Publications
310 results found
Shah I, Jin A, Wilson HCP, et al., 2015, Novel Computed Tomography-based Metric Reliably Estimates bone Strength, Offering Potentially Meaningful Enhancement in Clinical Fracture Risk Prediction, European Journal of Medicine, Vol: Vol. 10
Wilson HCP, Shah I, Abel P, et al., 2015, Re: Overdiagnosis of bone fragility in the quest to prevent hip fracture, BMJ, Vol: 2015; 350
Wilson H, Shah I, Abel P, et al., 2015, Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture, Central European Journal of Urology, Vol: 68, Pages: 165-168
Rice L, Harris S, Green MML, et al., 2015, Deep inspiration breath-hold (DIBH) technique applied in right breastradiotherapy to minimize liver radiation, British Journal of Radiology, Vol: Case Rep 2015; 2:20150038
Price P BRD, 2014, Ultra Staging to Unmask the Prescribing of Adjuvant Therapy in Cancer Patients: The Future Opportunity to Image Micrometastases Using Total-Body 18F-FDG PET Scanning, Journal of Nuclear Medicine
Shah S, Abel P, Duong T, et al., 2014, Parenteral oestrogen: Effective and safer than both oral oestrogen and contemporary androgen deprivation therapy for prostate cancer?, Scandinavian Journal of Urology, Vol: 2014 Early Online 1-2
Rembielak AI, Jain P, Jackson AS, et al., 2014, Phase II Trial of Cetuximab and Conformal Radiotherapy Only in Locally Advanced Pancreatic Cancer (PACER) with Concurrent Tissue Sampling Feasibility Study. press., Translational Oncology
Whitfield GA, Price P, Price GJ, et al., 2013, Automated delineation of radiotherapy volumes: are we going in the right direction?, Br J Radiol, Vol: 86, ISSN: 1748-880X
Rapid and accurate delineation of target volumes and multiple organs at risk, within the enduring International Commission on Radiation Units and Measurement framework, is now hugely important in radiotherapy, owing to the rapid proliferation of intensity-modulated radiotherapy and the advent of four-dimensional image-guided adaption. Nevertheless, delineation is still generally clinically performed with little if any machine assistance, even though it is both time-consuming and prone to interobserver variation. Currently available segmentation tools include those based on image greyscale interrogation, statistical shape modelling and body atlas-based methods. However, all too often these are not able to match the accuracy of the expert clinician, which remains the universally acknowledged gold standard. In this article we suggest that current methods are fundamentally limited by their lack of ability to incorporate essential human clinical decision-making into the underlying models. Hybrid techniques that utilise prior knowledge, make sophisticated use of greyscale information and allow clinical expertise to be integrated are needed. This may require a change in focus from automated segmentation to machine-assisted delineation. Similarly, new metrics of image quality reflecting fitness for purpose would be extremely valuable. We conclude that methods need to be developed to take account of the clinician's expertise and honed visual processing capabilities as much as the underlying, clinically meaningful information content of the image data being interrogated. We illustrate our observations and suggestions through our own experiences with two software tools developed as part of research council-funded projects.
Malietzis G, Monzon L, Hand J, et al., 2013, High-intensity focused ultrasound: advances in technology and experimental trials support enhanced utility of focused ultrasound surgery in oncology, Br J Radiol, Vol: 86, ISSN: 1748-880X
High-intensity focused ultrasound (HIFU) is a rapidly maturing technology with diverse clinical applications. In the field of oncology, the use of HIFU to non-invasively cause tissue necrosis in a defined target, a technique known as focused ultrasound surgery (FUS), has considerable potential for tumour ablation. In this article, we outline the development and underlying principles of HIFU, overview the limitations and commercially available equipment for FUS, then summarise some of the recent technological advances and experimental clinical trials that we predict will have a positive impact on extending the role of FUS in cancer therapy.
Whitfield G, Jain P, Green M, et al., 2012, Quantifying motion for pancreatic radiotherapy margin calculation, Radiother Oncol, Vol: 103, Pages: 360-366, ISSN: 1879-0887
BACKGROUND AND PURPOSE: Pancreatic radiotherapy (RT) is limited by uncertain target motion. We quantified 3D patient/organ motion during pancreatic RT and calculated required treatment margins. MATERIALS AND METHODS: Cone-beam computed tomography (CBCT) and orthogonal fluoroscopy images were acquired post-RT delivery from 13 patients with locally advanced pancreatic cancer. Bony setup errors were calculated from CBCT. Inter- and intra-fraction fiducial (clip/seed/stent) motion was determined from CBCT projections and orthogonal fluoroscopy. RESULTS: Using an off-line CBCT correction protocol, systematic (random) setup errors were 2.4 (3.2), 2.0 (1.7) and 3.2 (3.6)mm laterally (left-right), vertically (anterior-posterior) and longitudinally (cranio-caudal), respectively. Fiducial motion varied substantially. Random inter-fractional changes in mean fiducial position were 2.0, 1.6 and 2.6mm; 95% of intra-fractional peak-to-peak fiducial motion was up to 6.7, 10.1 and 20.6mm, respectively. Calculated clinical to planning target volume (CTV-PTV) margins were 1.4 cm laterally, 1.4 cm vertically and 3.0 cm longitudinally for 3D conformal RT, reduced to 0.9, 1.0 and 1.8 cm, respectively, if using 4D planning and online setup correction. CONCLUSIONS: Commonly used CTV-PTV margins may inadequately account for target motion during pancreatic RT. Our results indicate better immobilisation, individualised allowance for respiratory motion, online setup error correction and 4D planning would improve targeting.
Patterson DM, Zweifel M, Middleton MR, et al., 2012, Phase I clinical and pharmacokinetic evaluation of the vascular-disrupting agent OXi4503 in patients with advanced solid tumors, Clin Cancer Res, Vol: 18, Pages: 1415-1425, ISSN: 1078-0432
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 drug-related 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).
Zhou C, Simpson KL, Lancashire LJ, et al., 2012, Statistical considerations of optimal study design for human plasma proteomics and biomarker discovery, Journal of proteome research, Vol: 11, Pages: 2103-2113, ISSN: 1535-3907
A mass spectrometry-based plasma biomarker discovery workflow was developed to facilitate biomarker discovery. Plasma from either healthy volunteers or patients with pancreatic cancer was 8-plex iTRAQ labeled, fractionated by 2-dimensional reversed phase chromatography and subjected to MALDI ToF/ToF mass spectrometry. Data were processed using a q-value based statistical approach to maximize protein quantification and identification. Technical (between duplicate samples) and biological variance (between and within individuals) were calculated and power analysis was thereby enabled. An a priori power analysis was carried out using samples from healthy volunteers to define sample sizes required for robust biomarker identification. The result was subsequently validated with a post hoc power analysis using a real clinical setting involving pancreatic cancer patients. This demonstrated that six samples per group (e.g., pre- vs post-treatment) may provide sufficient statistical power for most proteins with changes>2 fold. A reference standard allowed direct comparison of protein expression changes between multiple experiments. Analysis of patient plasma prior to treatment identified 29 proteins with significant changes within individual patient. Changes in Peroxiredoxin II levels were confirmed by Western blot. This q-value based statistical approach in combination with reference standard samples can be applied with confidence in the design and execution of clinical studies for predictive, prognostic, and/or pharmacodynamic biomarker discovery. The power analysis provides information required prior to study initiation.
Cummings J, Zweifel M, Smith N, et al., 2012, Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial, Br J Cancer, Vol: 106, Pages: 1766-1771, ISSN: 1532-1827
BACKGROUND: OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1-3 h and secondary tumour cell necrosis between 6 and 72 h. METHODS: To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24h, day 8 and day 15). RESULTS: OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%). CONCLUSION: These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503.
Matthews JC, Reader AJ, Angelis GL, et al., 2012, Adaptive Parametric Kinetic Modelling for Improved Full Field of View Fitting of PET data, MIC IEEE conference 07/05/12
Jones T, Price P, 2012, Development and experimental medicine applications of PET in oncology: a historical perspective, The lancet oncology, Vol: 13, Pages: e116-e125, ISSN: 1474-5488
Nearly 90 years of scientific research have led to the use of PET and the ability to forge advances in the field of oncology. In this Historial Review we outline the key developments made with this imaging technique, including the evolution of cyclotrons and scanners, together with the associated advances made in image reconstruction, presentation, analysis of data, and radiochemistry. The applications of PET to experimental medicine are summarised, and we cover how these are related to the use and development of PET, especially in the assessment of tumour biology and pharmacology. The use of PET in clinical oncology and for tissue pharmacokinetic and pharmacodynamic studies as a means of supporting drug development is detailed. The current limitations of the technology are also discussed.
Langley RE, Price P, Abel PD, 2011, Re: Claude C. Schulman, Jacques Irani, Juan Morote, et al. Androgen-deprivation therapy in prostate cancer: a European expert panel review. Eur Urol suppl 2010;9:675-91, European Urology, Vol: 59, Pages: e24-e25, ISSN: 1873-7560
Monzon A, Wasan H, Leen E, et al., 2011, Transrectal high-intensity focused ultrasonography is feasible as a new therapeutic option for advanced recurrent rectal cancer: report on the first case worldwide, Ann R Coll Surg Engl, Vol: 93, Pages: e119-e121
Saleem A, Matthews JC, Ranson M, et al., 2011, Molecular Imaging and Pharmacokinetic Analysis of Carbon-11 Labeled Antisense Oligonucleotide LY2181308 in Cancer Patients, Theranostics, Vol: 1, Pages: 290-301, ISSN: 1838-7640
Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen. [(11)C]methylated-LY2181308 exposure increased in tumor, lung and muscle, whereas renal and hepatic exposure decreased. This suggests that biological barriers to ASO tumor uptake seen at micro-doses were overcome by therapeutic dosing. In addition, (18)F-labeled fluorodeoxyglucose (FDG) scans carried out in the same patient before and after treatment showed up to 40% decreased tumor metabolism. For the development of anti-cancer ASOs, the results provide evidence of LY2181308 tumor tissue delivery and add valuable in vivo pharmacological information. For the development of novel therapeutic agents in general, the study exemplifies the merits of applying PET imaging methodology early in clinical investigations.
Price PM, Green MM, 2011, Positron emission tomography (PET) imaging approaches for external beam radiation therapies: current status and future developments, The British journal of radiology, ISSN: 1748-880X
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 where 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 here, highlighting its advantages and drawbacks.
Langley R, Cafferty FH, Pollock P, et al., 2011, Letter to Editor: Re Toremifene to Reduce Fracture Risk in Men Receiving Androgen Deprivation Therapy for Prostate Cancer, Journal of Urology
Kotasidis FA, Matthews JC, Angelis GI, et al., 2011, Single scan parameterization of space-variant point spread functions in image space via a printed array: the impact for two PET/CT scanners, Phys Med Biol, Vol: 56, Pages: 2917-2942, ISSN: 1361-6560
Incorporation of a resolution model during statistical image reconstruction often produces images of improved resolution and signal-to-noise ratio. A novel and practical methodology to rapidly and accurately determine the overall emission and detection blurring component of the system matrix using a printed point source array within a custom-made Perspex phantom is presented. The array was scanned at different positions and orientations within the field of view (FOV) to examine the feasibility of extrapolating the measured point source blurring to other locations in the FOV and the robustness of measurements from a single point source array scan. We measured the spatially-variant image-based blurring on two PET/CT scanners, the B-Hi-Rez and the TruePoint TrueV. These measured spatially-variant kernels and the spatially-invariant kernel at the FOV centre were then incorporated within an ordinary Poisson ordered subset expectation maximization (OP-OSEM) algorithm and compared to the manufacturer's implementation using projection space resolution modelling (RM). Comparisons were based on a point source array, the NEMA IEC image quality phantom, the Cologne resolution phantom and two clinical studies (carbon-11 labelled anti-sense oligonucleotide [(11)C]-ASO and fluorine-18 labelled fluoro-l-thymidine [(18)F]-FLT). Robust and accurate measurements of spatially-variant image blurring were successfully obtained from a single scan. Spatially-variant resolution modelling resulted in notable resolution improvements away from the centre of the FOV. Comparison between spatially-variant image-space methods and the projection-space approach (the first such report, using a range of studies) demonstrated very similar performance with our image-based implementation producing slightly better contrast recovery (CR) for the same level of image roughness (IR). These results demonstrate that image-based resolution modelling within reconstruction is a valid alternative to projection-base
Nagengast WB, Lub-de Hooge MN, Oosting SF, et al., 2011, VEGF-PET imaging is a noninvasive biomarker showing differential changes in the tumor during sunitinib treatment, Cancer Res, Vol: 71, Pages: 143-153, ISSN: 1538-7445
Non-invasive imaging of angiogenesis could ease the optimization of antiangiogenesis treatments for cancer. In this study, we evaluated the role of VEGF-PET as a biomarker of dynamic angiogenic changes in tumors following treatment with the kinase inhibitor sunitinib. The effects of sunitinib treatment and withdrawal on the tumor was investigated using the new VEGF-PET tracer (89)Zr-ranibizumab as well as (18)F-FDG PET, and (15)O-water PET in mouse xenograft models of human cancer. The obtained imaging results were compared with tumor growth, VEGF plasma levels and immunohistologic analyzes. In contrast to (18)F-FDG and (15)O-water PET, VEGF-PET demonstrated dynamic changes during sunitinib treatment within the tumor with a strong decline in signal in the tumor center and only minimal reduction in tumor rim, with a pronounced rebound after sunitinib discontinuation. VEGF-PET results corresponded with tumor growth and immunohistochemical vascular- and tumor- markers. Our findings highlight the strengths of VEGF-PET imaging to allow serial analysis of angiogenic changes in different areas within a tumor.
Price P, 2011, The launch of the first UK charity devoted to radiotherapy: ACORRN -- Action Radiotherapy, Br J Radiol, Vol: 84, Pages: 2-4, ISSN: 1748-880X
The Academic Clinical Oncology and Radiobiology Research Network (ACORRN) was set up to support research and development in radiotherapy in the UK. This innovative networking initiative was launched initially by the National Cancer Research Institute in 2005 to harness the power of the radiation research base in the UK. Through an interactive website a co-ordinated network of multidisciplinary radiation researchers has been established. The network has developed to a stage where it can be self-funding and dedicated to improving radiotherapy for cancer. A patient interactive section and extended support for service development will ensure that anyone treated in the UK will have immediate access to the best knowledge in the country. This provides a solution for cost-effectiveness and future improvement of cancer care and is seen as a new model to support healthcare development and delivery. The charity ACORRN - Action Radiotherapy aims to support radiotherapy research and development and was launched in the House of Lords in July 2010.
Rembielak A, Green M, Saleem A, et al., 2011, Diagnostic and therapeutic imaging in oncology (Published Nov 2011), Cancer Biology and Imaging, Pages: 693-696
Jones T, Price PM, Tavitian B, 2011, Letter to the Editor: Realising the Full Potential of Positron Emission Tomography (PET) for Measuring the Biodistribution of Novel Anti-Cancer Agents, Journal of Nuclear Medicine
Price P, Asselin MC, Kotz B, et al., 2010, Phase I trial of OXi4503: positron emission tomography (PET) analysis shows early effects on tumour perfusion that predict metabolic response, 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 120-121, ISSN: 1359-6349
Kotasidis F, Matthews J, Angelis G, et al., 2010, Space-variant image-based resolution modeling kernels for enhanced whole-body oncology imaging with the HiRez PET/CT scanner, Publisher: SOC NUCLEAR MEDICINE INC, ISSN: 0161-5505
Talbot DC, Ranson M, Davies J, et al., 2010, Tumor survivin is downregulated by the antisense oligonucleotide LY2181308: a proof-of-concept, first-in-human dose study, Clin Cancer Res, Vol: 16, Pages: 6150-6158, ISSN: 1078-0432
PURPOSE: Enhanced tumor cell survival through expression of inhibitors of apoptosis (IAP) is a hallmark of cancer. Survivin, an IAP absent from most normal tissues, is overexpressed in many malignancies and associated with a poorer prognosis. We report the first-in-human dose study of LY2181308, a second-generation antisense oligonucleotide (ASO) directed against survivin mRNA. Patients and Methods: A dose-escalation study evaluating the safety, pharmacokinetics, and pharmacodynamics of LY2181308 administered intravenously for 3 hours as a loading dose on 3 consecutive days and followed by weekly maintenance doses. Patients were eligible after signing informed consent, had exhausted approved anticancer therapies and agreed to undergo pre- and posttreatment tumor biopsies to evaluate reduction of survivin protein and gene expression. RESULTS: A total of 40 patients were treated with LY2181308 at doses of 100 to 1,000 mg. Twenty-six patients were evaluated at the recommended phase 2 dose of 750 mg, at which level serial tumor sampling and [(11)C]LY2183108 PET (positron emission tomography) imaging demonstrated that ASO accumulated within tumor tissue, reduced survivin gene and protein expression by 20% and restored apoptotic signaling in tumor cells in vivo. Pharmacokinetics were consistent with preclinical modeling, exhibiting rapid tissue distribution, and terminal half-life of 31 days. CONCLUSIONS: The tumor-specific, molecularly targeted effects demonstrated by this ASO in man underpin confirmatory studies evaluating its therapeutic efficacy in cancer.
Walker MD, Matthews JC, Asselin MC, et al., 2010, Development and validation of a variance model for dynamic PET: uses in fitting kinetic data and optimizing the injected activity, Phys Med Biol, Vol: 55, Pages: 6655-6672, ISSN: 1361-6560
The precision of biological parameter estimates derived from dynamic PET data can be limited by the number of acquired coincidence events (prompts and randoms). These numbers are affected by the injected activity (A(0)). The benefits of optimizing A(0) were assessed using a new model of data variance which is formulated as a function of A(0). Seven cancer patients underwent dynamic [(15)O]H(2)O PET scans (32 scans) using a Biograph PET-CT scanner (Siemens), with A(0) varied (142-839 MBq). These data were combined with simulations to (1) determine the accuracy of the new variance model, (2) estimate the improvements in parameter estimate precision gained by optimizing A(0), and (3) examine changes in precision for different size regions of interest (ROIs). The new variance model provided a good estimate of the relative variance in dynamic PET data across a wide range of A(0)s and time frames for FBP reconstruction. Patient data showed that relative changes in estimate precision with A(0) were in reasonable agreement with the changes predicted by the model: Pearson's correlation coefficients were 0.73 and 0.62 for perfusion (F) and the volume of distribution (V(T)), respectively. The between-scan variability in the parameter estimates agreed with the estimated precision for small ROIs (<5 mL). An A(0) of 500-700 MBq was near optimal for estimating F and V(T) from abdominal [(15)O]H(2)O scans on this scanner. This optimization improved the precision of parameter estimates for small ROIs (<5 mL), with an injection of 600 MBq reducing the standard error on F by a factor of 1.13 as compared to the injection of 250 MBq, but by the more modest factor of 1.03 as compared to A(0) = 400 MBq.
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