Targeting tumor vasculature with an oncolytic virus.

Oncolytic viruses (OVs) have been engineered or selected for cancer cell-specific infection however, we have found that following intravenous administration of vesicular stomatitis virus (VSV), tumor cell killing rapidly extends far beyond the initial sites of infection. We show here for the first time that VSV directly infects and destroys tumor vasculature in vivo but leaves normal vasculature intact. Three-dimensional (3D) reconstruction of infected tumors revealed that the majority of the tumor mass lacks significant blood flow in contrast to uninfected tumors, which exhibit relatively uniform perfusion. VSV replication in tumor neovasculature and spread within the tumor mass, initiates an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels. Within 6 hours of intravenous administration of VSV and continuing for at least 24 hours, we observed the initiation of blood clots within the tumor vasculature whereas normal vasculature remained clot free. Blocking blood clot formation with thrombin inhibitors prevented tumor vascular collapse. Our results demonstrate that the therapeutic activity of an OV can go far beyond simple infection and lysis of malignant cells.

Towards a biomechanical-based method for assessing myocardial tissue viability.

This work presents the first steps towards the development and implementation of a novel 3D biomechanical-based method for assessing the viability of myocardial tissue, with particular interest for its application in myocardial infarction (MI) diagnosis. This assessment technique quantifies the myocardial contraction forces developed within the ventricular myofibrils in response to the electrophysiological stimulus. In this manuscript we provide a 3D finite element (FE) formulation of a contraction force reconstruction algorithm based on an inverse problem solution of linear elasticity, along with its implementation using clinical data. This algorithm has been applied to patient-specific models obtained by extracting anatomical features from high-resolution, high-contrast magnetic resonance (MR) cardiac images. The input consists of motion information extracted by nonrigid registration of the mid-diastole reference image to the remaining images of the 4D data set, acquired using ECG-gating throughout the cardiac cycle. The result consists of a display-map of the contraction force distribution superimposed on the anatomical ventricle model, which allows the clinician to identify regions of low contractility in the myocardium.

Techniques for efficient, real-time, 3D visualization of multi-modality cardiac data using consumer graphics hardware.

We exploit consumer graphics hardware to perform real-time processing and visualization of high-resolution, 4D cardiac data. We have implemented real-time, realistic volume rendering, interactive 4D motion segmentation of cardiac data, visualization of multi-modality cardiac data and 3D display of multiple series cardiac MRI. We show that an ATI Radeon 9700 Pro can render a 512x512x128 cardiac Computed Tomography (CT) study at 0.9 to 60 frames per second (fps) depending on rendering parameters and that 4D motion based segmentation can be performed in real-time. We conclude that real-time rendering and processing of cardiac data can be implemented on consumer graphics cards.

"Motion-frozen" display and quantification of myocardial perfusion.

UNLABELLED: Gated myocadial perfusion SPECT (MPS) incorporates functional and perfusion information of the left ventricle (LV). To improve the image quality and accuracy of gated MPS we propose to eliminate the influence of cardiac LV motion in the display and quantification by a novel "motion-frozen" (MF) technique. METHODS: Three-dimensional LV contours were identified on images of the individual time phases. Three-dimensional phase-to-phase motion vectors were derived by sampling of the epi- and endocardial surfaces. A nonlinear image warping (thin-plate spline) was applied to warp all image phases to fit the end-diastolic (ED) phase. Warped images were created to provide the LV image in the ED phase but containing counts from an arbitrary number of time intervals. MF quantification has been performed using the same phase-to-phase motion vectors. MF normal perfusion limits were created from (99m)Tc sestamibi gated MPS studies of 40 females and 40 males with low likelihood (<5%) of coronary artery disease. All MF processing was completely automated. In the initial evaluation, we assessed the display quality and quantification of stress images using MF processing in 51 consecutive patients with 16-frame electrocardiographic gating and available coronary angiography. RESULTS: The display quality was significantly better for MF images as assessed visually. The MF images had the appearance of ED frames but were less noisy and of higher resolution than the summed images. MF images had higher maximum count values in the LV (116% +/- 6%) and higher contrast (12.5 +/- 7.7 vs. 9.5 +/- 3.2) than the corresponding summed images. The area under the receiver operator characteristic curve for prediction of stenoses > or = 70% by the MF method was 0.92 +/- 0.04 versus 0.89 +/- 0.04 by standard quantification (P = not significant). The computation time for automated MF quantification and warping was <25 s for each case. CONCLUSION: We have developed a novel technique for display and quantification of gated myocardial perfusion images, which retrospectively eliminates blur due to cardiac motion. Such processing of gated MPS appears to improve the effective resolution of images. Initial evaluation indicates that it may improve the accuracy of gated MPS in detection of coronary artery disease.

Automated image registration of gated cardiac single-photon emission computed tomography and magnetic resonance imaging.

PURPOSE: To develop an automatic registration method for electrocardiogram-gated myocardial perfusion single-photon emission computed tomography (SPECT) and cardiac cine-magnetic resonance imaging (MRI). MATERIALS AND METHODS: Paired myocardial perfusion SPECT (MPS) and MRI from 20 patients were considered. MR images were presegmented by heart localization based on detection of cardiac motion and optimal thresholding. A registration algorithm based on mutual information was subsequently applied to all time frames or a selected subset from both modalities. RESULTS: A preprocessing step significantly improved the accuracy of the registration when compared to automatic registration performed without preprocessing. Errors in translation parameters (T(x), T(y), T(z)) averaged (1.0 +/- 1.5, 1.1 +/- 1.3, 0.9 +/- 0.9) pixels with MRI segmentation and (4.6 +/- 3.2, 3.4 +/- 2.6, 3.0 +/- 3.4) pixels without MRI segmentation. Errors in rotation parameters (R(x), R(y), R(z)) averaged (5.4 +/- 2.9, 3.4 +/- 2.7, 4.5 +/- 3.6) degrees with MRI segmentation and (9.3 +/- 6.1, 4.8 +/- 4.3, 14.6 +/- 12.6) degrees without MRI segmentation. Error was calculated as the absolute difference between the expert manual and the automatic registration transformation. CONCLUSION: Automatic registration of gated MPS and cine MRI is possible with the use of a mutual information-based technique when MR images are presegmented. Cardiac motion can be used to isolate the left ventricle (LV) on the MR images automatically, and subsequently the segmented MR images can be coregistered with gated MPS.

Automatic quantification of myocardial perfusion stress-rest change: a new measure of ischemia.

UNLABELLED: In myocardial perfusion SPECT (MPS), ischemia is typically quantified as the difference between stress and rest defect sizes obtained by separate comparisons with stress and rest normal limits. Such an approach is not optimal because images are not compared directly with each other and a complex set of stress and rest normal limits is required. METHODS: We developed a fully automatic technique to quantify stress-rest change. We applied it to 204 patients whose SPECT images were acquired using a same-day dual-isotope (99m)Tc/(201)Tl protocol and on whom coronary angiography had been performed. A 10-parameter registration of rest and stress images was performed by an iterative search of best translational, rotational, scaling, and optimal stress-rest count normalization parameters. Identical stress-rest 3-dimensional left ventricle (LV) contours were automatically derived from stress images. Integrated deficit counts (normalized rest-stress) within the LV volume were derived from registered image pairs. A global measure of ischemia (ISCH) was calculated as the ratio of the total deficit stress LV counts to the total rest LV counts. RESULTS: Registration and derivation of quantitative measures were fully automatic. The average processing time was <40 s on a 2-GHz processor. When compared for prediction of stenosis, the area under the receiver operating characteristic curve (0.88 +/- 0.03) was significantly better for ISCH than that obtained by existing quantitative approaches, which use reference databases (0.80-0.82 +/- 0.03). The normalized stress-rest change could be visualized and localized directly on raw patient images using overlay display. CONCLUSION: Automatic stress-rest MPS image registration allows a direct estimation of ischemia from SPECT that does not require comparisons with normal limits.

Automated 3-dimensional registration of stand-alone (18)F-FDG whole-body PET with CT.

UNLABELLED: Image registration and fusion of whole-body (18)F-FDG PET with thoracic CT would allow combination of anatomic detail from CT with functional PET information, which could lead to improved diagnosis or PET-based radiotherapy planning. METHODS: We have designed a practical and fully automated algorithm for the elastic 3-dimensional image registration of whole-body PET and CT images, which compensates for the nonlinear deformation due to breath-hold CT imaging. A set of 18 PET and CT patient datasets has been evaluated by the algorithm. Initially, a 9-parameter linear registration is performed by maximizing the mutual information (MI)-based cost function, between the CT and the combination of emission and transmission PET volumes, using progressively increased matrix sizes to increase speed and provide better convergence. Subsequently, lung contours on transmission maps and corresponding contours on CT volumes are automatically detected. A large number (few hundreds) of corresponding point pairs are automatically derived, defining a thin-plate-spline (TPS) elastic transformation of PET emission and transmission scans to match the CT scan. RESULTS: In all 18 patients the automatic linear registration with multiresolution converged close to the final alignment, but, in 10 cases, the nonlinear differences in the diaphragm position and chest wall were still clearly visible. The nonlinear adjustment, which was in the order of 40-75 mm, significantly improved the alignment between breath-hold CT and PET, especially in the areas of the diaphragm. Lung volumes measured from transmission and CT scans match closely after the warping has been applied. The average computation time is <40 s for the linear component and <30 s for the nonlinear component for a typical PET scan with 4-6 bed positions. CONCLUSION: We have developed a technique for automatic nonlinear registration of CT and PET whole-body images to common spatial coordinates. This technique may be applied for automatic fusion of PET with CT acquired on stand-alone scanners during normal breathing or breath-hold data acquisition.