Use of Dynamic Contrast Enhanced MRI in Multi-Centre Trials with Particular Reference to Breast Cancer Screening 15 Use of Dynamic Contrast-Enhanced MRI in Multi-Centre Trials with Particular Reference to Breast Cancer Screening in Women at Genetic Risk

Introduction This chapter considers issues concerned with developing multi-centre trials using dynamic contrast-enhanced MRI studies. As techniques have been considered in other chapters, emphasis is placed on issues that relate to trials, and particularly their implementation across centres. Both diagnostic and therapeutic trials are considered, although as yet most experience arises from diagnostic trials. Trials that have been reported are considered, and the UK study of magnetic resonance as a method of screening women at genetic risk of breast cancer (MARIBS) using dynamic contrastenhanced MRI is taken as an example. Issues of organisation, instrumentation, quality assurance and analysis are considered. Multi-Centre Trials New Diagnostic Techniques Development and evaluation of new techniques often occurs initially at single centres. Where new approaches are developed at a university or hospital, the centre evaluating the technique is often the same centre that developed the approach. This has the benefi t of maximising the expertise in the technique, and is often an essential part of the interactive process of developing and optimising a new clinical technique. Those involved are likely to be advocates of the approach, and the utility established in such a single-centre evaluation may not be representative of the effectiveness of an approach across a range of centres. Manufacturers may also initially pilot a new approach at a single centre, in this case because of the strong continuing interaction required to optimise development. Such a strong interaction allows resources to be focussed, and may lead to scientifi c publications, assisting the manufacturer's role in alerting the community to new methods and equipment. Often this preliminary stage is then followed by a stage of more widespread evaluation, defi ning the role of the technique at a number of centres CONTENT

Reconstructing the primordial power spectrum - a new algorithm

We propose an efficient and model independent method for reconstructing the primordial power spectrum from Cosmic Microwave Background (CMB) and large scale structure observations. The algorithm is based on a Monte Carlo principle and therefore very simple to incorporate into existing codes such as Markov Chain Monte Carlo. The algorithm has been used on present cosmological data to test for features in the primordial power spectrum. No significant evidence for features is found, although there is a slight preference for an overall bending of the spectrum, as well as a decrease in power at very large scales. We have also tested the algorithm on mock high precision CMB data, calculated from models with non-scale invariant primordial spectra. The algorithm efficiently extracts the underlying spectrum, as well as the other cosmological parameters in each case. Finally we have used the algorithm on a model where an artificial glitch in the CMB spectrum has been imposed, like the ones seen in the WMAP data. In this case it is found that, although the underlying cosmological parameters can be extracted, the recovered power spectrum can show significant spurious features, such as bending, even if the true spectrum is scale invariant.Comment: 22 pages, 12 figures, matches JCAP published versio

Minimally Invasive Pharmacokinetic and Pharmacodynamic Technologies in Hypothesis-Testing Clinical Trials of Innovative Therapies

Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encourage

Modulation of renal oxygenation and perfusion in rat kidney monitored by quantitative diffusion and blood oxygen level dependent magnetic resonance imaging on a clinical 1.5T platform

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Reproducibility of the lung anatomy under active breathing coordinator control:Dosimetric consequences for scanned proton treatments

Purpose The treatment of moving targets with scanned proton beams is challenging. For motion mitigation, an Active Breathing Coordinator (ABC) can be used to assist breath-holding. The delivery of pencil beam scanning fields often exceeds feasible breath-hold durations, requiring high breath-hold reproducibility. We evaluated the robustness of scanned proton therapy against anatomical uncertainties when treating nonsmall-cell lung cancer (NSCLC) patients during ABC controlled breath-hold. Methods Four subsequent MRIs of five healthy volunteers (3 male, 2 female, age: 25-58, BMI: 19-29) were acquired under ABC controlled breath-hold during two simulated treatment fractions, providing both intrafractional and interfractional information about breath-hold reproducibility. Deformation vector fields between these MRIs were used to deform CTs of five NSCLC patients. Per patient, four or five cases with different tumor locations were modeled, simulating a total of 23 NSCLC patients. Robustly optimized (3 and 5 mm setup uncertainty respectively and 3% density perturbation) intensity-modulated proton plans (IMPT) were created and split into subplans of 20 s duration (assumed breath-hold duration). A fully fractionated treatment was recalculated on the deformed CTs. For each treatment fraction the deformed CTs representing multiple breath-hold geometries were alternated to simulate repeated ABC breath-holding during irradiation. Also a worst-case scenario was simulated by recalculating the complete treatment plan on the deformed CT scan showing the largest deviation with the first deformed CT scan, introducing a systematic error. Both the fractionated breath-hold scenario and worst-case scenario were dosimetrically evaluated. Results Looking at the deformation vector fields between the MRIs of the volunteers, up to 8 mm median intra- and interfraction displacements (without outliers) were found for all lung segments. The dosimetric evaluation showed a median difference in D-98% between the planned and breath-hold scenarios of -0.1 Gy (range: -4.1 Gy to 2.0 Gy). D-98% target coverage was more than 57.0 Gy for 22/23 cases. The D-1 cc of the CTV increased for 21/23 simulations, with a median difference of 0.9 Gy (range: -0.3 to 4.6 Gy). For 14/23 simulations the increment was beyond the allowed maximum dose of 63.0 Gy, though remained under 66.0 Gy (110% of the prescribed dose of 60.0 Gy). Organs at risk doses differed little compared to the planned doses (difference in mean doses <0.9 Gy for the heart and lungs, <1.4% difference in V-35 [%] and V-20 [%] to the esophagus and lung). Conclusions When treating under ABC controlled breath-hold, robustly optimized IMPT plans show limited dosimetric consequences due to anatomical variations between repeated ABC breath-holds for most cases. Thus, the combination of robustly optimized IMPT plans and the delivery under ABC controlled breath-hold presents a safe approach for PBS lung treatments

Reproducibility of the lung anatomy using Active Breathing Control:Dosimetric consequences for scanned proton treatments

Purpose/Objective The treatment of moving targets with scanning proton beams is challenging. By controlling lung volumes, Active Breathing Control (ABC) assists breath-holding for motion mitigation. The delivery of proton treatment fractions often exceeds feasible breath-hold durations, requiring high breath-hold reproducibility. Therefore, we investigated dosimetric consequences of anatomical reproducibility uncertainties in the lung under ABC, evaluating robustness of scanned proton treatments during breath-hold. Material/Methods T1-weighted MRIs of five volunteers were acquired during ABC, simulating image acquisition during four subsequent breath-holds within one treatment fraction. Deformation vector fields obtained from these MRIs were used to deform 95% inspiration phase CTs of 3 randomly selected non-small-cell lung cancer patients (Figure 1). Per patient, an intensity-modulated proton plan was recalculated on the 3 deformed CTs, to assess the dosimetric influence of anatomical breath-hold inconsistencies. Results Dosimetric consequences were negligible for patient 1 and 2 (Figure 1). Patient 3 showed a decreased volume (95.2%) receiving 95% of the prescribed dose for one deformed CT. The volume receiving 105% of the prescribed dose increased from 0.0% to 9.9%. Furthermore, the heart volume receiving 5 Gy varied by 2.3%. Figure 2 shows dose volume histograms for all relevant structures in patient 3. Conclusion Based on the studied patients, our findings suggest that variations in breath-hold have limited effect on the dose distribution for most lung patients. However, for one patient, a significant decrease in target coverage was found for one of the deformed CTs. Therefore, further investigation of dosimetric consequences from intra-fractional breath-hold uncertainties in the lung under ABC is needed