Richard Wassenaar

Development and optimization of SPECT gated blood pool cluster analysis for the prediction of CRT outcome

PURPOSE Phase analysis of single photon emission computed tomography (SPECT) radionuclide angiography (RNA) has been investigated for its potential to predict the outcome of cardiac resynchronization therapy (CRT). However, phase analysis may be limited in its potential at predicting CRT outcome as valuable information may be lost by assuming that time-activity curves (TAC) follow a simple sinusoidal shape. A new method, cluster analysis, is proposed which directly evaluates the TACs and may lead to a better understanding of dyssynchrony patterns and CRT outcome. Cluster analysis algorithms were developed and optimized to maximize their ability to predict CRT response. METHODS About 49 patients (N = 27 ischemic etiology) received a SPECT RNA scan as well as positron emission tomography (PET) perfusion and viability scans prior to undergoing CRT. A semiautomated algorithm sampled the left ventricle wall to produce 568 TACs from SPECT RNA data. The TACs were then subjected to two different cluster analysis techniques, K-means, and normal average, where several input metrics were also varied to determine the optimal settings for the prediction of CRT outcome. Each TAC was assigned to a cluster group based on the comparison criteria and global and segmental cluster size and scores were used as measures of dyssynchrony and used to predict response to CRT. A repeated random twofold cross-validation technique was used to train and validate the cluster algorithm. Receiver operating characteristic (ROC) analysis was used to calculate the area under the curve (AUC) and compare results to those obtained for SPECT RNA phase analysis and PET scar size analysis methods. RESULTS Using the normal average cluster analysis approach, the septal wall produced statistically significant results for predicting CRT results in the ischemic population (ROC AUC = 0.73;p < 0.05 vs. equal chance ROC AUC = 0.50) with an optimal operating point of 71% sensitivity and 60% specificity. Cluster analysis results were similar to SPECT RNA phase analysis (ROC AUC = 0.78, p = 0.73 vs cluster AUC; sensitivity/specificity = 59%/89%) and PET scar size analysis (ROC AUC = 0.73, p = 1.0 vs cluster AUC; sensitivity/specificity = 76%/67%). CONCLUSIONS A SPECT RNA cluster analysis algorithm was developed for the prediction of CRT outcome. Cluster analysis results produced results equivalent to those obtained from Fourier and scar analysis.

Characterization of PET partial volume corrections for variable myocardial wall thicknesses

Limited scanner resolution and cardiac motion contribute to partial volume (PV) averaging of positron emission tomography (PET) images. An extravascular (EV) density image, created from the subtraction of a blood pool (BP) from a transmission (TX) image can be used to estimate PV losses in the myocardium (MYO). A phantom emulating the left ventricle myocardium, with a variable wall thickness (5 mm to 25 mm), was used to characterize the method for use in 3-D PET /sup 18/FDG studies. At a myocardial thickness of 5 mm, 40% recovery of the activity was obtained. At myocardial thicknesses greater than 20 mm, full recovery was seen. Prior to EV image creation, the morphological operators dilation/erosion were applied to the BP and TX images to account for the presence of the phantoms plastic walls, which would otherwise bias the EV values. Dividing MYO by the EV values improved the recovery to 95% at 5 mm, however, TX ring artifacts and the anisotropic nature of dilation/erosion contributed to errors in the EV image. Instead of using dilation/erosion, a second method, involving placement of adjusted ROIs on the BP and TX images was investigated. Use of these new EV values, as well as placement of the cardiac phantom in a chest phantom to reduce TX ring artifacts, allowed for 90% recovery of the activity at 5 mm. These results show that the EV density image can correct for PV averaging with 3-D PET over a range of myocardial thicknesses applicable to patient studies. However, in the thinnest regions, the method was found to be sensitive to errors in both the blood pool and transmission images.

Phantom studies investigating extravascular density imaging for partial volume correction of 3-D PET /sup 18/FDG studies

Limited scanner resolution and cardiac motion contribute to partial volume (PV) averaging of cardiac PET images. An extravascular (EV) density image, created from the subtraction of a blood pool scan from a transmission image, has been used to correct for PV averaging in H/sub 2//sup 15/O studies using 2-D imaging but not with 3-D imaging of other tracers such as /sup 18/FDG. A cardiac phantom emulating the left ventricle was used to characterize the method for use in 3-D PET studies. Measurement of the average myocardial activity showed PV losses of 32% below the true activity (p<0.001). Initial application of the EV density correction still yielded a myocardial activity 13% below the true value (p<0.001). This failure of the EV density image was due to the 1.66 mm thick plastic barrier separating the myocardial and ventricular chambers within the phantom. Upon removal of this artifact by morphological dilation of the blood pool, the corrected myocardial value was within 2% of the true value (p=ns). Spherical ROIs (diameter of 2 to 10 mm), evenly distributed about the myocardium, were also used to calculate the average activity. The EV density image was able to account for PV averaging throughout the range of diameters to within a 5% accuracy, however, a small bias was seen as the size of the ROIs increased. This indicated a slight mismatch between the emission and transmission image resolutions, a result of the difference in data acquisitions (i.e., span and ring difference) and default smoothing. These results show that the use of EV density image to correct for PV averaging is possible with 3-D PET. A method of correcting barrier effects in phantoms has been presented, as well as a process for evaluating resolution mismatch.

Enhancing expression of functional human sodium iodide symporter and somatostatin receptor in recombinant oncolytic vaccinia virus for in vivo imaging of tumors

Oncolytic virus (OV) therapy has emerged as a novel tool in our therapeutic arsenals for fighting cancer. As a live biologic agent, OV has the ability to target and selectively amplify at the tumor sites. We have reported that a vaccinia-based OV (Pexa-Vec) has shown good efficacy in preclinical models and in clinical trials. To give an additional tool to clinicians to allow both treatment of the tumor and improved visualization of tumor margins, we developed new viral-based platforms with 2 specific gene reporters. Methods: We incorporated the human sodium iodide symporter (hNIS) and the human somatostatin receptor 2 (hSSR2) in the vaccinia-based OV and tested viral constructs for their abilities to track and treat tumor development in vivo. Results: Early and high-level expression of hNIS is detrimental to the recombinant virus, leading to the aggregation of hNIS protein and early cell death. Putting hNIS under a late synthetic promoter allowed a higher functional expression of the protein and much stronger 123I or 99Tc uptake. In vivo, the hNIS-containing virus infected and amplified in the tumor site, showing a better efficacy than the parental virus. The hNIS expression at the tumor site allowed for the imaging of viral infection and tumor regression. Similarly, hSSR2-containing OV vaccinia infected and lysed cancer cells. Conclusion: When tumor-bearing mice were given hNIS- and hSSR2-containing OV, 99Tc and 111In signals coalesced at the tumor, highlighting the power of using these viruses for tumor diagnosis and treatment.

nSPECT: A Radioisotope-Free Approach to Nuclear Medicine Imaging

The imminent closure of NRU reactor in Canada and HFR reactor in Holland threatens ~ 70% of the worlds supply of 99mTc used in over 30 million medical applications yearly. Researchers around the globe are investigating alternative methods of production, mainly using accelerators. This paper presents a concept feasibility study of a novel technique dubbed nSPECT, in which non-radioactive isotopes administered to patients would be activated with slow neutrons to emit prompt gamma rays (PGNA). Although a common technique of elemental analysis, PGNA has not been used for medical imaging. This paper presents SPECT images of 131I at activity levels that could be reasonably produced by neutron activation of 149Sm in vivo. Simulated Compton noise from hydrogen was added to degrade the images to levels that would be expected in practice. Advantages of nSPECT are discussed. This concept feasibility study suggests that nSPECT might provide an alternative means for medical imaging should the accelerator-based methods fail to make sufficient quantities of 99mTc.

PET Detector Quality Assurance Using

Daily quality assurance of positron emission tomography detectors, to ensure accurate efficiency calibration of the system, typically requires the acquisition of coincidence data from a flood source. To obtain sufficient counts, long scan times on the order of an hour are required. The long acquisition time and necessity of an external activity source may make such a protocol impractical for daily use. A new protocol has been demonstrated for the ECAT ART scanner, using the two

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Cs Singles Transmission Imaging

Cs transmission sources. The new protocol produces a map of the counts per detector, as well as plots of the mean and standard deviation of the detector counts in a given block. Graphical outputs allow for quick recognition of problematic areas. The factory protocol requires 90 min to obtain a 1% statistical error on the individual detector counts. Due to the high activity of the

PET detector quality assurance using /sup 137/Cs singles transmission imaging

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SPECT gated blood pool phase analysis of lateral wall motion for prediction of CRT response.

Cs sources, a 1% statistical error is obtained with an 8 min scan using the new protocol. The new protocol provides information regarding the status of all blocks, reduces acquisition time, and alleviates the need for an external activity source. The protocol presented in this study can be implemented on other