Showing papers in "Physics in Medicine and Biology in 2013"

Optical properties of biological tissues: a review.

Abstract: A review of reported tissue optical properties summarizes the wavelength-dependent behavior of scattering and absorption. Formulae are presented for generating the optical properties of a generic tissue with variable amounts of absorbing chromophores (blood, water, melanin, fat, yellow pigments) and a variable balance between small-scale scatterers and large-scale scatterers in the ultrastructures of cells and tissues.

X-ray phase-contrast imaging: from pre-clinical applications towards clinics

Abstract: Phase-contrast x-ray imaging (PCI) is an innovative method that is sensitive to the refraction of the x-rays in matter. PCI is particularly adapted to visualize weakly absorbing details like those often encountered in biology and medicine. In past years, PCI has become one of the most used imaging methods in laboratory and preclinical studies: its unique characteristics allow high contrast 3D visualization of thick and complex samples even at high spatial resolution. Applications have covered a wide range of pathologies and organs, and are more and more often performed in vivo. Several techniques are now available to exploit and visualize the phase-contrast: propagation- and analyzer-based, crystal and grating interferometry and non-interferometric methods like the coded aperture. In this review, covering the last five years, we will give an overview of the main theoretical and experimental developments and of the important steps performed towards the clinical implementation of PCI.

A survey of MRI-based medical image analysis for brain tumor studies

Abstract: MRI-based medical image analysis for brain tumor studies is gaining attention in recent times due to an increased need for efficient and objective evaluation of large amounts of data. While the pioneering approaches applying automated methods for the analysis of brain tumor images date back almost two decades, the current methods are becoming more mature and coming closer to routine clinical application. This review aims to provide a comprehensive overview by giving a brief introduction to brain tumors and imaging of brain tumors first. Then, we review the state of the art in segmentation, registration and modeling related to tumor-bearing brain images with a focus on gliomas. The objective in the segmentation is outlining the tumor including its sub-compartments and surrounding tissues, while the main challenge in registration and modeling is the handling of morphological changes caused by the tumor. The qualities of different approaches are discussed with a focus on methods that can be applied on standard clinical imaging protocols. Finally, a critical assessment of the current state is performed and future developments and trends are addressed, giving special attention to recent developments in radiological tumor assessment guidelines.

In vivo proton range verification: a review

Abstract: Protons are an interesting modality for radiotherapy because of their well defined range and favourable depth dose characteristics. On the other hand, these same characteristics lead to added uncertainties in their delivery. This is particularly the case at the distal end of proton dose distributions, where the dose gradient can be extremely steep. In practice however, this gradient is rarely used to spare critical normal tissues due to such worries about its exact position in the patient. Reasons for this uncertainty are inaccuracies and non-uniqueness of the calibration from CT Hounsfield units to proton stopping powers, imaging artefacts (e.g. due to metal implants) and anatomical changes of the patient during treatment. In order to improve the precision of proton therapy therefore, it would be extremely desirable to verify proton range in vivo, either prior to, during, or after therapy. In this review, we describe and compare state-of-the art in vivo proton range verification methods currently being proposed, developed or clinically implemented.

A limited-angle CT reconstruction method based on anisotropic TV minimization.

Abstract: This paper presents a compressed sensing (CS)-inspired reconstruction method for limited-angle computed tomography (CT). Currently, CS-inspired CT reconstructions are often performed by minimizing the total variation (TV) of a CT image subject to data consistency. A key to obtaining high image quality is to optimize the balance between TV-based smoothing and data fidelity. In the case of the limited-angle CT problem, the strength of data consistency is angularly varying. For example, given a parallel beam of x-rays, information extracted in the Fourier domain is mostly orthogonal to the direction of x-rays, while little is probed otherwise. However, the TV minimization process is isotropic, suggesting that it is unfit for limited-angle CT. Here we introduce an anisotropic TV minimization method to address this challenge. The advantage of our approach is demonstrated in numerical simulation with both phantom and real CT images, relative to the TV-based reconstruction.

Chemical exchange saturation transfer (CEST) and MR Z-spectroscopy in vivo: a review of theoretical approaches and methods.

Abstract: Chemical exchange saturation transfer (CEST) of metabolite protons that undergo exchange processes with the abundant water pool enables a specific contrast for magnetic resonance imaging (MRI). The CEST image contrast depends on physical and physiological parameters that characterize the microenvironment such as temperature, pH, and metabolite concentration. However, CEST imaging in vivo is a complex technique because of interferences with direct water saturation (spillover effect), the involvement of other exchanging pools, in particular macromolecular systems (magnetization transfer, MT), and nuclear Overhauser effects (NOEs). Moreover, there is a strong dependence of the diverse effects on the employed parameters of radiofrequency irradiation for selective saturation which makes interpretation of acquired signals difficult. This review considers analytical solutions of the Bloch–McConnell (BM) equation system which enable deep insight and theoretical description of CEST and the equivalent off-resonant spinlock (SL) experiments. We derive and discuss proposed theoretical treatments in detail to understand the influence of saturation parameters on the acquired Z-spectrum and how the different effects interfere and can be isolated in MR Z-spectroscopy. Finally, we provide an overview of reported CEST effects in vivo and discuss proposed methods and technical approaches applicable to in vivo CEST studies on clinical MRI systems.

A compact, high performance atomic magnetometer for biomedical applications

Abstract: We present a highly sensitive room-temperature atomic magnetometer (AM), designed for use in biomedical applications. The magnetometer sensor head is only 2 × 2 × 5 cm3 and is constructed using readily available, low-cost optical components. The magnetic field resolution of the AM is <10 fT Hz–1/2, which is comparable to cryogenically cooled superconducting quantum interference device (SQUID) magnetometers. We present side-by-side comparisons between our AM and a SQUID magnetometer, and show that equally high quality magnetoencephalography and magnetocardiography recordings can be obtained using our AM.

Modelling the physics in the iterative reconstruction for transmission computed tomography

Abstract: There is an increasing interest in iterative reconstruction (IR) as a key tool to improve quality and increase applicability of x-ray CT imaging. IR has the ability to significantly reduce patient dose; it provides the flexibility to reconstruct images from arbitrary x-ray system geometries and allows one to include detailed models of photon transport and detection physics to accurately correct for a wide variety of image degrading effects. This paper reviews discretization issues and modelling of finite spatial resolution, Compton scatter in the scanned object, data noise and the energy spectrum. The widespread implementation of IR with a highly accurate model-based correction, however, still requires significant effort. In addition, new hardware will provide new opportunities and challenges to improve CT with new modelling.

Investigation of a method for generating synthetic CT models from MRI scans of the head and neck for radiation therapy

Abstract: Magnetic resonance (MR) images often provide superior anatomic and functional information over computed tomography (CT) images, but generally are not used alone without CT images for radiotherapy treatment planning and image guidance. This study aims to investigate the potential of probabilistic classification of voxels from multiple MRI contrasts to generate synthetic CT ('MRCT') images. The method consists of (1) acquiring multiple MRI volumes: T1-weighted, T2-weighted, two echoes from a ultra-short echo time (UTE) sequence, and calculated fat and water image volumes using a Dixon method, (2) classifying tissues using fuzzy c-means clustering with a spatial constraint, (3) assigning attenuation properties with weights based on the probability of individual tissue classes being present in each voxel, and (4) generating a MRCT image volume from the sum of attenuation properties in each voxel. The capability of each MRI contrast to differentiate tissues of interest was investigated based on a retrospective analysis of ten patients. For one prospective patient, the correlation of skull intensities between CT and MR was investigated, the discriminatory power of MRI in separating air from bone was evaluated, and the generated MRCT image volume was qualitatively evaluated. Our analyses showed that one MRI volume was not sufficient to separate all tissue types, and T2-weighted images was more sensitive to bone density variation compared to other MRI image types. The short echo UTE image showed significant improvement in contrasting air versus bone, but could not completely separate air from bone without false labeling. Generated MRCT and CT images showed similar contrast between bone and soft/solid tissues. These results demonstrate the potential of the presented method to generate synthetic CT images to support the workflow of radiation oncology treatment planning and image guidance.

Acoustic super-resolution with ultrasound and microbubbles.

Abstract: Ultrasound (US) is a widely used clinical imaging modality that offers penetration depths in tissue of >10 cm. However, the spatial resolution in US imaging is fundamentally limited by diffraction to approximately half the wavelength of the sound wave employed. The spatial resolution of optical microscopy is limited by the same fundamental physics, but in recent years super-resolution imaging techniques have been developed that overcome the diffraction limit through the localization of many spatially separated photo-switchable or photo-activatable fluorophores. In this paper, we apply a related approach to demonstrate super-resolution imaging with US. We imaged dilute suspensions of microbubble contrast agents flowing through narrow tube-based phantoms. By spatially localizing multiple spatially isolated microbubbles, we constructed super-resolved microbubble location density maps that clearly resolve features 5.1–2.2 times smaller than the US system point spread function full width half maximum in the lateral and axial directions respectively. Our initial characterization experiment using a fixed 100 µm diameter brass wire and a US frequency of 2 MHz suggests that for an ideal stationary point scatterer the ultimate resolution of the unmodified clinical US system used could be in the range of 2–4 µm.

Improving abdomen tumor low-dose CT images using a fast dictionary learning based processing.

Abstract: In abdomen computed tomography (CT), repeated radiation exposures are often inevitable for cancer patients who receive surgery or radiotherapy guided by CT images. Low-dose scans should thus be considered in order to avoid the harm of accumulative x-ray radiation. This work is aimed at improving abdomen tumor CT images from low-dose scans by using a fast dictionary learning (DL) based processing. Stemming from sparse representation theory, the proposed patch-based DL approach allows effective suppression of both mottled noise and streak artifacts. The experiments carried out on clinical data show that the proposed method brings encouraging improvements in abdomen low-dose CT images with tumors.

Dynamic whole-body PET parametric imaging: I. Concept, acquisition protocol optimization and clinical application

Abstract: Static whole-body PET/CT, employing the standardized uptake value (SUV), is considered the standard clinical approach to diagnosis and treatment response monitoring for a wide range of oncologic malignancies. Alternative PET protocols involving dynamic acquisition of temporal images have been implemented in the research setting, allowing quantification of tracer dynamics, an important capability for tumor characterization and treatment response monitoring. Nonetheless, dynamic protocols have been confined to single-bed-coverage limiting the axial field-of-view to ~15-20 cm, and have not been translated to the routine clinical context of whole-body PET imaging for the inspection of disseminated disease. Here, we pursue a transition to dynamic whole-body PET parametric imaging, by presenting, within a unified framework, clinically feasible multi-bed dynamic PET acquisition protocols and parametric imaging methods. We investigate solutions to address the challenges of: (i) long acquisitions, (ii) small number of dynamic frames per bed, and (iii) non-invasive quantification of kinetics in the plasma. In the present study, a novel dynamic (4D) whole-body PET acquisition protocol of ~45 min total length is presented, composed of (i) an initial 6 min dynamic PET scan (24 frames) over the heart, followed by (ii) a sequence of multi-pass multi-bed PET scans (six passes × seven bed positions, each scanned for 45 s). Standard Patlak linear graphical analysis modeling was employed, coupled with image-derived plasma input function measurements. Ordinary least squares Patlak estimation was used as the baseline regression method to quantify the physiological parameters of tracer uptake rate Ki and total blood distribution volume V on an individual voxel basis. Extensive Monte Carlo simulation studies, using a wide set of published kinetic FDG parameters and GATE and XCAT platforms, were conducted to optimize the acquisition protocol from a range of ten different clinically acceptable sampling schedules examined. The framework was also applied to six FDG PET patient studies, demonstrating clinical feasibility. Both simulated and clinical results indicated enhanced contrast-to-noise ratios (CNRs) for Ki images in tumor regions with notable background FDG concentration, such as the liver, where SUV performed relatively poorly. Overall, the proposed framework enables enhanced quantification of physiological parameters across the whole body. In addition, the total acquisition length can be reduced from 45 to ~35 min and still achieve improved or equivalent CNR compared to SUV, provided the true Ki contrast is sufficiently high. In the follow-up companion paper, a set of advanced linear regression schemes is presented to particularly address the presence of noise, and attempt to achieve a better trade-off between the mean-squared error and the CNR metrics, resulting in enhanced task-based imaging.

A Monte Carlo-based model of gold nanoparticle radiosensitization accounting for increased radiobiological effectiveness

Abstract: Radiosensitization using gold nanoparticles (AuNPs) has been shown to vary widely with cell line, irradiation energy, AuNP size, concentration and intracellular localization. We developed a Monte Carlo-based AuNP radiosensitization predictive model (ARP), which takes into account the detailed energy deposition at the nano-scale. This model was compared to experimental cell survival and macroscopic dose enhancement predictions. PC-3 prostate cancer cell survival was characterized after irradiation using a 300 kVp photon source with and without AuNPs present in the cell culture media. Detailed Monte Carlo simulations were conducted, producing individual tracks of photoelectric products escaping AuNPs and energy deposition was scored in nano-scale voxels in a model cell nucleus. Cell survival in our predictive model was calculated by integrating the radiation induced lethal event density over the nucleus volume. Experimental AuNP radiosensitization was observed with a sensitizer enhancement ratio (SER) of 1.21 ± 0.13. SERs estimated using the ARP model and the macroscopic enhancement model were 1.20 ± 0.12 and 1.07 ± 0.10 respectively. In the hypothetical case of AuNPs localized within the nucleus, the ARP model predicted a SER of 1.29 ± 0.13, demonstrating the influence of AuNP intracellular localization on radiosensitization.

On a dark-field signal generated by micrometer-sized calcifications in phase-contrast mammography

Abstract: We show that a distribution of micrometer-sized calcifications in the human breast which are not visible in clinical x-ray mammography at diagnostic dose levels can produce a significant dark-field signal in a grating-based x-ray phase-contrast imaging setup with a tungsten anode x-ray tube operated at 40 kVp. A breast specimen with invasive ductal carcinoma was investigated immediately after surgery by Talbot-Lau x-ray interferometry with a design energy of 25 keV. The sample contained two tumors which were visible in ultrasound and contrast-agent enhanced MRI but invisible in clinical x-ray mammography, in specimen radiography and in the attenuation images obtained with the Talbot-Lau interferometer. One of the tumors produced significant dark-field contrast with an exposure of 0.85 mGy air-kerma. Staining of histological slices revealed sparsely distributed grains of calcium phosphate with sizes varying between 1 and 40 μm in the region of this tumor. By combining the histological investigations with an x-ray wave-field simulation we demonstrate that a corresponding distribution of grains of calcium phosphate in the form of hydroxylapatite has the ability to produce a dark-field signal which would-to a substantial degree-explain the measured dark-field image. Thus we have found the appearance of new information (compared to attenuation and differential phase images) in the dark-field image. The second tumor in the same sample did not contain a significant fraction of these very fine calcification grains and was invisible in the dark-field image. We conclude that some tumors which are invisible in x-ray absorption mammography might be detected in the x-ray dark-field image at tolerable dose levels.

Interplay effects in proton scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters

Abstract: Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of five lung cancer patients of varying tumor size (50.4–167.1 cc) and motion amplitude (2.9–30.1 mm). Treatments were planned assuming delivery in 35 × 2.5 Gy(RBE) fractions. The spot size, time to change the beam energy (τes), time required for magnet settling (τss), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the five patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior–inferior motion amplitude alone. Larger spot sizes (σ ~ 9–16 mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0 ± 4.4% (1 standard deviation) in a single fraction compared to 86.1 ± 13.1% for smaller spots (σ ~ 2–4 mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes respectively. The interplay effect is highly patient specific, depending on the motion amplitude, tumor location and the delivery parameters. Large degradations of the dose distribution in a single fraction were observed, but improved significantly using conventional fractionation.

In vivo characterization of tumor vasculature using iodine and gold nanoparticles and dual energy micro-CT

Abstract: Tumor blood volume and vascular permeability are well established indicators of tumor angiogenesis and important predictors in cancer diagnosis, planning and treatment. In this work, we establish a novel preclinical imaging protocol which allows quantitative measurement of both metrics simultaneously. First, gold nanoparticles are injected and allowed to extravasate into the tumor, and then liposomal iodine nanoparticles are injected. Combining a previously optimized dual energy micro-CT scan using high-flux polychromatic x-ray sources (energies: 40?kVp, 80?kVp) with a novel post-reconstruction spectral filtration scheme, we are able to decompose the results into 3D iodine and gold maps, allowing simultaneous measurement of extravasated gold and intravascular iodine concentrations. Using a digital resolution phantom, the mean limits of detectability (mean CNR = 5) for each element are determined to be 2.3?mg?mL?1?(18?mM) for iodine and 1.0?mg?mL?1?(5.1?mM) for gold, well within the observed in vivo concentrations of each element (I: 0?24?mg?mL?1, Au: 0?9?mg?mL?1) and a factor of 10 improvement over the limits without post-reconstruction spectral filtration. Using a calibration phantom, these limits are validated and an optimal sensitivity matrix for performing decomposition using our micro-CT system is derived. Finally, using a primary mouse model of soft-tissue sarcoma, we demonstrate the in vivo application of the protocol to measure fractional blood volume and vascular permeability over the course of five days of active tumor growth.

A reference dataset for deformable image registration spatial accuracy evaluation using the COPDgene study archive.

Abstract: Landmark point-pairs provide a strategy to assess deformable image registration (DIR) accuracy in terms of the spatial registration of the underlying anatomy depicted in medical images. In this study, we propose to augment a publicly available database (www.dir-lab.com) of medical images with large sets of manually identified anatomic feature pairs between breath-hold computed tomography (BH-CT) images for DIR spatial accuracy evaluation. Ten BH-CT image pairs were randomly selected from the COPDgene study cases. Each patient had received CT imaging of the entire thorax in the supine position at one-fourth dose normal expiration and maximum effort full dose inspiration. Using dedicated in-house software, an imaging expert manually identified large sets of anatomic feature pairs between images. Estimates of inter- and intra-observer spatial variation in feature localization were determined by repeat measurements of multiple observers over subsets of randomly selected features. 7298 anatomic landmark features were manually paired between the 10 sets of images. Quantity of feature pairs per case ranged from 447 to 1172. Average 3D Euclidean landmark displacements varied substantially among cases, ranging from 12.29 (SD: 6.39) to 30.90 (SD: 14.05) mm. Repeat registration of uniformly sampled subsets of 150 landmarks for each case yielded estimates of observer localization error, which ranged in average from 0.58 (SD: 0.87) to 1.06 (SD: 2.38) mm for each case. The additions to the online web database (www.dir-lab.com) described in this work will broaden the applicability of the reference data, providing a freely available common dataset for targeted critical evaluation of DIR spatial accuracy performance in multiple clinical settings. Estimates of observer variance in feature localization suggest consistent spatial accuracy for all observers across both four-dimensional CT and COPDgene patient cohorts.

Automated segmentation of pulmonary structures in thoracic computed tomography scans: a review

Abstract: Computed tomography (CT) is the modality of choice for imaging the lungs in vivo. Sub-millimeter isotropic images of the lungs can be obtained within seconds, allowing the detection of small lesions and detailed analysis of disease processes. The high resolution of thoracic CT and the high prevalence of lung diseases require a high degree of automation in the analysis pipeline. The automated segmentation of pulmonary structures in thoracic CT has been an important research topic for over a decade now. This systematic review provides an overview of current literature. We discuss segmentation methods for the lungs, the pulmonary vasculature, the airways, including airway tree construction and airway wall segmentation, the fissures, the lobes and the pulmonary segments. For each topic, the current state of the art is summarized, and topics for future research are identified.

Sub-200 ps CRT in monolithic scintillator PET detectors using digital SiPM arrays and maximum likelihood interaction time estimation

Abstract: Digital silicon photomultiplier (dSiPM) arrays have favorable characteristics for application in monolithic scintillator detectors for time-of-flight positron emission tomography (PET). To fully exploit these benefits, a maximum likelihood interaction time estimation (MLITE) method was developed to derive the time of interaction from the multiple time stamps obtained per scintillation event. MLITE was compared to several deterministic methods. Timing measurements were performed with monolithic scintillator detectors based on novel dSiPM arrays and LSO:Ce,0.2%Ca crystals of 16 × 16 × 10 mm3, 16 × 16 × 20 mm3, 24 × 24 × 10 mm3, and 24 × 24 × 20 mm3. The best coincidence resolving times (CRTs) for pairs of identical detectors were obtained with MLITE and measured 157 ps, 185 ps, 161 ps, and 184 ps full-width-at-half-maximum (FWHM), respectively. For comparison, a small reference detector, consisting of a 3 × 3 × 5 mm3 LSO:Ce,0.2%Ca crystal coupled to a single pixel of a dSiPM array, was measured to have a CRT as low as 120 ps FWHM. The results of this work indicate that the influence of the optical transport of the scintillation photons on the timing performance of monolithic scintillator detectors can at least partially be corrected for by utilizing the information contained in the spatio-temporal distribution of the collection of time stamps registered per scintillation event.

Distributions of secondary particles in proton and carbon-ion therapy: a comparison between GATE/Geant4 and FLUKA Monte Carlo codes.

Abstract: Monte Carlo simulations play a crucial role for in-vivo treatment monitoring based on PET and prompt gamma imaging in proton and carbon-ion therapies. The accuracy of the nuclear fragmentation models implemented in these codes might affect the quality of the treatment verification. In this paper, we investigate the nuclear models implemented in GATE/Geant4 and FLUKA by comparing the angular and energy distributions of secondary particles exiting a homogeneous target of PMMA. Comparison results were restricted to fragmentation of (16)O and (12)C. Despite the very simple target and set-up, substantial discrepancies were observed between the two codes. For instance, the number of high energy (>1 MeV) prompt gammas exiting the target was about twice as large with GATE/Geant4 than with FLUKA both for proton and carbon ion beams. Such differences were not observed for the predicted annihilation photon production yields, for which ratios of 1.09 and 1.20 were obtained between GATE and FLUKA for the proton beam and the carbon ion beam, respectively. For neutrons and protons, discrepancies from 14% (exiting protons-carbon ion beam) to 57% (exiting neutrons-proton beam) have been identified in production yields as well as in the energy spectra for neutrons.

Multi-sensor magnetoencephalography with atomic magnetometers

Abstract: The authors have detected magnetic fields from the human brain with two independent, simultaneously operating rubidium spin-exchange-relaxation-free magnetometers Evoked responses from auditory stimulation were recorded from multiple subjects with two multi-channel magnetometers located on opposite sides of the head Signal processing techniques enabled by multi-channel measurements were used to improve signal quality This is the first demonstration of multi-sensor atomic magnetometer magnetoencephalography and provides a framework for developing a non-cryogenic, whole-head magnetoencephalography array for source localization

Energy- and time-resolved detection of prompt gamma-rays for proton range verification

Abstract: In this work, we present experimental results of a novel prompt gamma-ray detector for proton beam range verification. The detection system features an actively shielded cerium-doped lanthanum(III) bromide scintillator, coupled to a digital data acquisition system. The acquisition was synchronized to the cyclotron radio frequency to separate the prompt gamma-ray signals from the later-arriving neutron-induced background. We designed the detector to provide a high energy resolution and an effective reduction of background events, enabling discrete proton-induced prompt gamma lines to be resolved. Measuring discrete prompt gamma lines has several benefits for range verification. As the discrete energies correspond to specific nuclear transitions, the magnitudes of the different gamma lines have unique correlations with the proton energy and can be directly related to nuclear reaction cross sections. The quantification of discrete gamma lines also enables elemental analysis of tissue in the beam path, providing a better prediction of prompt gamma-ray yields. We present the results of experiments in which a water phantom was irradiated with proton pencil-beams in a clinical proton therapy gantry. A slit collimator was used to collimate the prompt gamma-rays, and measurements were performed at 27 positions along the path of proton beams with ranges of 9, 16 and 23 g cm −2 in water. The magnitudes of discrete gamma lines at 4.44, 5.2 and 6.13 MeV were quantified. The prompt gamma lines were found to be clearly resolved in dimensions of energy and time, and had a reproducible correlation with the proton depth-dose curve. We conclude that the measurement of discrete prompt gamma-rays for in vivo range verification of clinical proton beams is feasible, and plan to further study methods and detector designs for clinical use.

Towards reference dosimetry for the MR-linac: magnetic field correction of the ionization chamber reading.

Abstract: In the UMC Utrecht a prototype MR-linac has been installed. The system consists of a 6 MV Elekta (Crawley, UK) linear accelerator and a 1.5 T Philips (Best, The Netherlands) Achieva MRI system. This paper investigates the feasibility to correct the ionization chamber reading for the magnetic field within the dosimetry calibration method described by Almond et al (1999 Med. Phys. 26 1847–70). Firstly, the feasibility of using an ionization chamber in an MR-linac was assessed by investigating possible influences of the magnetic field on NE2571 Farmer-type ionization chamber characteristics: linearity, repeatability, orientation in the magnetic field; and AAPM TG51 correction factor for voltage polarity and ion recombination. We found that these AAPM correction factors for the NE2571 chamber were not influenced by the magnetic field. Secondly, the influence of the permanent 1.5 T magnetic field on the NE2571 chamber reading was quantified. The reading is influenced by the magnetic field; therefore, a correction factor has been added. For the standardized setup used in this paper, the NE2571 chamber reading increases by 4.9% (± 0.2%) due to the transverse 1.5 T magnetic field. Dosimetry measurements in an MR-linac are feasible, if a setup-specific magnetic field correction factor (P1.5 T) for the charge reading is introduced. For the setup investigated in this paper, the P1.5 T has a value of 0.953.

Gauging the likelihood of stable cavitation from ultrasound contrast agents

Abstract: The mechanical index (MI) was formulated to gauge the likelihood of adverse bioeffects from inertial cavitation. However, the MI formulation did not consider bubble activity from stable cavitation. This type of bubble activity can be readily nucleated from ultrasound contrast agents (UCAs) and has the potential to promote beneficial bioeffects. Here, the presence of stable cavitation is determined numerically by tracking the onset of subharmonic oscillations within a population of bubbles for frequencies up to 7 MHz and peak rarefactional pressures up to 3 MPa. In addition, the acoustic pressure rupture threshold of an UCA population was determined using the Marmottant model. The threshold for subharmonic emissions of optimally sized bubbles was found to be lower than the inertial cavitation threshold for all frequencies studied. The rupture thresholds of optimally sized UCAs were found to be lower than the threshold for subharmonic emissions for either single cycle or steady state acoustic excitations. Because the thresholds of both subharmonic emissions and UCA rupture are linearly dependent on frequency, an index of the form ICAV = Pr/f (where Pr is the peak rarefactional pressure in MPa and f is the frequency in MHz) was derived to gauge the likelihood of subharmonic emissions due to stable cavitation activity nucleated from UCAs.

Nanoparticle encapsulation in red blood cells enables blood-pool magnetic particle imaging hours after injection

Abstract: Magnetic particle imaging (MPI) is a new medical imaging approach that is based on the nonlinear magnetization response of super-paramagnetic iron oxide nanoparticles (SPIOs) injected into the blood stream. To date, real-time MPI of the bolus passage of an approved MRI SPIO contrast agent injected into the tail vein of living mice has been demonstrated. However, nanoparticles are rapidly removed from the blood stream by the mononuclear phagocyte system. Therefore, imaging applications for long-term monitoring require the repeated administration of bolus injections, which complicates quantitative comparisons due to the temporal variations in concentration. Encapsulation of SPIOs into red blood cells (RBCs) has been suggested to increase the blood circulation time of nanoparticles. This work presents first evidence that SPIO-loaded RBCs can be imaged in the blood pool of mice several hours after injection using MPI. This finding is supported by magnetic particle spectroscopy performed to quantify the iron concentration in blood samples extracted from the mice 3 and 24 h after injection of SPIO-loaded RBCs. Based on these results, new MPI applications can be envisioned, such as permanent 3D real-time visualization of the vessel tree during interventional procedures, bleeding monitoring after stroke, or long-term monitoring and treatment control of cardiovascular diseases.

Deriving effective atomic numbers from DECT based on a parameterization of the ratio of high and low linear attenuation coefficients

Abstract: Dual energy computed tomography (DECT) can provide simultaneous estimation of relative electron density ?e?and effective atomic number Zeff. The ability to obtain these quantities (?e, Zeff) has been shown to benefit selected radiotherapy applications where tissue characterization is required. The conventional analysis method (spectral method) relies on knowledge of the CT scanner photon spectra which may be difficult to obtain accurately. Furthermore an approximate empirical attenuation correction of the photon spectrum through the patient is necessary. We present an alternative approach based on a parameterization of the measured ratio of low and high kVp linear attenuation coefficients for deriving Zeff?which does not require the estimation of the CT scanner spectra. In a first approach, the tissue substitute method (TSM), the Rutherford parameterization of the linear attenuation coefficients was employed to derive a relation between Zeff?and the ratio of the linear attenuation coefficients measured at the low and high kVp of the CT scanner. A phantom containing 16 tissue mimicking inserts was scanned with a dual source DECT scanner at 80 and 140 kVp. The data from the 16 inserts phantom was used to obtain model parameters for the relation between Zeff?and . The accuracy of the method was evaluated with a second phantom containing 4 tissue mimicking inserts. The TSM was compared to a more complex approach, the reference tissue method (RTM), which requires the derivation of stoichiometric fit parameters. These were derived from the 16 inserts phantom scans and used to calculate CT numbers at 80 and 140 kVp for a set of tabulated reference human tissues. Model parameters for the parameterization of were estimated for this reference tissue dataset and compared to the results of the TSM. Residuals on Zeff?for the reference tissue dataset for both TSM and RTM were compared to those obtained from the spectral method. The tissue substitutes were well fitted by the TSM with R2?= 0.9930. Residuals on Zeff?for the phantoms were similar between the TSM and spectral methods for Zeff < 8 while they were improved by the TSM for higher Zeff. The RTM fitted the reference tissue dataset well with R2 = 0.9999. Comparing the Zeff?extracted from TSM and the more complex RTM to the known values from the reference tissue dataset yielded errors of up to 0.3 and 0.15 units of Zeff?respectively. The parameterization approach yielded standard deviations which were up to 0.3 units of Zeff?higher than those observed with the spectral method for Zeff?around 7.5. Procedures for the DECT estimation of Zeff?removing the need for estimates of the CT scanner spectra have been presented. Both the TSM and the more complex RTM performed better than the spectral method. The RTM yielded the best results for the reference human tissue dataset reducing errors from up to 0.3 to 0.15 units of Zeff?compared to the simpler TSM. Both TSM and RTM are simpler to implement than the spectral method which requires estimates of the CT scanner spectra.

First characterization of a digital SiPM based time-of-flight PET detector with 1 mm spatial resolution

Abstract: Monolithic scintillator detectors can offer a combination of spatial resolution, energy resolution, timing performance, depth-of-interaction information, and detection efficiency that make this type of detector a promising candidate for application in clinical, time-of-flight (TOF) positron emission tomography (PET). In such detectors the scintillation light is distributed over a relatively large number of photosensor pixels and the light intensity per pixel can be relatively low. Therefore, monolithic scintillator detectors are expected to benefit from the low readout noise offered by a novel photosensor called the digital silicon photomultiplier (dSiPM). Here, we present a first experimental characterization of a TOF PET detector comprising a 24 × 24 × 10 mm3 LSO:Ce,0.2%Ca scintillator read out by a dSiPM array (DPC-6400–44–22) developed by Philips Digital Photon Counting. A spatial resolution of ~1 mm full-width-at-half-maximum (FWHM) averaged over the entire crystal was obtained (varying from just below 1 mm FWHM in the detector center to ~1.2 mm FWHM close to the edges). Furthermore, the bias in the position estimation at the crystal edges that is typically found in monolithic scintillators is well below 1 mm even in the corners of the crystal.

Adequate margin definition for scanned particle therapy in the incidence of intrafractional motion.

Abstract: Advanced 4D dose calculations (4DDCs) for scanned particle therapy show that in the incidence of motion, it is insufficient to use target contours defined on one reference CT phase. ICRU Report 62 (ICRU 1999 ICRU Report 62 (Bethesda, MD: ICRU)) advises that variations in size, shape and position of CTVs relative to anatomic reference points have to be considered for internal target volumes (ITVs). In addition to geometrical margin adaption, changes of water equivalent path length have to be considered for particle therapy. Different ITV concepts have been applied to six representative patients (liver and lung indications) based on 4DCT. Geometrical ITVs (gITV) were calculated by combining deformed CTVs over all motion phases. To take into account path length changes, range adapted ITVs (raITV) were established as the union of range adapted CTVs in all phases. For gated delivery, gat_gITVs and gat_raITVs were calculated. Extensive 4DDCs have been performed for two exemplary patients to illustrate that neither re-scanning nor gating can sufficiently compensate for motion effects if no appropriate margins are employed and to evaluate the effectiveness of gITVs and raITVs. CTVs significantly differ from gITVs and raITVs in size (up to a factor 2 in volume). But also raITVs and gITVs differ significantly in size and are spatially displaced, particularly for lung patients. raITVs show a strong field dependence in shape. All volumes are reduced in size when gating is applied and considered during margin adaption. 4D dose distributions show big improvements when gITV or raITV are used compared to CTVs. However, the use of either gITVs or raITVs do not result in significant differences. If raITVs are used, slightly better target coverage is gained at the cost of more healthy tissue exposure. Our results emphasize that adapted target volumes have to be used for scanned particle therapy in the presence of motion. However, even though gITVs and raITVs differ significantly in shape and size, this difference does not necessarily translate into significant differences in the resultant 4D dose distributions.

Combined Ultrasound and MR Imaging to Guide Focused Ultrasound Therapies in the Brain

Abstract: Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation?the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood?brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood?brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.