Gary J. Royle

X-ray scatter signatures for normal and neoplastic breast tissues

Measurements of breast tissue scattering properties have been made in an energy dispersive x-ray diffraction system over the momentum transfer range of 0.70 to 3.50 nm(-1). One hundred samples of excised tissue have been used. Results from the diffraction system have been compared with the histological analysis for each individual sample. It has been found that tissue types can be characterized on the basis of the shape of the scatter spectrum and on its relative intensity. The shapes are significantly different between tissue types in the range 1.0 to 1.8 nm(-1) and suggest that if particular values of momentum transfer are monitored, a discriminating signal could be obtained. Analysis of the maximum intensity in the signature also reveals a change of up to a factor of 2 between adipose and fat-free tissues.

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer

PURPOSE An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. METHODS AND MATERIALS The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the targets distal surface. RESULTS The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. CONCLUSIONS A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

Empirical electro-optical and x-ray performance evaluation of CMOS active pixels sensor for low dose, high resolution x-ray medical imaging

Monolithic complementary metal oxide semiconductor (CMOS) active pixel sensors with high performance have gained attention in the last few years in many scientific and space applications. In order to evaluate the increasing capabilities of this technology, in particular where low dose high resolution x-ray medical imaging is required, critical electro-optical and physical x-ray performance evaluation was determined. The electro-optical performance includes read noise, full well capacity, interacting quantum efficiency, and pixels cross talk. The x-ray performance, including x-ray sensitivity, modulation transfer function, noise power spectrum, and detection quantum efficiency, has been evaluated in the mammographic energy range. The sensor is a 525 x 525 standard three transistor CMOS active pixel sensor array with more than 75% fill factor and 25 x 25 microm pixel pitch. Reading at 10 f/s, it is found that the sensor has 114 electrons total additive noise, 10(5) electrons full well capacity with shot noise limited operation, and 34% interacting quantum efficiency at 530 nm. Two different structured CsI:Tl phosphors with thickness 95 and 115 microm, respectively, have been optically coupled via a fiber optic plate to the array resulting in two different system configurations. The sensitivity of the two different system configurations was 43 and 47 electrons per x-ray incident on the sensor. The MTF at 10% of the two different system configurations was 9.5 and 9 cycles/mm with detective quantum efficiency of 0.45 and 0.48, respectively, close to zero frequency at approximately 0.44 microC/kg (1.72 mR) detector entrance exposure. The detector was quantum limited at low spatial frequencies and its performance was comparable with high resolution a: Si and charge coupled device based x-ray imagers. The detector also demonstrates almost an order of magnitude lower noise than active matrix flat panel imagers. The results suggest that CMOS active pixel sensors when coupled to structured CsI:Tl can be used for conventional and advanced digital mammography due to their low noise, high resolution performance.

A soft deformable tissue-equivalent phantom for diffuse optical tomography.

A recipe is presented for the manufacture of highly compressible phantoms for diffuse optical tomography. The recipe is based on polyvinyl alcohol (PVA) slime, a viscoelastic fluid which readily deforms under moderate pressure. Scattering particles and absorbing compounds can be added to provide a uniform material with stable and reproducible optical properties. A linear relationship between the concentration of scattering particles (either titanium dioxide or microspheres) and the transport scatter coefficient is demonstrated. Phantoms of an arbitrary size and shape may be produced by containing the slime within a thin latex shell, and a stability over a period of at least 3 months has been established. The deformable phantoms may be used to test and calibrate optical tomography systems designed for use on patients with irregular or variable geometries.

Quantitative X-ray diffraction analysis of bone and marrow volumes in excised femoral head samples

The aim of this paper is to apply the technique of quantitative x-ray diffraction analysis (QXDA) to trabecular bone tissue to demonstrate that quantitative data of the ratio of bone and marrow volumes within the trabecular region can be obtained. Apparatus has been constructed for measuring energy dispersive x-ray diffraction spectra of human femoral head samples in the diagnostic x-ray energy range. Individual diffraction peaks due to bone and marrow tissue were identified in the measured spectra. The relative intensities of the two peaks within the spectra quantify the relative proportions of the two components, and so the bone to marrow peak ratio is proposed as a parameter which is capable of providing information on the osteoporotic state of trabecular tissue. Preliminary results indicate a significant correlation between this method and the bone density measurement techniques of quantitative computed tomography and Compton scatter densitometry. Results have shown that the use of a synthetically prepared calibration curve can enable absolute measurement of bone or marrow volumes.

Correlation of energy dispersive diffraction signatures and microCT of small breast tissue samples with pathological analysis

Identification of specific tissue types in conventional mammographic examinations is extremely limited. However, the use of x-ray diffraction effects during imaging has the potential to characterize the tissue types present due to the fact that each tissue type produces its own unique diffraction signature. Nevertheless, the analysis and categorization of these diffraction signatures by tissue type can be hampered by the inhomogeneous nature of breast tissue, leading to categorization errors where several types are present. This work aims to reduce sample categorization errors by combining spectral diffraction signature collection with sample imaging, giving more detailed data on the composition of each sample. Diffraction microCT was carried out on 19 unfixed breast tissue samples using an energy resolving translate-rotate CT system. High-resolution transmission microCT images were also recorded for comparison and sample composition analysis. Following imaging, the samples were subjected to histopathological analysis. Reconstructing on various momentum transfer regions allows different tissue types to be identified in the diffraction images. Results show a correlation between measured x-ray diffraction images and stained histopathological tissue sections. X-ray diffraction signatures generated from the measured data were categorized and analysed, with a t-test indicating that they have the potential for use in tissue type identification.

A CMOS active pixel sensor system for laboratory- based x-ray diffraction studies of biological tissue.

X-ray diffraction studies give material-specific information about biological tissue. Ideally, a large area, low noise, wide dynamic range digital x-ray detector is required for laboratory-based x-ray diffraction studies. The goal of this work is to introduce a novel imaging technology, the CMOS active pixel sensor (APS) that has the potential to fulfil all these requirements, and demonstrate its feasibility for coherent scatter imaging. A prototype CMOS APS has been included in an x-ray diffraction demonstration system. An industrial x-ray source with appropriate beam filtration is used to perform angle dispersive x-ray diffraction (ADXRD). Optimization of the experimental set-up is detailed including collimator options and detector operating parameters. Scatter signatures are measured for 11 different materials, covering three medical applications: breast cancer diagnosis, kidney stone identification and bone mineral density calculations. Scatter signatures are also recorded for three mixed samples of known composition. Results are verified using two independent models for predicting the APS scatter signature: (1) a linear systems model of the APS and (2) a linear superposition integral combining known monochromatic scatter signatures with the input polychromatic spectrum used in this case. Cross validation of experimental, modelled and literature results proves that APS are able to record biologically relevant scatter signatures. Coherent scatter signatures are sensitive to multiple materials present in a sample and provide a means to quantify composition. In the future, production of a bespoke APS imager for x-ray diffraction studies could enable simultaneous collection of the transmitted beam and scattered radiation in a laboratory-based coherent scatter system, making clinical transfer of the technique attainable.

The physics of Cerenkov light production during proton therapy

There is increasing interest in using Cerenkov emissions for quality assurance and in vivo dosimetry in photon and electron therapy. Here, we investigate the production of Cerenkov light during proton therapy and its potential applications in proton therapy. A primary proton beam does not have sufficient energy to generate Cerenkov emissions directly, but we have demonstrated two mechanisms by which such emissions may occur indirectly: (1) a fast component from fast electrons liberated by prompt gamma (99.13%) and neutron (0.87%) emission; and (2) a slow component from the decay of radioactive positron emitters. The fast component is linear with dose and doserate but carries little spatial information; the slow component is non-linear but may be localised. The properties of the two types of emission are explored using Monte Carlo modelling in GEANT4 with some experimental verification. We propose that Cerenkov emissions could contribute to the visual sensation reported by some patients undergoing proton therapy of the eye and we discuss the feasibility of some potential applications of Cerenkov imaging in proton therapy.

A quantitative x-ray detection system for gold nanoparticle tumour biomarkers

X-ray fluorescence techniques have proven beneficial for identifying and quantifying trace elements in biological tissues. A novel approach is being developed that employs x-ray fluorescence with an aim to locate heavy nanoparticles, such as gold, which are embedded into tissues. Such nanoparticles can be functionalized to act as markers for tumour characteristics to map the disease state, with the future aim of imaging them to inform cancer therapy regimes. The uptake of functionalized nanoparticles by cancer cells will also enable detection of small clusters of infiltrating cancer cells which are currently missed by commonly used imaging modalities. The novel system, consisting of an energy-resolving silicon drift detector with high spectral resolution, shows potential in both quantification of and sensitivity to nanoparticle concentrations typically found in tumours. A series of synchrotron measurements are presented; a linear relationship between fluorescence intensity and gold nanoparticle (GNP) concentration was found down to 0.005 mgAu ml(-1), the detection limit of the system. Successful use of a bench-top source, suitable for possible future clinical use, is also demonstrated, and found not to degrade the detection limit or accuracy of the GNP concentration measurement. The achieved system sensitivity suggests possible future clinical usefulness in measuring tumour uptake in vivo, particularly in shallow tumour sites and small animals, in ex vivo tissue and in 3D in vitro research samples.

The potential of dual‐energy CT to reduce proton beam range uncertainties

Purpose Dual‐energy CT (DECT) promises improvements in estimating stopping power ratios (SPRs) for proton therapy treatment planning. Although several comparable mathematical formalisms have been proposed in literature, the optimal techniques to characterize human tissue SPRs with DECT in a clinical environment are not fully established. The aim of this work is to compare the most robust DECT methods against conventional single‐energy CT (SECT) in conditions reproducing a clinical environment, where CT artifacts and noise play a major role on the accuracy of these techniques. Methods Available DECT tissue characterization methods are investigated and their ability to predict SPRs is compared in three contexts: (a) a theoretical environment using the XCOM cross section database; (b) experimental data using a dual‐source CT scanner on a calibration phantom; (c) simulations of a virtual humanoid phantom with the ImaSim software. The latter comparison accounts for uncertainties caused by CT artifacts and noise, but leaves aside other sources of uncertainties such as CT grid size and the I‐values. To evaluate the clinical impact, a beam range calculation model is used to predict errors from the probability distribution functions determined with ImaSim simulations. Range errors caused by SPR errors in soft tissues and bones are investigated. Results Range error estimations demonstrate that DECT has the potential of reducing proton beam range uncertainties by 0.4% in soft tissues using low noise levels of 12 and 8 HU in DECT, corresponding to 7 HU in SECT. For range uncertainties caused by the transport of protons through bones, the reduction in range uncertainties for the same levels of noise is found to be up to 0.6 to 1.1 mm for bone thicknesses ranging from 1 to 5 cm, respectively. We also show that for double the amount noise, i.e., 14 HU in SECT and 24 and 16 HU for DECT, the advantages of DECT in soft tissues are lost over SECT. In bones however, the reduction in range uncertainties is found to be between 0.5 and 0.9 mm for bone thicknesses ranging from 1 to 5 cm, respectively. Conclusion DECT has a clear potential to improve proton beam range predictions over SECT in proton therapy. However, in the current state high levels of noise remain problematic for DECT characterization methods and do not allow getting the full benefits of this technology. Future work should focus on adapting DECT methods to noise and investigate methods based on raw‐data to reduce CT artifacts.