• 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.
    • New look at mesoblastic nephroma.

      Marsden, Henry B; Newton, W A; From the *Children's Tumour Registry, Department of Epidemiology and Social Research, Christie Hospital and holt Radium Institute, Manchester (1986-05)
      Thirty eight mesoblastic nephromas were studied. The age range of the patients was between the neonatal period and 18 months. The presence of cartilage is consistent with a mesoblastic origin, but squamous epithelium was a feature in three tumours. Particular attention was given to the adjacent renal tissue in which various histological features were noted: vacuolated and dysplastic tubules; cysts; and subcapsular epithelial tumourlets. The findings had aspects in common with both dysplastic kidneys and nephroblastoma. Classification of the tumours as normocellular and hypercellular was attempted, but there was considerable overlap. The behaviour of the tumour was good in all cases, although follow up was relatively short on some patients, and deaths from non-neoplastic causes occurred.
    • A new method for the high-precision assessment of tumor changes in response to treatment.

      Tar, P; Thacker, N; Babur, M; Watson, Y; Cheung, S; Little, R; Gieling, R; Williams, K; O'Connor, James P B; Division of Informatics, Imaging and Data Science, University of Manchester, Manchester, UK (2018-03-14)
      Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both normal development and also in response to treatment. The large variations observed in control group tumors can obscure detection of significant therapeutic effects due to the ambiguity in attributing causes of change. This can hinder development of effective therapies due to limitations in experimental design, rather than due to therapeutic failure. An improved method to model biological variation and heterogeneity in imaging signals is described. Specifically, Linear Poisson modelling (LPM) evaluates changes in apparent diffusion co-efficient (ADC) before and 72 hours after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes are compared to those attainable using a conventional t-test analysis on basic ADC distribution parameters.
    • A new method to reconstruct in 3D the emission position of the prompt gamma rays following proton beam irradiation

      Panaino, Costanza MV; Mackay, Ranald I; Kirkby, Karen J; Taylor, Michael J; Division of Cancer Sciences, University of Manchester, M13 9PL (2019)
      A new technique for range verification in proton beam therapy has been developed. It is based on the detection of the prompt ? rays that are emitted naturally during the delivery of the treatment. A spectrometer comprising 16 LaBr3(Ce) detectors in a symmetrical configuration is employed to record the prompt ? rays emitted along the proton path. An algorithm has been developed that takes as inputs the LaBr3(Ce) detector signals and reconstructs the maximum ?-ray intensity peak position, in full 3 dimensions. For a spectrometer radius of 8?cm, which could accommodate a paediatric head and neck case, the prompt ?-ray origin can be determined from the width of the detected peak with a ? of 4.17?mm for a 180?MeV proton beam impinging a water phantom. For spectrometer radii of 15 and 25?cm to accommodate larger volumes this value increases to 5.65 and 6.36?mm. For a 8?cm radius, with a 5 and 10?mm undershoot, the ? is 4.31 and 5.47?mm. These uncertainties are comparable to the range uncertainties incorporated in treatment planning. This work represents the first step towards a new accurate, real-time, 3D range verification device for spot-scanning proton beam therapy.
    • A new missense mutation in the growth hormone-releasing hormone receptor gene in familial isolated GH deficiency.

      Carakushansky, Mauri; Whatmore, Andrew J; Clayton, Peter E; Shalet, Stephen M; Gleeson, Helena K; Price, David A; Levine, Michael A; Salvatori, Roberto; Divisions of Pediatric Endocrinology and Endocrinology and The Ilyssa Center for Molecular and Cellular Endocrinology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. (2003-01)
      OBJECTIVE: Mutations in the GH-releasing hormone (GHRH) receptor (GHRHR) gene (GHRHR) cause autosomal recessive familial isolated GH deficiency (IGHD). We searched for GHRHR mutations in two siblings with IGHD type IB and a history of parental consanguinity. DESIGN: We analyzed peripheral genomic DNA of an index patient. After identifying a novel mutation in the GHRHR, we performed functional studies in order to confirm that the mutation causes receptor malfunction. METHODS: The entire GHRHR was analyzed in the index case by denaturing gradient gel electrophoresis. Abnormally migrating bands were isolated and sequenced. The mutated area was then sequenced in all family members whose DNA was available. The newly found mutation was inserted into a GHRHR cDNA. Wild-type and mutant cDNAs were expressed into CHO cells and the cyclic AMP (cAMP) response to GHRH was measured. In order to determine whether the mutant receptor was properly expressed on the cell membrane surface, CHO cells were transfected with wild-type or mutant GHRHR cDNA containing a FLAG epitope tag in the extracellular N-terminus. RESULTS: Both patients were homozygous for a new missense mutation in codon 176, corresponding to the second transmembrane domain of the receptor protein that replaces alanine with valine (A176V). The mother and three unaffected siblings were heterozygous for the mutation; DNA from the father was not available. Cells expressing the A176V receptor had a significantly reduced cAMP response to GHRH, despite appropriate expression on the cell surface. CONCLUSIONS: We describe two siblings with IGHD due to a new mutation in the GHRHR that disrupts GHRH signaling and leads to GHRH resistance.
    • A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients.

      Rosso, Lula; Brock, Cathryn S; Gallo, James M; Saleem, Azeem; Price, Patricia M; Turkheimer, Federico E; Aboagye, E O; Clinical Sciences Centre, Imperial College, Faculty of Medicine, Hammersmith Hospital Campus, London, UK. (2009-01-01)
      Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.
    • New molecular and immunotherapeutic approaches in biliary cancer.

      Goldstein, D; Lemech, C; Valle, Juan W; Department of Medical Oncology at the Nelune Cancer Centre, Prince of Wales Hospital, Sydney, New South Wales (2017)
      Biliary tract carcinoma is a collective term for a group of rare gastrointestinal cancers. This overview outlines the key pathways and specialised therapeutics in biliary cancer and the emerging role of immunotherapy by highlighting the rationale and selected examples of studies in each area.
    • A new nodal delineation protocol for upper third oesophageal cancers in the SCOPE 2 trial

      Nicholas, O.; Radhakrishna, Ganesh; Banner, R.; Mukherjee, S.; Hawkins, M.; Crosby, T; Gwynne, S. H.; Swansea Bay University Health Board, South West Wales Cancer Centre, Swansea, (2020)
      Purpose or Objective SCOPE 2 is a randomised Phase II/III trial studying radiotherapy dose escalation and positron emission tomography (PET) response in patients with oesophageal cancer treated with definitive chemoradiation. Patients with upper third oesophageal tumours >15cm ab oral with supraclavicular fossa (SCF) nodal involvement (N+ by TNM criteria) are eligible for participation, providing total contiguous disease length is <10cm. The current radiotherapy guidance does not specifically cover the scenario of involved SCF nodes. There are no widely available delineation protocols for this group of patients. Therefore, we developed a new protocol to provide guidance for clinicians and to ensure consistency of nodal outlining within the trial. Material and Methods A literature search was performed to review existing evidence for elective nodal irradiation (ELNI) and upper third oesophagus nodal anatomy. Existing nodal outlining atlases were reviewed, adapted and incorporated into existing SCOPE 2 radiotherapy guidance to produce the new protocol. Results There is no clinical evidence to recommend ELNI of the SCF in node negative patients, so this guidance only applies to patients with positive nodes in the SCF. The lymphatics of the proximal third oesophagus drain into bilateral deep cervical nodes that are contained within the SCF (2). Therefore, we have recommended that patients with positive SCF nodes receive irradiation of whole ipsilateral SCF and contralateral SCF. There is no randomisation to the dose escalation arm of GTVn in SCOPE 2 so CTVscf is treated to 5000cGy in 25#. Conclusion This new delineation protocol provides a standardised approach that can be adopted by the wider radiotherapy community. Using this protocol within the context of a randomised trial allows for assessment of loco-regional control rates, survival data and monitors for unexpected toxicity. Trial clinical outcome data will inform further versions of the delineation protocol.
    • New options for the medical treatment of Cushing's syndrome.

      Trainer, Peter J; Department of Endocrinology, The Christie NHS Foundation Trust, Manchester, United Kingdom. (2013-03)
      A number of drugs have been advocated for the medical management of Cushing's syndrome but few have gained widespread acceptance. The most reliably effective agents are metyrapone and ketoconazole as monotherapy, or in combination. Cabergoline may be of value in a minority of patients but pasireotide is a more reliable and effective agent that lowers cortisol secretion in the great majority of patients, although only normalises UFC in a minority. The potential for combination of an agent that blocks adrenal steroidogenesis with inhibition of ACTH secretion by pasireotide needs to be explored.
    • New perspectives in lung cancer. 2. Growth factors and lung cancer.

      Woll, Penella J; Department of Medical Oncology, Christie Hospital, Manchester. (1991-12)
    • New perspectives in lung cancer. 4. Haematopoietic growth factors and lung cancer treatment.

      Thatcher, Nick; Department of Medical Oncology, Christie Hospital and Holt Radium Institute, Manchester. (1992-02)
    • A new ProTide, NUC-1031, combined with cisplatin for the first-line treatment of advanced biliary tract cancer (ABC-08)

      McNamara, Mairead G; Bridgewater, J; Palmer, D; Wasan, H; Ryder, W David J; Gnanaranjan, C; Ghazaly, E; Evans, T; Valle, Juan W; Medical Oncology, The Christie NHS Foundation Trust, Manchester (2018)
    • New radiotherapy approaches in locally advanced non-small cell lung cancer.

      Christodoulou, M; Bayman, Neil A; McCloskey, Paula; Rowbottom, Carl G; Faivre-Finn, Corinne; The University of Manchester, Oxford Road, Greater Manchester, United Kingdom (2014-02)
      Radiotherapy plays a major role in the treatment of patients with locally advanced non-small cell lung cancer (NSCLC), particularly since most patients are not suitable for surgery due to the extent of their disease, advanced age and multiple co-morbidities. Despite advances in local and systemic therapies local control and survival remain poor and there is a sense that a therapeutic plateau has been reached with conventional approaches. Strategies for the intensification of radiotherapy such as dose escalation have shown encouraging results in phase I-II trials, but the outcome of the phase III Radiation Therapy Oncology Group 0617 trial was surprisingly disappointing. Hyperfractionated and/or accelerated fractionating schedules have demonstrated superior survival compared to conventional fractionation at the expense of greater oesophageal toxicity. Modern radiotherapy techniques such as the integration of 4-dimensional computed tomography for planning, intensity modulated radiotherapy and image-guided radiotherapy have substantially enhanced the accuracy of the radiotherapy delivery through improved target conformality and incorporation of tumour respiratory motion. A number of studies are evaluating personalised radiation treatment including the concept of isotoxic radiotherapy and the boosting of the primary tumour based on functional imaging. Proton beam therapy is currently under investigation in locally advanced NSCLC. These approaches, either alone or in combination could potentially allow for further dose escalation and improvement of the therapeutic ratio and survival for patients with NSCLC.
    • New research findings on clinical benefits of bisphosphonates in patients with advanced prostate cancer

      Clarke, Noel W; Christie Hospital, Department of Surgery, Wilmslow Road, Manchester, M20 4BX, United Kingdom (2006)
    • A new step-wedge for the volumetric measurement of mammographic density

      Diffey, Jennifer; Hufton, Alan P; Astley, Susan; North Western Medical Physics, Christie Hospital, Withington, Manchester M20 4BX (2006)
    • New strategies for the treatment of chronic myeloid leukemia.

      Dexter, T Michael; Chang, James; Department of Experimental Haematology, Paterson Institute for Cancer Research (1994-08-01)
    • A new sustained-release preparation of human growth hormone and its pharmacokinetic, pharmacodynamic and safety profile.

      Jostel, Andreas; Mukherjee, Annice; Alenfall, Jan; Smethurst, Linda E; Shalet, Stephen M; Department of Endocrinology, Christie Hospital, Manchester, UK. andreas.jostel@christie-tr.nwest.nhs.uk (2005-05)
      OBJECTIVE: Adult GH replacement is currently given by daily subcutaneous (sc) injections. Recently, sustained-release (SR) preparations of GH have been developed, the preparations being characterized by a dominant early release, resulting in supraphysiological early GH peaks, and a rapid decline thereafter. We present data on a new SR GH preparation. DESIGN: Phase I/II study of hGH-Biosphere(R) (SkyePharma AB, Malmo, Sweden), a new SR preparation of recombinant human GH in amylopectin microspheres coated with polylactide-coglycolide. PATIENTS: Eight adults with severe, untreated GH deficiency (stimulated GH peaks between < 1 and 1.7 microg/l), aged 36.1 years (range 22-49 years) in good general health. MEASUREMENTS: Pharmacokinetic (PK), pharmacodynamic (PD) and safety data over a period of 28 days. RESULTS: The systemic and local tolerability of the drug was satisfactory, and no serious adverse events occurred. PK analysis showed a smaller early serum hGH peak followed by a broad sustained second peak of hGH (C(max) 1.20 microg/l at 7.2 days), and hGH levels were maintained above baseline for at least 14 days. The mean GH level never exceeded 1.1 microg/l, making the GH fluctuations comparable to continuous sc infusion. Resultant IGF-I concentrations were characterized by sustained elevation at a level near C(max) of 103 microg/l (at t(max) of 9.7 days), equal to an SD score of +0.8. IGF-I generation per administered GH was more efficient compared with reports of other SR preparations. CONCLUSION: hGH-Biosphere(R) is a well-tolerated SR GH preparation with superior efficacy in achieving target IGF-I levels without causing supraphysiological GH concentrations. Our data suggest the suitability of this preparation for longer-term trials in adults with injection frequencies of no more than once every 2-3 weeks.
    • A new X-linked mental retardation (XLMR) syndrome with late-onset primary testicular failure, short stature and microcephaly maps to Xq25-q26

      Cilliers, Deirdre D; Parveen, Rahat; Clayton, Peter E; Cairns, Stephen A; Clarke, Sheila; Shalet, Stephen M; Black, G C; Newman, William G; Clayton-Smith, Jill; Academic Department of Medical Genetics and Regional Genetic Services, St Mary's Hospital, University of Manchester, Manchester, UK. deirdre.cilliers@icr.ac.uk (2007-01-07)
      X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25-Xq27 encompassing 13.7Mb with a maximum LOD score of 1.1 for marker DXS8038 at theta=0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome.
    • Next generation medical therapy for Cushing's Syndrome-can we measure a benefit?

      Trainer, Peter J; The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom (2014-04)
    • A next generation sequencing (NGS) RNA-scan multiplex panel (QIAseq) to identify gene-rearranged non-small cell lung cancer

      Tay, Rebecca; Huang, S; Carter, Mathew; Wallace, A; Blackhall, Fiona H; Medical Oncology, The Christie NHS Foundation Trust, Manchester/GB (2018)