• Blood-brain barrier permeability of normal-appearing white matter in patients with vestibular schwannoma: a new hybrid approach for analysis of T1 -W DCE-MRI.

      Li, Ka-Loh; Zhu, Xiaoping; Zhao, Sha; Jackson, Alan; Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK (2017-07)
      To develop and assess a "hybrid" method that combines a first-pass analytical approach and the Patlak plot (PP) to improve assessment of low blood-brain barrier permeability from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) data.
    • Comparison of normal tissue R1 and R*2 modulation by oxygen and carbogen.

      O'Connor, James P B; Naish, Josephine H; Jackson, Alan; Waterton, John C; Watson, Yvonne; Cheung, Susan; Buckley, David L; McGrath, Deirdre M; Buonaccorsi, Giovanni A; Mills, Samantha J; et al. (2009-01)
      Magnetic resonance imaging has shown promise for evaluating tissue oxygenation. In this study differences in the tissue longitudinal relaxation rate (R(1)) and effective transverse relaxation rate (R(*)(2)), induced by inhalation of pure oxygen and carbogen, were evaluated in 10 healthy subjects. Significant reductions in R(1) were demonstrated following both oxygen and carbogen inhalation in the spleen (both P < 0.001), liver (P = 0.002 air vs. oxygen; P = 0.001 air vs. carbogen), skeletal muscle (both P < 0.001), and renal cortex (P = 0.005 air vs. oxygen; P = 0.008 air vs. carbogen). No significant change in R(*)(2) occurred following pure oxygen in any organ. However, a significant increase in R(*)(2) was observed in the spleen (P < 0.001), liver (P = 0.001), skeletal muscle (P = 0.026), and renal cortex (P = 0.001) following carbogen inhalation, an opposite effect to that observed in many studies of tumor pathophysiology. Changes in R(1) and R(*)(2) were independent of the gas administration order in the spleen and skeletal muscle. These findings suggest that the R(1) and R(*)(2) responses to hyperoxic gases are independent biomarkers of oxygen physiology.
    • DCE-MRI biomarkers in the clinical evaluation of antiangiogenic and vascular disrupting agents.

      O'Connor, James P B; Jackson, Alan; Parker, Geoff J M; Jayson, Gordon C; Imaging Science and Biomedical Engineering, University of Manchester, Oxford Road, Manchester M13 9PT, UK.james.o'connor@manchester.ac.uk (2007-01-29)
      Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is now frequently used in early clinical trial assessment of antiangiogenic and vascular disrupting compounds. Evidence of drug efficacy and dose-dependent response has been demonstrated with some angiogenesis inhibitors. This review highlights the critical issues that influence T(1)-weighted DCE-MRI data acquisition and analysis, identifies important areas for future development and reviews the clinical trial findings to date.
    • Enhancing fraction predicts clinical outcome following first-line chemotherapy in patients with epithelial ovarian carcinoma.

      O'Connor, James P B; Jayson, Gordon C; Jackson, Alan; Ghiorghiu, Dana; Carrington, Bernadette M; Rose, Chris J; Mills, Samantha J; Swindell, Ric; Roberts, Caleb; Mitchell, Claire L; et al. (2007-10-15)
      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, rho = 0.553 for 50 HU; P < 0.001, rho = 0.565 for 60 HU; P < 0.001, rho = 0.553 for 70 HU; P = 0.001, rho = 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, rho = 0.336) and 70 HU (P = 0.042; rho = 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.
    • Experimentally-derived functional form for a population-averaged high-temporal-resolution arterial input function for dynamic contrast-enhanced MRI.

      Parker, Geoff J M; Roberts, Caleb; Macdonald, Andrew; Buonaccorsi, Giovanni A; Cheung, Susan; Buckley, David L; Jackson, Alan; Watson, Yvonne; Davies, Karen; Jayson, Gordon C; et al. (2006-11)
      Rapid T(1)-weighted 3D spoiled gradient-echo (GRE) data sets were acquired in the abdomen of 23 cancer patients during a total of 113 separate visits to allow dynamic contrast-enhanced MRI (DCE-MRI) analysis of tumor microvasculature. The arterial input function (AIF) was measured in each patient at each visit using an automated AIF extraction method following a standardized bolus administration of gadodiamide. The AIFs for each patient were combined to obtain a mean AIF that is representative for any individual. The functional form of this general AIF may be useful for studies in which AIF measurements are not possible. Improvements in the reproducibility of DCE-MRI model parameters (K(trans), v(e), and v(p)) were observed when this new, high-temporal-resolution population AIF was used, indicating the potential for increased sensitivity to therapy-induced change.
    • Imaging tumor vascular heterogeneity and angiogenesis using dynamic contrast-enhanced magnetic resonance imaging

      Jackson, Alan; O'Connor, James P B; Parker, Geoff J M; Jayson, Gordon C; Imaging Science and Biomedical Engineering, University of Manchester, Manchester, United Kingdom. (2007-06-15)
      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.
    • Implementing diffusion-weighted MRI for body imaging in prospective multicentre trials: current considerations and future perspectives.

      deSouza, N; Winfield, J; Waterton, John C; Weller, A; Papoutsaki, M-V; Doran, S; Collins, D; Fournier, L; Sullivan, D; Chenevert, T; et al. (2017-09-27)
      For body imaging, diffusion-weighted MRI may be used for tumour detection, staging, prognostic information, assessing response and follow-up. Disease detection and staging involve qualitative, subjective assessment of images, whereas for prognosis, progression or response, quantitative evaluation of the apparent diffusion coefficient (ADC) is required. Validation and qualification of ADC in multicentre trials involves examination of i) technical performance to determine biomarker bias and reproducibility and ii) biological performance to interrogate a specific aspect of biology or to forecast outcome. Unfortunately, the variety of acquisition and analysis methodologies employed at different centres make ADC values non-comparable between them. This invalidates implementation in multicentre trials and limits utility of ADC as a biomarker. This article reviews the factors contributing to ADC variability in terms of data acquisition and analysis. Hardware and software considerations are discussed when implementing standardised protocols across multi-vendor platforms together with methods for quality assurance and quality control. Processes of data collection, archiving, curation, analysis, central reading and handling incidental findings are considered in the conduct of multicentre trials. Data protection and good clinical practice are essential prerequisites. Developing international consensus of procedures is critical to successful validation if ADC is to become a useful biomarker in oncology.
    • Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.

      Jayson, Gordon C; Zweit, Jamal; Jackson, Alan; Mulatero, Clive; Julyan, Peter J; Ranson, Malcolm R; Broughton, Lynn; Wagstaff, John; Hakannson, L; Groenewegen, Gerard; et al. (2002-10-02)
      BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic cytokine, and various inhibitory agents, including specific antibodies, have been developed to block VEGF-stimulated angiogenesis. We developed HuMV833, a humanized version of a mouse monoclonal anti-VEGF antibody (MV833) that has antitumor activity against a number of human tumor xenografts, and investigated the distribution and biologic effects of HuMV833 in patients in a phase I trial. METHODS: Twenty patients with progressive solid tumors were treated with various doses of HuMV833 (0.3, 1, 3, or 10 mg/kg). Positron emission tomography with (124)I-HuMV833 was used to measure the antibody distribution in and clearance from tissues. Magnetic resonance imaging was used to measure the vascular permeability surface area product with a first-pass pharmacokinetic model (k(fp)) to determine tumor vascular permeability. RESULTS: The antibody was generally well tolerated, although the incremental dose, phase I study design, and pharmacodynamic endpoints could not identify the optimum biologically active dose. Antibody distribution and clearance were markedly heterogeneous between and within patients and between and within individual tumors. HuMV833 distribution to normal tissues also varied among patients, but the antibody was cleared from these tissues in a homogeneous fashion. Permeability was strongly heterogeneous between and within patients and between and within individual tumors. All tumors showed a reduction in k(fp) 48 hours after the first treatment (median = 44%; range = 4%-91%). CONCLUSIONS: Because of the heterogeneity in tumor biology with respect to antibody uptake and clearance, we suggest that either intrapatient dose escalation approaches or larger, more precisely defined patient cohorts would be preferable to conventional strategies in the design of phase I studies with antiangiogenic compounds like HuMV833.
    • Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times.

      O'Connor, James P B; Jackson, Alan; Buonaccorsi, Giovanni A; Buckley, David L; Roberts, Caleb; Watson, Yvonne; Cheung, Susan; McGrath, Deirdre M; Naish, Josephine H; Rose, Chris J; et al. (2007-09)
      Molecular oxygen has been previously shown to shorten longitudinal relaxation time (T1) in the spleen and renal cortex, but not in the liver or fat. In this study, the magnitude and temporal evolution of this effect were investigated. Medical air, oxygen, and carbogen (95% oxygen/5% CO2) were administered sequentially in 16 healthy volunteers. T1 maps were acquired using spoiled gradient echo sequences (TR=3.5 ms, TE=0.9 ms, alpha=2 degrees/8 degrees/17 degrees) with six acquisitions on air, 12 on oxygen, 12 on carbogen, and six to 12 back on air. Mean T1 values and change in relaxation rate were compared between each phase of gas inhalation in the liver, spleen, skeletal muscle, renal cortex, and fat by one-way analysis of variance. Oxygen-induced T1-shortening occurred in the liver in fasted subjects (P<0.001) but not in non-fasted subjects (P=0.244). T1-shortening in spleen and renal cortex (both P<0.001) were greater than previously reported. Carbogen induced conflicting responses in different organs, suggesting a complex relationship with organ vasculature. Shortening of tissue T1 by oxygen is more pronounced and more complex than previously recognized. The effect may be useful as a biomarker of arterial flow and oxygen delivery to vascular beds.
    • Phase I evaluation of a fully human anti-alphav integrin monoclonal antibody (CNTO 95) in patients with advanced solid tumors

      Mullamitha, Saifee A; Ton, Nhuan C; Parker, Geoff J M; Jackson, Alan; Julyan, Peter J; Roberts, Caleb; Buonaccorsi, Giovanni A; Watson, Yvonne; Davies, Karen; Cheung, Susan; et al. (2007-04-01)
      PURPOSE: A fully human monoclonal antibody to anti-alpha(v) integrins (CNTO 95) has been shown to inhibit angiogenesis and tumor growth in preclinical studies. We assessed the safety and pharmacokinetics of CNTO 95 in patients with advanced refractory solid tumors. EXPERIMENTAL DESIGN: In this phase I trial, CNTO 95 (0.1, 0.3, 1.0, 3.0, and 10.0 mg/kg) was infused on days 0, 28, 35, and 42, and clinical assessments, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and [(18)F]-2-fluorodeoxyglucose positron emission tomography (FDG-PET) were done. Patients achieving stable disease or better were eligible for extended dosing every 3 weeks for up to 12 months. RESULTS: Among the 24 enrolled patients, CNTO 95 was associated with one episode of grade III and four episodes of grade II infusion-related fever (all responded to acetaminophen). Of the six patients who received extended dosing, one patient (10.0 mg/kg), with cutaneous angiosarcoma, had a 9-month partial response. Pre- and post-treatment lesion biopsies confirmed tumor cell alpha(v) integrin expression, as well as CNTO 95 penetration of the tumor and localization to tumor cells in association with reduced bcl-2 expression. A lesion in one patient (10.0 mg/kg) with stable ovarian carcinosarcoma was no longer detectable by FDG-PET by day 49. Exposure to CNTO 95 seemed to increase in a greater-than-dose-proportional manner; dose-dependent mean half-life ranged from 0.26 to 6.7 days. CONCLUSIONS: CNTO 95 was generally well tolerated. Six patients received extended therapy, including one patient with a prolonged response. Biopsy data confirmed tumor localization and pharmacodynamic activity.
    • Phase I evaluation of CDP791, a PEGylated di-Fab' conjugate that binds vascular endothelial growth factor receptor 2.

      Ton, Nhuan C; Parker, Geoff J M; Jackson, Alan; Mullamitha, Saifee A; Buonaccorsi, Giovanni A; Roberts, Caleb; Watson, Yvonne; Davies, Karen; Cheung, Susan; Hope, Lynn; et al. (2007-12-01)
      PURPOSE: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report the first phase I clinical trial evaluation of CDP791, a PEGylated di-Fab' conjugate that binds VEGFR-2. EXPERIMENTAL DESIGN: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses. RESULTS: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising 28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), there was a significant dose level-related reduction in tumor growth. While challenging the recent dogma that active VEGF inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no partial or complete responses were seen. CONCLUSION: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered at 10 mg/kg or more every 3 weeks.
    • Phase I investigation of recombinant anti-human vascular endothelial growth factor antibody in patients with advanced cancer.

      Jayson, Gordon C; Mulatero, Clive; Ranson, Malcolm R; Zweit, Jamal; Jackson, Alan; Broughton, Lynn; Wagstaff, John; Hakansson, Leif; Groenewegen, Gerard; Lawrance, Jeremy A L; et al. (2005-03)
      We assessed the tolerability, safety, pharmacokinetics and dose-limiting toxicity (DLT) of the recombinant humanized IgG4 anti-vascular endothelial growth factor (VEGF) monoclonal antibody, HuMV833, in patients with advanced cancer. Cohorts of patients with progressive solid tumours received escalating doses of HuMV833 as a 1-h intravenous (I.V.) infusion on days 1, 15, 22, and 29. Twenty patients (median Eastern Cooperative Oncology Group (ECOG) score 1) were accrued. HuMV833 infusions were well tolerated and there were no grade III or IV toxicities definitely related to the antibody. Grade I or II toxicities probably related to the antibody included fatigue, dyspnoea and rash. There were two episodes of asymptomatic hypocalcaemia, one at grade III and one grade IV, which were recorded in early follow-up. There were eight grade I episodes of asymptomatic elevation of activated partial thromboplastin time (APTT) and two grade III events; one in a patient receiving 1 mg/kg and the other receiving extended doses of 10 mg/kg. Pharmacokinetic analysis revealed a non-linear kinetic and an elimination half-life of between 8.2 (0.3 mg/kg) and 18.7 (10 mg/kg) days. One patient with ovarian cancer experienced a partial response (PR) of 9 months duration and eight had disease stabilisation (SD) including one patient with colorectal carcinoma whose disease was stable for 14 months. In 13 of the 14 samples taken from 12 patients, the plasma concentration of hepatocyte growth factor (HGF) was reduced 24 h after drug administration. HuMV833 is safe and lacked DLT at doses up to 10 mg/kg on this schedule. Multiple doses were well tolerated, despite occasional asymptomatic elevations in APTT. By combining pharmacokinetic, pharmacodynamic and toxicity data, we can identify doses of 1 and 3mg/kg for further investigation. HuMV833 appears to possess some clinical activity.
    • Quantifying antivascular effects of monoclonal antibodies to vascular endothelial growth factor: insights from imaging.

      O'Connor, James P B; Carano, Richard A D; Clamp, Andrew R; Ross, Jed; Ho, Calvin C K; Jackson, Alan; Parker, Geoff J M; Rose, Chris J; Peale, Franklin V; Friesenhahn, Michel; et al. (2009)
    • Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives.

      O'Connor, James P B; Jackson, Alan; Asselin, Marie-Claude; Buckley, David L; Parker, Geoff J M; Jayson, Gordon C; Imaging Science and Biomedical Engineering, University of Manchester, Manchester, UK. james.o'connor@manchester.ac.uk (2008-08)
      Targeted therapeutics have challenged how imaging techniques assess tumour response to treatment because many new agents are thought to cause cytostasis rather than cytotoxicity. Advanced tracer development, image acquisition, and image analysis have been used to produce quantitative biomarkers of pathophysiology, with particular focus on measurement of tumour vascular characteristics. Here, we critically appraise strategies available to generate imaging biomarkers for use in development of targeted therapeutics. We consider important practical and technical features of data acquisition and analysis because these factors determine the precise physiological meaning of every biomarker. We discuss the merits of volume-based and other size-based metrics for assessment of targeted therapeutics, and we examine the strengths and weaknesses of CT, MRI, and PET biomarkers derived from conventional clinical data. We review imaging biomarkers of tumour microvasculature and discuss imaging strategies that probe other physiological processes including cell proliferation, apoptosis, and tumour invasion. We conclude on the need to develop comprehensive compound-specific imaging biomarkers that are appropriate for every class of targeted therapeutics, and to investigate the complementary information given in multimodality imaging studies of targeted therapeutics.
    • Tracer kinetic model-driven registration for dynamic contrast-enhanced MRI time-series data.

      Buonaccorsi, Giovanni A; O'Connor, James P B; Caunce, Angela; Roberts, Caleb; Cheung, Susan; Watson, Yvonne; Davies, Karen; Hope, Lynn; Jackson, Alan; Jayson, Gordon C; et al. (2007-11)
      Dynamic contrast-enhanced MRI (DCE-MRI) time series data are subject to unavoidable physiological motion during acquisition (e.g., due to breathing) and this motion causes significant errors when fitting tracer kinetic models to the data, particularly with voxel-by-voxel fitting approaches. Motion correction is problematic, as contrast enhancement introduces new features into postcontrast images and conventional registration similarity measures cannot fully account for the increased image information content. A methodology is presented for tracer kinetic model-driven registration that addresses these problems by explicitly including a model of contrast enhancement in the registration process. The iterative registration procedure is focused on a tumor volume of interest (VOI), employing a three-dimensional (3D) translational transformation that follows only tumor motion. The implementation accurately removes motion corruption in a DCE-MRI software phantom and it is able to reduce model fitting errors and improve localization in 3D parameter maps in patient data sets that were selected for significant motion problems. Sufficient improvement was observed in the modeling results to salvage clinical trial DCE-MRI data sets that would otherwise have to be rejected due to motion corruption.