McHugh, D.J.
Porta, N.
Little, R.A.
Cheung, S.
Watson, Y.
Parker, G.J.
Jayson, G.C.
O'Connor, J.P.
(2021). Image Contrast, Image Pre-Processing, and T1 Mapping Affect MRI Radiomic Feature Repeatability in Patients with Colorectal Cancer Liver Metastases. Cancers,
Vol.13
(2).
show abstract
Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T1- and T2-weighted images, pre-contrast quantitative T1 maps (qT1), and contrast-enhanced T1-weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box-Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T1- and T2-weighted images, and decrease ICCs for qT1 maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context..
Skwarski, M.
McGowan, D.R.
Belcher, E.
Di Chiara, F.
Stavroulias, D.
McCole, M.
Derham, J.L.
Chu, K.-.
Teoh, E.
Chauhan, J.
O'Reilly, D.
Harris, B.H.
Macklin, P.S.
Bull, J.A.
Green, M.
Rodriguez-Berriguete, G.
Prevo, R.
Folkes, L.K.
Campo, L.
Ferencz, P.
Croal, P.L.
Flight, H.
Qi, C.
Holmes, J.
O'Connor, J.P.
Gleeson, F.V.
McKenna, W.G.
Harris, A.L.
Bulte, D.
Buffa, F.M.
Macpherson, R.E.
Higgins, G.S.
(2021). Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer. Clinical cancer research : an official journal of the american association for cancer research,
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show abstract
Purpose Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).Patients and methods Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: cohort 1 received oral atovaquone at the standard clinical dose of 750 mg twice daily, while cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Intercohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.Results Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction, with median change -28% [95% confidence interval (CI), -58.2 to -4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, -6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24%-74%) lower in cohort 1 compared with cohort 2 ( P = 0.004), adjusting for cohort, tumor volume, and baseline HV. A key pharmacodynamics endpoint was reduction in hypoxia-regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.Conclusions This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant antitumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC..
Fournier, L.
Costaridou, L.
Bidaut, L.
Michoux, N.
Lecouvet, F.E.
de Geus-Oei, L.-.
Boellaard, R.
Oprea-Lager, D.E.
Obuchowski, N.A.
Caroli, A.
Kunz, W.G.
Oei, E.H.
O'Connor, J.P.
Mayerhoefer, M.E.
Franca, M.
Alberich-Bayarri, A.
Deroose, C.M.
Loewe, C.
Manniesing, R.
Caramella, C.
Lopci, E.
Lassau, N.
Persson, A.
Achten, R.
Rosendahl, K.
Clement, O.
Kotter, E.
Golay, X.
Smits, M.
Dewey, M.
Sullivan, D.C.
van der Lugt, A.
deSouza, N.M.
European Society Of Radiology,
(2021). Incorporating radiomics into clinical trials: expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers. European radiology,
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show abstract
Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. KEY POINTS: • Data-driven processes like radiomics risk false discoveries due to high-dimensionality of the dataset compared to sample size, making adequate diversity of the data, cross-validation and external validation essential to mitigate the risks of spurious associations and overfitting. • Use of radiomic signatures within clinical trials requires multistep standardisation of image acquisition, image analysis and data mining processes. • Biological correlation may be established after clinical validation but is not mandatory..
Tar, P.D.
Thacker, N.A.
Deepaisarn, S.
O'Connor, J.P.
McMahon, A.W.
(2020). A reformulation of pLSA for uncertainty estimation and hypothesis testing in bio-imaging. Bioinformatics (oxford, england),
Vol.36
(13),
pp. 4080-4087.
show abstract
MOTIVATION:Probabilistic latent semantic analysis (pLSA) is commonly applied to describe mass spectra (MS) images. However, the method does not provide certain outputs necessary for the quantitative scientific interpretation of data. In particular, it lacks assessment of statistical uncertainty and the ability to perform hypothesis testing. We show how linear Poisson modelling advances pLSA, giving covariances on model parameters and supporting χ2 testing for the presence/absence of MS signal components. As an example, this is useful for the identification of pathology in MALDI biological samples. We also show potential wider applicability, beyond MS, using magnetic resonance imaging (MRI) data from colorectal xenograft models. RESULTS:Simulations and MALDI spectra of a stroke-damaged rat brain show MS signals from pathological tissue can be quantified. MRI diffusion data of control and radiotherapy-treated tumours further show high sensitivity hypothesis testing for treatment effects. Successful χ2 and degrees-of-freedom are computed, allowing null-hypothesis thresholding at high levels of confidence. AVAILABILITY AND IMPLEMENTATION:Open-source image analysis software available from TINA Vision, www.tina-vision.net. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online..
Fornacon-Wood, I.
Faivre-Finn, C.
O'Connor, J.P.
Price, G.J.
(2020). Radiomics as a personalized medicine tool in lung cancer: Separating the hope from the hype. Lung cancer (amsterdam, netherlands),
Vol.146,
pp. 197-208.
show abstract
Radiomics has become a popular image analysis method in the last few years. Its key hypothesis is that medical images harbor biological, prognostic and predictive information that is not revealed upon visual inspection. In contrast to previous work with a priori defined imaging biomarkers, radiomics instead calculates image features at scale and uses statistical methods to identify those most strongly associated to outcome. This builds on years of research into computer aided diagnosis and pattern recognition. While the potential of radiomics to aid personalized medicine is widely recognized, several technical limitations exist which hinder biomarker translation. Aspects of the radiomic workflow lack repeatability or reproducibility under particular circumstances, which is a key requirement for the translation of imaging biomarkers into clinical practice. One of the most commonly studied uses of radiomics is for personalized medicine applications in Non-Small Cell Lung Cancer (NSCLC). In this review, we summarize reported methodological limitations in CT based radiomic analyses together with suggested solutions. We then evaluate the current NSCLC radiomics literature to assess the risk associated with accepting the published conclusions with respect to these limitations. We review different complementary scoring systems and initiatives that can be used to critically appraise data from radiomics studies. Wider awareness should improve the quality of ongoing and future radiomics studies and advance their potential as clinically relevant biomarkers for personalized medicine in patients with NSCLC..
McHugh, D.J.
Lipowska-Bhalla, G.
Babur, M.
Watson, Y.
Peset, I.
Mistry, H.B.
Hubbard Cristinacce, P.L.
Naish, J.H.
Honeychurch, J.
Williams, K.J.
O'Connor, J.P.
Parker, G.J.
(2020). Diffusion model comparison identifies distinct tumor sub-regions and tracks treatment response. Magnetic resonance in medicine,
Vol.84
(3),
pp. 1250-1263.
show abstract
PURPOSE:MRI biomarkers of tumor response to treatment are typically obtained from parameters derived from a model applied to pre-treatment and post-treatment data. However, as tumors are spatially and temporally heterogeneous, different models may be necessary in different tumor regions, and model suitability may change over time. This work evaluates how the suitability of two diffusion-weighted (DW) MRI models varies spatially within tumors at the voxel level and in response to radiotherapy, potentially allowing inference of qualitatively different tumor microenvironments. METHODS:DW-MRI data were acquired in CT26 subcutaneous allografts before and after radiotherapy. Restricted and time-independent diffusion models were compared, with regions well-described by the former hypothesized to reflect cellular tissue, and those well-described by the latter expected to reflect necrosis or oedema. Technical and biological validation of the percentage of tissue described by the restricted diffusion microstructural model (termed %MM) was performed through simulations and histological comparison. RESULTS:Spatial and radiotherapy-related variation in model suitability was observed. %MM decreased from a mean of 64% at baseline to 44% 6 days post-radiotherapy in the treated group. %MM correlated negatively with the percentage of necrosis from histology, but overestimated it due to noise. Within MM regions, microstructural parameters were sensitive to radiotherapy-induced changes. CONCLUSIONS:There is spatial and radiotherapy-related variation in different models' suitability for describing diffusion in tumor tissue, suggesting the presence of different and changing tumor sub-regions. The biological and technical validation of the proposed %MM cancer imaging biomarker suggests it correlates with, but overestimates, the percentage of necrosis..
Fornacon-Wood, I.
Mistry, H.
Ackermann, C.J.
Blackhall, F.
McPartlin, A.
Faivre-Finn, C.
Price, G.J.
O'Connor, J.P.
(2020). Reliability and prognostic value of radiomic features are highly dependent on choice of feature extraction platform. Eur radiol,
Vol.30
(11),
pp. 6241-6250.
show abstract
OBJECTIVE: To investigate the effects of Image Biomarker Standardisation Initiative (IBSI) compliance, harmonisation of calculation settings and platform version on the statistical reliability of radiomic features and their corresponding ability to predict clinical outcome. METHODS: The statistical reliability of radiomic features was assessed retrospectively in three clinical datasets (patient numbers: 108 head and neck cancer, 37 small-cell lung cancer, 47 non-small-cell lung cancer). Features were calculated using four platforms (PyRadiomics, LIFEx, CERR and IBEX). PyRadiomics, LIFEx and CERR are IBSI-compliant, whereas IBEX is not. The effects of IBSI compliance, user-defined calculation settings and platform version were assessed by calculating intraclass correlation coefficients and confidence intervals. The influence of platform choice on the relationship between radiomic biomarkers and survival was evaluated using univariable cox regression in the largest dataset. RESULTS: The reliability of radiomic features calculated by the different software platforms was only excellent (ICC > 0.9) for 4/17 radiomic features when comparing all four platforms. Reliability improved to ICC > 0.9 for 15/17 radiomic features when analysis was restricted to the three IBSI-compliant platforms. Failure to harmonise calculation settings resulted in poor reliability, even across the IBSI-compliant platforms. Software platform version also had a marked effect on feature reliability in CERR and LIFEx. Features identified as having significant relationship to survival varied between platforms, as did the direction of hazard ratios. CONCLUSION: IBSI compliance, user-defined calculation settings and choice of platform version all influence the statistical reliability and corresponding performance of prognostic models in radiomics. KEY POINTS: • Reliability of radiomic features varies between feature calculation platforms and with choice of software version. • Image Biomarker Standardisation Initiative (IBSI) compliance improves reliability of radiomic features across platforms, but only when calculation settings are harmonised. • IBSI compliance, user-defined calculation settings and choice of platform version collectively affect the prognostic value of features..
O'Connor, J.P.
Robinson, S.P.
Waterton, J.C.
(2019). Imaging tumour hypoxia with oxygen-enhanced MRI and BOLD MRI. Br j radiol,
Vol.92
(1095),
pp. 20180642-20180642.
show abstract
Hypoxia is known to be a poor prognostic indicator for nearly all solid tumours and also is predictive of treatment failure for radiotherapy, chemotherapy, surgery and targeted therapies. Imaging has potential to identify, spatially map and quantify tumour hypoxia prior to therapy, as well as track changes in hypoxia on treatment. At present no hypoxia imaging methods are available for routine clinical use. Research has largely focused on positron emission tomography (PET)-based techniques, but there is gathering evidence that MRI techniques may provide a practical and more readily translational alternative. In this review we focus on the potential for imaging hypoxia by measuring changes in longitudinal relaxation [R1; termed oxygen-enhanced MRI or tumour oxygenation level dependent (TOLD) MRI] and effective transverse relaxation [R2*; termed blood oxygenation level dependent (BOLD) MRI], induced by inhalation of either 100% oxygen or the radiosensitising hyperoxic gas carbogen. We explain the scientific principles behind oxygen-enhanced MRI and BOLD and discuss significant studies and their limitations. All imaging biomarkers require rigorous validation in order to translate into clinical use and the steps required to further develop oxygen-enhanced MRI and BOLD MRI into decision-making tools are discussed..
Waterhouse, D.J.
Fitzpatrick, C.R.
Pogue, B.W.
O’Connor, J.P.
Bohndiek, S.E.
(2019). A roadmap for the clinical implementation of optical-imaging biomarkers. Nature biomedical engineering,
Vol.3
(5),
pp. 339-353.
Waterton, J.C.
Hines, C.D.
Hockings, P.D.
Laitinen, I.
Ziemian, S.
Campbell, S.
Gottschalk, M.
Green, C.
Haase, M.
Hassemer, K.
Juretschke, H.-.
Koehler, S.
Lloyd, W.
Luo, Y.
Mahmutovic Persson, I.
O'Connor, J.P.
Olsson, L.E.
Pindoria, K.
Schneider, J.E.
Sourbron, S.
Steinmann, D.
Strobel, K.
Tadimalla, S.
Teh, I.
Veltien, A.
Zhang, X.
Schütz, G.
(2019). Repeatability and reproducibility of longitudinal relaxation rate in 12 small-animal MRI systems. Magnetic resonance imaging,
Vol.59,
pp. 121-129.
show abstract
Background Many translational MR biomarkers derive from measurements of the water proton longitudinal relaxation rate R 1 , but evidence for between-site reproducibility of R 1 in small-animal MRI is lacking.Objective To assess R 1 repeatability and multi-site reproducibility in phantoms for preclinical MRI.Methods R 1 was measured by saturation recovery in 2% agarose phantoms with five nickel chloride concentrations in 12 magnets at 5 field strengths in 11 centres on two different occasions within 1-13 days. R 1 was analysed in three different regions of interest, giving 360 measurements in total. Root-mean-square repeatability and reproducibility coefficients of variation (CoV) were calculated. Propagation of reproducibility errors into 21 translational MR measurements and biomarkers was estimated. Relaxivities were calculated. Dynamic signal stability was also measured.Results CoV for day-to-day repeatability (N = 180 regions of interest) was 2.34% and for between-centre reproducibility (N = 9 centres) was 1.43%. Mostly, these do not propagate to biologically significant between-centre error, although a few R 1 -based MR biomarkers were found to be quite sensitive even to such small errors in R 1 , notably in myocardial fibrosis, in white matter, and in oxygen-enhanced MRI. The relaxivity of aqueous Ni 2+ in 2% agarose varied between 0.66 s -1 mM -1 at 3 T and 0.94 s -1 mM -1 at 11.7T.Interpretation While several factors affect the reproducibility of R 1 -based MR biomarkers measured preclinically, between-centre propagation of errors arising from intrinsic equipment irreproducibility should in most cases be small. However, in a few specific cases exceptional efforts might be required to ensure R 1 -reproducibility..
Salem, A.
Little, R.A.
Latif, A.
Featherstone, A.K.
Babur, M.
Peset, I.
Cheung, S.
Watson, Y.
Tessyman, V.
Mistry, H.
Ashton, G.
Behan, C.
Matthews, J.C.
Asselin, M.-.
Bristow, R.G.
Jackson, A.
Parker, G.J.
Faivre-Finn, C.
Williams, K.J.
O'Connor, J.P.
(2019). Oxygen-enhanced MRI Is Feasible, Repeatable, and Detects Radiotherapy-induced Change in Hypoxia in Xenograft Models and in Patients with Non-small Cell Lung Cancer. Clinical cancer research : an official journal of the american association for cancer research,
Vol.25
(13),
pp. 3818-3829.
show abstract
Purpose Hypoxia is associated with poor prognosis and is predictive of poor response to cancer treatments, including radiotherapy. Developing noninvasive biomarkers that both detect hypoxia prior to treatment and track change in tumor hypoxia following treatment is required urgently.Experimental design We evaluated the ability of oxygen-enhanced MRI (OE-MRI) to map and quantify therapy-induced changes in tumor hypoxia by measuring oxygen-refractory signals in perfused tissue (perfused Oxy-R). Clinical first-in-human study in patients with non-small cell lung cancer (NSCLC) was performed alongside preclinical experiments in two xenograft tumors (Calu6 NSCLC model and U87 glioma model).Results MRI perfused Oxy-R tumor fraction measurement of hypoxia was validated with ex vivo tissue pathology in both xenograft models. Calu6 and U87 experiments showed that MRI perfused Oxy-R tumor volume was reduced relative to control following single fraction 10-Gy radiation and fractionated chemoradiotherapy ( P < 0.001) due to both improved perfusion and reduced oxygen consumption rate. Next, evaluation of 23 patients with NSCLC showed that OE-MRI was clinically feasible and that tumor perfused Oxy-R volume is repeatable [interclass correlation coefficient: 0.961 (95% CI, 0.858-0.990); coefficient of variation: 25.880%]. Group-wise perfused Oxy-R volume was reduced at 14 days following start of radiotherapy ( P = 0.015). OE-MRI detected between-subject variation in hypoxia modification in both xenograft and patient tumors.Conclusions These findings support applying OE-MRI biomarkers to monitor hypoxia modification, to stratify patients in clinical trials of hypoxia-modifying therapies, to identify patients with hypoxic tumors that may fail treatment with immunotherapy, and to guide adaptive radiotherapy by mapping regional hypoxia..
Marti, F.E.
Jayson, G.C.
Manoharan, P.
O'Connor, J.
Renehan, A.G.
Backen, A.C.
Mistry, H.
Ortega, F.
Li, K.
Simpson, K.L.
Allen, J.
Connell, J.
Underhill, S.
Misra, V.
Williams, K.J.
Stratford, I.
Jackson, A.
Dive, C.
Saunders, M.P.
(2019). Novel phase I trial design to evaluate the addition of cediranib or selumetinib to preoperative chemoradiotherapy for locally advanced rectal cancer: the DREAMtherapy trial. European journal of cancer,
Vol.117,
pp. 48-59.
deSouza, N.M.
Achten, E.
Alberich-Bayarri, A.
Bamberg, F.
Boellaard, R.
Clément, O.
Fournier, L.
Gallagher, F.
Golay, X.
Heussel, C.P.
Jackson, E.F.
Manniesing, R.
Mayerhofer, M.E.
Neri, E.
O'Connor, J.
Oguz, K.K.
Persson, A.
Smits, M.
van Beek, E.J.
Zech, C.J.
European Society of Radiology,
(2019). Validated imaging biomarkers as decision-making tools in clinical trials and routine practice: current status and recommendations from the EIBALL* subcommittee of the European Society of Radiology (ESR). Insights into imaging,
Vol.10
(1),
pp. 87-?.
show abstract
Observer-driven pattern recognition is the standard for interpretation of medical images. To achieve global parity in interpretation, semi-quantitative scoring systems have been developed based on observer assessments; these are widely used in scoring coronary artery disease, the arthritides and neurological conditions and for indicating the likelihood of malignancy. However, in an era of machine learning and artificial intelligence, it is increasingly desirable that we extract quantitative biomarkers from medical images that inform on disease detection, characterisation, monitoring and assessment of response to treatment. Quantitation has the potential to provide objective decision-support tools in the management pathway of patients. Despite this, the quantitative potential of imaging remains under-exploited because of variability of the measurement, lack of harmonised systems for data acquisition and analysis, and crucially, a paucity of evidence on how such quantitation potentially affects clinical decision-making and patient outcome. This article reviews the current evidence for the use of semi-quantitative and quantitative biomarkers in clinical settings at various stages of the disease pathway including diagnosis, staging and prognosis, as well as predicting and detecting treatment response. It critically appraises current practice and sets out recommendations for using imaging objectively to drive patient management decisions..
Salem, A.
Asselin, M.-.
Reymen, B.
Jackson, A.
Lambin, P.
West, C.M.
O'Connor, J.P.
Faivre-Finn, C.
(2018). Targeting Hypoxia to Improve Non-Small Cell Lung Cancer Outcome. Journal of the national cancer institute,
Vol.110
(1).
show abstract
Oxygen deprivation (hypoxia) in non-small cell lung cancer (NSCLC) is an important factor in treatment resistance and poor survival. Hypoxia is an attractive therapeutic target, particularly in the context of radiotherapy, which is delivered to more than half of NSCLC patients. However, NSCLC hypoxia-targeted therapy trials have not yet translated into patient benefit. Recently, early termination of promising evofosfamide and tarloxotinib bromide studies due to futility highlighted the need for a paradigm shift in our approach to avoid disappointments in future trials. Radiotherapy dose painting strategies based on hypoxia imaging require careful refinement prior to clinical investigation. This review will summarize the role of hypoxia, highlight the potential of hypoxia as a therapeutic target, and outline past and ongoing hypoxia-targeted therapy trials in NSCLC. Evidence supporting radiotherapy dose painting based on hypoxia imaging will be critically appraised. Carefully selected hypoxia biomarkers suitable for integration within future NSCLC hypoxia-targeted therapy trials will be examined. Research gaps will be identified to guide future investigation. Although this review will focus on NSCLC hypoxia, more general discussions (eg, obstacles of hypoxia biomarker research and developing a framework for future hypoxia trials) are applicable to other tumor sites..
Barnes, A.
Alonzi, R.
Blackledge, M.
Charles-Edwards, G.
Collins, D.J.
Cook, G.
Coutts, G.
Goh, V.
Graves, M.
Kelly, C.
Koh, D.-.
McCallum, H.
Miquel, M.E.
O'Connor, J.
Padhani, A.
Pearson, R.
Priest, A.
Rockall, A.
Stirling, J.
Taylor, S.
Tunariu, N.
van der Meulen, J.
Walls, D.
Winfield, J.
Punwani, S.
(2018). UK quantitative WB-DWI technical workgroup: consensus meeting recommendations on optimisation, quality control, processing and analysis of quantitative whole-body diffusion-weighted imaging for cancer. Br j radiol,
Vol.91
(1081),
pp. 20170577-20170577.
show abstract
OBJECTIVE: Application of whole body diffusion-weighted MRI (WB-DWI) for oncology are rapidly increasing within both research and routine clinical domains. However, WB-DWI as a quantitative imaging biomarker (QIB) has significantly slower adoption. To date, challenges relating to accuracy and reproducibility, essential criteria for a good QIB, have limited widespread clinical translation. In recognition, a UK workgroup was established in 2016 to provide technical consensus guidelines (to maximise accuracy and reproducibility of WB-MRI QIBs) and accelerate the clinical translation of quantitative WB-DWI applications for oncology. METHODS: A panel of experts convened from cancer centres around the UK with subspecialty expertise in quantitative imaging and/or the use of WB-MRI with DWI. A formal consensus method was used to obtain consensus agreement regarding best practice. Questions were asked about the appropriateness or otherwise on scanner hardware and software, sequence optimisation, acquisition protocols, reporting, and ongoing quality control programs to monitor precision and accuracy and agreement on quality control. RESULTS: The consensus panel was able to reach consensus on 73% (255/351) items and based on consensus areas made recommendations to maximise accuracy and reproducibly of quantitative WB-DWI studies performed at 1.5T. The panel were unable to reach consensus on the majority of items related to quantitative WB-DWI performed at 3T. CONCLUSION: This UK Quantitative WB-DWI Technical Workgroup consensus provides guidance on maximising accuracy and reproducibly of quantitative WB-DWI for oncology. The consensus guidance can be used by researchers and clinicians to harmonise WB-DWI protocols which will accelerate clinical translation of WB-DWI-derived QIBs..
Little, R.A.
Barjat, H.
Hare, J.I.
Jenner, M.
Watson, Y.
Cheung, S.
Holliday, K.
Zhang, W.
O'Connor, J.P.
Barry, S.T.
Puri, S.
Parker, G.J.
Waterton, J.C.
(2018). Evaluation of dynamic contrast-enhanced MRI biomarkers for stratified cancer medicine: How do permeability and perfusion vary between human tumours?. Magnetic resonance imaging,
Vol.46,
pp. 98-105.
show abstract
Solid tumours exhibit enhanced vessel permeability and fenestrated endothelium to varying degree, but it is unknown how this varies in patients between and within tumour types. Dynamic contrast-enhanced (DCE) MRI provides a measure of perfusion and permeability, the transfer constant Ktrans, which could be employed for such comparisons in patients.To test the hypothesis that different tumour types exhibit systematically different Ktrans.DCE-MRI data were retrieved from 342 solid tumours in 230 patients. These data were from 18 previous studies, each of which had had a different analysis protocol. All data were reanalysed using a standardised workflow using an extended Tofts model. A model of the posterior density of median Ktrans was built assuming a log-normal distribution and fitting a simple Bayesian hierarchical model.12 histological tumour types were included. In glioma, median Ktrans was 0.016min-1 and for non-glioma tumours, median Ktrans ranged from 0.10 (cervical) to 0.21min-1 (prostate metastatic to bone). The geometric mean (95% CI) across all the non-glioma tumours was 0.15 (0.05, 0.45)min-1. There was insufficient separation between the posterior densities to be able to predict the Ktrans value of a tumour given the tumour type, except that the median Ktrans for gliomas was below 0.05min-1 with 80% probability, and median Ktrans measurements for the remaining tumour types were between 0.05 and 0.4min-1 with 80% probability.With the exception of glioma, our hypothesis that different tumour types exhibit different Ktrans was not supported. Studies in which tumour permeability is believed to affect outcome should not simply seek tumour types thought to exhibit high permeability. Instead, Ktrans is an idiopathic parameter, and, where permeability is important, Ktrans should be measured in each tumour to personalise that treatment..
Hudson, A.
Chan, C.
Woolf, D.
McWilliam, A.
Hiley, C.
O'Connor, J.
Bayman, N.
Blackhall, F.
Faivre-Finn, C.
(2018). Is heterogeneity in stage 3 non-small cell lung cancer obscuring the potential benefits of dose-escalated concurrent chemo-radiotherapy in clinical trials?. Lung cancer (amsterdam, netherlands),
Vol.118,
pp. 139-147.
show abstract
The current standard of care for the management of inoperable stage 3 non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy (cCRT) using radiotherapy dose-fractionation and chemotherapy regimens that were established 3 decades ago. In an attempt to improve the chances of long-term control from cCRT, dose-escalation of the radiotherapy dose was assessed in the RTOG 0617 randomised control study comparing the standard 60 Gy in 30 fractions with a high-dose arm receiving 74 Gy in 37 fractions. Following the publication of this trial the thoracic oncology community were surprised to learn that there was worse survival in the dose-escalated arm and that for now the standard of care must remain with the lower dose. In this article we review the RTOG 0617 paper with subsequent analyses and studies to explore why the use of dose-escalated cCRT in stage 3 NSCLC has not shown the benefits that were expected. The overarching theme of this opinion piece is how heterogeneity between stage 3 NSCLC cases in terms of patient, tumour, and clinical factors may obscure the potential benefits of dose-escalation by causing imbalances in the arms of studies such as RTOG 0617. We also examine recent advances in the staging, management, and technological delivery of radiotherapy in NSCLC and how these may be employed to optimise cCRT trials in the future and ensure that any potential benefits of dose-escalation can be detected..
Featherstone, A.K.
O'Connor, J.P.
Little, R.A.
Watson, Y.
Cheung, S.
Babur, M.
Williams, K.J.
Matthews, J.C.
Parker, G.J.
(2018). Data-driven mapping of hypoxia-related tumor heterogeneity using DCE-MRI and OE-MRI. Magnetic resonance in medicine,
Vol.79
(4),
pp. 2236-2245.
show abstract
Purpose Previous work has shown that combining dynamic contrast-enhanced (DCE)-MRI and oxygen-enhanced (OE)-MRI binary enhancement maps can identify tumor hypoxia. The current work proposes a novel, data-driven method for mapping tissue oxygenation and perfusion heterogeneity, based on clustering DCE/OE-MRI data.Methods DCE-MRI and OE-MRI were performed on nine U87 (glioblastoma) and seven Calu6 (non-small cell lung cancer) murine xenograft tumors. Area under the curve and principal component analysis features were calculated and clustered separately using Gaussian mixture modelling. Evaluation metrics were calculated to determine the optimum feature set and cluster number. Outputs were quantitatively compared with a previous non data-driven approach.Results The optimum method located six robustly identifiable clusters in the data, yielding tumor region maps with spatially contiguous regions in a rim-core structure, suggesting a biological basis. Mean within-cluster enhancement curves showed physiologically distinct, intuitive kinetics of enhancement. Regions of DCE/OE-MRI enhancement mismatch were located, and voxel categorization agreed well with the previous non data-driven approach (Cohen's kappa = 0.61, proportional agreement = 0.75).Conclusion The proposed method locates similar regions to the previous published method of binarization of DCE/OE-MRI enhancement, but renders a finer segmentation of intra-tumoral oxygenation and perfusion. This could aid in understanding the tumor microenvironment and its heterogeneity. Magn Reson Med 79:2236-2245, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited..
Jayson, G.C.
Zhou, C.
Backen, A.
Horsley, L.
Marti-Marti, K.
Shaw, D.
Mescallado, N.
Clamp, A.
Saunders, M.P.
Valle, J.W.
Mullamitha, S.
Braun, M.
Hasan, J.
McEntee, D.
Simpson, K.
Little, R.A.
Watson, Y.
Cheung, S.
Roberts, C.
Ashcroft, L.
Manoharan, P.
Scherer, S.J.
Del Puerto, O.
Jackson, A.
O'Connor, J.P.
Parker, G.J.
Dive, C.
(2018). Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer. Nature communications,
Vol.9
(1),
pp. 4672-?.
show abstract
Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, K trans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi..
Tar, P.D.
Thacker, N.A.
Babur, M.
Watson, Y.
Cheung, S.
Little, R.A.
Gieling, R.G.
Williams, K.J.
O'Connor, J.P.
(2018). A new method for the high-precision assessment of tumor changes in response to treatment. Bioinformatics (oxford, england),
Vol.34
(15),
pp. 2625-2633.
show abstract
Motivation:Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both 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 modeling (LPM) evaluates changes in apparent diffusion co-efficient between baseline and 72 h after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes is compared to those attainable using a conventional t-test analysis on basic apparent diffusion co-efficient distribution parameters. Results:When LPMs were applied to treated tumors, the LPMs detected highly significant changes. The analyses were significant for all tumors, equating to a gain in power of 4-fold (i.e. equivalent to having a sample size 16 times larger), compared with the conventional approach. In contrast, highly significant changes are only detected at a cohort level using t-tests, restricting their potential use within personalized medicine and increasing the number of animals required during testing. Furthermore, LPM enabled the relative volumes of responding and non-responding tissue to be estimated for each xenograft model. Leave-one-out analysis of the treated xenografts provided quality control and identified potential outliers, raising confidence in LPM data at clinically relevant sample sizes. Availability and implementation:TINA Vision open source software is available from www.tina-vision.net. Supplementary information:Supplementary data are available at Bioinformatics online..
Little, R.A.
Jamin, Y.
Boult, J.K.
Naish, J.H.
Watson, Y.
Cheung, S.
Holliday, K.F.
Lu, H.
McHugh, D.J.
Irlam, J.
West, C.M.
Betts, G.N.
Ashton, G.
Reynolds, A.R.
Maddineni, S.
Clarke, N.W.
Parker, G.J.
Waterton, J.C.
Robinson, S.P.
O'Connor, J.P.
(2018). Mapping Hypoxia in Renal Carcinoma with Oxygen-enhanced MRI: Comparison with Intrinsic Susceptibility MRI and Pathology. Radiology,
Vol.288
(3),
pp. 739-747.
show abstract
Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients. Materials and Methods Preclinical studies in nine 786-0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (∆R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ∆R1 were compared with values of R2* and ∆R2*. Tumor regions with dynamic contrast agent-enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ∆R2* values in each tumor subregion were compared by using one-way analysis of variance. Results Tumor-wise and voxel-wise ∆R1 and ∆R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec-1 vs 81.7 sec-1) and greater negative ∆R2* (-22.9 sec-1 vs -5.4 sec-1), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003). Conclusion Intrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation. Published under a CC BY 4.0 license. Online supplemental material is available for this article..
Datta, A.
Aznar, M.C.
Dubec, M.
Parker, G.J.
O'Connor, J.P.
(2018). Delivering Functional Imaging on the MRI-Linac: Current Challenges and Potential Solutions. Clinical oncology,
Vol.30
(11),
pp. 702-710.
Tomaszewski, M.R.
Gonzalez, I.Q.
O'Connor, J.P.
Abeyakoon, O.
Parker, G.J.
Williams, K.J.
Gilbert, F.J.
Bohndiek, S.E.
(2017). Oxygen Enhanced Optoacoustic Tomography (OE-OT) Reveals Vascular Dynamics in Murine Models of Prostate Cancer. Theranostics,
Vol.7
(11),
pp. 2900-2913.
show abstract
Poor oxygenation of solid tumours has been linked with resistance to chemo- and radio-therapy and poor patient outcomes, hence non-invasive imaging of oxygen supply and demand in tumours could improve disease staging and therapeutic monitoring. Optoacoustic tomography (OT) is an emerging clinical imaging modality that provides static images of endogenous haemoglobin concentration and oxygenation. Here, we demonstrate oxygen enhanced (OE)-OT, exploiting an oxygen gas challenge to visualise the spatiotemporal heterogeneity of tumour vascular function. We show that tracking oxygenation dynamics using OE-OT reveals significant differences between two prostate cancer models in nude mice with markedly different vascular function (PC3 & LNCaP), which appear identical in static OT. LNCaP tumours showed a spatially heterogeneous response within and between tumours, with a substantial but slow response to the gas challenge, aligned with ex vivo analysis, which revealed a generally perfused and viable tumour with marked areas of haemorrhage. PC3 tumours had a lower fraction of responding pixels compared to LNCaP with a high disparity between rim and core response. While the PC3 core showed little or no dynamic response, the rim showed a rapid change, consistent with our ex vivo findings of hypoxic and necrotic core tissue surrounded by a rim of mature and perfused vasculature. OE-OT metrics are shown to be highly repeatable and correlate directly on a per-tumour basis to tumour vessel function assessed ex vivo. OE-OT provides a non-invasive approach to reveal the complex dynamics of tumour vessel perfusion, permeability and vasoactivity in real time. Our findings indicate that OE-OT holds potential for application in prostate cancer patients, to improve delineation of aggressive and indolent disease as well as in patient stratification for chemo- and radio-therapy..
O'Connor, J.P.
Aboagye, E.O.
Adams, J.E.
Aerts, H.J.
Barrington, S.F.
Beer, A.J.
Boellaard, R.
Bohndiek, S.E.
Brady, M.
Brown, G.
Buckley, D.L.
Chenevert, T.L.
Clarke, L.P.
Collette, S.
Cook, G.J.
deSouza, N.M.
Dickson, J.C.
Dive, C.
Evelhoch, J.L.
Faivre-Finn, C.
Gallagher, F.A.
Gilbert, F.J.
Gillies, R.J.
Goh, V.
Griffiths, J.R.
Groves, A.M.
Halligan, S.
Harris, A.L.
Hawkes, D.J.
Hoekstra, O.S.
Huang, E.P.
Hutton, B.F.
Jackson, E.F.
Jayson, G.C.
Jones, A.
Koh, D.-.
Lacombe, D.
Lambin, P.
Lassau, N.
Leach, M.O.
Lee, T.-.
Leen, E.L.
Lewis, J.S.
Liu, Y.
Lythgoe, M.F.
Manoharan, P.
Maxwell, R.J.
Miles, K.A.
Morgan, B.
Morris, S.
Ng, T.
Padhani, A.R.
Parker, G.J.
Partridge, M.
Pathak, A.P.
Peet, A.C.
Punwani, S.
Reynolds, A.R.
Robinson, S.P.
Shankar, L.K.
Sharma, R.A.
Soloviev, D.
Stroobants, S.
Sullivan, D.C.
Taylor, S.A.
Tofts, P.S.
Tozer, G.M.
van Herk, M.
Walker-Samuel, S.
Wason, J.
Williams, K.J.
Workman, P.
Yankeelov, T.E.
Brindle, K.M.
McShane, L.M.
Jackson, A.
Waterton, J.C.
(2017). Imaging biomarker roadmap for cancer studies. Nat rev clin oncol,
Vol.14
(3),
pp. 169-186.
show abstract
Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use..
O'Connor, J.P.
(2017). Cancer heterogeneity and imaging. Seminars in cell & developmental biology,
Vol.64,
pp. 48-57.
show abstract
There is interest in identifying and quantifying tumor heterogeneity at the genomic, tissue pathology and clinical imaging scales, as this may help better understand tumor biology and may yield useful biomarkers for guiding therapy-based decision making. This review focuses on the role and value of using x-ray, CT, MRI and PET based imaging methods that identify, measure and map tumor heterogeneity. In particular we highlight the potential value of these techniques and the key challenges required to validate and qualify these biomarkers for clinical use..
O'Connor, J.P.
(2017). Rethinking the role of clinical imaging. Elife,
Vol.6.
show abstract
Radiomics has the potential to improve the management of cancer patients, but further research is required before it can be adopted into routine clinical practice..
Waterton, J.C.
McShane, L.M.
O'Connor, J.P.
(2017). Erratum: Imaging biomarkers exist and they underpin clinical decision-making. Nature reviews clinical oncology,
Vol.14
(11),
pp. 694-694.
Salem, A.
O’Connor, J.P.
(2016). Assessment of Tumor Angiogenesis. Magnetic resonance imaging clinics of north america,
Vol.24
(1),
pp. 45-56.
O'Connor, J.P.
Boult, J.K.
Jamin, Y.
Babur, M.
Finegan, K.G.
Williams, K.J.
Little, R.A.
Jackson, A.
Parker, G.J.
Reynolds, A.R.
Waterton, J.C.
Robinson, S.P.
(2016). Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models. Cancer research,
Vol.76
(4),
pp. 787-795.
show abstract
There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic..
Wallace, T.E.
Patterson, A.J.
Abeyakoon, O.
Bedair, R.
Manavaki, R.
McLean, M.A.
O'Connor, J.P.
Graves, M.J.
Gilbert, F.J.
(2016). Detecting gas-induced vasomotor changes via blood oxygenation level-dependent contrast in healthy breast parenchyma and breast carcinoma. Journal of magnetic resonance imaging : jmri,
Vol.44
(2),
pp. 335-345.
show abstract
Purpose To evaluate blood oxygenation level-dependent (BOLD) contrast changes in healthy breast parenchyma and breast carcinoma during administration of vasoactive gas stimuli.Materials and methods Magnetic resonance imaging (MRI) was performed at 3T in 19 healthy premenopausal female volunteers using a single-shot fast spin echo sequence to acquire dynamic T2 -weighted images. 2% (n = 9) and 5% (n = 10) carbogen gas mixtures were interleaved with either medical air or oxygen in 2-minute blocks, for four complete cycles. A 12-minute medical air breathing period was used to determine background physiological modulation. Pixel-wise correlation analysis was applied to evaluate response to the stimuli in breast parenchyma and these results were compared to the all-air control. The relative BOLD effect size was compared between two groups of volunteers scanned in different phases of the menstrual cycle. The optimal stimulus design was evaluated in five breast cancer patients.Results Of the four stimulus combinations tested, oxygen vs. 5% carbogen produced a response that was significantly stronger (P < 0.05) than air-only breathing in volunteers. Subjects imaged during the follicular phase of their cycle when estrogen levels typically peak exhibited a significantly smaller BOLD response (P = 0.01). Results in malignant tissue were variable, with three out of five lesions exhibiting a diminished response to the gas stimulus.Conclusion Oxygen vs. 5% carbogen is the most robust stimulus for inducing BOLD contrast, consistent with the opposing vasomotor effects of these two gases. Measurements may be confounded by background physiological fluctuations and menstrual cycle changes. J. Magn. Reson. Imaging 2016;44:335-345..
Sharma, R.A.
Plummer, R.
Stock, J.K.
Greenhalgh, T.A.
Ataman, O.
Kelly, S.
Clay, R.
Adams, R.A.
Baird, R.D.
Billingham, L.
Brown, S.R.
Buckland, S.
Bulbeck, H.
Chalmers, A.J.
Clack, G.
Cranston, A.N.
Damstrup, L.
Ferraldeschi, R.
Forster, M.D.
Golec, J.
Hagan, R.M.
Hall, E.
Hanauske, A.-.
Harrington, K.J.
Haswell, T.
Hawkins, M.A.
Illidge, T.
Jones, H.
Kennedy, A.S.
McDonald, F.
Melcher, T.
O'Connor, J.P.
Pollard, J.R.
Saunders, M.P.
Sebag-Montefiore, D.
Smitt, M.
Staffurth, J.
Stratford, I.J.
Wedge, S.R.
NCRI CTRad Academia-Pharma Joint Working Group,
(2016). Clinical development of new drug-radiotherapy combinations. Nature reviews. clinical oncology,
Vol.13
(10),
pp. 627-642.
show abstract
In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer..
Ferl, G.Z.
O'Connor, J.P.
Parker, G.J.
Carano, R.A.
Acharya, S.J.
Jayson, G.C.
Port, R.E.
(2015). Mixed-effects modeling of clinical DCE-MRI data: Application to colorectal liver metastases treated with bevacizumab. Journal of magnetic resonance imaging,
Vol.41
(1),
pp. 132-141.
Doblas, S.
Almeida, G.S.
Blé, F.-.
Garteiser, P.
Hoff, B.A.
McIntyre, D.J.
Wachsmuth, L.
Chenevert, T.L.
Faber, C.
Griffiths, J.R.
Jacobs, A.H.
Morris, D.M.
O'Connor, J.P.
Robinson, S.P.
Van Beers, B.E.
Waterton, J.C.
(2015). Apparent diffusion coefficient is highly reproducible on preclinical imaging systems: Evidence from a seven-center multivendor study. Journal of magnetic resonance imaging,
Vol.42
(6),
pp. 1759-1764.
O'Connor, J.P.
Rose, C.J.
Waterton, J.C.
Carano, R.A.
Parker, G.J.
Jackson, A.
(2015). Imaging Intratumor Heterogeneity: Role in Therapy Response, Resistance, and Clinical Outcome. Clinical cancer research,
Vol.21
(2),
pp. 249-257.
show abstract
Abstract
Tumors exhibit genomic and phenotypic heterogeneity, which has prognostic significance and may influence response to therapy. Imaging can quantify the spatial variation in architecture and function of individual tumors through quantifying basic biophysical parameters such as CT density or MRI signal relaxation rate; through measurements of blood flow, hypoxia, metabolism, cell death, and other phenotypic features; and through mapping the spatial distribution of biochemical pathways and cell signaling networks using PET, MRI, and other emerging molecular imaging techniques. These methods can establish whether one tumor is more or less heterogeneous than another and can identify subregions with differing biology. In this article, we review the image analysis methods currently used to quantify spatial heterogeneity within tumors. We discuss how analysis of intratumor heterogeneity can provide benefit over more simple biomarkers such as tumor size and average function. We consider how imaging methods can be integrated with genomic and pathology data, instead of being developed in isolation. Finally, we identify the challenges that must be overcome before measurements of intratumoral heterogeneity can be used routinely to guide patient care. Clin Cancer Res; 21(2); 249–57. ©2014 AACR..
Rose, C.J.
O'Connor, J.P.
Cootes, T.F.
Taylor, C.J.
Jayson, G.C.
Parker, G.J.
Waterton, J.C.
(2014). Indexed distribution analysis for improved significance testing of spatially heterogeneous parameter maps: Application to dynamic contrast-enhanced MRI biomarkers. Magnetic resonance in medicine,
Vol.71
(3),
pp. 1299-1311.
Linnik, I.V.
Scott, M.L.
Holliday, K.F.
Woodhouse, N.
Waterton, J.C.
O'Connor, J.P.
Barjat, H.
Liess, C.
Ulloa, J.
Young, H.
Dive, C.
Hodgkinson, C.L.
Ward, T.
Roberts, D.
Mills, S.J.
Thompson, G.
Buonaccorsi, G.A.
Cheung, S.
Jackson, A.
Naish, J.H.
Parker, G.J.
(2014). Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma. Magnetic resonance in medicine,
Vol.71
(5),
pp. 1854-1862.
Hammond, E.M.
Asselin, M.-.
Forster, D.
O'Connor, J.P.
Senra, J.M.
Williams, K.J.
(2014). The Meaning, Measurement and Modification of Hypoxia in the Laboratory and the Clinic. Clinical oncology,
Vol.26
(5),
pp. 277-288.
Eccles, S.A.
Aboagye, E.O.
Ali, S.
Anderson, A.S.
Armes, J.
Berditchevski, F.
Blaydes, J.P.
Brennan, K.
Brown, N.J.
Bryant, H.E.
Bundred, N.J.
Burchell, J.M.
Campbell, A.M.
Carroll, J.S.
Clarke, R.B.
Coles, C.E.
Cook, G.J.
Cox, A.
Curtin, N.J.
Dekker, L.V.
dos Santos Silva, I.
Duffy, S.W.
Easton, D.F.
Eccles, D.M.
Edwards, D.R.
Edwards, J.
Evans, D.G.
Fenlon, D.F.
Flanagan, J.M.
Foster, C.
Gallagher, W.M.
Garcia-Closas, M.
Gee, J.M.
Gescher, A.J.
Goh, V.
Groves, A.M.
Harvey, A.J.
Harvie, M.
Hennessy, B.T.
Hiscox, S.
Holen, I.
Howell, S.J.
Howell, A.
Hubbard, G.
Hulbert-Williams, N.
Hunter, M.S.
Jasani, B.
Jones, L.J.
Key, T.J.
Kirwan, C.C.
Kong, A.
Kunkler, I.H.
Langdon, S.P.
Leach, M.O.
Mann, D.J.
Marshall, J.F.
Martin, L.A.
Martin, S.G.
Macdougall, J.E.
Miles, D.W.
Miller, W.R.
Morris, J.R.
Moss, S.M.
Mullan, P.
Natrajan, R.
O’Connor, J.P.
O’Connor, R.
Palmieri, C.
Pharoah, P.D.
Rakha, E.A.
Reed, E.
Robinson, S.P.
Sahai, E.
Saxton, J.M.
Schmid, P.
Smalley, M.J.
Speirs, V.
Stein, R.
Stingl, J.
Streuli, C.H.
Tutt, A.N.
Velikova, G.
Walker, R.A.
Watson, C.J.
Williams, K.J.
Young, L.S.
Thompson, A.M.
(2013). Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast cancer research,
Vol.15
(5).
O'Connor, J.P.
Jackson, A.
Parker, G.J.
Roberts, C.
Jayson, G.C.
(2012). Dynamic contrast-enhanced MRI in clinical trials of antivascular therapies. Nature reviews clinical oncology,
Vol.9
(3),
pp. 167-177.
Asselin, M.-.
O’Connor, J.P.
Boellaard, R.
Thacker, N.A.
Jackson, A.
(2012). Quantifying heterogeneity in human tumours using MRI and PET. European journal of cancer,
Vol.48
(4),
pp. 447-455.
O'Connor, J.P.
Jayson, G.C.
(2012). Do imaging biomarkers relate to outcome in patients treated with VEGF inhibitors?. Clinical cancer research : an official journal of the american association for cancer research,
Vol.18
(24),
pp. 6588-6598.
show abstract
The management of solid tumors has been transformed by the advent of VEGF pathway inhibitors. Early clinical evaluation of these drugs has used pharmacodynamic biomarkers derived from advanced imaging such as dynamic MRI, computed tomography (CT), and ultrasound to establish proof of principle. We have reviewed published studies that used these imaging techniques to determine whether the same biomarkers relate to survival in renal, hepatocellular, and brain tumors in patients treated with VEGF inhibitors. Data show that in renal cancer, pretreatment measurements of K(trans) and early pharmacodynamic reduction in tumor enhancement and density have prognostic significance in patients treated with VEGF inhibitors. A weaker, but significant, relationship is seen with subtle early size change (10% in one dimension) and survival. Data from high-grade glioma suggest that pretreatment fractional blood volume and K(trans) were prognostic of overall survival. However, lack of control data with other therapies prevents assessment of the predictive nature of these biomarkers, and such studies are urgently required..
Greystoke, A.
O'Connor, J.P.
Linton, K.
Taylor, M.B.
Cummings, J.
Ward, T.
Maders, F.
Hughes, A.
Ranson, M.
Illidge, T.M.
Radford, J.
Dive, C.
(2011). Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma. British journal of cancer,
Vol.104
(4),
pp. 719-725.
O'Connor, J.P.
Rose, C.J.
Jackson, A.
Watson, Y.
Cheung, S.
Maders, F.
Whitcher, B.J.
Roberts, C.
Buonaccorsi, G.A.
Thompson, G.
Clamp, A.R.
Jayson, G.C.
Parker, G.J.
(2011). DCE-MRI biomarkers of tumour heterogeneity predict CRC liver metastasis shrinkage following bevacizumab and FOLFOX-6. British journal of cancer,
Vol.105
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pp. 139-145.
Mitchell, C.L.
O’Connor, J.P.
Roberts, C.
Watson, Y.
Jackson, A.
Cheung, S.
Evans, J.
Spicer, J.
Harris, A.
Kelly, C.
Rudman, S.
Middleton, M.
Fielding, A.
Tessier, J.
Young, H.
Parker, G.J.
Jayson, G.C.
(2011). A two-part Phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics. Cancer chemotherapy and pharmacology,
Vol.68
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pp. 631-641.
Thompson, G.
Mills, S.J.
Coope, D.J.
O’connor, J.P.
Jackson, A.
(2011). Imaging biomarkers of angiogenesis and the microvascular environment in cerebral tumours. The british journal of radiology,
Vol.84
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pp. S127-S144.
O'Connor, J.P.
Tofts, P.S.
Miles, K.A.
Parkes, L.M.
Thompson, G.
Jackson, A.
(2011). Dynamic contrast-enhanced imaging techniques: CT and MRI. The british journal of radiology,
Vol.84
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pp. S112-S120.
Donaldson, S.B.
Buckley, D.L.
O'Connor, J.P.
Davidson, S.E.
Carrington, B.M.
Jones, A.P.
West, C.M.
(2010). Enhancing fraction measured using dynamic contrast-enhanced MRI predicts disease-free survival in patients with carcinoma of the cervix. British journal of cancer,
Vol.102
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pp. 23-26.
Zee, Y.-.
O'Connor, J.P.
Parker, G.J.
Jackson, A.
Clamp, A.R.
Taylor, M.B.
Clarke, N.W.
Jayson, G.C.
(2010). Imaging angiogenesis of genitourinary tumors. Nature reviews urology,
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Mills, S.J.
Soh, C.
O'Connor, J.P.
Rose, C.J.
Buonaccorsi, G.
Cheung, S.
Zhao, S.
Parker, G.J.
Jackson, A.
(2010). Enhancing Fraction in Glioma and Its Relationship to the Tumoral Vascular Microenvironment: A Dynamic Contrast-Enhanced MR Imaging Study. American journal of neuroradiology,
Vol.31
(4),
pp. 726-731.
Mitchell, C.L.
O'Connor, J.P.
Jackson, A.
Parker, G.J.
Roberts, C.
Watson, Y.
Cheung, S.
Davies, K.
Buonaccorsi, G.A.
Clamp, A.R.
Hasan, J.
Byrd, L.
Backen, A.
Dive, C.
Jayson, G.C.
(2010). Identification of early predictive imaging biomarkers and their relationship to serological angiogenic markers in patients with ovarian cancer with residual disease following cytotoxic therapy. Annals of oncology,
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pp. 1982-1989.
Buonaccorsi, G.A.
Rose, C.J.
O’Connor, J.P.
Roberts, C.
Watson, Y.
Jackson, A.
Jayson, G.C.
Parker, G.J.
(2010). Cross-Visit Tumor Sub-segmentation and Registration with Outlier Rejection for Dynamic Contrast-Enhanced MRI Time Series Data. ,
,
pp. 121-128.
O'Connor, J.P.
Carano, R.A.
Clamp, A.R.
Ross, J.
Ho, C.C.
Jackson, A.
Parker, G.J.
Rose, C.J.
Peale, F.V.
Friesenhahn, M.
Mitchell, C.L.
Watson, Y.
Roberts, C.
Hope, L.
Cheung, S.
Reslan, H.B.
Go, M.A.
Pacheco, G.J.
Wu, X.
Cao, T.C.
Ross, S.
Buonaccorsi, G.A.
Davies, K.
Hasan, J.
Thornton, P.
del Puerto, O.
Ferrara, N.
van Bruggen, N.
Jayson, G.C.
(2009). Quantifying Antivascular Effects of Monoclonal Antibodies to Vascular Endothelial Growth Factor: Insights from Imaging. Clinical cancer research,
Vol.15
(21),
pp. 6674-6682.
show abstract
Abstract
Purpose: Little is known concerning the onset, duration, and magnitude of direct therapeutic effects of anti–vascular endothelial growth factor (VEGF) therapies. Such knowledge would help guide the rational development of targeted therapeutics from bench to bedside and optimize use of imaging technologies that quantify tumor function in early-phase clinical trials.
Experimental Design: Preclinical studies were done using ex vivo microcomputed tomography and in vivo ultrasound imaging to characterize tumor vasculature in a human HM-7 colorectal xenograft model treated with the anti-VEGF antibody G6-31. Clinical evaluation was by quantitative magnetic resonance imaging in 10 patients with metastatic colorectal cancer treated with bevacizumab.
Results: Microcomputed tomography experiments showed reduction in perfused vessels within 24 to 48 h of G6-31 drug administration (P ≤ 0.005). Ultrasound imaging confirmed reduced tumor blood volume within the same time frame (P = 0.048). Consistent with the preclinical results, reductions in enhancing fraction and fractional plasma volume were detected in patient colorectal cancer metastases within 48 h after a single dose of bevacizumab that persisted throughout one cycle of therapy. These effects were followed by resolution of edema (P = 0.0023) and tumor shrinkage in 9 of 26 tumors at day 12.
Conclusion: These data suggest that VEGF-specific inhibition induces rapid structural and functional effects with downstream significant antitumor activity within one cycle of therapy. This finding has important implications for the design of early-phase clinical trials that incorporate physiologic imaging. The study shows how animal data help interpret clinical imaging data, an important step toward the validation of image biomarkers of tumor structure and function. (Clin Cancer Res 2009;15(21):6674–82).
O'Connor, J.P.
Naish, J.H.
Jackson, A.
Waterton, J.C.
Watson, Y.
Cheung, S.
Buckley, D.L.
McGrath, D.M.
Buonaccorsi, G.A.
Mills, S.J.
Roberts, C.
Jayson, G.C.
Parker, G.J.
(2009). Comparison of normal tissue R
1
and R
*2 modulation by oxygen and carbogen. Magnetic resonance in medicine,
Vol.61
(1),
pp. 75-83.
Mills, S.J.
Soh, C.
O’Connor, J.P.
Rose, C.J.
Buonaccorsi, G.A.
Cheung, S.
Zhao, S.
Parker, G.J.
Jackson, A.
(2009). Tumour enhancing fraction (EnF) in glioma: relationship to tumour grade. European radiology,
Vol.19
(6),
pp. 1489-1498.
Rose, C.J.
Mills, S.J.
O'Connor, J.P.
Buonaccorsi, G.A.
Roberts, C.
Watson, Y.
Cheung, S.
Zhao, S.
Whitcher, B.
Jackson, A.
Parker, G.J.
(2009). Quantifying spatial heterogeneity in dynamic contrast-enhanced MRI parameter maps. Magnetic resonance in medicine,
Vol.62
(2),
pp. 488-499.
O'Connor, J.P.
Naish, J.H.
Parker, G.J.
Waterton, J.C.
Watson, Y.
Jayson, G.C.
Buonaccorsi, G.A.
Cheung, S.
Buckley, D.L.
McGrath, D.M.
West, C.M.
Davidson, S.E.
Roberts, C.
Mills, S.J.
Mitchell, C.L.
Hope, L.
Ton, N.C.
Jackson, A.
(2009). Preliminary Study of Oxygen-Enhanced Longitudinal Relaxation in MRI: A Potential Novel Biomarker of Oxygenation Changes in Solid Tumors. International journal of radiation oncology*biology*physics,
Vol.75
(4),
pp. 1209-1215.
McGrath, D.M.
Naish, J.H.
O'Connor, J.P.
Hutchinson, C.E.
Waterton, J.C.
Taylor, C.J.
Parker, G.J.
(2008). Oxygen-induced changes in longitudinal relaxation times in skeletal muscle. Magnetic resonance imaging,
Vol.26
(2),
pp. 221-227.
Roberts, C.
Parker, G.J.
Rose, C.J.
Watson, Y.
O'Connor, J.P.
Stivaros, S.M.
Jackson, A.
Rushton, V.E.
(2008). Glandular Function in Sjögren Syndrome: Assessment with Dynamic Contrast-enhanced MR Imaging and Tracer Kinetic Modeling—Initial Experience. Radiology,
Vol.246
(3),
pp. 845-853.
O'Connor, J.P.
Jackson, A.
Asselin, M.-.
Buckley, D.L.
Parker, G.J.
Jayson, G.C.
(2008). Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives. The lancet oncology,
Vol.9
(8),
pp. 766-776.
O'Connor, J.P.
Jackson, A.
Parker, G.J.
Jayson, G.C.
(2007). DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents. British journal of cancer,
Vol.96
(2),
pp. 189-195.
O'Connor, J.P.
Jackson, A.
Buonaccorsi, G.A.
Buckley, D.L.
Roberts, C.
Watson, Y.
Cheung, S.
McGrath, D.M.
Naish, J.H.
Rose, C.J.
Dark, P.M.
Jayson, G.C.
Parker, G.J.
(2007). Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times. Magnetic resonance in medicine,
Vol.58
(3),
pp. 490-496.
Buonaccorsi, G.A.
O'Connor, J.P.
Caunce, A.
Roberts, C.
Cheung, S.
Watson, Y.
Davies, K.
Hope, L.
Jackson, A.
Jayson, G.C.
Parker, G.J.
(2007). Tracer kinetic model–driven registration for dynamic contrast-enhanced MRI time-series data. Magnetic resonance in medicine,
Vol.58
(5),
pp. 1010-1019.
O'Connor, J.P.
Jayson, G.C.
Jackson, A.
Ghiorghiu, D.
Carrington, B.M.
Rose, C.J.
Mills, S.J.
Swindell, R.
Roberts, C.
Mitchell, C.L.
Parker, G.J.
(2007). Enhancing Fraction Predicts Clinical Outcome following First-Line Chemotherapy in Patients with Epithelial Ovarian Carcinoma. Clinical cancer research,
Vol.13
(20),
pp. 6130-6135.
show abstract
Abstract
Purpose: To define a simple radiologic biomarker of prognosis in patients with advanced epithelial ovarian carcinoma on first-line chemotherapy.
Experimental Design: Twenty-seven patients receiving platinum-based chemotherapy with >2 cm residual disease [International Federation of Gynecology and Obstetrics (FIGO) stages IIIC or IV] after surgery were identified. The proportion of enhancing tumor tissue—the enhancing fraction—was calculated on pre-chemotherapy computed tomography scans at four Hounsfield unit (HU) thresholds and assessed for correlation with CA125 response, Response Evaluation Criteria in Solid Tumors (RECIST) radiologic response, and time to progression. Discriminative power was assessed by leave-one-out discriminant analysis.
Results: Pre-chemotherapy residual tumor volume did not correlate with clinical outcome. Pre-chemotherapy enhancing fraction at all thresholds significantly correlated with CA125 response (P < 0.001, ρ = 0.553 for 50 HU; P < 0.001, ρ = 0.565 for 60 HU; P < 0.001, ρ = 0.553 for 70 HU; P = 0.001, ρ = 0.516 for 80 HU). Significant correlations were also shown for radiologic response at all thresholds. Enhancing fraction predicted CA125 response with 81.9% to 86.4% specificity and Response Evaluation Criteria in Solid Tumors response with 74.9% to 76.8% specificity at 95% sensitivity (dependent on threshold). Enhancing fraction correlated with time to progression at the 60 HU (P = 0.045, ρ = 0.336) and 70 HU (P = 0.042; ρ = 0.340) thresholds.
Conclusion: Pre-chemotherapy enhancing fraction is a simple quantitative radiologic measure. Further evaluation in larger trials is required to confirm the potential of enhancing fraction as a predictive factor, particularly for patients who may benefit from the addition of antiangiogenic therapy..
Jackson, A.
O'Connor, J.P.
Parker, G.J.
Jayson, G.C.
(2007). Imaging Tumor Vascular Heterogeneity and Angiogenesis using Dynamic Contrast-Enhanced Magnetic Resonance Imaging. Clinical cancer research,
Vol.13
(12),
pp. 3449-3459.
show abstract
Abstract
This article reviews the application of dynamic contrast-enhanced magnetic resonance imaging in both clinical studies and early-phase trials of angiogenesis inhibitors. Emphasis is placed on how variation in image acquisition and analysis affects the meaning and use of derived variables. We then review the potential for future developments, with particular reference to the application of dynamic contrast-enhanced magnetic resonance imaging to evaluate the heterogeneity of tumor tissues..
Buonaccorsi, G.A.
Roberts, C.
Cheung, S.
Watson, Y.
O’Connor, J.P.
Davies, K.
Jackson, A.
Jayson, G.C.
Parker, G.J.
(2006). Comparison of the Performance of Tracer Kinetic Model-Driven Registration for Dynamic Contrast Enhanced MRI Using Different Models of Contrast Enhancement. Academic radiology,
Vol.13
(9),
pp. 1112-1123.
Hofmann, U.
O'Connor, J.P.
Biyani, C.S.
Harnden, P.
Selby, P.
Weston, P.M.
(2006). Retroperitoneal metastatic squamous cell carcinoma of the tonsil (with elevated beta human chorionic gonadotrophin): a misdiagnosis as extra-gonadal germ cell tumour. The journal of laryngology & otology,
Vol.120
(10),
pp. 885-887.
show abstract
Head and neck cancers usually spread first to the regional lymph nodes but rarely may metastasize to distant sites. Metastasis to distant lymph node groups is a rare event. Furthermore, delayed multiple metastases without local recurrence is relatively uncommon. A case of retroperitoneal metastasis from a squamous cell carcinoma of the tonsil, secreting beta human chorionic gonadotrophin (β-hCG), is reported.A 58-year-old man had undergone a tonsillectomy and chemo-radiotherapy for squamous cell carcinoma of the left tonsil and 13 months later presented with non-specific abdominal pain. The serum β-hCG levels were high and an abdominal ultrasound scan revealed hydronephrosis on the left side. A computed tomography scan demonstrated para-aortic retroperitoneal lymphadenopathy. The patient underwent an open lymph node biopsy. The initial pathological analysis was interpreted as extra-gonadal germ cell tumour and the patient received chemotherapy. A subsequent review was consistent with a metastatic squamous cell carcinoma of the tonsil, as immunohistochemical studies showed positive staining for epithelial membrane antigen and cytokeratins 5/6 but a negative reaction to placental alkaline phosphatase. Following this, the chemotherapy regimen was changed; however, a restaging scan demonstrated progression, and the patient died from aspiration pneumonia secondary to alcohol intoxication.To our knowledge, this is the first reported case of retroperitoneal metastasis from a squamous cell carcinoma of the tonsil, secreting β-hCG and causing hydronephrosis. This case highlights the necessity of using clinical, histological, immunohistological and ultrastructural examination to establish precise diagnosis and to avoid inappropriate treatment..
Sooriakumaran, P.
O'Connor, J.
Underwood, T.
(2005). Trainees advisory group for the international campaign to revitalise academic medicine: Have your say in shaping the future of medical education, research and clinical practice. International journal of surgery,
Vol.3
(1),
pp. 99-100.
O'Connor, J.P.
(2004). Academic medicine: time for reinvention: Medical education, training, and research are under threat because academic medicine is undervalued. Bmj,
Vol.328
(7430).
O'Connor, J.P.
Biyani, C.S.
Taylor, J.
Agarwal, V.
Curley, P.J.
Browning, A.J.
(2004). Laparoscopic Nephrectomy for Renal-Cell Carcinoma during Pregnancy. Journal of endourology,
Vol.18
(9),
pp. 871-874.
(2004). Objective assessment of technical skills in surgery. Bmj,
Vol.328
(7436),
pp. 403.2-403.2.
O'Connor, J.P.
(2003). Thomas Willis and the background to Cerebri Anatome. Jrsm,
Vol.96
(3),
pp. 139-143.
Hindle, A.
(2003). Managing acute renal colic. Bmj,
Vol.326
(7387),
pp. 502-502.
O’CONNOR, J.P.
BIYANI, C.S.
AUSTIN, O.M.
BROWNING, A.J.
(2003). Necrotizing Fasciitis: A Rare Complication of an Infected Urachal Remnant in Adults. Journal of urology,
Vol.170
(3),
pp. 920-921.
BIYANI, C.S.
O’CONNOR, J.P.
BROWNING, A.J.
(2003). Laparoscopic Removal Of Retained Nephrostomy Tubing. Journal of urology,
Vol.170
(3),
pp. 916-917.
Mahmood, R.D.
Shaw, D.
Descamps, T.
Zhou, C.
Morgan, R.D.
Mullamitha, S.
Saunders, M.
Mescallado, N.
Backen, A.
Morris, K.
Little, R.A.
Cheung, S.
Watson, Y.
O'Connor, J.P.
Jackson, A.
Parker, G.J.
Dive, C.
Jayson, G.C.
Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study. Bmc cancer,
Vol.21
(1),
pp. 354-?.
show abstract
Background Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers.Methods A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS).Results Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, K trans , increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025).Conclusions In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, K trans , offers promise to direct molecularly targeted therapies such as anti-angiogenic agents..