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PURPOSE: Electronic portal imaging devices (EPIDs) lend themselves to beams-eye view clinical applications, such as tumor tracking, but are limited by low contrast and detective quantum efficiency (DQE). We characterize a novel EPID prototype consisting of multiple layers and investigate its suitability for use under clinical conditions. MATERIALS AND METHOD: A prototype multilayer imager (MLI) was constructed utilizing four conventional EPID layers, each consisting of a copper plate, a Gd2O2S:Tb (GOS) phosphor scintillator, and an amorphous silicon flat panel array detector. We measured the detector’s response to a 6 MV photon beam with regards to modulation transfer function (MTF), noise power spectrum (NPS), DQE, contrast to noise ratio (CNR), signal to noise ratio (SNR), and the linearity of the detector’s response to dose. Additionally, we compared MLI performance to the single top layer of the MLI and the standard Varian AS-1200 detector. Pre-clinical imaging was done on an anthropomorphic phantom, and the detector’s CNR, SNR and spatial resolution were assessed in a clinical environment. Images obtained from spine and liver patient treatment deliveries were analyzed to verify CNR and SNR improvements. RESULTS: The MLI has a DQE(0) of 9.7%, about 5.7 times the reference AS-1200 detector. Improved noise performance largely drives the increase. CNR and SNR of clinical images improved three-fold compared to reference. CONCLUSION: A novel MLI was characterized and prepared for clinical translation. The MLI substantially improved DQE and CNR performance while maintaining the same resolution. Pre-clinical tests on an anthropomorphic phantom demonstrated improved performance as predicted theoretically. Preliminary patient data were analyzed, confirming improved CNR and SNR. Clinical applications are anticipated to include more accurate soft tissue tracking.

Monte Carlo simulation (MCS) is one of the most accurate computation methods for dose calculation and image formation in radiation therapy. However, the high computational complexity and long execution time of MCS limits its broad use. In this paper, we present a novel strategy to accelerate MCS using a graphic processing unit (GPU), and we demonstrate the application in mega-voltage (MV) cone-beam computed tomography (CBCT) simulation. A new framework that generates a series of MV projections from a single simulation run is designed specifically for MV-CBCT acquisition. A Geant4-based GPU code for photon simulation is incorporated into the framework for the simulation of photon transport through a phantom volume. The FastEPID method, which accelerates the simulation of MV images, is modified and integrated into the framework. The proposed GPU-based simulation strategy was tested for its accuracy and efficiency in a Catphan 604 phantom and an anthropomorphic pelvis phantom with beam energies at 2.5 MV, 6 MV, and 6 MV FFF. In all cases, the proposed GPU-based simulation demonstrated great simulation accuracy and excellent agreement with measurement and CPU-based simulation in terms of reconstructed image qualities. The MV-CBCT simulation was accelerated by factors of roughly 900–2300 using an NVIDIA Tesla V100 GPU card against a 2.5 GHz AMD Opteron™ Processor 6380.

International audience; This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Purpose Hypoxia measurements can provide crucial information regarding tumor aggressiveness, however current preclinical approaches are limited. Blood oxygen level dependent (BOLD) Magnetic Resonance Imaging (MRI) has the potential to continuously monitor tumor pathophysiology (including hypoxia). The aim of this preliminary work was to develop and evaluate BOLD MRI followed by post-image analysis to identify regions of hypoxia in a murine glioblastoma (GBM) model. Methods A murine orthotopic GBM model (GL261-luc2) was used and independent images were generated from multiple slices in four different mice. Image slices were randomized and split into training and validation cohorts. A 7 T MRI was used to acquire anatomical images using a fast-spin-echo (FSE) T2-weighted sequence. BOLD images were taken with a T2*-weighted gradient echo (GRE) and an oxygen challenge. Thirteen images were evaluated in a training cohort to develop the MRI sequence and optimize post-image analysis. An in-house MATLAB code was used to evaluate MR images and generate hypoxia maps for a range of thresholding and ΔT2* values, which were compared against respective pimonidazole sections to optimize image processing parameters. The remaining (n = 6) images were used as a validation group. Following imaging, mice were injected with pimonidazole and collected for immunohistochemistry (IHC). A test of correlation (Pearson's coefficient) and agreement (Bland-Altman plot) were conducted to evaluate the respective MRI slices and pimonidazole IHC sections. Results For the training cohort, the optimized parameters of “thresholding” (20 ≤ T2* ≤ 35 ms) and ΔT2* (±4 ms) yielded a Pearson's correlation of 0.697. These parameters were applied to the validation cohort confirming a strong Pearson's correlation (0.749) when comparing the respective analyzed MR and pimonidazole images. Conclusion Our preliminary study supports the hypothesis that BOLD MRI is correlated with pimonidazole measurements of hypoxia in an orthotopic GBM mouse model. This technique has further potential to monitor hypoxia during tumor development and therapy.

Tumor tracking during radiotherapy treatment can improve dose accuracy, conformity and sparing of healthy tissue. Many methods have been introduced to tackle this challenge utilizing multiple imaging modalities, including a template matching based approach using the megavoltage (MV) on-board portal imager demonstrated on 3D conformal treatments. However, the complexity of treatments is evolving with the introduction of VMAT and IMRT, and successful motion management is becoming more important due to a trend towards hypofractionation. We have developed a markerless lung tumor tracking algorithm, utilizing the electronic portal imager (EPID) of the treatment machine. The algorithm has been specifically adapted to track during complex treatment deliveries with gantry and MLC motion. The core of the algorithm is an adaptive template matching method that relies on template stability metrics and local relative orientations to perform multiple feature tracking simultaneously. Only a single image is required to initialize the algorithm and features are automatically added, modified or removed in response to the input images. This algorithm was evaluated against images collected during VMAT arcs of a dynamic thorax phantom. Dynamic phantom images were collected during radiation delivery for multiple lung SBRT breathing traces and an example patient data set. The tracking error was 1.34 mm for the phantom data and 0.68 mm for the patient data. A multi-region, markerless tracking algorithm has been developed, capable of tracking multiple features simultaneously without requiring any other a priori information. This novel approach delivers robust target localization during complex treatment delivery. The reported tracking error is similar to previous reports for 3D conformal treatments.

Simultaneous acquisition of cone beam CT (CBCT) projections using both the kV and MV imagers of an image guided radiotherapy system reduces set-up scan times-a benefit to lung cancer radiation oncology patients-but increases noise in the 3D reconstruction. In this article, we present a kV-MV scan time reduction technique that uses two noise-reducing measures to achieve superior performance. The first is a high-DQE multi-layer MV imager prototype. The second is a beam hardening correction algorithm which combines poly-energetic modeling with edge-preserving, regularized smoothing of the projections. Performance was tested in real acquisitions of the Catphan 604 and a thorax phantom. Percent noise was quantified from voxel values in a soft tissue volume of interest (VOI) while edge blur was quantified from a VOI straddling a boundary between air and soft material. Comparisons in noise/resolution performance trade-off were made between our proposed approach, a dose-equivalent kV-only scan, and a kV-MV reconstruction technique previously published by Yinet al(2005Med. Phys.329). The proposed technique demonstrated lower noise as a function of spatial resolution than the baseline kV-MV method, notably a 50% noise reduction at typical edge blur levels. Our proposed method also exhibited fainter non-uniformity artifacts and in some cases superior contrast. Overall, we find that the combination of a multi-layer MV imager, acquiring at a LINAC source energy of 2.5 MV, and a denoised beam hardening correction algorithm enables noise, resolution, and dose performance comparable to standard kV-imager only set-up CBCT, but with nearly half the gantry rotation time.

We have previously demonstrated that endothelial targeting of gold nanoparticles followed by external beam irradiation can cause specific tumor vascular disruption in mouse models of cancer. The induced vascular damage may lead to changes in tumor physiology, including tumor hypoxia, thereby compromising future therapeutic interventions. In this study, we investigate the dynamic changes in tumor hypoxia mediated by targeted gold nanoparticles and clinical radiation therapy (RT). By using noninvasive whole-body fluorescence imaging, tumor hypoxia was measured at baseline, on day 2 and day 13, post-tumor vascular disruption. A 2.5-fold increase (P

Purpose The Small Animal Radiation Research Platform (SARRP) has been developed for conformal microirradiation with on-board cone beam CT (CBCT) guidance. The graphics processing unit (GPU)-accelerated Superposition-Convolution (SC) method for dose computation has been integrated into the treatment planning system (TPS) for SARRP. This paper describes the validation of the SC method for the kilovoltage energy by comparing with EBT2 film measurements and Monte Carlo (MC) simulations. Methods MC data were simulated by EGSnrc code with 3 × 108 -1.5 × 109 histories, while 21 photon energy bins were used to model the 220 kVp x-rays in the SC method. Various types of phantoms including plastic water, cork, graphite, and aluminum were used to encompass the range of densities of mouse organs. For the comparison, percentage depth dose (PDD) of SC, MC, and film measurements were analyzed. Cross beam (x,y) dosimetric profiles of SC and film measurements are also presented. Correction factors (CFz) to convert SC to MC dose-to-medium are derived from the SC and MC simulations in homogeneous phantoms of aluminum and graphite to improve the estimation. Results The SC method produces dose values that are within 5% of film measurements and MC simulations in the flat regions of the profile. The dose is less accurate at the edges, due to factors such as geometric uncertainties of film placement and difference in dose calculation grids. Conclusion The GPU-accelerated Superposition-Convolution dose computation method was successfully validated with EBT2 film measurements and MC calculations. The SC method offers much faster computation speed than MC and provides calculations of both dose-to-water in medium and dose-to-medium in medium.

PURPOSE/OBJECTIVE(S) Beams-eye view (BEV) imaging during radiation therapy can be used for real-time localization of the treatment target. However, clinical implementation is limited by the poor performance of current electronic portal imaging devices (EPIDs). A novel multilayer imager (MLI), consisting of four stacked conventional flat-panel imagers, was recently shown to have 5.7 times the detective quantum efficiency and nearly 2 times the contrast-to-noise ratio of a conventional EPID. In the current study, we compare the MLI against a single layer imager for the application of fiducial tracking during liver SBRT procedures. The hypothesis is that the MLI will provide more accurate and efficient fiducial tracking. MATERIALS/METHODS The prototype MLI was installed in the standard MV imager housing on a clinical LINAC, replacing the conventional EPID. The MV imager arm was extended during volumetric modulated arc therapy (VMAT) SBRT treatments for passive data acquisition. Six patients with liver metastases receiving SBRT in 3-5 fractions (900-1200 cGy/fx) were studied. Data was acquired for two fractions of each treatment course, one fraction with the MLI using all 4 layers and one with the MLI using the top layer only. Automatic fiducial localization was performed using a modification of a previously published algorithm. Truth data was derived using external surrogate respiratory traces combined with manual tracking. Results for 4- and 1-layer modes were compared against truth data to determine tracking accuracy and efficiency. Tracking and noise improvements were assessed for any correlation. RESULTS Between 2771 to 6505 image frames were acquired for each patient, with roughly half of each corresponding to acquisition in 1-layer mode and the other half 4-layer mode. Tracking accuracy with the 1-layer imager returned a root mean square error (RMSE) of 2.1 mm compared to 4-layer RMSE of 1.5 mm, a statistically significant (P < 0.001) improvement of 0.6 mm. Successful tracking efficiency with 4 layers improved to 82.8% versus 58.4% for the 1-layer mode, a relative improvement of 41.8% (P < 0.001). There was a strong correlation (r = 0.913) between the increase in successfully tracked frames and reduction in noise when using the 4-layer mode. CONCLUSION Noise reduction and increased MV photon detection efficiency achieved by utilizing a multi-layer MV imager results in improved fiducial tracking for liver SBRT treatments. Future BEV clinical applications may be improved by pursuing similar noise reduction and photon detection enhancement strategies.

Purpose: Electronic portal image devices (EPIDs) have been investigated previously for beams-eye view (BEV) applications such as tumor tracking but are limited by low contrast-to-noise ratio (CNR) and detective quantum efficiency (DQE). A novel multilayer imager (MLI), consisting of four stacked flat-panels was used to measure improvements in fiducial tracking during liver stereotactic body radiation therapy (SBRT) procedures compared to a single layer EPID. Methods: The prototype MLI was installed on a clinical TrueBeam linac in place of the conventional DMI single-layer EPID. The panel was extended during volumetric modulated arc therapy SBRT treatments in order to passively acquire data during therapy. Images were acquired for six patients receiving SBRT to liver metastases over two fractions each, one with the MLI using all 4 layers and one with the MLI using the top layer only, representing a standard EPID. The acquired frames were processed by a previously published tracking algorithm modified to identify implanted radiopaque fiducials. Truth data was determined using respiratory traces combined with partial manual tracking. Results for 4- and 1-layer mode were compared against truth data for tracking accuracy and efficiency. Tracking and noise improvements as a function of gantry angle were determined. Results: Tracking efficiency with 4-layers improved to 82.8% versus 58.4% for the 1-layer mode, a relative improvement of 41.7%. Fiducial tracking with 1-layer returned a root mean square error (RMSE) of 2.1mm compared to 4-layer RMSE of 1.5mm, a statistically significant (p

Purpose We hypothesized that combining multiple amorphous silicon flat panel layers increases photon detection efficiency in an electronic portal imaging device (EPID), improving image quality and tracking accuracy of low-contrast targets during radiotherapy. Methods The prototype imager evaluated in this study contained four individually programmable layers each with a copper converter layer, Gd2O2S scintillator, and active-matrix flat panel imager (AMFPI). The imager was placed on a Varian TrueBeam linac and a Las Vegas phantom programmed with sinusoidal motion (peak-to-peak amplitude = 20 mm, period = 3.5 s) was imaged at a frame rate of 10 Hz with one to four layers activated. Number of visible circles and CNR of least visible circle (depth = 0.5 mm, diameter = 7 mm) was computed to assess the image quality of single and multiple layers. A previously validated tracking algorithm was employed for auto-tracking. Tracking error was defined as the difference between the programmed and tracked positions of the circle. Pearson correlation coefficient (R) of CNR and tracking errors was computed. Results Motion-induced blurring significantly reduced circle visibility. During four cycles of phantom motion, the number of visible circles varied from 11–23, 13–24, 15–25, and 16–26 for one-, two-, three-, and four-layer imagers, respectively. Compared with using only a single layer, combining two, three, and four layers increased the median CNR by factors of 1.19, 1.42, and 1.71, respectively and reduced the average tracking error from 3.32 mm to 1.67 mm to 1.47 mm, and 0.74 mm, respectively. Significant correlations (P~10−9) were found between the tracking error and CNR. Conclusion Combination of four conventional EPID layers significantly improves the EPID image quality and tracking accuracy for a poorly visible object which is moving with a frequency and amplitude similar to respiratory motion.

Purpose A novel Megavoltage (MV) multi-layer imager (MLI) design featuring higher detective quantum efficiency and lower noise than current conventional MV imagers in clinical use has been recently reported. Optimization of the MLI design for multiple applications including tumor tracking, MV-CBCT and portal dosimetry requires a computational model that will provide insight into the physics processes that affect the overall and individual components’ performance. The purpose of the current work was to develop and validate a comprehensive computational model that can be used for MLI optimization. Methods The MLI model was built using the Geant4 Application for Tomographic Emission (GATE) application. The model includes x-ray and charged particle interactions as well as the optical transfer within the phosphor. A first prototype MLI device featuring a stack of four detection layers was used for model validation. Each layer of the prototype contains (copper buildup sheet, phosphor screen, photodiode array). The model was validated against measured data of Modulation Transfer Function (MTF), Noise Power Spectrum (NPS) and Detective Quantum Efficiency (DQE). MTF was computed using a slanted slit with 2.3° angle and 0.1 mm width. NPS was obtained using the autocorrelation function technique. DQE was calculated from MTF and NPS data. The comparison metrics between simulated and measured data were the Pearson's correlation coefficient (r) and the normalized root-mean-square error (NRMSE). Results Good agreement between measured and simulated MTF and NPS values was observed. Pearson's correlation coefficient for the combined signal from all layers of the MLI was equal to 0.9991 for MTF and 0.9992 for NPS; NRMSE was 0.0121 for MTF and 0.0194 for NPS. Similarly, the DQE correlation coefficient for the combined signal was 0.9888 and the NRMSE was 0.0686. Conclusions A comprehensive model of the novel MLI design was developed using the GATE toolkit and validated against measured MTF, NPS and DQE data acquired with a prototype device featuring four layers. This model will be used for further optimization of the imager components and configuration for clinical radiotherapy applications. This article is protected by copyright. All rights reserved.

Close resemblance of murine and human trials is essential to achieve the best predictive value of animal-based translational cancer research. Kras-driven genetically engineered mouse models of non-small-cell lung cancer faithfully predict the response of human lung cancers to systemic chemotherapy. Owing to development of multifocal disease, however, these models have not been usable in studies of outcomes following focal radiotherapy (RT). We report the development of a preclinical platform to deliver state-of-the-art image-guided RT in these models. Presence of a single tumour as usually diagnosed in patients is modelled by confined injection of adenoviral Cre recombinase. Furthermore, three-dimensional conformal planning and state-of-the-art image-guided dose delivery are performed as in humans. We evaluate treatment efficacies of two different radiation regimens and find that Kras-driven tumours can temporarily be stabilized upon RT, whereas additional loss of either Lkb1 or p53 renders these lesions less responsive to RT.

Effective drug delivery is restricted by pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, poorly-permeable blood vessels limit the intratumoral permeation and penetration of chemo or nanotherapeutic drugs. New and clinically viable strategies are urgently sought to breach the neoplastic barriers that prevent effective drug delivery. Here, we present an original idea to boost drug delivery by selectively knocking down the tumor vascular barrier in a human pancreatic cancer model. Clinical radiation activates the tumor endothelial-targeted gold nanoparticles to induce a physical vascular damage due to the high photoelectric interactions. Active modulation of these tumor neovessels lead to distinct changes in tumor vascular permeability. Noninvasive MRI and fluorescence studies, using a short-circulating nanocarrier with MR-sensitive gadolinium and a long-circulating nanocarrier with fluorescence-sensitive nearinfrared dye, demonstrate more than two-fold increase in nanodrug delivery, post tumor vascular modulation. Functional changes in altered tumor blood vessels and its downstream parameters, particularly, changes in Ktrans (permeability), Kep (flux rate), and Ve (extracellular interstitial volume), reflect changes that relate to augmented drug delivery. The proposed dual-targeted therapy effectively invades the tumor vascular barrier and improve nanodrug delivery in a human pancreatic tumor model and it may also be applied to other nonresectable, intransigent tumors that barely respond to standard drug therapies.

We have developed a novel method for fast image simulation of flat panel detectors, based on the photon energy deposition efficiency and the optical spread function (OSF). The proposed method, FastEPID, determines the photon detection using photon energy deposition and replaces particle transport within the detector with precalculated OSFs. The FastEPID results are validated against experimental measurement and conventional Monte Carlo simulation in terms of modulation transfer function (MTF), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), contrast, and relative difference of pixel value, obtained with a slanted slit image, Las Vegas phantom, and anthropomorphic pelvis phantom. Excellent agreement is observed between simulation and measurement in all cases. Without degrading image quality, the FastEPID method is capable of reducing simulation time up to a factor of 150. Multiple applications, such as imager design optimization for planar and volumetric imaging, are expected to benefit from the implementation of the FastEPID method.

International audience; AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

In radiation therapy, improvements in treatment conformality are often limited by movement of target tissue. To better treat the target, tumor tracking strategies involving beam's-eye-view (BEV) have been explored. However, localization surrogates like implanted fiducial markers may sometimes leave the field-of-view (FOV), as defined by the linear accelerator (LINAC) multi-leaf collimator (MLC). Radiation leakage through the MLC has been measured previously at approximately 1%-2%. High sensitivity prototype detectors imagers may improve the ability to visualize objects outside of the MLC FOV during treatment. The present study presents a proof-of-concept for tracking fiducial markers outside the MLC FOV by employing high sensitivity detectors using a high-efficiency, prototype scintillating glass called LKH-5 and also investigates the impact of multi-layer imager (MLI) architecture. It was found that by improving the detector efficiency, using either of these methods results in a reduction of dose required for fiducial marker visibility. Further, image correction by a rectangular median filter will improve fiducial marker representation in the MLC blocked images. Quantified by measuring the peak-to-sidelobe ratio (PSR) of the normalized cross correlation (NCC) between a template of the fiducial marker with the blocked MLC acquisition, visibility has been found at a threshold of roughly 5 for all configurations with a 3 × 3 cm2 ROI. For typical gadolinium oxysulfide (GOS) detectors in single and simulated 4-layer configurations, the minimum dose required for visualization was 20 and 10 MU, respectively. For LKH-5 detectors in single and simulated 4-layer configurations, this minimum dose was reduced to 4 and 2 MU, respectively. With a 6 MV flattening filter free (FFF) beam dose rate of 1400 MU min-1, the maximum detector frame rate while maintaining fiducial visibility is approximately 12 fps for a 4-layer LKH-5 configuration.

Beams-eye-view imaging applications such as real-time soft-tissue motion estimation are hindered by the inherently low image contrast of electronic portal imaging devices (EPID) currently available for clinical use. We introduce and characterize a novel EPID design that provides substantially increased detective quantum efficiency (DQE), contrast-to-noise ratio (CNR) and sensitivity without degradation in spatial resolution. The prototype design features a stack of four conventional EPID layers combined with low noise integrated readout electronics. Each layer consists of a copper plate, a scintillator ([Formula: see text]) and a photodiode/TFT-switch (aSi:H). We characterize the prototype's signal response to a 6 MV photon beam in terms of modulation transfer function (MTF), DQE and CNR. The presampled MTF is estimated using a slanted slit technique, the DQE is calculated from measured normalized noise power spectra (nNPS) and the MTF and CNR is estimated using a Las Vegas contrast phantom. The prototype has been designed and built to be interchangeable with the current clinical EPID on the Varian TrueBeam platform (AS-1200) in terms of size and data output specifications. Performance evaluation is conducted in absolute values as well as in relative terms using the Varian AS-1200 EPID as a reference detector. A fivefold increase of DQE(0) to about 6.7% was observed by using the four-layered design versus the AS-1200 reference detector. No substantial differences are observed between each layer's individual MTF and the one for all four layers operating combined indicating that defocusing due to beam divergence is negligible. Also, using four layers instead of one increases the signal to noise ratio by a factor of 1.7.

Nanoparticles containing high-Z elements are known to boost the efficacy of radiation therapy. Gadolinium (Gd) is particularly attractive because this element is also a positive contrast agent for MRI, which allows for the simultaneous use of imaging to guide the irradiation and to delineate the tumor. In this study, we used the Gd-based nanoparticles, AGuIX®. After intravenous injection into animals bearing B16F10 tumors, some nanoparticles remained inside the tumor cells for more than 24 hours, indicating that a single administration of nanoparticles might be sufficient for several irradiations. Combining AGuIX® with radiation therapy increases tumor cell death, and improves the life spans of animals bearing multiple brain melanoma metastases. These results provide preclinical proof-of-concept for a phase I clinical trial., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: Previous studies have introduced gold nanoparticles as vascular-disrupting agents during radiation therapy. Crucial to this concept is the low energy photon content of the therapy radiation beam. The authors introduce a new mode of delivery including a linear accelerator target that can toggle between low Z and high Z targets during beam delivery. In this study, the authors examine the potential increase in tumor blood vessel endothelial cell radiation dose enhancement with the low Z target. Methods: The authors use Monte Carlo methods to simulate delivery of three different clinical photon beams: (1) a 6 MV standard (Cu/W) beam, (2) a 6 MV flattening filter free (Cu/W), and (3) a 6 MV (carbon) beam. The photon energy spectra for each scenario are generated for depths in tissue-equivalent material: 2, 10, and 20 cm. The endothelial dose enhancement for each target and depth is calculated using a previously published analytic method. Results: It is found that the carbon target increases the proportion of low energy (

Intensive computation time is required to simulate images of electronic portal imaging device (EPID) using Monte Carlo (MC) technique, limiting the development of applications associated with EPID, such as mega-voltage cone-beam computed tomography (MV-CBCT). In this study, a fast, accurate simulation strategy for MV-CBCT utilizing the FastEPID technique has been developed and validated. During FastEPID simulation, photon detection was determined by pre-calculated photon energy deposition efficiency (η) and particle transport within the EPID was replaced with a pre-calculated optical photon spread function. This method is capable of reducing the time required for EPID image simulation by a factor of 90–140, without compromising image quality. MV-CBCT images reconstructed from the FastEPID simulated projections have been validated against measurement in terms of mean Hounsfield unit (HU), noise, and cupping artifact. These images were obtained with both a Catphan 604 phantom and an anthropomorphic pelvis phantom, under treatment beam energies of 2.5 MV, 6 MV, and 6 MV flattening filter free. The agreement between measurement and simulation was excellent in all cases. This novel strategy was capable of reducing the run time of a full scan simulation of MV-CBCT performed on a CPU cluster to a matter of hours, rather than weeks or months required by a conventional approach. Multiple applications associated with MV-CBCT (e.g. imager design optimization) are anticipated to gain from the implementation of this novel simulation strategy.

A cost-effective method for serial in vivo imaging of tumor microvasculature has been developed. We evaluated acoustic angiography (AA) for visualizing and assessing non-small cell lung tumor (A549) microvasculature in mice prior to and following tumor vascular disruption by vascular-targeted gold nanoparticles (GNPs) and radiotherapy. Standard B-mode and microbubble-enhanced AA images were acquired at pre- and post-treatment time points. Using these modes, a new metric, 50% Vessel Penetration Depth (VPD(50)) was developed to characterize the 3D spatial heterogeneity of microvascular networks. We observed an increase in tumor perfusion after radiation-induced vascular disruption, relative to control animals. This was also visualized in vessel morphology mode, which showed a loss in vessel integrity. We found that tumors with poorly perfused vasculature at day 0 exhibited a reduced growth rate over time. This suggested a new method for reducing in-group treatment response variability by using pre-treatment microvessel maps to objectively identify animals for study removal.

Purpose The purpose of this study was to evaluate the performance of a prototype electric portal imaging device (EPID) with a high detective quantum efficiency (DQE) scintillator, LKH-5. Specifically, image quality in context of both planar and megavoltage (MV) cone-beam computed tomography (CBCT) is analyzed. Methods Planar image quality in terms of modulation transfer function (MTF), noise power spectrum (NPS), and DQE are measured and compared to an existing EPID (AS-1200) using the 6 MV beamline for a Varian TrueBeam linac. Imager performance is contextualized for three-dimensional (3D), MV-CBCT performance by measuring imager lag and analyzing the expected degradation of the DQE as a function of dose. Finally, comparisons between reconstructed images of the Catphan phantom in terms of qualitative quality and signal-difference-to-noise ratio (SDNR) are made for 6 MV images using both conventional and LKH-5 EPIDs as well as for the kilovoltage (kV) on-board imager (OBI). Results Analysis of the NPS reveals linearity at all measured doses using the prototype LKH-5 detector. While the first zero of the MTF is much lower for the LKH-5 detector than the conventional EPID (0.6 cycles/mm vs 1.6 cycles/mm), the normalized NPS (NNPS) multiplied by total quanta (qNNPS) of the LKH-5 detector is roughly a factor of seven to eight times lower, yielding a DQE(0) of approximately 8%. First, second, and third frame lag were measured at approximately 23%, 5%, and 1%, respectively, although no noticeable image artifacts were apparent in reconstructed volumes. Analysis of low-dose performance reveals that DQE(0) remains at 80% of its maximum value at a dose as low as 7.5 × 10-6 MU. For a 400 projection technique, this represents a total scan dose of 0.0030 MU, suggesting that if imaging doses are increased to a value typical of kV-CBCT scans (~2.7 cGy), the LKH-5 detector will retain quantum noise limited performance. Finally, comparing Catphan scans, the prototype detector exhibits much lower image noise than the conventional EPID, resulting in improved small object representation. Furthermore, SDNR of H2 O and polystyrene cylinders improved from -1.95 and 2.94 to -15 and 18.7, respectively. Conclusions Imaging performance of the prototype LKH-5 detector was measured and analyzed for both planar and 3D contexts. Improving noise transfer of the detector results in concurrent improvement of DQE(0). For 3D imaging, temporal characteristics were adequate for artifact-free performance and at relevant doses, the detector retained quantum noise limited performance. Although quantitative MTF measurements suggest poorer resolution, small object representation of the prototype imager is qualitatively improved over the conventional detector due to the measured reduction in noise.

Effective drug delivery is severely restricted by the presence of complex pathophysiological barriers in solid tumors. In human pancreatic adenocarcinoma, mature and hypopermeable tumor blood vessels limit the permeation and penetration of chemo or nanotherapeutics to cancer cells and substantially reduce the treatment efficacy. New, clinically-viable strategies are therefore sought to breach the neoplastic barriers that prevent optimal tumor-specific drug delivery. Here, we present an original idea to boost targeted drug delivery by selectively knocking down the tumor vascular barrier in a poorly permeable human pancreatic cancer model. For the first time, we demonstrate that clinical irradiation (10 Gy, 6 MV) can induce tumor vascular modulation when combined with tumor endothelial-targeting gold nanoparticles. Active disruption of tumor blood vessels by nanoparticle-combined radiotherapy led to increased vessel permeability and improved tumor uptake of two prototypical model nanodrugs: i) a short-circulating nanocarrier with MR-sensitive gadolinium (Gad-NC; 8 kDa; t1/2=1.5 h) and ii) a long-circulating nanocarrier with fluorescence-sensitive NIR dye (FL-NC; 30 kDa; t1/2=25 h). Functional changes in the altered tumor vessel dynamics, measured by relative changes in permeability (Ktrans), flux rate (Kep) and extracellular interstitial volume (Ve) were consistent with the concomitant increase in nanodrug delivery. This combination of radiation-induced antivascular and nanodrug-mediated anti-tumor treatment offers high therapeutic benefit for tumors with pathophysiology that restricts efficient drug delivery.

Radiation therapy is an effective, personalized cancer treatment that has benefited from technological advances associated with the growing ability to identify and target tumors with accuracy and precision. Given that these advances have played a central role in the success of radiation therapy as a major component of comprehensive cancer care, the American Society for Radiation Oncology (ASTRO), the American Association of Physicists in Medicine (AAPM), and the National Cancer Institute (NCI) sponsored a workshop entitled "Technology for Innovation in Radiation Oncology," which took place at the National Institutes of Health (NIH) in Bethesda, Maryland, on June 13 and 14, 2013. The purpose of this workshop was to discuss emerging technology for the field and to recognize areas for greater research investment. Expert clinicians and scientists discussed innovative technology in radiation oncology, in particular as to how these technologies are being developed and translated to clinical practice in the face of current and future challenges and opportunities. Technologies encompassed topics in functional imaging, treatment devices, nanotechnology, and information technology. The technical, quality, and safety performance of these technologies were also considered. A major theme of the workshop was the growing importance of innovation in the domain of process automation and oncology informatics. The technologically advanced nature of radiation therapy treatments predisposes radiation oncology research teams to take on informatics research initiatives. In addition, the discussion on technology development was balanced with a parallel conversation regarding the need for evidence of efficacy and effectiveness. The linkage between the need for evidence and the efforts in informatics research was clearly identified as synergistic.

Purpose: The purpose of this work is to develop a clinically feasible method of calculating actual delivered dose distributions for patients who have significant respiratory motion during the course of stereotactic body radiation therapy (SBRT). Methods: A novel approach was proposed to calculate the actual delivered dose distribution for SBRT lung treatment. This approach can be specified in three steps. (1) At the treatment planning stage, a patient-specific motion model is created from planning 4DCT data. This model assumes that the displacement vector field (DVF) of any respiratory motion deformation can be described as a linear combination of some basis DVFs. (2) During the treatment procedure, 2D time-varying projection images (either kV or MV projections) are acquired, from which time-varying “fluoroscopic” 3D images of the patient are reconstructed using the motion model. The DVF of each timepoint in the time-varying reconstruction is an optimized linear combination of basis DVFs such that the 2D projection of the 3D volume at this timepoint matches the projection image. (3) 3D dose distribution is computed for each timepoint in the set of 3D reconstructed fluoroscopic images, from which the total effective 3D delivered dose is calculated by accumulating deformed dose distributions. This approach wasmore » first validated using two modified digital extended cardio-torso (XCAT) phantoms with lung tumors and different respiratory motions. The estimated doses were compared to the dose that would be calculated for routine 4DCT-based planning and to the actual delivered dose that was calculated using “ground truth” XCAT phantoms at all timepoints. The approach was also tested using one set of patient data, which demonstrated the application of our method in a clinical scenario. Results: For the first XCAT phantom that has a mostly regular breathing pattern, the errors in 95% volume dose (D95) are 0.11% and 0.83%, respectively for 3D fluoroscopic images reconstructed from kV and MV projections compared to the ground truth, which is clinically comparable to 4DCT (0.093%). For the second XCAT phantom that has an irregular breathing pattern, the errors are 0.81% and 1.75% for kV and MV reconstructions, both of which are better than that of 4DCT (4.01%). In the case of real patient, although it is impossible to obtain the actual delivered dose, the dose estimation is clinically reasonable and demonstrates differences between 4DCT and MV reconstruction-based dose estimates. Conclusions: With the availability of kV or MV projection images, the proposed approach is able to assess delivered doses for all respiratory phases during treatment. Compared to the planning dose based on 4DCT, the dose estimation using reconstructed 3D fluoroscopic images was as good as 4DCT for regular respiratory pattern and was a better dose estimation for the irregular respiratory pattern.« less

3D fluoroscopic images represent volumetric patient anatomy during treatment with high spatial and temporal resolution. 3D fluoroscopic images estimated using motion models built using 4DCT images, taken days or weeks prior to treatment, do not reliably represent patient anatomy during treatment. In this study we developed and performed initial evaluation of techniques to develop patient-specific motion models from 4D cone-beam CT (4DCBCT) images, taken immediately before treatment, and used these models to estimate 3D fluoroscopic images based on 2D kV projections captured during treatment. We evaluate the accuracy of 3D fluoroscopic images by comparison to ground truth digital and physical phantom images. The performance of 4DCBCT-based and 4DCT-based motion models are compared in simulated clinical situations representing tumor baseline shift or initial patient positioning errors. The results of this study demonstrate the ability for 4DCBCT imaging to generate motion models that can account for changes that cannot be accounted for with 4DCT-based motion models. When simulating tumor baseline shift and patient positioning errors of up to 5 mm, the average tumor localization error and the 95th percentile error in six datasets were 1.20 and 2.2 mm, respectively, for 4DCBCT-based motion models. 4DCT-based motion models applied to the same six datasets resulted in average tumor localization error and the 95th percentile error of 4.18 and 5.4 mm, respectively. Analysis of voxel-wise intensity differences was also conducted for all experiments. In summary, this study demonstrates the feasibility of 4DCBCT-based 3D fluoroscopic image generation in digital and physical phantoms and shows the potential advantage of 4DCBCT-based 3D fluoroscopic image estimation when there are changes in anatomy between the time of 4DCT imaging and the time of treatment delivery.

We assess the feasibility of clinical megavoltage (MV) spectral imaging for material and bone separation with a novel multi-layer imager (MLI) prototype. The MLI provides higher detective quantum efficiency and lower noise than conventional electronic portal imagers. Simulated experiments were performed using a validated Monte Carlo model of the MLI to estimate energy absorption and energy separation between the MLI components. Material separation was evaluated experimentally using solid water and aluminum (Al), copper (Cu) and gold (Au) for 2.5 MV, 6 MV and 6 MV flattening filter free (FFF) clinical photon beams. An anthropomorphic phantom with implanted gold fiducials was utilized to further demonstrate bone/gold separation. Weighted subtraction imaging was employed for material and bone separation. The weighting factor (w) was iteratively estimated, with the optimal w value determined by minimization of the relative signal difference ([Formula: see text]) and signal-difference-to-noise ratio (SDNR) between material (or bone) and the background. Energy separation between layers of the MLI was mainly the result of beam hardening between components with an average energy separation between 34 and 47 keV depending on the x-ray beam energy. The minimum average energy of the detected spectrum in the phosphor layer was 123 keV in the top layer of the MLI with the 2.5 MV beam. The w values that minimized [Formula: see text] and SDNR for Al, Cu and Au were 0.89, 0.76 and 0.64 for 2.5 MV; for 6 MV FFF, w was 0.98, 0.93 and 0.77 respectively. Bone suppression in the anthropomorphic phantom resulted in improved visibility of the gold fiducials with the 2.5 MV beam. Optimization of the MLI design is required to achieve optimal separation at clinical MV beam energies.

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Purpose: To track prostate motion during clinical arc radiotherapy using a novel statistical motion tracking algorithm in both phantom and patient systems. Methods: For the phantom study, a dynamic phantom with a custom tumor model and radiopaque fiducials was used. For the patient study, the clinical data from two prostate patients were acquired during volumetric modulated arc therapy (VMAT). For each patient, two gold fiducials (X‐Mark, 1cm and 2cm in length) were implanted in the prostate. A total of 35 fractions with 2‐field full arcs were delivered. Beam's‐eye‐ view (BEV) images were acquired in cine mode every five fractions at a frame rate of 2 fps.The prostate motion was measured by two sequential steps: fiducial detection and motion estimation. In the first step, a wavelet‐ based block matching filter was used to suppress the noise and enhance the fiducials in the BEV images. A trajectory of detected fiducials was generated along the projection angles. Sequentially, the prostate motion was tracked using a statistical maximum a posteriori (MAP) algorithm. The 3‐D fiducial position was estimated by maximizing the probability of displacement of 2‐D projections. Results: A total of 8,400 BEV images were processed for this study. The phantom experiments showed that the baseline accuracy of estimation is 0.69+/−0.56 mm. For patient 1, intra‐ fraction prostate motion was measured to be 0.98+/−0.51 mm for all fractions, and individual fraction motion less than 1 mm. For patient 2, intra‐ fraction motion was 1.12+/−0.65 mm for all fractions. However, an exceptionally large displacement was measured as 4.9+/−0.74mm in one of the fractions. Conclusions: Prostate motion during arc‐therapy can be rigorously tracked to an accuracy of one millimeter. This technique is well suited for in‐treatment room target tracking and post‐therapy evaluation. Varian Medical Systems Inc

Purpose: To simulate the process of generating fluoroscopic 3D treatment images from 4DCT and measured 2D x‐ray projections using a realistic modified XCAT phantom based on measured patient 3D tumor trajectories. Methods: First, the existing XCAT phantom is adapted to incorporate measured patient lungtumor trajectories. Realistic diaphragm and chest wall motion are automatically generated based on input tumor motion and position, producing synchronized, realistic motion in the phantom. Based on 4DCT generated with the XCAT phantom, we derive patient‐specific motion models that are used to generate 3D fluoroscopic images. Patient‐specific models are created in two steps: first, the displacement vector fields (DVFs) are obtained through deformable image registration of each phase of 4DCT with respect to a reference image (typically peak‐exhale). Each phase is registered to the reference image to obtain (n‐1) DVFs. Second, the most salient characteristics in the DVFs are captured in a compact representation through principal component analysis (PCA). Since PCA is a linear decomposition method, all the DVFs can be represented as linear combinations of eigenvectors. Fluoroscopic 3D images are obtained using the projection image to determine optimal weights for the eigenvectors. These weights are determined through iterative optimization of a cost function relating the projection image to the 3D image via the PCA lung motion model and a projection operator. Constructing fluoroscopic 3D images is thus reduced to finding optimal weights for the eigenvectors.Results: Fluoroscopic 3D treatment images were generated using the modified XCAT phantom. The average relative error of the reconstructed image over 30 sec is 0.0457 HU and the standard deviation is 0.0063. Conclusions: The XCAT phantom was modified to produce realistic images by incorporating patient tumor trajectories. The modified XCAT phantom can be used to simulate the process of generating fluoroscopic 3D treatment images from 4DCT and 2D x‐ray projections.

Modern amorphous silicon flat panel-based electronic portal imaging devices that utilize thin gadolinium oxysulfide scintillators suffer from low quantum efficiencies (QEs). Thick two dimensionally (2D) pixelated scintillator arrays offer an effective but expensive option for increasing QE. To reduce costs, we have investigated the possibility of combining a thick one dimensional (1D) pixelated scintillator (PS) with an orthogonally placed 1D structured optical filter to provide for overall good 2D spatial resolution. In this work, we studied the potential for using a 1D video screen privacy film (PF) to serve as a directional optical attenuator and filter. A Geant4 model of the PF was built based on reflection and transmission measurements taken with a laser-based optical reflectometer. This information was incorporated into a Geant4-based x-ray detector simulator to generate modulation transfer functions (MTFs), noise power spectra (NPS), and detective quantum efficiencies (DQEs) for various 1D and 2D configurations. It was found that the 1D array with PF can provide the MTFs and DQEs of 2D arrays. Although the PF significantly reduced the amount of optical photons detected by the flat panel, we anticipate using a scintillator with an inherently high optical yield (e.g. cesium iodide) for MV imaging, where fluence rates are inherently high, will still provide adequate signal intensities for the imaging tasks associated with radiotherapy.

Selective killing of cancer cells while minimizing damage to healthy tissues is the goal of clinical radiation therapy. This therapeutic ratio can be improved by image-guided radiation delivery and selective radiosensitization of cancer cells. Here, we have designed and tested a novel trimodal theranostic nanoparticle made of bismuth and gadolinium for on-site radiosensitization and image contrast enhancement to improve the efficacy and accuracy of radiation therapy. We demonstrate in vivo magnetic resonance (MR), computed tomography (CT) contrast enhancement, and tumor suppression with prolonged survival in a non-small cell lung carcinoma model during clinical radiation therapy. Histological studies show minimal off-target toxicities due to the nanoparticles or radiation. By mimicking existing clinical workflows, we show that the bismuth-gadolinium nanoparticles are highly compatible with current CT-guided radiation therapy and emerging MR-guided approaches. This study reports the first in vivo proof-of-principle for image-guided radiation therapy with a new class of theranostic nanoparticles.

Radiation therapy (RT) is the treatment of cancer and other diseases with ionizing radiation. The ultimate goal of RT is to destroy all the disease cells while sparing healthy tissue. Towards this goal, RT has advanced significantly over the past few decades in part due to new technologies including: multileaf collimator-assisted modulation of radiation beams, improved computer-assisted inverse treatment planning, image guidance, robotics with more precision, better motion management strategies, stereotactic treatments and hypofractionation. With recent advances in nanotechnology, targeted RT with gold nanoparticles (GNPs) is actively being investigated as a means to further increase the RT therapeutic ratio. In this review, we summarize the current status of research and development towards the use of GNPs to enhance RT. We highlight the promising emerging modalities for targeted RT with GNPs and the corresponding preclinical evidence supporting such promise towards potential clinical translation. Future prospects and perspectives are discussed.

Purpose We have established a high-throughput Gafchromic film dosimetry protocol for narrow kilovoltage beams in homogeneous and heterogeneous media for small-animal radiotherapy applications. The kV beam characterization is based on extensive Gafchromic film dosimetry data acquired in homogeneous and heterogeneous media. An empirical model is used for parameterization of depth and off-axis dependence of measured data. Methods We have modified previously published methods of film dosimetry to suit the specific tasks of the study. Unlike film protocols used in previous studies, our protocol employs simultaneous multi-channel scanning and analysis of up to nine Gafchromic films per scan. A scanner and background correction were implemented to improve accuracy of the measurements. Measurements were taken in homogeneous and inhomogeneous phantoms at 220 kVp and a field size of 5 × 5 mm 2 . The results were compared against Monte Carlo simulations. Results Dose differences caused by variations in background signal were effectively removed by the corrections applied. Measurements in homogeneous phantoms were used to empirically characterize beam data in homogeneous and heterogeneous media. Film measurements in inhomogeneous phantoms and their empirical parameterization differed by about 2%–3%. The model differed from MC by about 1% (water, lung) to 7% (bone). Good agreement was found for measured and modelled off-axis ratios. Conclusions EBT2 films are a valuable tool for characterization of narrow kV beams, though care must be taken to eliminate disturbances caused by varying background signals. The usefulness of the empirical beam model in interpretation and parameterization of film data was demonstrated.

International audience; Nanoparticles (NPs) made of high atomic number (Z) elements have been shown to sensitize cancer cells to radiation beams generated from linacs in vitro and in vivo. This effect occurs due to the emission of secondary photoelectrons and Auger electrons. Gold (GNP) and gadolinium (GdNP) based nanoparticles are biocompatible, and accumulate passively in tumours due to the enhanced permeability and retention effect, and there is growing evidence that localized radiation-induced tumour vascular damage can be used to clinical advantage.