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The purpose of this study was to quantitatively evaluate the visibility and artifacts of commercially available fiducial markers in order to optimize their selection for image-guided stereotactic body radiation therapy (SBRT). From six different vendors, we selected 11 fiducials commonly used in image-guided radiation therapy (IGRT); the fiducials varied in material composition (gold, platinum, carbon), shape (cylindrical, notched/linear, coiled, ball-like, step), and size measured in terms of diameter (0.28-1.0 mm) and length (3.0-20.0 mm). Each fiducial was centered in 4-mm bolus within a 13-cm-thick water-equivalent phantom. Fiducials were imaged with use of a simulation computed tomography (CT) scanner, a CT-on-rails system, and an onboard cone-beam CT system. Acquisition parameters were set according to clinical protocols. Visibility was assessed in terms of contrast and the Michelson visibility metric. Artifacts were quantified in terms of relative standard deviation and relative streak artifacts level (rSAL). Twelve radiation oncologists ranked each fiducial in terms of clinical usefulness. Contrast and artifacts increased with fiducial size. For CT imaging, maximum contrast (2722 HU) and artifacts (rSAL=2.69) occurred for the largest-diameter (0.75 mm) platinum fiducial. Minimum contrast (551 HU) and reduced artifacts (rSAL=0.65) were observed for the smallest-diameter (0.28 mm) gold fiducial. Carbon produced the least severe artifacts (rSAL = 0.29). The survey indicated that physicians preferred gold fiducials with a 0.35- to 0.43-mm diameter, 5- to 10-mm length, and a coiled or cylindrical shape that balanced contrast and artifacts. We evaluated 11 different fiducials in terms of visibility and artifacts. The results of this study may assist radiation oncologists who seek to maximize contrast, minimize artifacts, and/or balance contrast versus artifacts by fiducial selection., 22 pages

MRI offers outstanding soft tissue contrast that may reduce uncertainties in target and organ-at-risk delineation and enable online adaptive image-guided treatment. Spatial distortions resulting from non-linearities in the gradient fields and non-uniformity in the main magnetic field must be accounted for across the imaging field-of-view to prevent systematic errors during treatment delivery. This work presents a modular phantom and software application to characterize geometric distortion (GD) within the large field-of-view MRI images required for radiation therapy simulation. The modular phantom is assembled from a series of rectangular foam blocks containing high-contrast fiducial markers in a known configuration. The modular phantom design facilitates transportation of the phantom between different MR scanners and MR-guided linear accelerators and allows the phantom to be adapted to fit different sized bores or coils. The phantom was evaluated using a 1.5T MR-guided linear accelerator (MR-Linac) and 1.5T and 3.0T diagnostic scanners. Performance was assessed by varying acquisition parameters to induce image distortions in a known manner. Imaging was performed using T1 and T2 weighted pulse sequences with 2D and 3D distortion correction algorithms and the receiver bandwidth (BW) varied as 250-815 Hz/pixel. Phantom set-up reproducibility was evaluated across independent set-ups. The software was validated by comparison with a non-modular phantom. Average geometric distortion was 0.94+/-0.58 mm for the MR-Linac, 0.90+/-0.53 mm for the 1.5 T scanner, and 1.15+/-0.62 mm for the 3.0T scanner, for a 400 mm diameter volume-of-interest. GD increased, as expected, with decreasing BW, and with the 2D versus 3D correction algorithm. Differences in GD attributed to phantom set-up were 0.13 mm or less. Differences in GD for the two software applications were less than 0.07 mm., 25 pages

Treating multiple brain metastases with a single isocenter improves efficiency but requires margins to account for rotation induced shifts that increase with target-to-isocenter distance. A method to select the single isocenter position that minimizes the total volume of normal tissue treated during multi-target stereotactic radiosurgery (SRS) is presented. A statistical framework was developed to quantify the impact of uncertainties on planning target volumes (PTV). Translational and rotational shifts were modeled with independent, zero mean, Gaussian distributions in three dimensions added in quadrature. The standard deviations of errors were varied from 0.5-2.0 mm and 0.5°-2.0°. The volume of normal tissue treated due to margin expansions required to maintain a 95% probability of target coverage was computed. Tumors were modeled as 4-40 mm diameter spheres. Target separation distance was varied from 40-100 mm for two- and three-lesion scenarios. The percent increase in PTV was determined relative to an isocenter at the geometric centroid of the targets for the optimal isocenter that minimized the total normal tissue treated, and isocenters at the center-of-mass (COM) and center-of-surface-area (CSA). For two targets, isocenter placement at the optimal location, COM, and CSA, reduced the total margin versus an isocenter at midline up to 17.8%, 17.7%, and 17.8%, respectively, for 0.5 mm and 0.5° errors. For three targets, optimal isocenter placement reduced the margin volume up to 21%, 19%, and 14%, for uncertainties of (0.5 mm, 0.5°), (1.0 mm, 1.0°), and (2.0 mm, 2.0°), respectively. COM and CSA provide useful approximations to select the optimal isocenter for multi-target single-isocenter SRS for two or three targets with maximum dimensions ⩽ 40 mm and separation distances ⩽ 100 mm when uncertainties are ⩽ 1.0 mm and ⩽ 1.0°. CSA provides a more accurate approximation than COM. Optimal treatment isocenter selection for multiple targets of large size differences can significantly reduce total margin volume.

Purpose: Image registration between standard x-ray fluoroscopy and transesophageal echocardiography (TEE) has recently been proposed. Scanning-beam digital x-ray (SBDX) is an inverse geometry fluoroscopy system designed for cardiac procedures. This study presents a method for 3D registration of SBDX and TEE images based on the tomosynthesis and 3D tracking capabilities of SBDX. Methods: The registration algorithm utilizes the stack of tomosynthetic planes produced by the SBDX system to estimate the physical 3D coordinates of salient key-points on the TEE probe. The key-points are used to arrive at an initial estimate of the probe pose, which is then refined using a 2D/3D registration method adapted for inverse geometry fluoroscopy. A phantom study was conducted to evaluate probe pose estimation accuracy relative to the ground truth, as defined by a set of coregistered fiducial markers. This experiment was conducted with varying probe poses and levels of signal difference-to-noise ratio (SDNR). Additional phantom and in vivo studies were performed to evaluate the correspondence of catheter tip positions in TEE and x-rayimages following registration of the two modalities. Results: Target registration error (TRE) was used to characterize both pose estimation and registration accuracy. In the study of pose estimation accuracy, successful pose estimates (3D TRE < 5.0 mm) were obtained in 97% of cases when the SDNR was 5.9 or higher in seven out of eight poses. Under these conditions, 3D TRE was 2.32 ± 1.88 mm, and 2D (projection) TRE was 1.61 ± 1.36 mm. Probe localization error along the source-detector axis was 0.87 ± 1.31 mm. For the in vivo experiments, mean 3D TRE ranged from 2.6 to 4.6 mm and mean 2D TRE ranged from 1.1 to 1.6 mm. Anatomy extracted from the echo images appeared well aligned when projected onto the SBDX images. Conclusions: Full 6 DOF image registration between SBDX and TEE is feasible and accurate to within 5 mm. Future studies will focus on real-time implementation and application-specific analysis.

We investigate the use of tomosynthesis in 4D DSA to improve the accuracy of reconstructed vessel time-attenuation curves (TACs). It is hypothesized that a narrow-angle tomosynthesis dataset for each time point can be exploited to reduce artifacts caused by vessel overlap in individual projections. 4D DSA reconstructs time-resolved 3D angiographic volumes from a typical 3D DSA scan consisting of mask and iodine-enhanced C-arm rotations. Tomosynthesis projections are obtained either from a conventional C-arm rotation, or from an inverse geometry scanning-beam digital x-ray (SBDX) system. In the proposed method, rays of the tomosynthesis dataset which pass through multiple vessels can be ignored, allowing the non-overlapped rays to impart temporal information to the 4D DSA. The technique was tested in simulated scans of 2 mm diameter vessels separated by 2 to 5 cm, with TACs following either early or late enhancement. In standard 4D DSA, overlap artifacts were clearly present. Use of tomosynthesis projections in 4D DSA reduced TAC artifacts caused by vessel overlap, when a sufficient fraction of non-overlapped rays was available in each time frame. In cases where full overlap between vessels occurred, information could be recovered via a proposed image space interpolation technique. SBDX provides a tomosynthesis scan for each frame period in a rotational acquisition, whereas a standard C-arm geometry requires the grouping of multiple frames.

The scanning-beam digital x-ray (SBDX) system is an inverse geometry x-ray fluoroscopy technology that performs real-time tomosynthesis at planes perpendicular to the source-detector axis. The live display is a composite image which portrays sharp features (e.g. coronary arteries) extracted from a 16 cm thick reconstruction volume. We present a method for automatically determining the position of the cardiac volume prior to acquisition of a coronary angiogram. In the algorithm, a single non-contrast frame is reconstructed over a 44 cm thickness using shift-and-add digital tomosynthesis. Gradient filtering is applied to each plane to emphasize features such as the cardiomediastinal contour, diaphragm, and lung texture, and then sharpness vs. plane position curves are generated. Three sharpness metrics were investigated: average gradient in the bright field, maximum gradient, and the number of normalized gradients exceeding 0.5. A model correlating the peak sharpness in a non-contrast frame and the midplane of the coronary arteries in a contrast-enhanced frame was established using 37 SBDX angiographic loops (64-136 kg human subjects, 0-30° cranial- caudal). The average gradient in the bright field (primarily lung) and the number of normalized gradients >0.5 each yielded peaks correlated to the coronary midplane. The rms deviation between the predicted and true midplane was 1.57 cm. For a 16 cm reconstruction volume and the 5.5-11.5 cm thick cardiac volumes in this study, midplane estimation errors of 2.25-5.25 cm were tolerable. Tomosynthesis-based localization of cardiac volume is feasible. This technique could be applied prior to coronary angiography, or to assist in isocentering the patient for rotational angiography.

Fluoroscopic image guidance for minimally invasive procedures in the thorax and abdomen suffers from respiratory and cardiac motion, which can cause severe subtraction artifacts and inaccurate image guidance. This work proposes novel techniques for respiratory motion tracking in native fluoroscopic images as well as a model based estimation of vessel deformation. This would allow compensation for respiratory motion during the procedure and therefore simplify the workflow for minimally invasive procedures such as liver embolization. The method first establishes dynamic motion models for both the contrast-enhanced vasculature and curvilinear background features based on a native (non-contrast) and a contrast-enhanced image sequence acquired prior to device manipulation, under free breathing conditions. The model of vascular motion is generated by applying the diffeomorphic demons algorithm to an automatic segmentation of the subtraction sequence. The model of curvilinear background features is based on feature tracking in the native sequence. The two models establish the relationship between the respiratory state, which is inferred from curvilinear background features, and the vascular morphology during that same respiratory state. During subsequent fluoroscopy, curvilinear feature detection is applied to determine the appropriate vessel mask to display. The result is a dynamic motioncompensated vessel mask superimposed on the fluoroscopic image. Quantitative evaluation of the proposed methods was performed using a digital 4D CT-phantom (XCAT), which provides realistic human anatomy including sophisticated respiratory and cardiac motion models. Four groups of datasets were generated, where different parameters (cycle length, maximum diaphragm motion and maximum chest expansion) were modified within each image sequence. Each group contains 4 datasets consisting of the initial native and contrast enhanced sequences as well as a sequence, where the respiratory motion is tracked. The respiratory motion tracking error was between 1.00 % and 1.09 %. The estimated dynamic vessel masks yielded a Sorensen-Dice coefficient between 0.94 and 0.96. Finally, the accuracy of the vessel contours was measured in terms of the 99th percentile of the error, which ranged between 0.64 and 0.96 mm. The presented results show that the approach is feasible for respiratory motion tracking and compensation and could therefore considerably improve the workflow of minimally invasive procedures in the thorax and abdomen

Scanning-beam digital x-ray (SBDX) is an inverse geometry x-ray fluoroscopy system capable of tomosynthesis-based 3D tracking of catheter electrodes concurrent with fluoroscopic display. To facilitate respiratory motion-compensated 3D catheter tracking, an automated coronary sinus (CS) catheter detection algorithm for SBDX was developed. The technique uses the 3D localization capability of SBDX and prior knowledge of the catheter shape. Candidate groups of points representing the CS catheter are obtained from a 3D shape-constrained search. A cost function is then minimized over the groups to select the most probable CS catheter candidate. The algorithm was implemented in MATLAB and tested offline using recorded image sequences of a chest phantom containing a CS catheter, ablation catheter, and fiducial clutter. Fiducial placement was varied to create challenging detection scenarios. Table panning and elevation was used to simulate motion. The CS catheter detection method had 98.1% true positive rate and 100% true negative rate in 2755 frames of imaging. Average processing time was 12.7 ms/frame on a PC with a 3.4 GHz CPU and 8 GB memory. Motion compensation based on 3D CS catheter tracking was demonstrated in a moving chest phantom with a fixed CS catheter and an ablation catheter pulled along a fixed trajectory. The RMS error in the tracked ablation catheter trajectory was 1.41 mm, versus 10.35 mm without motion compensation. A computationally efficient method of automated 3D CS catheter detection has been developed to assist with motion-compensated 3D catheter tracking and registration of 3D cardiac models to tracked catheters.

Scanning-beam digital x-ray (SBDX) is an inverse geometry x-ray fluoroscopy system capable of tomosynthesis-based 3-D catheter tracking. This work proposes a method of dose-reduced 3-D catheter tracking using dynamic electronic collimation (DEC) of the SBDX scanning x-ray tube. This is achieved through the selective deactivation of focal spot positions not needed for the catheter tracking task. The technique was retrospectively evaluated with SBDX detector data recorded during a phantom study. DEC imaging of a catheter tip at isocenter required 340 active focal spots per frame versus 4473 spots in full field-of-view (FOV) mode. The dose-area product (DAP) and peak skin dose (PSD) for DEC versus full FOV scanning were calculated using an SBDX Monte Carlo simulation code. The average DAP was reduced to 7.8% of the full FOV value, consistent with the relative number of active focal spots (7.6%). For image sequences with a moving catheter, PSD was 33.6% to 34.8% of the full FOV value. The root-mean-squared-deviation between DEC-based 3-D tracking coordinates and full FOV 3-D tracking coordinates was less than 0.1 mm. The 3-D distance between the tracked tip and the sheath centerline averaged 0.75 mm. DEC is a feasible method for dose reduction during SBDX 3-D catheter tracking.

Background Radiation exposure increases the risk of coronary artery disease (CAD). We explored the association of CAD with coronary artery dose-volume parameters in patients treated with 3D-planned radiation therapy (RT). Methods Patients who received thoracic RT and were evaluated by cardiac computed tomography ≥ 1 year later were included. Demographic data and cardiac risk factors were retrospectively collected. Dosimetric data (mean heart dose, dmax, dmean, V50 - V₅) were collected for the whole heart and for each coronary artery. A coronary artery calcium (CAC) Agatston score was calculated on a per-coronary basis and as a total score. Multivariable generalized linear mixed models were generated. The predicted probabilities were used for receiver operating characteristic analyses. Results Twenty patients with a median age of 53 years at the time of RT were included. Nine patients (45%) had ≥ 3/6 conventional cardiac risk factors. Patients received RT for breast cancer (10, 50%), lung cancer (6, 30%), or lymphoma/myeloma (4, 20%) with a median dose of 60 Gy. CAC scans were performed a median of 32 months after RT. CAC score was significantly associated with radiation dose and presence of diabetes. In a multivariable model adjusted for diabetes, segmental coronary artery dosimetric parameters (dmax, dmean, V₅₀, V₄₀ V₃₀, V₂₀, V₁₀, and V₅) were significantly associated with CAC score > 0. V₅₀ had the highest area under the ROC curve (0.89, 95% confidence interval, 0.80-0.97). Conclusions Coronary artery radiation exposure is strongly correlated with subsequent segmental CAC score. Coronary calcification may occur soon after RT and in individuals with conventional cardiac risk factors.

Accurate and artifact-free reconstruction of tomographic images requires precise knowledge of the imaging system geometry. A projection matrix-based calibration method to enable C-arm inverse geometry CT (IGCT) is proposed. The method is evaluated for scanning-beam digital x-ray (SBDX), a C-arm mounted inverse geometry fluoroscopic technology. A helical configuration of fiducials is imaged at each gantry angle in a rotational acquisition. For each gantry angle, digital tomosynthesis is performed at multiple planes and a composite image analogous to a cone-beam projection is generated from the plane stack. The geometry of the C-arm, source array, and detector array is determined at each angle by constructing a parameterized three-dimensional-to-two-dimensional projection matrix that minimizes the sum-of-squared deviations between measured and projected fiducial coordinates. Simulations were used to evaluate calibration performance with translations and rotations of the source and detector. The relative root-mean-square error in a reconstruction of a numerical thorax phantom was 0.4% using the calibration method versus 7.7% without calibration. In phantom studies, reconstruction of SBDX projections using the proposed method eliminated artifacts present in noncalibrated reconstructions. The proposed IGCT calibration method reduces image artifacts when uncertainties exist in system geometry.

Accurate and artifact free reconstruction of tomographic images requires precise knowledge of the imaging system geometry. This work proposes a novel projection matrix (P-matrix) based calibration method to enable C-arm inverse geometry CT (IGCT). The method is evaluated for scanning-beam digital x-ray (SBDX), a C-arm mounted inverse geometry fluoroscopic technology. A helical configuration of fiducials is imaged at each gantry angle in a rotational acquisition. For each gantry angle, digital tomosynthesis is performed at multiple planes and a composite image analogous to a cone-beam projection is generated from the plane stack. The geometry of the C-arm, source array, and detector array is determined at each angle by constructing a parameterized 3D-to-2D projection matrix that minimizes the sum-of-squared deviations between measured and projected fiducial coordinates. Simulations were used to evaluate calibration performance with translations and rotations of the source and detector. In a geometry with 1 mm translation of the central ray relative to the axis-of-rotation and 1 degree yaw of the detector and source arrays, the maximum error in the recovered translational parameters was 0.4 mm and maximum error in the rotation parameter was 0.02 degrees. The relative rootmean- square error in a reconstruction of a numerical thorax phantom was 0.4% using the calibration method, versus 7.7% without calibration. Changes in source-detector-distance were the most challenging to estimate. Reconstruction of experimental SBDX data using the proposed method eliminated double contour artifacts present in a non-calibrated reconstruction. The proposed IGCT geometric calibration method reduces image artifacts when uncertainties exist in system geometry.

This study investigates the feasibility of obtaining CT-derived 3D surfaces from data provided by the scanning-beam digital x-ray (SBDX) system. Simulated SBDX short-scan acquisitions of a Shepp-Logan and a thorax phantom containing a high contrast spherical volume were generated. 3D reconstructions were performed using a penalized weighted least squares method with total variation regularization (PWLS-TV), as well as a more efficient variant employing gridding of projection data to parallel rays (gPWLS-TV). Voxel noise, edge blurring, and surface accuracy were compared to gridded filtered back projection (gFBP). PWLS reconstruction of a noise-free reduced-size Shepp-Logan phantom had 1.4% rRMSE. In noisy gPWLS-TV reconstructions of a reduced-size thorax phantom, 99% of points on the segmented sphere perimeter were within 0.33, 0.47, and 0.70 mm of the ground truth, respectively, for fluences comparable to imaging through 18.0, 27.2, and 34.6 cm acrylic. Surface accuracies of gFBP and gPWLS-TV were similar at high fluences, while gPWLS-TV offered improvement at the lowest fluence. The gPWLS-TV voxel noise was reduced by 60% relative to gFBP, on average. High-contrast linespread functions measured 1.25 mm and 0.96 mm (FWHM) for gPWLS-TV and gFBP. In a simulation of gated and truncated projection data from a full-sized thorax, gPWLS-TV reconstruction yielded segmented surface points which were within 1.41 mm of ground truth. Results support the feasibility of 3D surface segmentation with SBDX. Further investigation of artifacts caused by data truncation and patient motion is warranted.

Scanning-Beam Digital X-ray (SBDX) is a technology for low-dose fluoroscopy that employs inverse geometry x-ray beam scanning. To assist with rapid modeling of inverse geometry x-ray systems, we have developed a Monte Carlo (MC) simulation tool based on the MC-GPU framework. MC-GPU version 1.3 was modified to implement a 2D array of focal spot positions on a plane, with individually adjustable x-ray outputs, each producing a narrow x-ray beam directed toward a stationary photon-counting detector array. Geometric accuracy and blurring behavior in tomosynthesis reconstructions were evaluated from simulated images of a 3D arrangement of spheres. The artifact spread function from simulation agreed with experiment to within 1.6% (rRMSD). Detected x-ray scatter fraction was simulated for two SBDX detector geometries and compared to experiments. For the current SBDX prototype (10.6 cm wide by 5.3 cm tall detector), x-ray scatter fraction measured 2.8–6.4% (18.6–31.5 cm acrylic, 100 kV), versus 2.1–4.5% in MC simulation. Experimental trends in scatter versus detector size and phantom thickness were observed in simulation. For dose evaluation, an anthropomorphic phantom was imaged using regular and regional adaptive exposure (RAE) scanning. The reduction in kerma-area-product resulting from RAE scanning was 45% in radiochromic film measurements, versus 46% in simulation. The integral kerma calculated from TLD measurement points within the phantom was 57% lower when using RAE, versus 61% lower in simulation. This MC tool may be used to estimate tomographic blur, detected scatter, and dose distributions when developing inverse geometry x-ray systems.

Scanning-beam digital x-ray (SBDX) is an inverse geometry fluoroscopy system for low dose cardiac imaging. The use of a narrow scanned x-ray beam in SBDX reduces detected x-ray scatter and improves dose efficiency, however the tight beam collimation also limits the maximum achievable x-ray fluence. To increase the fluence available for imaging, we have constructed a new SBDX prototype with a wider x-ray beam, larger-area detector, and new real-time image reconstructor. Imaging is performed with a scanning source that generates 40,328 narrow overlapping projections from 71 x 71 focal spot positions for every 1/15 s scan period. A high speed 2-mm thick CdTe photon counting detector was constructed with 320x160 elements and 10.6 cm x 5.3 cm area (full readout every 1.28 s), providing an 86% increase in area over the previous SBDX prototype. A matching multihole collimator was fabricated from layers of tungsten, brass, and lead, and a multi-GPU reconstructor was assembled to reconstruct the stream of captured detector images into full field-of-view images in real time. Thirty-two tomosynthetic planes spaced by 5 mm plus a multiplane composite image are produced for each scan frame. Noise equivalent quanta on the new SBDX prototype measured 63%-71% higher than the previous prototype. X-ray scatter fraction was 3.9-7.8% when imaging 23.3-32.6 cm acrylic phantoms, versus 2.3- 4.2% with the previous prototype. Coronary angiographic imaging at 15 frame/s was successfully performed on the new SBDX prototype, with live display of either a multiplane composite or single plane image.

Purpose: To obtain ECG-gated CT images from truncated projection data acquired with a C-arm based inverse geometry fluoroscopy system, for the purpose of cardiac chamber mapping in interventional procedures. Methods: Scanning-beam digital x-ray (SBDX) is an inverse geometry fluoroscopy system with a scanned multisource x-ray tube and a photon-counting detector mounted to a C-arm. In the proposed method, SBDX short-scan rotational acquisition is performed followed by inverse geometry CT (IGCT) reconstruction and segmentation of contrast-enhanced objects. The prior image constrained compressed sensing (PICCS) framework was adapted for IGCT reconstruction to mitigate artifacts arising from data truncation and angular undersampling due to cardiac gating. The performance of the reconstruction algorithm was evaluated in numerical simulations of truncated and non-truncated thorax phantoms containing a dynamic ellipsoid to represent a moving cardiac chamber. The eccentricity of the ellipsoid was varied at frequencies from 1–1.5 Hz. Projection data were retrospectively sorted into 13 cardiac phases. Each phase was reconstructed using IGCT-PICCS, with a nongated gridded FBP (gFBP) prior image. Surface accuracy was determined using Dice similarity coefficient and a histogram of the point distances between the segmented surface and ground truth surface. Results: The gated IGCT-PICCS algorithm improved surface accuracy and reduced streaking and truncation artifacts when compared to nongated gFBP. For the non-truncated thorax with 1.25 Hz motion, 99% of segmented surface points were within 0.3 mm of the 15 mm diameter ground truth ellipse, versus 1.0 mm for gFBP. For the truncated thorax phantom with a 40 mm diameter ellipse, IGCT-PICCS surface accuracy measured 0.3 mm versus 7.8 mm for gFBP. Dice similarity coefficient was 0.99–1.00 (IGCT-PICCS) versus 0.63–0.75 (gFBP) for intensity-based segmentation thresholds ranging from 25–75% maximum contrast. Conclusions: The PICCS algorithm was successfully applied to reconstruct truncated IGCT projection data with angular undersampling resulting from simulated cardiac gating. Research supported by the National Heart, Lung, and Blood Institute of the NIH under award number R01HL084022. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.