    • 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.
    • New iterative cone beam CT reconstruction software: parameter optimisation and convergence study.

      Qiu, W; Tong, J R; Mitchell, C N; Marchant, Thomas E; Spencer, P; Moore, Christopher J; Soleimani, M; Department of Electronic and Electrical Engineering, University of Bath, Bath, BA2 7AY, UK. (2010-11)
      Cone beam computed tomography (CBCT) provides a volumetric image reconstruction from tomographic projection data. Image quality is the main concern for reconstruction in comparison to conventional CT. The reconstruction algorithm used is clearly important and should be carefully designed, developed and investigated before it can be applied clinically. The Multi-Instrument Data Analysis System (MIDAS) tomography software originally designed for geophysical applications has been modified to CBCT image reconstruction. In CBCT reconstruction algorithms, iterative methods offer the potential to generate high quality images and would be an advantage especially for down-sampling projection data. In this paper, studies of the CBCT iterative algorithms implemented in MIDAS are presented. Stability, convergence rate, quality of reconstructed image and edge recovery are suggested as the main criteria for monitoring reconstructive performance. Accordingly, the selection of relaxation parameter and number of iterations are studied in detail. Results are presented, where images are reconstructed from full and down-sampled cone beam CT projection data using iterative algorithms. Various iterative algorithms have been implemented and the best selection of the iteration number and relaxation parameters are investigated for ART. Optimal parameters are chosen where the errors in projected data as well as image errors are minimal.
    • Education and training for intensity-modulated radiotherapy in the UK.

      Routsis, D; Staffurth, J; Beardmore, C; Mackay, Ranald I; Oncology Centre, Addenbrooke's Hospital, Cambridge University Hospital NHS Trust, Cambridge, UK. donna.routsis@addenbrookes.nhs.uk (2010-10)
      A growing body of evidence as to the benefits of intensity-modulated radiotherapy (IMRT) has led to the recommendation for its adoption as a treatment option for cancer patients within the UK. Routine clinical implementation of this technology has been slow. One of the causal factors was identified as being the need to improve confidence by improving the understanding and technical skills for IMRT of clinical oncology staff. This report determines and describes the additional knowledge and skills required for IMRT practice for clinical oncologists, clinical scientists (radiotherapy physicists) and radiographers, derived from reviewing evidence from other nations' IMRT practices and adapting them to UK needs. This knowledge and skills specification can be used to inform IMRT educational curricula. Novel educational methods to maintain the required understanding and skills are also described.
    • The implementation of intensity-modulated radiotherapy in the UK.

      Williams, M V; Cooper, T; Mackay, Ranald I; Staffurth, J; Routsis, D; Burnet, N; Oncology Centre, Addenbrooke's Hospital, Cambridge University Hospital NHS Trust, Cambridge, UK. (2010-10)
    • UK guidelines for the safe delivery of intensity-modulated radiotherapy.

      Mackay, Ranald I; Staffurth, J; Poynter, A; Routsis, D; The Christie NHS Foundation Trust, Manchester, UK. ranald.mackay@physics.cr.man.ac.uk (2010-10)
      This paper outlines the guidelines for the development of intensity-modulated radiotherapy (IMRT) in the UK. The guidelines are designed to cover the complete implementation of IMRT, with guidelines in the following categories: commissioning, quality, clinical, audit, and training and education. These guidelines have been compiled by the Radiotherapy Development Board of the Royal College of Radiologists and will support the safe application of IMRT in the UK.
    • A VMAT planning solution for prostate patients using a commercial treatment planning system.

      Boylan, C J; Golby, C; Rowbottom, Carl G; North Western Medical Physics, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. hristopher.Boylan@physics.cr.man.ac.uk (2010-07-21)
      Volumetric modulated arc therapy (VMAT) is a rotational delivery technique which offers the potential of improved dose distributions and shorter treatment times when compared to fixed-beam intensity-modulated radiation therapy (IMRT). This note describes the use of an existing treatment planning system (Philips Pinnacle(3) v.8.0), supplemented by in-house software, to produce a single-arc VMAT prostate plan. While a number of planning systems for the Elekta VMAT platform are commercially available, the use of an in-house solution has allowed more detailed investigations of VMAT planning, as well as greater control over the optimization process. The solution presented here begins with a static step-and-shoot IMRT approach to provide initial segment shapes, which are then modified and sequenced into 60 equally spaced control points in a 360 degrees arc. Dose-volume histogram comparisons demonstrate that this VMAT planning method offers multiple dose level target coverage comparable to that from a standard IMRT approach. The VMAT plans also show superior sparing of critical structures such as the rectum and bladder. Delivery times are reduced with the VMAT method, and the results of dosimetric verification, resilience and repeatability tests indicate that the solution is robust.
    • Long-term outcomes of breast cancer in women aged 30 years or younger, based on family history, pathology and BRCA1/BRCA2/TP53 status.

      Evans, D Gareth R; Moran, Anthony; Hartley, Roger; Dawson, J; Bulman, B; Knox, F; Howell, Anthony; Lalloo, Fiona; Manchester Academic Health Science Centre, Genetic Medicine, St Mary's Hospital, Central Manchester Hospitals Foundation Trust, Manchester M13 9WL, UK. gareth.evans@cmft.nhs.uk (2010-03-30)
      BACKGROUND: There are relatively few articles addressing long-term follow-up in women with breast cancer at very young ages. METHODS: We have updated and extended our population-based analysis of breast cancer diagnosed at the age < or =30 years in North-west England to include an extra 15 patients with mutation testing in BRCA1, BRCA2 and TP53, with 115 of 288 consecutive cases being tested. Kaplan-Meier curves were generated to assess overall survival, contralateral breast cancer and other second primaries. RESULTS: Survival analysis of all 288 patients showed poor overall survival, although this improved from a 15-year survival of only 46% in those diagnosed between 1980 and 1989 to 58% in those diagnosed between 1990 and 1997 (P=0.05). Contralateral breast cancer rates were at a steady rate of 0.6 per 1000, although the rates in mutation carriers were approximately 2 per 1000. Altogether, 16 BRCA1, 9 BRCA2 and 6 TP53 mutations have now been found among the 115 cases on whom DNA analysis has been performed. BRCAPRO accurately predicted the number of carriers for BRCA1 and BRCA2 and was sensitive and specific at the 10 and 20% threshold, respectively. However, BRCAPRO did not seem to give any weight to DCIS, which accounted for two BRCA1 carriers and three TP53 carriers and overpredicted mutations at the high end of the spectrum, with only 6 of 11 (54%) with a >90% probability having identifiable BRCA1/2 mutations. INTERPRETATION: Rates of new primaries are predicted to some extent by mutation status. BRCAPRO is useful at determining those patients aged < or =30 years to be tested.
    • Assessing the effect of a contouring protocol on postprostatectomy radiotherapy clinical target volumes and interphysician variation.

      Mitchell, Darren M; Perry, Lesley A; Smith, Steve; Elliott, Tony; Wylie, James P; Cowan, Richard A; Livsey, Jacqueline E; Logue, John P; Department of Clinical Oncology, Christie Hospital, Manchester, United Kingdom. dmmitchell@doctors.org.uk (2009-11-15)
      PURPOSE: To compare postprostatectomy clinical target volume (CTV) delineation before and after the introduction of a contouring protocol and to investigate its effect on interphysician variability METHODS AND MATERIALS: Six site-specialized radiation oncologists independently delineated a CTV on the computed tomography (CT) scans of 3 patients who had received postprostatectomy radiotherapy. At least 3 weeks later this was repeated, but with the physicians adhering to the contouring protocol from the Medical Research Council's Radiotherapy and Androgen Deprivation In Combination After Local Surgery (RADICALS) trial. The volumes obtained before and after the protocol were compared and the effect of the protocol on interphysician variability assessed. RESULTS: An increase in mean CTV for all patients of 40.7 to 53.9 cm(3) was noted as a result of observing the protocol, with individual increases in the mean CTV of 65%, 15%, and 24% for Patients 1, 2, and 3 respectively. A reduction in interphysician variability was noted when the protocol was used. CONCLUSIONS: Substantial interphysician variation in target volume delineation for postprostatectomy radiotherapy exists, which can be reduced by the use of a contouring protocol. The RADICALS contouring protocol increases the target volumes when compared with those volumes typically applied at our center. The effect of treating larger volumes on the therapeutic ratio and resultant toxicity should be carefully monitored, particularly if the same dose-response as documented in radical prostate radiotherapy applies to the adjuvant and salvage setting. Prostate cancer, Postprostatectomy, Radiotherapy, Target volume.
    • 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.
    • 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.