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Purpose: The use of whole-body PET for re-staging of renal cell carcinoma has not been investigated. The aim of the current study was to examine the diagnostic accuracy and clinical usefulness of whole-body PET imaging for re-staging of renal cell cancer. Patients and methods: Clinical PET was performed for re-staging in 36 patients with advanced renal cell cancer. Written reports of imaging studies (including CT, MRI, US, plain film and bone scan), patient history, and extensive chart notes were used to define the clinical stage before PET (pre-PET stage). The written PET report was used to define the clinical stage after PET (PET stage). Reports were used to determine the accuracy of PET for re-staging renal cell cancer and for defining biopsy proven lesions. Clinical parameters and biopsy proven lesions served as reference for the accuracy of PET for re-staging renal cell cancer. Results: PET classified the clinical stage correctly in 32/36 patients (89%) and was incorrect in 4/36(11%) (sensitivity and specificity: 87% and 100%). In 20 patients, 25 suspicious lesions were biopsied within 3.2 ± 6.7 months of the PET study. Of these, 17 were malignant and 8 were benign. PET correctly classified 21/25 (84%) of the biopsied lesions (sensitivity and specificity: 88% and 75%). Conclusion: PET re-stages renal cell cancer with a diagnostic accuracy of 89%. Its diagnostic accuracy for classifying biopsy proven anatomic lesions as malignant or benign was 84%. These findings suggest that PET is useful in characterizing anatomic lesions of unknown significance in patients with renal cell cancer.

Biodistribution, magnitude and duration of a therapeutic transgene's expression may be assessed by linking it to the expression of a positron emission tomography (PET) reporter gene (PRG) and then imaging the PRG's expression by a PET reporter probe (PRP) in living animals. We validate the simple approach of co-administering two distinct but otherwise identical adenoviruses, one expressing a therapeutic transgene and the other expressing the PRG, to track the therapeutic gene's expression. Two PET reporter genes, a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) and dopamine-2 receptor (D(2)R), each regulated by the same cytomegalovirus (CMV) promoter, have been inserted into separate adenoviral vectors (Ad). We demonstrate that cells co-infected with equivalent titers of Ad-CMV-HSV1-sr39tk and Ad-CMV-D(2)R express both reporter genes with good correlation (r(2) = 0.93). Similarly, a high correlation (r(2) = 0.97) was observed between the expression of both PRGs in the livers of mice co-infected via tail-vein injection with equivalent titers of these two adenoviruses. Finally, microPET imaging of HSV1-sr39tk and D(2)R expression with 9-(4-[(18)F]fluoro-3-hydroxymethylbutyl) guanine ([(18)F]FHBG) and 3-(2-[(18)F]fluoroethyl)spiperone ([(18)F]FESP), utilizing several adenovirus-mediated delivery routes, illustrates the feasibility of evaluating relative levels of transgene expression in living animals, using this approach.

Reporter genes (e.g. beta-galactosidase, chloramphenicol-acetyltransferase, green fluorescent protein, luciferase) play critical roles in investigating mechanisms of gene expression in transgenic animals and in developing gene delivery systems for gene therapy. However, measuring expression of these reporter genes requires biopsy or death. We now report a procedure to image reporter gene expression repetitively and non-invasively in living animals with positron emission tomography (PET), using the dopamine type 2 receptor (D2R) as a reporter gene and 3-(2'-[18F]fluoroethyl)spiperone (FESP) as a reporter probe. We use a viral delivery system to demonstrate the ability of this PET reporter gene/PET reporter probe system to image reporter gene expression following somatic gene transfer. In mice injected intravenously with replication-deficient adenovirus carrying a D2R reporter gene, PET in vivo measures of hepatic [18F] retention are proportional to in vitro measures of hepatic FESP retention, D2R ligand binding and D2R mRNA. We use tumor-forming cells carrying a stably transfected D2R gene to demonstrate imaging of this PET reporter gene/PET reporter probe system in 'tissues'. Tumors expressing the transfected D2R reporter gene retain substantially more FESP than control tumors. The D2R/FESP reporter gene/reporter probe system should be a valuable technique to monitor, in vivo, expression from both gene therapy vectors and transgenes.

The ROI method applied to Ga-68 EDTA PET dynamic study data for the quantitative determination of brain tumor BBB permeability assumes that the tumor is homogeneous in terms of Ga-68 EDTA kinetics, even though it is known that brain tumors are highly heterogeneous in structure. The relatively high image noise of Ga-68 PET studies have prevented the examination of Ga-68 EDTA kinetics by nonlinear regression on a single pixel basis. In this study, we have developed an efficient and effective method to separate brain tumor tissue into sub-regions with different Ga-68 EDTA kinetics on a pixel-by-pixel basis. Computer simulation and ten Ga-68 EDTA PET patient studies were used to evaluate the performance of the new method. During a PET dynamic study (total 64 min), 20-25 arterial samples were taken for the input function. Whole-tumor ROIs were defined on T1-weighted MRI images and then copied to the registered PET dynamic images to measure whole-tumor time activity curves. The method uses a two-compartment model to extract three component factors (vascular component, fast and slow component factors) from whole-tumor kinetics by model fitting. The kinetics in each pixel were expressed as a linear combination of the three factors. The three coefficients in the expression can be estimated by the linear least-square method and produce three factor images corresponding, respectively, to the permeability of the fast and the slow component factors and the plasma volume. Whole-tumor regions were separated into two regions-one with mainly fast kinetics that was evident in the fast factor images and one with slow kinetics that was evident in slow factor images. The two regions have markedly different uptake (0.036/spl plusmn/0.015 ml/min/g and 0.009/spl plusmn/0.006 ml/min/g for fast and slow kinetic sub-regions, respectively) and clearance rates (0.22/spl plusmn/0.15 /min and 0.023/spl plusmn/0.021 /min for fast and slow sub-regions, respectively). The overlap of the two resulting sub-regions is small (3.5/spl plusmn/1.7% of the two regions). Computer simulation and patient studies show that the method is robust for a wide range of noise levels. This method has combined the advantages of statistical factor analysis and the modeling approach.

✓ The bradykinin analog, RMP-7, was investigated for its ability to increase selectively the transport of 68Ga ethylenediamine tetraacetic acid (EDTA) into recurrent malignant gliomas in nine patients. For each patient, two positron emission tomography (PET) studies (one with and one without RMP-7) were performed. For studies with RMP-7, 10 to 300 ng/kg of the compound was infused into the supraophthalmic carotid artery over 15 minutes. In each PET study, a sequence of PET scans was initiated simultaneously with an intravenous bolus of 68Ga EDTA (5–10 mCi). Arterial samples were taken to provide the input function. All PET scans were coregistered to the magnetic resonance (MR) images of the patient. Regions of interest were defined for tumor and normal tissue regions on MR images and were copied to the coregistered PET dynamic images to provide brain tissue—time activity curves. The constant (Ki) for the transport of gallium-68 from plasma to brain tissue was determined using a simple compartmental model. Intracarotid infusion of RMP-7 significantly increased transport into tumor regions with an average increase of 46 ± 42% (mean ± standard deviation, p < 0.05). Permeability in normal tissue regions was not significantly increased. Tumors in three of six patients treated with 300 ng/kg RMP-7 and carboplatin had at least a 50% reduction in tumor volume as measured by MR imaging. Intracarotid infusion of RMP-7 is a novel technique for selective delivery of antitumor compounds into brain tumors.

PETbox4 is a new, fully tomographic bench top PET scanner dedicated to high sensitivity and high resolution imaging of mice. This manuscript characterizes the performance of the prototype system using the National Electrical Manufacturers Association (NEMA) NU 4–2008 standards, including studies of sensitivity, spatial resolution, energy resolution, scatter fraction, count-rate performance and image quality. The PETbox4 performance is also compared with the performance of PETbox, a previous generation limited angle tomography system. PETbox4 consists of four opposing flat-panel type detectors arranged in a box like geometry. Each panel is made by a 24 × 50 pixelated array of 1.82 × 1.82 × 7mm bismuth germanate (BGO) scintillation crystals with a crystal pitch of 1.90mm. Each of these scintillation arrays is coupled to two Hamamatsu H8500 photomultiplier tubes via a glass light guide. Volumetric images for a 45 × 45 × 95 mm field of view (FOV) are reconstructed with a maximum likelihood expectation maximization (ML-EM) algorithm incorporating a system model based on a parameterized detector response. With an energy window of 150–650 keV, the peak absolute sensitivity is approximately 18% at the center of FOV. The measured crystal energy resolution ranges from 13.5% to 48.3% full width at half maximum (FWHM), with a mean of 18.0%. The intrinsic detector spatial resolution is 1.5mm FWHM in both transverse and axial directions. The reconstructed image spatial resolution for different locations in the FOV ranges from 1.32mm to 1.93 mm, with an average of 1.46 mm. The peak noise equivalent count rate for the mouse-sized phantom is 35 kcps for a total activity of 1.5 MBq (40 µCi) and the scatter fraction is 28%. The standard deviation in the uniform region of the image quality phantom is 5.7%. The recovery coefficients range from 0.10 to 0.93. In comparison to the first generation two panel PETbox system, PETbox4 achieves substantial improvements on sensitivity and spatial resolution. The overall performance demonstrates that the PETbox4 scanner is suitable for producing high quality images for molecular imaging based biomedical research.

The use of positron emission tomography (PET) in quantitative fluorodeoxyglucose (FDG) studies of aging and dementia has been limited by partial volume effects. A general method for correction of partial volume effects (PVE) in PET involves the following common procedures: segmentation of MRI brain images into gray matter (GM), white matter (WM), cerebral spinal fluid (CSF), and muscle (MS) components: MRI PET registration; and generation of simulated PET images. Afterward, two different approaches can be taken. The first approach derives first a pixel-by-pixel correction map as the ratio of the measured image to the simulated image [with realistic full-width at half-maximum (FWHM)]. The correction map was applied to the MRI segmentation image. Regions of interest (ROI's) can then be applied to give results free of partial volume effects. The second approach uses the ROI values of the simulated "pure" image (with negligible FWHM) and those of the simulated and the measured PET images to correct for the PVE effect. By varying the ratio of radiotracer concentrations for different tissue components, the in-plane FWHM's of a three-dimensional point spread function, and the ROI size, the authors evaluated the performance of these two approaches in terms of their accuracy and sensitivity to different simulation configurations. The results showed that both approaches are more robust than the approach developed by Muller-Gartner et al. (1992), and the second approach is more accurate and more robust than the first. In conclusion, the authors recommend that the second approach should be used on FDG PET images to correct for partial volume effects and to determine whether an apparent change in GM radiotracer concentration is truly due to metabolic changes.

Experimental traumatic brain injury produces a series of cellular events contributing to a neurochemical and neurometabolic cascade. This cascade is defined by the release of neurotransmitters resulting in a massive ionic flux, which, consequently, produces an increase in glycolysis. This increase in glycolysis is followed by a metabolic diaschisis, which is related to the degree and extent of behavioral deficits. Clinical efforts have now determined that a similar cascade occurs in human head injury, validating the animal model as well as providing new assessment strategies for the management and treatment of brain injury.

We propose to develop a high resolution positron emission tomography (PET) detector designed for animal imaging. The detector consists of a 2-D array of small bismuth germanate (BGO) crystals coupled via optical fibers to a multi-channel photomultiplier tube (MC-PMT). Though this approach offers several advantages over the conventional BGO block design, it does require that a sufficient number of scintillation photons be transported from the crystal, down the fiber and into the PMT. In this study we use simulations and experimental data to determine how to maximize the signal reaching the PMT. This involves investigating factors such as crystal geometry, crystal surface treatment, the use of reflectors, choice of optical fiber, coupling of crystal to the optical fiber and optical fiber properties. Our results indicate that using 2/spl times/2/spl times/10 mm BGO crystals coupled to 30 cm of clad optical fiber, roughly 50 photoelectrons are produced at the PMT photocathode for a 511 keV interaction. This is sufficient to clearly visualize the photopeak and provide adequate timing resolution for PET. Based on these encouraging results, a prototype detector will now be constructed. >

'Patlak analysis' is a common approach used in Fdopa PET studies to calculate the uptake constant (Ki) of the tracer. It is assumed in the Patlak analysis that the reversible compartment of tissue radioactivity used is in effective equilibrium with the tracer in plasma. Therefore, using the data prior to equilibrium is in conflict with the assumption, and its effect on the estimate thus needs to be examined. In this study, we used simulations to investigate the errors due to the violation of the equilibrium assumption. Two factors affecting the estimate of Ki were examined--the eigenvalue of the model response function and the shape of the input function. The Ki estimate obtained from the Patlak analysis was found to be markedly biased because the system is not in equilibrium during the first 2 h post Fdopa injection. The magnitude of the bias was found to be dependent on the time interval used in the analysis (10% difference when comparing results from intervals 30-120 min and 60-120 min) and on the eigenvalue of the response function (10% change in Ki when the eigenvalue was changed by 20% around the nominal value). The estimates are also affected by the intersubject variations in the plasma time-activity curves. Therefore, Patlak analysis users should interpret their results with caution, particularly when examining small intersubject differences and small changes due to physiological or pharmacological interventions.

A technique that can register anatomic/structural brain images (e.g., MRI) with various functional images (e.g., PET-FDG and PET-FDOPA) of the same subject has been developed. The procedure of this technique includes the following steps: (1) segmentation of MRI brain images into gray matter (GM), white matter (WM), cerebral spinal fluid (CSF), and, muscle (MS) components, (2) assignment of appropriate radio-tracer concentrations to various components depending on the kind of functional image that is being registered, (3) generation of simulated functional images to have a spatial resolution that is comparable to that of the measured ones, (4) alignment of the measured functional images to the simulated ones that are based on MRI images. A self-organization clustering method is used to segment the MRI images. The image alignment is based on the criterion of least squares of the pixel-by-pixel differences between the two sets of images that are being matched and on the Powell's algorithm for minimization. The technique was applied successfully for registering the MRI, PET-FDG, and PET-FDOPA images. This technique offers a general solution to the registration of structural images to functional images and to the registration of different functional images of markedly different distributions. >

PETBox4, currently under development at the Crump Institute is a new tomograph dedicated to preclinical imaging of mice. This system presents a significant improvement on sensitivity and spatial resolution compared to the first generation PETBox. We report here on its design and initial performance characteristics.

BACKGROUND Previous studies suggested the presence of myocardial ischemia in symptomatic patients with hypertrophic cardiomyopathy. Positron emission tomography, a technique that can identify metabolic consequences of ischemia in coronary artery disease, permits the noninvasive measurements of regional myocardial blood flow and glucose metabolism. This new quantitative imaging approach should therefore be suitable for detecting a possible enhancement of glucose utilization in myocardium of patients with hypertrophic cardiomyopathy and thus may help to elucidate the pathomechanism of ischemia in this disease. METHODS AND RESULTS In 13 symptomatic patients with hypertrophic cardiomyopathy, myocardial blood flow and glucose utilization were measured with intravenous N-13-ammonia and F-18 deoxyglucose at rest and, in four patients, again during supine bicycle exercise. At rest, blood flow was significantly lower in hypertrophied than in normal myocardium (0.78 +/- 0.19 versus 0.99 +/- 0.13 mL.min-1.g-1, p < 0.025), whereas rates of glucose utilization were similar (0.88 +/- 0.31 versus 0.87 +/- 0.35 mumol.min-1.g-1). With exercise, blood flow and glucose utilization failed to increase in hypertrophic and normal segments but became more heterogeneously distributed throughout the left ventricular myocardium. Blood flow-metabolism mismatches indicative of myocardial ischemia were noted in three patients at rest and in three of the four patients during exercise and were due to reduced flow in the presence of maintained glucose uptake. The discordance between flow and glucose metabolism in hypertrophied myocardium was significantly more prominent in younger than in older patients. CONCLUSIONS Normal or even elevated rates of glucose utilization and the presence of diminished blood flow in hypertrophied relative to normal myocardium suggest the presence of myocardial ischemia in symptomatic hypertrophic cardiomyopathy. The age dependence of blood flow metabolism disparity suggests differences in the underlying pathophysiology or severity of disease.

PETbox is designed to be a low cost and easy to use bench top small animal PET scanner dedicated for high throughput quantitative pharmacokinetic and pharmacodynamic studies. To achieve this goal, the scanner is integrated with a complete animal management system that provides life support including reproducible positioning, temperature control, anesthesia, real-time monitoring of animal respiration and a pathogen barrier. This approach minimizes the overall cost and complexity of preclinical PET imaging and should enable non-imaging scientists to embrace the technology. The system uses two opposing detector heads, each one consisting of a pixilated BGO array coupled to two H8500 multi-channel photomultiplier tubes. The BGO crystals were segmented into 20 × 44 arrays with a pixel pitch of 2.2 mm and a total active area of 44 mm × 96.8 mm. Position and timing signals from the photomultiplier tube readout circuitry were connected to a field programmable gate array (FPGA) board with eight ADC channels, each running at 100MHz. Signal processing algorithms were developed for the FPGA to process received PET events and raw list-mode data were generated by the FPGA board and transferred to a host PC for storage. Basic system performance parameters were measured. The system has an average intrinsic spatial resolution of 1.72mm FWHM along detector long axis and 1.84mm FWHM along detector short axis. The coincidence timing resolution was measured to be 4.1ns FWHM. The average energy resolution of the crystals was 19.8% and the absolute sensitivity of the system was measured to be 3.8% at the center of the gantry. Initial imaging studies were also performed with live mice. A mouse tumor xenograft was imaged 1 hour after a 32uCi [18F]FDG injection for 20 minutes. 3D images were generated using a ML-EM method. Results demonstrate the capability and potential of the PETbox system for dedicated high throughput mouse studies such as biodistribution and organ uptake quantification.

To minimize blood loss in a mouse during quantitative PET imaging, we developed an automated blood sampling device using microfluidic technology. The integrated technology was proven reliable in measuring the cerebral glucose metabolism. In this study, we validated the performance of the microfluidic device using in vivo mouse studies. We examined the stability of the mouse in sequential PET scans to access the feasibility of acquiring multiple measurements from the same mouse over time. Cardiac output and body temperature were chosen as physiological indicators of mouse stability. Three control and three tumor-bearing mice were studied. Sixty minutes of PET data were acquired for each mouse following a bolus injection of 3'-deoxy-3'-[F- 18]fluorothymidine (FLT; ~250 muCi). 18 serial blood samples, 0.25 mul each, were taken from the femoral artery using the microfluidic device. Body temperatures were monitored before and after the scan. Immediately following the FLT scan, a 40-minute quantitative FDG (~300 muCi) PET scan was performed on the tumor-bearing mouse. Using a previously described first-pass angiographic method, we calculated two cardiac outputs for each mouse using the first 15-second data of the FLT and FDG scans respectively. The FLT data showed that the image-derived blood curve correlated (R squares > 0.95) well with the blood curve derived from the 18 arterial blood samples. The body temperatures (mean: 32.1degC) of the animal varied < 1% after the FLT studies. The cardiac outputs of the three tumor- bearing mice before the 18 blood samples were taken were 19.2, 15.7, 18.3 and were 18.7, 16.3, 18.9 ml/min afterward (i.e. < 4% change). We validated the performance of the microfluidic device using in vivo FLT-PET imaging. The physiology of the animal remained stable after the imaging and blood sampling procedure. Reliable longitudinal measurements using PET imaging are expected to be feasible with a protected arterial catheter.

Quantitative microPET imaging provides the capability of performing biochemical and physiological investigations. The collection of multiple blood samples over time is necessary for quantitative analysis. The procedure is challenging because the amount of blood volume is small in rats and mice. To overcome this issue, an automatic blood sampling system was developed using a novel microfluidic chip design to take serial blood samples (

Factor analysis (FA) is used for extracting the properties of dynamic sets. Objective: FA was applied to dynamic PET studies to create factor images, from which ROIs were derived and input and output functions generated. These functions were subsequently used for kinetic modeling. This non-invasive, automated, and image based analysis should permit routine application of quantitative PET in cancer patients. Methods: in men with prostate cancer, dynamic PET studies were acquired on an ECAT HR+ system. After administration of 250-300 MBq of C-11 labeled acetate, data were acquired during 20 min. The framing rate was 12/spl times/10, 9/spl times/20, 5/spl times/60, 2/spl times/300 sec with a total of 28 frames. The images were reconstructed with iterative algorithms, a MAP for transmission, and OS-MLEM for emission scans. The body contour was determined with a 40% threshold on the transmission images. This threshold assured exclusion of the bed. All voxels included in the body contour were used for further processing. FA then extracted the shape of the pure time activity curves (TACs) of vascular input and tumor output functions. The factors were used to create functional images, from which ROIs could be generated with thresholding techniques. The ROIs were used to create image based TACs. Results: The automated procedure generated reliable curves in all patients. Since the magnitude of the factors is normalized, TACs have to be adjusted using a scale factor. Two methods were utilized: (1) reversed normalization, (2) image based parameters. In principle, the factors generated by FA have no spillover and are pure vascular curves. The method is operator independent and reproducible. Processing time was 7 min/patient on an UltraSPARC5. Conclusion: FA can noninvasively generate input and output functions from dynamic PET data. The automated procedure generated curves corresponding to vessels and tumors, and had a success rate of about 80%. This processing tool facilitates PET as a reproducible quantification method in routine oncological applications.

Anatomic and metabolic imaging is important in cancer patients. "Mechanical" fusion with CT and PET is in-vogue because of improved lesion localization. Tumor volume imaging with CT and PET is more complex. Spheres varying from 1-20 ml were used to simulate tumors. For CT. spheres were filled with: 1) air, or 2) iodine contrast 6 mg/ml. with water as background. CT collimation was I mm and pitch 1-2. For PET, spheres were filled with C-11 and the background with F-18. yielding varying contrasts during the 5-hr acquisition. PET acquisition was 2D and 3D, reconstruction FBP and OSEM. CT volume was determined with a 50% tumor/background threshold. and PET volume with 30-80% isocontours. Contrast difference for CT was 60-80 HU. CT volume was significantly different for spheres with air than contrast. related to the wall thickness. PET contrast ratios decreased from 250 to 0.5 Generally. volumes by PET were larger than CT for small lesions. PET volume was unreliable for lesions less than 10 mm. Lesion contrast had to be more than 1.5 to obtain accurate results. Volume can be accurately measured with CT and PET. Both modalities can be calibrated to provide the correct volume. PET produces significant deviations for contrast ratios

This article focuses on bringing together mice to patients with microPET to PET and molecular imaging probes and drugs for molecular diagnostics and molecular therapeutics. In the latter there is a common disease target in which near massless amounts of a molecular imaging probe is used to image the presence and function of the target and then to use the same molecule, or analogs of it, in mass amounts to modify the function of the target therapeutically. The biological world has gone molecular from the revolutionary paradigm shift from the genome, proteome and systems biology to molecular biology, molecular pharmacology, molecular therapeutics, molecular diagnostics, molecular medicine and molecular imaging. The heart of this movement is the molecular basis of instructions, communication, regulation and function of the cellular make up of the body. Classical nomenclature and descriptions of disease are giving way to molecular descriptions of disease to define the diagnostic and disease information required to select and evaluate molecular therapies. As the basis of disease and its therapeutic management shifts to the molecular basis of the biology of disease, imaging diagnostics must shift to this basis also. Many advances in various molecular and anatomical techniques are occurring to meet this challenge from research to clinical practice.

Inter-subject anatomic differences prohibits direct image-wise statistical evaluation of brain FDG-PET images of Alzheimer's disease (AD) patients. In this study, the authors propose a MRI-based elastic-mapping method which enables image-wise evaluation. The method involves intra-subject MR-PET registration, 3-D elastic mapping of two set of MR images, and elastically transforming the co-registered PET images. The MR-PET registration used simulated PET images, which were based on segmentation of MR images. In the 3-D elastic mapping stage, first a global linear scaling was applied to compensate for brain size difference, then a deformation field was obtained by minimizing the regional sum of squared difference between the two sets of MR images. Two groups (AD patient and normal control), each with three subjects, were included in the current study. After processing, images from all subjects have similar shapes. Averaging the images across all subjects (either within the individual group or for both groups) give images indistinguishable from original single subject FDG images (i.e. without much spatial resolution loss), except with lower image noise level. The method is expected to allow statistical image-wise analysis to be performed across different subjects.

Regional myocardial blood flow (MBF) can be measured by /sup 13/N-ammonia PET dynamic imaging using the conventional modeling approach that requires blood sampling, region-of-interest (ROI) drawing and a time-consuming nonlinear regression on each time activity curve (TAC). In this study, the factor analysis of dynamic structures (FADS) was used to extract the "pure" blood pool TAC and generate a parametric image of MBF (pixel unit: ml/min/g) which can map the myocardial perfusion accurately, Ten dynamic /sup 13/N-ammonia dog PET studies (3 baseline, 5 hyperemia, and 2 occlusion) were included. Three factors (TACs) and their corresponding factor images (the tight and left ventricular (RV and LV) blood pools and myocardial activities) were extracted from each study. The LV factors matched well with the plasma TACs, The factor image of myocardium was then converted to parametric image of MBF using a relationship derived from a two-compartment model, The results showed that the MBF obtained from PADS correlated well with MBF by two-compartment model fitting (correlation coefficient (r)t 0.98, slope=0.83) and by microsphere technique (r=0.98, slope=0.95). The FADS generated MIBF images have good image quality and lower noise levels compared to those generated by Patlak graphical analysis (PGA). It is concluded that regional myocardial blood flow can be measured accurately and noninvasively from /sup 13/N-ammonia dynamic PET imaging and FADS technique. FADS provides a simple method to map the distribution and magnitude of myocardial perfusion accurately and generate parametric image of MBF without requiring blood sampling and spillover correction. >

New PET scanners have higher axial and in-plane spatial resolutions but at the expense of reduced per plane sensitivity, which prevents the higher resolution to be fully realized. Normally, Gaussian weighted interplane axial smoothing is used to reduce noise. In this study, the authors developed a new algorithm to first elastically map from adjacent planes to an expected plane location, then by simple averaging with the measured image at the corresponding axial plane location to reduce the image noise level. Compared with those images obtained by conventional axial-directional smoothing method, the images of the new method which are based on matching image features of adjacent planes have improved signal-to-noise ratio. To quantify the observation, both simulated cardiac images and real cardiac PET images were studied. The effective in-plane resolution loss was measured by the "effective global Gaussian resolution" and the noise reduction was evaluated by the cross-correlation coefficient. Various Hanning reconstruction filters with cutoff frequency=0.5, 0.7, 1.0/spl times/Nyquist frequency and Ramp 1.0 filter were tested on simulated images. Results showed that the new method was robust to various noise levels and indicated larger noise reduction or better image feature preservation than by the conventional method.

The authors report the results from a new high resolution gamma ray imaging detector designed for use in a positron emission tomography (PET) system dedicated to small animal imaging. The detectors consist of an 8/spl times/8 array of 2/spl times/2/spl times/10 mm bismuth germanate (BGO) crystals coupled by 2 mm diameter double clad optical fibers to a 64 pixel multi-channel photomultiplier tube (MC-PMT). A charge division readout board is used to convert the 64 output channels into four position sensitive signals which determine the crystal of interaction. Measurements with a pair of these detectors demonstrate an intrinsic spatial resolution of 1.4 mm, a coincidence timing resolution of 15 ns and an energy resolution ranging between 35 and 60%. Based on these encouraging results, the design for a dedicated animal PET tomograph is proposed and simulations of this system project a reconstructed resolution of less than 2 mm within a 5 cm diameter transaxial field of view.

Methods to repeatedly, non-invasively, and quantitatively image gene expression in living animals are rapidly emerging and should fundamentally change studies of gene expression in vivo. We previously developed assays utilizing positron emission tomography (PET) to image reporter gene expression. In this paper we: (1) describe a new bi-directional, tetracycline-inducible system that can be used to pharmacologically induce target gene expression and to quantitatively image induced expression by using a PET reporter gene; (2) demonstrate the potential of this system in transient and stable cell transfection assays; and (3) demonstrate the ability to repetitively and quantitatively image tetracycline and tetracycline analog induction of gene expression in living animals. We utilize the dopamine type-2 receptor (D(2)R) and the mutant herpes-simplex virus type 1 thymidine kinase (HSV1-sr39tk) reporter genes to validate this system. We utilize microPET technology to show that quantitative tomographic imaging of gene induction is possible. We find a high correlation (r(2) = 0.98) between 'target' and reporter gene expression. This work establishes a new technique for imaging time-dependent variation of gene expression both from vectors with inducible promoters and in transgenic animals in which pharmacologic induction of gene expression must be monitored. These techniques may be applied both in gene therapy and for the study of gene expression in transgenic animals.

The potential impact of Sestamibi scintimammography (SSMM) on the cost effective management of women with dense breasts is not known. This study addresses this issue quantitatively by examining the impact of SSMM based screening strategies on the approximately 3,000,000 women over 40 with very dense breasts (DY patterns) without palpable masses and who have had one or more prior mammograms, who undergo routine screening each year. Quantitative decision tree sensitivity analysis was used to compare the conventional mammography (MM) strategy (strategy A), which does not subject patients with negative mammograms to any further examination until their next screening, with two decision strategies for screening with SSMM; SSMM after a negative mammogram (strategy B) or SSMM as the only screening test for women already identified as having dense breasts by a previous mammogram (strategy C). Cost effectiveness was measured by calculating the incremental cost effectiveness ratio (ICER) of strategies B and C, which is the cost of achieving an additional year of life in the screening population by choosing a SSMM based decision strategy rather than the conventional strategy. Strategies B and C reduced the number of false negative diagnoses by 62% and 8%, respectively. The ICER was $632,000 and $3.18M per life year for strategy B and C, respectively. To be cost effective, the pre-test probability of cancer in the study population must be greater than 3% for strategy B or the cost of SSMM must be less than $50 for strategy C. These results show the ICER of an SSMM based breast cancer screening strategy in the management of patients with dense breasts is not currently within the range (approximately $50,000 per year life saved) of other commonly performed medical interventions that are considered cost effective.

Background Studies of patients with coronary artery disease and left ventricular dysfunction have shown that preoperative quantification of myocardial viability may be clinically useful to identify those patients who will benefit most from revascularization both functionally and prognostically. However, the relation between preoperative extent of viability and change in heart failure symptoms has not been documented carefully. We assessed the relation between the magnitude of improvement in heart failure symptoms after coronary artery bypass surgery (CABG) and the extent of myocardial viability as assessed by use of quantitative analysis of preoperative positron emission tomography (PET) images. Methods and Results We studied 36 patients with ischemic cardiomyopathy (mean left ventricular ejection fraction, 28±6%) undergoing CABG. Preoperative extent and severity of perfusion abnormalities and myocardial viability (flow-metabolism mismatch) were assessed by use of quantitative analysis of PET images with 13 N ammonia and fluorine-18-deoxyglucose. Each patient’s functional status was determined before and after CABG by use of a Specific Activity Scale. Mean perfusion defect size and severity were 63±13% and 33±12%, respectively. Total extent of a PET mismatch correlated linearly and significantly with percent improvement in functional status after CABG ( r =.87, P P =.009). This resulted in an improvement of 107% in patients with large mismatches compared with only 34% in patients with minimal or no PET mismatch. Conclusions In patients with ischemic cardiomyopathy, the magnitude of improvement in heart failure symptoms after CABG is related to the preoperative extent and magnitude of myocardial viability as assessed by use of PET imaging. Patients with large perfusion-metabolism mismatches exhibit the greatest clinical benefit after CABG.

In dynamic cardiac PET FDG studies for measurement of myocardial metabolic rate of glucose (MMRGlc), the plasma FDG time-activity curve (input function) is commonly obtained from the left ventricular (LV) region on the PET images. The input function is contaminated by spillover of radioactivity from the surrounding myocardium and this could cause significant error in the estimated MMRGlc. In this study, the authors determined the effect of myocardial to blood pool spillover on MMRGlc and developed a method to correct for this spillover of activity. The method is based on a reformulation of the FDG model equation in terms of the spillover contaminated input function that includes both the myocardium to blood pool and blood pool to myocardium spillover fractions as variable parameters (Fmb and Fbm) The reformulated model equation can be used to fit the global myocardial tissue activity curve to estimate Fmb and thus yields a spillover corrected input function. The MMRGlc estimate with the corrected input function was within 95% of the true value (compared to 85% using the uncorrected input function) in a set of computer simulation studies. Dynamic PET FDG data were obtained in eight human studies and blood samples were obtained during the study. As compared to the results with the uncorrected input function, the estimates of k4 by the new method were reduced by 69% into a range consistent with in vitro results. The method is effective in correcting Fmb spillover and leads to more accurate estimates of MMRGlc. The method also allows larger regions of interest (up to 150 mm2) to be drawn over the LV in dynamic PET images, thereby reducing the noise level in the input function.

A modelling approach is developed to generate the full time course of an injected radiotracer and its labelled metabolites in plasma/blood, based on measurements of the total radioactivities in withdrawn plasma/blood samples. A compartmental model is used to describe the conversion of an injected tracer to its metabolites in the body. The model equation is formulated with the total radioactivity concentration curve as the input function. The utility and characteristics of the approach in quantitative positron emission tomographic (PET) studies are shown with two examples. In the first example, using the tracer 6-[18F]fluoro-L-dopa (FDOPA), the approach is shown to derive the full time course of plasma FDOPA and its metabolites. In the second example of dynamic 15O oxygen PET, the approach is used to solve a deconvolution problem to give separated time-activity curves of 15O oxygen and 15O water in blood. The modelling approach improves the separation of blood/plasma time-activity curves and leads to better quantitative interpretation of PET results.

Positron-emission tomography with 13N-ammonia and 18F-2-deoxyglucose was used to assess regional perfusion and glucose utilization in 31 chronic electrocardiographic Q wave regions in 20 patients. With previously published criteria, regions of infarction were identified by a concordant reduction in regional perfusion and glucose utilization, and regions of ischemia were identified by preservation of glucose utilization in regions of diminished perfusion. Only 10 of the 31 regions (32%) exhibited myocardial infarction tomographically. In contrast, positron tomography revealed ischemia in six regions (20%) and was normal in 15 regions (48%). Even when Q wave regions were reassigned and consolidated to enhance the specificity of the electrocardiogram, uptake of 18F-2-deoxyglucose was noted in the majority (54%) of the regions. Neither electrocardiographic ST-T changes nor severity of associated wall motion abnormality reliably distinguished tomographically identified regions of ischemia from infarction. Thus positron tomography reveals evidence of persistent tissue metabolism in a high proportion of chronic electrocardiographic Q wave regions, and commonly used clinical tests do not reliably distinguish hypoperfused but viable regions from tomographically defined regions of myocardial infarction.

The isolated arterially perfused rabbit interventricular septum was used to study the relationship between flow (F) and myocardial uptake and subsequent clearance of bolus injections of 13N-labeled ammonia (13NH3). Multiple 13NH3 injections were delivered to a total of 19 septa at perfusion rates (F/g) ranging from 0.2-4.0 ml.min-1.g-1. Ten septa were studied at 37 degrees C and nine were studied at 28 degrees C to obtain uptake and clearance data at different metabolic rates. The septa were perfused without recirculation with a modified Tyrode solution. Analysis of the time-activity curves generated by the injections of 13NH3 revealed that the data was best described by three components. The first two components exhibited short clearance times (t1/2s less than 7 min) in contrast to prolonged clearance times (30-500 min) for component 3. Component 1 was consistent with a freely diffusible 13NH3 compartment. Component 3 persists and permits myocardial imaging 15 min or more after 13NH3 injection. At each perfusion rate the extraction fraction of component 3 was twice as large, and the clearance time of component 3 was twice as fast at 37 as at 28 degrees C, implying that the extraction and washout of this third component are dependent on enzymatic reactions. The total myocardial extraction into component 3 from a systemic injection is determined by multiplying the extraction fraction by the perfusion rate (EF(3) X F/g) and was directly related to the perfusion rate at both 28 and 37 degrees C.

The evaluation of a multiplane tomograph designed for brain imaging requires particular attention to certain design parameters that tend to be comprised in such designs. These parameters include resolution uniformity, axial slice thickness uniformity with emphasis on the interplane slices, scatter fraction, accidentals fraction, and system dead time. In addition, the final performance specifications should be relevant to the manner in which the system will actually be employed in the clinic. These specifications should be measured under realistic scatter and count rate conditions using the same reconstruction techniques that are employed in patient imaging. These parameters were evaluated on the NeuroECAT positron tomograph (1,2) and the effect of choice of manner of presentation and type of measurement condition on the apparent performance of the system is shown. The results indicate that clearly defined conditions are a necessity in evaluating the true performance of a positron tomograph.

The isolated arterial perfused rabbit interventricular septum was used to measure myocardial metabolic rate for glucose (MMRGlc) and rate constants and lumped constant (LC) for the glucose analogue (/sup 18/F)fluorodeoxyglucose (FDG) using a tracer kinetic model. FDG was delivered by constant infusion during coincidence counting of tissue /sup 18/F radioactivity. The MMRGlc was measured by the Fick method. Control septa were paced at 72 beats/min and perfused at 1.5 ml/min with oxygenated perfusate containing 5.6 mM glucose and 5 mU/ml insulin. The following conditions were tested: 3.0 and 4.5 ml/min; insulin increased to 25 mU/ml; insulin omitted; 2.8 mM and 11.2 mM glucose; 144 beats/min and 96 paired stimuli/min; and anoxia. Under all conditions studied the phosphorylation (hexokinase) reaction was rate limiting relative to transport. Compared with control conditions, the phosphorylation rate constant was significantly increased with 2.8 mM glucose as well as in anoxia. With 4.5 ml/min and 11.2 mM glucose, conditions that should increase glucose flux into tissue without increasing demand, the phosphorylation rate constant decreased significantly. With 11.2 mM glucose, 96 paired stimuli/min, and anoxia without insulin, a significant increase in the hydrolysis rate of FDG 6-phosphate was observed and suggests that hydrolysis is also an importantmore » mechanism for regulating the MMRGlc. Increased transport rate constants were observed with increased flow rates, 96 paired stimuli/min, and anoxia at 96 beats/min. The LC was not significantly different from control in 11 of 14 conditions studied. Therefore, under most conditions in average LC can be used to calculate MMRGlc estimates.« less

The possibility of detecting mild coronary stenoses with positron computed tomography and nitrogen (N-13) ammonia administered during pharmacologic coronary vasodilation was previously demonstrated in chronically instrumented dogs. The feasibility of using this technique in human beings and its sensitivity in determining the degree and extent of coronary artery disease were examined in 13 young normal healthy volunteers and 32 patients with angiographically documented coronary artery disease. N-13 ammonia was administered intravenously and its distribution in the left ventricular myocardium recorded at rest and during dipyridamole-induced coronary hyperemia. In the 13 volunteers, N-13 activity was homogeneous at rest and during hyperemia, whereas 31 of the 32 patients had regional defects on the hyperemic images not present during rest. All six patients with double, all 10 with triple and 15 of 16 patients with single vessel disease (97 percent) were correctly identified with the technique. Two vessel involvement was correctly identified in five of the six patients with double vessel disease and three vessel disease in six of 10 patients. Of all 58 coronary stenoses, 52 (90 percent) were correctly identified. In a subgroup of 11 patients, the technique was compared with exercise thallium-201 planar images, which were abnormal in 10 (91 percent) whereas N-13 images were abnormal in all 11. Of the 19 stenosed coronary arteries in this subgroup, 11 (58 percent) were correctly identified with thallium-201 and 17 (89 percent) with tomography (p less than 0.01). It is concluded that cross-sectional imaging of the myocardial distribution of N-13 ammonia administered during pharmacologic coronary vasodilation is a highly sensitive and accurate means for noninvasive detection of coronary stenoses in human beings and for estimating the extent of coronary artery disease.

13N-labeled ammonia was used to investigate 1) the cerebral extraction and clearance of ammonia, 2) the mechanism by which capillaries accommodate changes in cerebral blood flow (CBF) and 3) its use for the measurement of CBF. The unidirectional extraction of 13NH3 in rhesus monkeys was measured during PaCO2 induced changes in CBF and dog studies were performed using in vitro tissue counting techniques to examine 13NH3 extraction in gray and white matter, mixed tissue and cerebellum during variations in CBF produced by combinations of embolization, local brain compression, and changes in PaCO2. The single pass extraction fraction of 13NH3 varied from about 70 to 20% over a CBF range of 12 to 140 cc/min/100 g. Capillary permeability-surface area product (PS) estimates with a Renkin/Crone model show PS increasing with CBF. The magnitude and rate of increase in PS with CBF was highest in gray matter greater than mixed tissue greater than white matter. Tissue extraction of 13NH3 vs CBF relationship was best described by a unidirectional transport model in which CBF increases by both recruitment of capillaries and by increases of blood velocity in open capillaries. This saturable-recruitment model provides a possible explanation for the mechanism of flow changes at the capillary level. The net 13NH3 extraction subsequent to an i.v. injection increases non-linearly with CBF. Doubling or halving basal CBF produced from 35 to 50% changes in the 13N tissue concentrations with further increases in CBF associated with progressively smaller changes in 13N concentrations.

To examine the use of 2-deoxy-2-[ 18 F]fluoro-D-glucose (2-FDG) as a glucose analog for measuring glucose utilization rate in myocardium, dual-tracer kinetic experiments with 2-FDG and 2-[ 3 H]glucose were performed in the perfused, isolated rabbit interventricular septum to measure simultaneously the transport and phosphorylation rates of glucose and 2-FDG. Results of the present study indicated that, in the septum, (i) the transport rate constants of 2-FDG and glucose were similar in magnitude, (ii) the phosphorylation rate constant for 2-FDG was about 60% of that of glucose, (iii) hypoxia caused an increase in phosphorylation rates of glucose and 2-FDG without affecting transport.