Table of contents

Advances in conformal radiation therapy and advancements in pre-clinical radiotherapy research have recently stimulated the development of precise micro-irradiators for small animals such as mice and rats. These devices are often kilovolt x-ray radiation sources combined with high-resolution CT imaging equipment for image guidance, as the latter allows precise and accurate beam positioning. This is similar to modern human radiotherapy practice. These devices are considered a major step forward compared to the current standard of animal experimentation in cancer radiobiology research. The availability of this novel equipment enables a wide variety of pre-clinical experiments on the synergy of radiation with other therapies, complex radiation schemes, sub-target boost studies, hypofractionated radiotherapy, contrast-enhanced radiotherapy and studies of relative biological effectiveness, to name just a few examples. In this review we discuss the required irradiation and imaging capabilities of small animal radiation research platforms. We describe the need for improved small animal radiotherapy research and highlight pioneering efforts, some of which led recently to commercially available prototypes. From this, it will be clear that much further development is still needed, on both the irradiation side and imaging side. We discuss at length the need for improved treatment planning tools for small animal platforms, and the current lack of a standard therein. Finally, we mention some recent experimental work using the early animal radiation research platforms, and the potential they offer for advancing radiobiology research.

Cone-beam imaging with C-arm systems has become a valuable tool in interventional radiology. Currently, a simple circular trajectory is used, but future applications should use more sophisticated source trajectories, not only to avoid cone-beam artifacts but also to allow extended volume imaging. One attractive strategy to achieve these two goals is to use a source trajectory that consists of two parallel circular arcs connected by a line segment, possibly with repetition. In this work, we address the question of R-line coverage for such a trajectory. More specifically, we examine to what extent R-lines for such a trajectory cover a central cylindrical region of interest (ROI). An R-line is a line segment connecting any two points on the source trajectory. Knowledge of R-line coverage is crucial because a general theory for theoretically exact and stable image reconstruction from axially truncated data is only known for the points in the scanned object that lie on R-lines. Our analysis starts by examining the R-line coverage for the elemental trajectories consisting of (i) two parallel circular arcs and (ii) a circular arc connected orthogonally to a line segment. Next, we utilize our understanding of the R-lines for the aforementioned elemental trajectories to determine the R-line coverage for the trajectory consisting of two parallel circular arcs connected by a tightly fit line segment. For this trajectory, we find that the R-line coverage is insufficient to completely cover any central ROI. Because extension of the line segment beyond the circular arcs helps to increase the R-line coverage, we subsequently propose a trajectory composed of two parallel circular arcs connected by an extended line. We show that the R-lines for this trajectory can fully cover a central ROI if the line extension is long enough. Our presentation includes a formula for the minimum line extension needed to achieve full R-line coverage of an ROI with a specified size, and also includes a preliminary study on the required detector size, showing that the R-lines added by the line extension are not constraining.

An ongoing project is being carried out to develop a high purity germanium (HPGe) Compton camera for medical applications. The Compton camera offers many potential advantages over the conventional gamma camera. The camera reported in this paper comprises two pixellated germanium detector planes housed 9.6 cm apart in the same vacuum housing. The camera has 177 pixels, 152 in the scatter detector and 25 in the absorption detector. The pixels are 4 × 4 mm² with a thickness of 4 mm in the scatter detector and 10 mm in the absorption detector. Images have been taken for a variety of test objects including point sources, a ring source and a Perspex phantom. The measured angular resolution is 9.4° ± 0.4° for a 662 keV gamma-ray source at 3 cm. Due to the limited number of readout modules a multiple-view technique was used to image the source distributions from different angles and simulate the pixel arrangement in the full camera.

X-ray luminescence tomography (XLT) has recently been proposed as a new imaging modality for biological imaging applications. This modality utilizes phosphor nanoparticles which luminesce near-infrared light when excited by x-ray photons. The advantages of this modality are that it uniquely combines the high sensitivity of radioluminescent nanoparticles and the high spatial localization of collimated x-ray beams. Currently, XLT has been demonstrated using x-ray spatial encoding to resolve the imaging volume. However, there are applications where the x-ray excitation may be limited by geometry, where increased temporal resolution is desired, or where a lower dose is mandatory. This paper extends the utility of XLT to meet these requirements by incorporating a photon propagation model into the reconstruction algorithm in an x-ray limited-angle (LA) geometry. This enables such applications as image-guided surgery, where the ability to resolve lesions at depths of several centimeters can be the key to successful resection. The hybrid x-ray/diffuse optical model is first formulated and then demonstrated in a breast-sized phantom, simulating a breast lumpectomy geometry. Both numerical and experimental phantoms are tested, with lesion-simulating objects of various sizes and depths. Results show localization accuracy with median error of 2.2 mm, or 4% of object depth, for small 2–14 mm diameter lesions positioned from 1 to 4.5 cm in depth. This compares favorably with fluorescence optical imaging, which is not able to resolve such small objects at this depth. The recovered lesion size has lower size bias in the x-ray excitation direction than the optical direction, which is expected due to the increased optical scatter. However, the technique is shown to be quite invariant in recovered size with respect to depth, as the standard deviation is less than 2.5 mm. Sensitivity is a function of dose; radiological doses are found to provide sufficient recovery for µg ml⁻¹ concentrations, while therapy dosages provide recovery for ng ml⁻¹ concentrations. Experimental phantom results agree closely with the numerical results, with positional errors recovered within 8.6% of the effective depth for a 5 mm object, and within 5.2% of the depth for a 10 mm object. Object-size median error is within 2.3% and 2% for the 5 and 10 mm objects, respectively. For shallow-to-medium depth applications where optical and radio-emission imaging modalities are not ideal, such as in intra-operative procedures, LAXLT may be a useful tool to detect molecular signatures of disease.

The purpose of the study was to evaluate the feasibility of microbubbles as phase contrast imaging (PCI) agents for angiography applications. The hypothesis was that the introduction of microbubbles into tissue produces a significant change in the refractive index and highlights the lumen of the vessel in PCI. The absorption and phase contrast images of commercially available microbubbles were obtained and compared in vitro. A further increase in contrast was observed in PCI. Microbubbles highlighted the lumen of the renal microvessels, acting as a positive contrast medium in ex vivo imaging. In addition, home-made microbubbles with larger diameters were introduced for image contrast enhancement in living tumor-bearing mice, demonstrating the feasibility of microbubble-based x-ray phase-contrast imaging for tumor vasculature in vivo.

The purpose of this study is to characterize the x-ray properties of a dual-modality, anthropomorphic breast phantom whose MRI properties have been previously evaluated. The goal of this phantom is to provide a platform for optimization and standardization of two- and three-dimensional x-ray and MRI breast imaging modalities for the purpose of lesion detection and discrimination. The phantom is constructed using a mixture of lard and egg whites, resulting in a variable, tissue-mimicking structure with separate adipose- and glandular-mimicking components. The phantom can be produced with either a compressed or uncompressed shape. Mass attenuation coefficients of the phantom materials were estimated using elemental compositions from the USDA National Nutrient Database for Standard Reference and the atomic interaction models from the Monte Carlo code PENELOPE and compared with human values from the literature. The image structure was examined quantitatively by calculating and comparing spatial covariance matrices of the phantom and patient mammography images. Finally, a computerized version of the phantom was created by segmenting a computed tomography scan and used to simulate x-ray scatter of the phantom in a mammography geometry. Mass attenuation coefficients of the phantom materials were within 20% and 15% of the values for adipose and glandular tissues, respectively, which is within the estimation error of these values. Matching was improved at higher energies (>20 keV). Tissue structures in the phantom have a size similar to those in the patient data, but are slightly larger on average. Correlations in the patient data appear to be longer than those in the phantom data in the anterior–posterior direction; however, they are within the error bars of the measurement. Simulated scatter-to-primary ratio values of the phantom images were as high as 85% in some areas and were strongly affected by the heterogeneous nature of the phantom. Key physical x-ray properties of the phantom have been quantitatively evaluated and shown to be comparable to those of breast tissue. Since the MRI properties of the phantom have been previously evaluated, we believe it is a useful tool for quantitative evaluation of two- and three-dimensional x-ray and MRI breast imaging modalities for the purpose of lesion detection and characterization.

New thermal compensation methods suitable for p-channel MOSFET (pMOS) dosimeters with the usual dose readout procedure based on a constant drain current are presented. Measuring the source–drain voltage shifts for two or three different drain currents and knowing the value of the zero-temperature coefficient drain current, I_ZTC, the thermal drift of source–drain or threshold voltages can be significantly reduced. Analytical expressions for the thermal compensation have been theoretically deduced on the basis of a linear dependence on temperature of the parameters involved. The proposed thermal modelling has been experimentally proven. These methods have been applied to a group of ten commercial pMOS transistors (3N163). The thermal coefficients of the source–drain voltage and the threshold voltage were reduced from −3.0 mV °C⁻¹, in the worst case, down to −70 µV °C⁻¹. This means a thermal drift of −2.4 mGy °C⁻¹ for the dosimeter. When analysing the thermal drifts of all the studied transistors, in the temperature range from 19 to 36 °C, uncertainty was obtained in the threshold voltage due to a thermal drift of ±9mGy (2 SD), a commonly acceptable value in most radiotherapy treatments. The procedures described herein provide thermal drift reduction comparable to that of other technological or numerical strategies, but can be used in a very simple and low-cost dosimetry sensor.

A slotted surface coil inspired by the hole-and-slot cavity magnetron was developed for magnetic resonance imaging of obese rats at 4 T. Full-wave analysis of the magnetic field was carried out at 170 MHz for both the slotted and circular-shaped coils. The noise figure values of two coils were investigated via the numerical calculation of the quality factors. Fat simulated phantoms to mimic overweight rats were included in the analysis with weights ranging from 300 to 900 g. The noise figures were 1.2 dB for the slotted coil and 2.4 dB for the circular coil when loaded with 600 g of simulated phantom. A slotted surface coil with eight circular slots and a circular coil with similar dimensions were built and operated in the transceiver mode, and their performances were experimentally compared. The imaging tests in phantoms demonstrated that the slotted surface coil has a deeper RF-sensitivity and better field uniformity than the single-loop RF-coil. High quality images of two overweight Zucker rats were acquired simultaneously with the slotted surface coil using standard spin-echo pulse sequences. Experimental results showed that the slotted surface coil outperformed the circular coil for imaging considerably overweight rats. Thus, the slotted surface coil can be a good tool for MRI experiments in rats on a human whole-body 4 T scanner.

A novel architecture for a phased-array high intensity focused ultrasound (HIFU) device was investigated, aiming to increase the capabilities of electronic steering without reducing the size of the elementary emitters. The principal medical application expected to benefit from these developments is the time-effective sonication of large tumours in moving organs. The underlying principle consists of dividing the full array of transducers into multiple sub-arrays of different resonance frequencies, with the reorientation of these individual emitters, such that each sub-array can focus within a given spatial zone. To enable magnetic resonance (MR) compatibility of the device and the number of output channels from the RF generator to be halved, a passive spectral multiplexing technique was used, consisting of parallel wiring of frequency-shifted paired piezoceramic emitters with intrinsic narrow-band response. Two families of 64 emitters (circular, 5 mm diameter) were mounted, with optimum efficiency at 0.96 and 1.03 MHz, respectively. Two different prototypes of the HIFU device were built and tested, each incorporating the same two families of emitters, but differing in the shape of the rapid prototyping plastic support that accommodated the transducers (spherical cap with radius of curvature/aperture of 130 mm/150 mm and, respectively, 80 mm/110 mm). Acoustic measurements, MR-acoustic radiation force imaging (ex vivo) and MR-thermometry (ex vivo and in vivo) were used for the characterization of the prototypes. Experimental results demonstrated an augmentation of the steering range by 80% along one preferentially chosen axis, compared to a classic spherical array of the same total number of elements. The electric power density provided to the piezoceramic transducers exceeded 50 W cm⁻² CW, without circulation of coolant water. Another important advantage of the current approach is the versatility of reshaping the array at low cost.

We apply wavelet-based time-localized phase coherence to investigate the relationship between blood flow and skin temperature, and between blood flow and instantaneous heart rate (IHR), during vasoconstriction and vasodilation provoked by local cooling or heating of the skin. A temperature-controlled metal plate (≈10 cm²) placed on the volar side of the left arm was used to provide the heating and cooling. Beneath the plate, the blood flow was measured by laser Doppler flowmetry and the adjacent skin temperature by a thermistor. Two 1 h datasets were collected from each of the ten subjects. In each case a 30 min basal recording was followed by a step change in plate temperature, to either 24 °C or 42 °C. The IHR was derived from simultaneously recorded ECG. We confirm the changes in the energy and frequency of blood flow oscillations during cooling and heating reported earlier. That is, during cooling, there was a significant decrease in the average frequency of myogenic blood flow oscillations (p < 0.05) and the myogenic spectral peak became more prominent. During heating, there was a significant (p < 0.05) general increase in spectral energy, associated with vasodilation, except in the myogenic interval. Weak phase coherence between temperature and blood flow was observed for unperturbed skin, but it increased in all frequency intervals as a result of heating. It was not significantly affected by cooling. We also show that significant (p < 0.05) phase coherence exists between blood flow and IHR in the respiratory and myogenic frequency intervals. Cooling did not affect this phase coherence in any of the frequency intervals, whereas heating enhanced the phase coherence in the respiratory and myogenic intervals. This can be explained by the reduction in vascular resistance produced by heating, a process where myogenic mechanisms play a key role. We conclude that the mechanisms of vasodilation and vasoconstriction, in response to temperature change, are oscillatory in nature and are independent of central sources of variability.

We investigated the feasibility of designing an Anger-logic PET detector module using large-area high-gain avalanche photodiodes (APDs) for a brain-dedicated PET/MRI system. Using Monte Carlo simulations, we systematically optimized the detector design with regard to the scintillation crystal, optical diffuser, surface treatment, layout of large-area APDs, and signal-to-noise ratio (SNR, defined as the 511 keV photopeak position divided by the standard deviation of noise floor in an energy spectrum) of the APD devices. A detector prototype was built comprising an 8 × 8 array of 2.75 × 3.00 × 20.0 mm³ LYSO (lutetium-yttrium-oxyorthosilicate) crystals and a 22.0 × 24.0 × 9.0 mm³ optical diffuser. From the four designs of the optical diffuser tested, two designs employing a slotted diffuser are able to resolve all 64 crystals within the block with good uniformity and peak-to-valley ratio. Good agreement was found between the simulation and experimental results. For the detector employing a slotted optical diffuser, the energy resolution of the global energy spectrum after normalization is 13.4 ± 0.4%. The energy resolution of individual crystals varies between 11.3 ± 0.3% and 17.3 ± 0.4%. The time resolution varies between 4.85 ± 0.04 (center crystal), 5.17 ± 0.06 (edge crystal), and 5.18 ± 0.07 ns (corner crystal). The generalized framework proposed in this work helps to guide the design of detector modules for selected PET system configurations, including scaling the design down to a preclinical PET system, scaling up to a whole-body clinical scanner, as well as replacing APDs with other novel photodetectors that have higher gain or SNR such as silicon photomultipliers.

We investigated the relationship between noise equivalent count (NEC) and axial field of view (AFOV) for PET scanners with AFOVs ranging from one-half to twice those of current clinical scanners. PET scanners with longer or shorter AFOVs could fulfill different clinical needs depending on exam volumes and site economics. Using previously validated Monte Carlo simulations, we modeled true, scattered and random coincidence counting rates for a PET ring diameter of 88 cm with 2, 4, 6, and 8 rings of detector blocks (AFOV 7.8, 15.5, 23.3, and 31.0 cm). Fully 3D acquisition mode was compared to full collimation (2D) and partial collimation (2.5D) modes. Counting rates were estimated for a 200 cm long version of the 20 cm diameter NEMA count-rate phantom and for an anthropomorphic object based on a patient scan. We estimated the live-time characteristics of the scanner from measured count-rate data and applied that estimate to the simulated results to obtain NEC as a function of object activity. We found NEC increased as a quadratic function of AFOV for 3D mode, and linearly in 2D mode. Partial collimation provided the highest overall NEC on the 2-block system and fully 3D mode provided the highest NEC on the 8-block system for clinically relevant activities. On the 4-, and 6-block systems 3D mode NEC was highest up to ∼300 MBq in the anthropomorphic phantom, above which 3D NEC dropped rapidly, and 2.5D NEC was highest. Projected total scan time to achieve NEC-density that matches current clinical practice in a typical oncology exam averaged 9, 15, 24, and 61 min for the 8-, 6-, 4-, and 2-block ring systems, when using optimal collimation. Increasing the AFOV should provide a greater than proportional increase in NEC, potentially benefiting patient throughput-to-cost ratio. Conversely, by using appropriate collimation, a two-ring (7.8 cm AFOV) system could acquire whole-body scans achieving NEC-density levels comparable to current standards within long, but feasible, scan times.

A simple in vitro alpha radiation exposure system (ARES) was designed to study the biological effects of alpha particle radiation. The ARES consists of six ²⁴¹Am electroplated stainless steel discs with activities averaging 66 kBq and Mylar-based culture dishes to allow the transmission of alpha particles. The dosimetry of the exposure system was calculated using the GEANT4 Monte Carlo simulation toolkit with the source code adapted from the open-source Microbeam example. The average dose rate and linear energy transfer of the system was simulated to be 0.98 ± 0.01 (statistical)^+0.18 _{− 0.00} (systematic) Gy h⁻¹ and 127.4 ± 0.4 (statistical)⁺²³ _{− 0} (systematic) keV µm⁻¹, respectively. The system was characterized by a comparison of the survival curves of gamma and alpha irradiated cell lines which showed a relative biological effectiveness of 6.3. This is in good agreement with values obtained using other published alpha particle exposure systems. Results show that the ARES provides a simple, cost-effective exposure platform for research into the biological effects of alpha particle radiation using in vitro modelling of cell cultures.

We have previously developed an online adaptive replanning technique to rapidly adapt the original plan according to daily CT. This paper reports the quality assurance (QA) developments in its clinical implementation for prostate cancer patients. A series of pre-clinical validation tests were carried out to verify the overall accuracy and consistency of the online replanning procedure. These tests include (a) phantom measurements of 22 individual patient adaptive plans to verify their accuracy and deliverability and (b) efficiency and applicability of the online replanning process. A four-step QA procedure was established to ensure the safe and accurate delivery of an adaptive plan, including (1) offline phantom measurement of the original plan, (2) online independent monitor unit (MU) calculation for a redundancy check, (3) online verification of plan-data transfer using an in-house software and (4) offline validation of actually delivered beam parameters. The pre-clinical validations demonstrate that the newly implemented online replanning technique is dosimetrically accurate and practically efficient. The four-step QA procedure is capable of identifying possible errors in the process of online adaptive radiotherapy and to ensure the safe and accurate delivery of the adaptive plans. Based on the success of this work, the online replanning technique has been used in the clinic to correct for interfractional changes during the prostate radiation therapy.

In the multi-criteria optimization approach to IMRT planning, a given dose distribution is evaluated by a number of convex objective functions that measure tumor coverage and sparing of the different organs at risk. Within this context optimizing the intensity profiles for any fixed set of beams yields a convex Pareto set in the objective space. However, if the number of beam directions and irradiation angles are included as free parameters in the formulation of the optimization problem, the resulting Pareto set becomes more intricate. In this work, a method is presented that allows for the comparison of two convex Pareto sets emerging from two distinct beam configuration choices. For the two competing beam settings, the non-dominated and the dominated points of the corresponding Pareto sets are identified and the distance between the two sets in the objective space is calculated and subsequently plotted. The obtained information enables the planner to decide if, for a given compromise, the current beam setup is optimal. He may then re-adjust his choice accordingly during navigation. The method is applied to an artificial case and two clinical head neck cases. In all cases no configuration is dominating its competitor over the whole Pareto set. For example, in one of the head neck cases a seven-beam configuration turns out to be superior to a nine-beam configuration if the highest priority is the sparing of the spinal cord. The presented method of comparing Pareto sets is not restricted to comparing different beam angle configurations, but will allow for more comprehensive comparisons of competing treatment techniques (e.g. photons versus protons) than with the classical method of comparing single treatment plans.

The dosimetric measurement and modeling of small radiation treatment fields (<2 × 2 cm²) are difficult to perform and prone to error. Measurements of small fields are often adversely influenced by the properties of the detectors used to make them. The dosimetric properties of small fields have been difficult to accurately model due to the effects of source occlusion caused by the collimating jaws. In this study, small longitudinal slice widths (SWs) of the TomoTherapy® Hi-Art® machine are characterized by performing dosimetric measurements topographically. By using a static gantry, opening the central 16 MLC leaves during the irradiations, and symmetrically scanning detectors 10 cm through each longitudinal SW, integral doses to a 'TomoTherapy equivalent' 10 × 10 cm² area are topographically measured. To quantify the effects of source occlusion for TomoTherapy, a quantity referred to as the integral scanned dose to slice width ratio (D/SW) is introduced. (D/SW) ratios are measured for SWs ranging from 0.375 to 5 cm in size using ion chambers and a radiographic film. The measurements of the (D/SW) ratio are shown to be insensitive to the detectors used in this study. The (D/SW) ratios for TomoTherapy have values of unity in the range of SW sizes from 5 cm to approximately 2 cm. For SWs smaller than 2 cm in size, the source-occlusion effect substantially reduces the measured machine output and the value of the (D/SW) ratios. The topographic measurement method presented provides a way to directly evaluate the accuracy of the small-field source model parameters used in dose calculation algorithms. As an example, the electron source spot size of a Penelope Monte Carlo (MC) model of TomoTherapy was varied to match computed and measured (D/SW) ratios. It was shown that the MC results for small SW sizes were sensitive to that particular parameter.

Filtered backprojection is the basis for many CT reconstruction tasks. It assumes constant attenuation values of the object during the acquisition of the projection data. Reconstruction artifacts can arise if this assumption is violated. For example, contrast flow in perfusion imaging with C-arm CT systems, which have acquisition times of several seconds per C-arm rotation, can cause this violation. In this paper, we derived and validated a novel spatio-temporal model to describe these kinds of artifacts. The model separates the temporal dynamics due to contrast flow from the scan and reconstruction parameters. We introduced derivative-weighted point spread functions to describe the spatial spread of the artifacts. The model allows prediction of reconstruction artifacts for given temporal dynamics of the attenuation values. Furthermore, it can be used to systematically investigate the influence of different reconstruction parameters on the artifacts. We have shown that with optimized redundancy weighting function parameters the spatial spread of the artifacts around a typical arterial vessel can be reduced by about 70%. Finally, an inversion of our model could be used as the basis for novel dynamic reconstruction algorithms that further minimize these artifacts.

A recent study investigated the feasibility to develop a bench-top x-ray fluorescence computed tomography (XFCT) system capable of determining the spatial distribution and concentration of gold nanoparticles (GNPs) in vivo using a diagnostic energy range polychromatic (i.e. 110 kVp) pencil-beam source. In this follow-up study, we examined the feasibility of a polychromatic cone-beam implementation of XFCT by Monte Carlo (MC) simulations using the MCNP5 code. In the current MC model, cylindrical columns with various sizes (5–10 mm in diameter) containing water loaded with GNPs (0.1–2% gold by weight) were inserted into a 5 cm diameter cylindrical polymethyl methacrylate phantom. The phantom was then irradiated by a lead-filtered 110 kVp x-ray source, and the resulting gold fluorescence and Compton-scattered photons were collected by a series of energy-sensitive tallies after passing through lead parallel-hole collimators. A maximum-likelihood iterative reconstruction algorithm was implemented to reconstruct the image of GNP-loaded objects within the phantom. The effects of attenuation of both the primary beam through the phantom and the gold fluorescence photons en route to the detector were corrected during the image reconstruction. Accurate images of the GNP-containing phantom were successfully reconstructed for three different phantom configurations, with both spatial distribution and relative concentration of GNPs well identified. The pixel intensity of regions containing GNPs was linearly proportional to the gold concentration. The current MC study strongly suggests the possibility of developing a bench-top, polychromatic, cone-beam XFCT system for in vivo imaging.