Introduction to the National Cancer Imaging Translational Accelerator (NCITA): a UK-wide infrastructure for multicentre clinical translation of cancer imaging biomarkers.

The National Cancer Imaging Translational Accelerator (NCITA) is creating a UK national coordinated infrastructure for accelerated translation of imaging biomarkers for clinical use. Through the development of standardised protocols, data integration tools and ongoing training programmes, NCITA provides a unique scalable infrastructure for imaging biomarker qualification using multicentre clinical studies.

Edge effects in 3D dosimetry: characterisation and correction of the non-uniform dose response of PRESAGE®.

Previous work has shown that PRESAGE® can be used successfully to perform 3D dosimetric measurements of complex radiotherapy treatments. However, measurements near the sample edges are known to be difficult to achieve. This is an issue when the doses at air-material interfaces are of interest, for example when investigating the electron return effect (ERE) present in treatments delivered by magnetic resonance (MR)-linac systems. To study this effect, a set of 3.5 cm-diameter cylindrical PRESAGE® samples was uniformly irradiated with multiple dose fractions, using either a conventional linac or an MR-linac. The samples were imaged between fractions using an optical-CT, to read out the corresponding accumulated doses. A calibration between TPS-predicted dose and optical-CT pixel value was determined for individual dosimeters as a function of radial distance from the axis of rotation. This data was used to develop a correction that was applied to four additional samples of PRESAGE® of the same formulation, irradiated with 3D-CRT and IMRT treatment plans, to recover significantly improved 3D measurements of dose. An alternative strategy was also tested, in which the outer surface of the sample was physically removed prior to irradiation. Results show that for the formulation studied here, PRESAGE® samples have a central region that responds uniformly and an edge region of 6-7 mm where there is gradual increase in dosimeter response, rising to an over-response of 24%-36% at the outer boundary. This non-uniform dose response increases in both extent and magnitude over time. Both mitigation strategies investigated were successful. In our four exemplar studies, we show how discrepancies at edges are reduced from 13%-37% of the maximum dose to between 2 and 8%. Quantitative analysis shows that the 3D gamma passing rates rise from 90.4, 69.3, 63.7 and 43.6% to 97.3, 99.9, 96.7 and 98.9% respectively.

Implementing diffusion-weighted MRI for body imaging in prospective multicentre trials: current considerations and future perspectives.

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. KEY POINTS: • Standardised acquisition/analysis allows quantification of imaging biomarkers in multicentre trials. • Establishing "precision" of the measurement in the multicentre context is essential. • A repository with traceable data of known provenance promotes further research.

Social interaction plays a critical role in neurogenesis and recovery after stroke.

Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20-25 g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72 h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain-derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2'-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury.

A CCD-based optical CT scanner for high-resolution 3D imaging of radiation dose distributions: equipment specifications, optical simulations and preliminary results.

Methods based on magnetic resonance imaging for the measurement of three-dimensional distributions of radiation dose are highly developed. However, relatively little work has been done on optical computed tomography (OCT). This paper describes a new OCT scanner based on a broad beam light source and a two-dimensional charge-coupled device (CCD) detector. A number of key design features are discussed including the light source; the scanning tank, turntable and stepper motor control; the diffuser screen onto which images are projected and the detector. It is shown that the non-uniform pixel sensitivity of the low-cost CCD detector used and the granularity of the diffuser screen lead to a serious ring artefact in the reconstructed images. Methods are described for eliminating this. The problems arising from reflection and refraction at the walls of the gel container are explained. Optical ray-tracing simulations are presented for cylindrical containers with a variety of radii and verified experimentally. Small changes in the model parameters lead to large variations in the signal intensity observed in the projection data. The effect of imperfect containers on data quality is discussed and a method based on a 'correction scan' is shown to be successful in correcting many of the related image artefacts. The results of two tomography experiments are presented. In the first experiment, a radiochromic Fricke gel sample was exposed four times in different positions to a 100 kVp x-ray beam perpendicular to the plane of imaging. Images of absorbed dose with slice thickness of 140 microm were acquired. with 'true' in-plane resolution of 560 x 560 microm2 at the edge of the 72 mm field of view and correspondingly higher resolution at the centre. The nominal doses measured correlated well with the known exposure times. The second experiment demonstrated the well known phenomenon of diffusion in the dosemeter gels and yielded a value of (0.12 +/- 0.02) mm2 s(-1) for the diffusion coefficient of the xylenol orange/iron complex. Finally, the overall implications of the above findings for dosimetry using OCT are discussed.

Burst excitation for quantitative diffusion imaging with multiple b-values.

A quantitative imaging sequence has been developed to exploit the intrinsic sensitivity of Burst NMR data to molecular diffusion. In the scan time of a single spin echo experiment, it is possible to acquire many images of the same slice, with a different T(2) and diffusion weighting. Under favorable conditions, it is possible to obtain both the diffusion coefficient and T(2) from the same experiment; or, by correcting for T(2) relaxation using a control image, more precise diffusion coefficients may be measured. The quantitative values in rat brain are in agreement with those from conventional experiments. The major gains of this method are the potentially reduced scan time, the higher number of acquired images corresponding to different diffusion weightings, the reduced sensitivity to inter-scan motion artifact and to local variations in magnetic susceptibility, and an automatic co-registration between T(2) and diffusion images. Problems with the sequence include a lower signal-to-noise ratio than is achievable with diffusion-weighted spin-echo imaging, the limitation of measuring only in-plane components of diffusion and, at present, single-slice acquisition.

Burst imaging: rotation artifacts and how to correct them.

The effect of coherent rotational motion on images acquired with the ultrafast single-shot spin-echo Burst sequence has been analyzed. Previous experience has demonstrated that sample rotation during Burst experiments has the potential to cause severe image artifacts. In this paper we show that no distortions are visible when the readout gradient is parallel to the rotation axis, but that there is a very distinctive behavior for the case of the rotation axis orthogonal to the imaging plane. The mathematical expression that describes the resulting signal is presented and is used as a basis for a method of correcting the k-space data. The conditions under which undistorted images may be recovered are discussed. It is shown that there is an asymmetry, dependent on the rotation direction, in both the manifestation of the artifact and the range of angular velocities over which one can correct the images. Data from an agar gel phantom rotating at a known rate are used to show how the theory is successful at reconstructing images, with no free parameters. The range of angular velocities over which correction is possible depends on the timing parameters of the pulse sequence, but for these data was -0.016 < omega less, similar 0.1 revolutions/s. Volunteer experiments have confirmed that the theory is applicable to patient motion and can correct motional distortion even when the exact rate is not known a priori. By optimizing the reconstruction to restore a known sample geometry/aspect ratio, an estimate of the rotation angular frequency is obtained with a precision of +/-10%.

Dynamics of polymerization in polyacrylamide gel (PAG) dosimeters: (II) modeling oxygen diffusion.

Oxygen contamination of a polyacrylamide gel (PAG) dosimeter can have a significant detrimental effect upon the performance characteristics of the gel as a dosimeter. Oxygen contamination can occur during preparation, but can also arise from the diffusion of atmospheric oxygen through vessel walls. Even 'trace' amounts of oxygen present in any gaseous space (usually nitrogen filled) between the surface of the PAG and the vessel seal can have a detectable effect. This paper describes a method used to quantify the detrimental effects of a range of oxygen concentrations upon the performance of the PAG. The results of diffusion studies for air and pure oxygen diffusing into the PAG over time are presented and coupled with a novel method of calculating oxygen concentrations in the PAG. Results obtained suggest that the diffusion is Fickian. The coefficient of diffusion D has been calculated to be (8+/-2) x 10(-6) cm2 s(-1) for oxygen diffusing into PAG stored at 4 degrees C, under the assumption that the diffusion mechanism is independent of the concentration of the diffusing species. In addition, a quantitative relation has been established between the transverse relaxation rate R2 of the PAG and the concentration of oxygen present. The implications of these findings for polymer gel dosimetry are discussed.

STEAM-Burst: a single-shot, multi-slice imaging sequence without rapid gradient switching.

The stimulated-echo acquisition mode-Burst sequence is a single-shot, multi-slice imaging technique that does not involve rapid gradient switching. A Burst excitation pulse train is followed by a 90 degrees hard pulse and, after a mixing time, by a 90 degrees slice-selective pulse. A read gradient refocuses a set of stimulated echoes, which can be phase-encoded to form an image. By repeating the selective pulse N times, each time with the carrier frequency offset differently, it is possible to sample N slices in a single-shot. A comparison is made of the sequence with other three-dimensional single-shot methods. Experiments implementing the technique on a 3 T whole-body imaging system and a 2 T, 31-cm bore animal imager are described. Both phantom and brain images are presented. The principal advantages of the new sequence are its speed, the absence of rapid gradient switching and corresponding freedom from artifacts, its insensitivity to static magnetic field inhomogeneities, and its low acoustic noise. The main disadvantages are the low signal-to-noise ratio of the images produced and the concomitant limitation in resolution.

Rapid repetition of the "burst" sequence: the role of diffusion and consequences for imaging.

When the Burst pulse sequence (Hennig et al. MAGMA 1, 39-48 (1993)) is applied with elementary pulses of finite flip angle, a non-uniform longitudinal magnetization is created, in the form of a series of fine bands of saturated spins. Both during and after the pulse train, the molecules contained within these bands diffuse. In this paper a full description is given of the evolution of the non-uniform longitudinal magnetization subsequent to the pulse train and the theory is verified experimentally. The value of the diffusion coefficient influences strongly the signal obtained when the Burst sequence is repeated rapidly. The consequences of this for imaging are discussed and, in particular, for the so-called "frequency-shifted" Burst technique.

Echo-time-encoded burst imaging (EBI): a novel technique for spectroscopic imaging.

A new technique for rapid spectroscopic imaging is presented. The proposed experiment enables a complete mapping of the two-dimensional reciprocal space kx, k sigma, and thus the acquisition of a 1D spectroscopic image in a single scan. The properties of the pulse sequence, based on the use of a burst of low flip angle pulses, are analyzed in the framework of linear response theory, and it is shown that chemical shift information may be introduced into the spatially encoded echoes. First experimental results are presented demonstrating that 32 x 32 proton spectroscopic images may be acquired within less than 1 min with a conventional imaging system.