Myocardial blood flow measurement with a conventional dual-head SPECT/CT with spatiotemporal iterative reconstructions - a clinical feasibility study.

Cardiac single photon emission computed tomography (SPECT) cameras typically rotate too slowly around a patient to capture changes in the blood pool activity distribution and provide accurate kinetic parameters. A spatiotemporal iterative reconstruction method to overcome these limitations was investigated. Dynamic rest/stress (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) SPECT/CT was performed along with reference standard rest/stress dynamic positron emission tomography (PET/CT) (13)N-NH3 in five patients. The SPECT data were reconstructed using conventional and spatiotemporal iterative reconstruction methods. The spatiotemporal reconstruction yielded improved image quality, defined here as a statistically significant (p<0.01) 50% contrast enhancement. We did not observe a statistically significant difference between the correlations of the conventional and spatiotemporal SPECT myocardial uptake K 1 values with PET K 1 values (r=0.25, 0.88, respectively) (p<0.17). These results indicate the clinical feasibility of quantitative, dynamic SPECT/CT using (99m)Tc-MIBI and warrant further investigation. Spatiotemporal reconstruction clearly provides an advantage over a conventional reconstruction in computing K 1.

Combining dynamic and ECG-gated 8²Rb-PET for practical implementation in the clinic.

OBJECTIVES: For many cardiac clinics, list-mode PET is impractical. Therefore, separate dynamic and ECG-gated acquisitions are needed to detect harmful stenoses, indicate affected coronary arteries, and estimate stenosis severity. However, physicians usually order gated studies only because of dose, time, and cost limitations. These gated studies are limited to detection. In an effort to remove these limitations, we developed a novel curve-fitting algorithm [incomplete data (ICD)] to accurately calculate coronary flow reserve (CFR) from a combined dynamic-ECG protocol of a length equal to a typical gated scan. METHODS: We selected several retrospective dynamic studies to simulate shortened dynamic acquisitions of the combined protocol and compared (a) the accuracy of ICD and a nominal method in extrapolating the complete functional form of arterial input functions (AIFs); and (b) the accuracy of ICD and ICD-AP (ICD with a-posteriori knowledge of complete-data AIFs) in predicting CFRs. RESULTS: According to the Akaike information criterion, AIFs predicted by ICD were more accurate than those predicted by the nominal method in 11 out of 12 studies. CFRs predicted by ICD and ICD-AP were similar to complete-data predictions (PICD=0.94 and PICD-AP=0.91) and had similar average errors (eICD=2.82% and eICD-AP=2.79%). CONCLUSION: According to a nuclear cardiologist and an expert analyst of PET data, both ICD and ICD-AP predicted CFR values with sufficient accuracy for the clinic. Therefore, by using our method, physicians in cardiac clinics would have access to the necessary amount of information to differentiate between single-vessel and triple-vessel disease for treatment decision making.

Investigation of dynamic SPECT measurements of the arterial input function in human subjects using simulation, phantom and human studies.

Computer simulations, a phantom study and a human study were performed to determine whether a slowly rotating single-photon computed emission tomography (SPECT) system could provide accurate arterial input functions for quantification of myocardial perfusion imaging using kinetic models. The errors induced by data inconsistency associated with imaging with slow camera rotation during tracer injection were evaluated with an approach called SPECT/P (dynamic SPECT from positron emission tomography (PET)) and SPECT/D (dynamic SPECT from database of SPECT phantom projections). SPECT/P simulated SPECT-like dynamic projections using reprojections of reconstructed dynamic (94)Tc-methoxyisobutylisonitrile ((94)Tc-MIBI) PET images acquired in three human subjects (1 min infusion). This approach was used to evaluate the accuracy of estimating myocardial wash-in rate parameters K(1) for rotation speeds providing 180° of projection data every 27 or 54 s. Blood input and myocardium tissue time-activity curves (TACs) were estimated using spatiotemporal splines. These were fit to a one-compartment perfusion model to obtain wash-in rate parameters K(1). For the second method (SPECT/D), an anthropomorphic cardiac torso phantom was used to create real SPECT dynamic projection data of a tracer distribution derived from (94)Tc-MIBI PET scans in the blood pool, myocardium, liver and background. This method introduced attenuation, collimation and scatter into the modeling of dynamic SPECT projections. Both approaches were used to evaluate the accuracy of estimating myocardial wash-in parameters for rotation speeds providing 180° of projection data every 27 and 54 s. Dynamic cardiac SPECT was also performed in a human subject at rest using a hybrid SPECT/CT scanner. Dynamic measurements of (99m)Tc-tetrofosmin in the myocardium were obtained using an infusion time of 2 min. Blood input, myocardium tissue and liver TACs were estimated using the same spatiotemporal splines. The spatiotemporal maximum-likelihood expectation-maximization (4D ML-EM) reconstructions gave more accurate reconstructions than did standard frame-by-frame static 3D ML-EM reconstructions. The SPECT/P results showed that 4D ML-EM reconstruction gave higher and more accurate estimates of K(1) than did 3D ML-EM, yielding anywhere from a 44% underestimation to 24% overestimation for the three patients. The SPECT/D results showed that 4D ML-EM reconstruction gave an overestimation of 28% and 3D ML-EM gave an underestimation of 1% for K(1). For the patient study the 4D ML-EM reconstruction provided continuous images as a function of time of the concentration in both ventricular cavities and myocardium during the 2 min infusion. It is demonstrated that a 2 min infusion with a two-headed SPECT system rotating 180° every 54 s can produce measurements of blood pool and myocardial TACs, though the SPECT simulation studies showed that one must sample at least every 30 s to capture a 1 min infusion input function.

Searching for alternatives to full kinetic analysis in 18F-FDG PET: an extension of the simplified kinetic analysis method.

UNLABELLED: The most accurate way to estimate the glucose metabolic rate (or its influx constant) from (18)F-FDG PET is to perform a full kinetic analysis (or its simplified Patlak version), requiring dynamic imaging and the knowledge of arterial activity as a function of time. To avoid invasive arterial blood sampling, a simplified kinetic analysis (SKA) has been proposed, based on blood curves measured from a control group. Here, we extend the SKA by allowing for a greater variety of arterial input function (A(t)) curves among patients than in the original SKA and by accounting for unmetabolized (18)F-FDG in the tumor. METHODS: Ten A(t)s measured in patients were analyzed using a principal-component analysis to derive 2 principal components describing most of the variability of the A(t). The mean distribution volume of (18)F-FDG in tumors for these patients was used to estimate the corresponding quantity in other patients. In subsequent patient studies, the A(t) was described as a linear combination of the 2 principal components, for which the 2 scaling factors were obtained from an early and a late venous sample drawn for the patient. The original and extended SKA (ESKA) were assessed using fifty-seven (18)F-FDG PET scans with various tumor types and locations and using different injection and acquisition protocols, with the K(i) derived from Patlak analysis as a reference. RESULTS: ESKA improved the accuracy or precision of the input function (area under the blood curve) for all protocols examined. The mean errors (±SD) in K(i) estimates were -12% ± 33% for SKA and -7% ± 22% for ESKA for a 20-s injection protocol with a 55-min postinjection PET scan, 20% ± 42% for SKA and 1% ± 29% for ESKA (P < 0.05) for a 120-s injection protocol with a 55-min postinjection PET scan, and -37% ± 19% for SKA and -4% ± 6% for ESKA (P < 0.05) for a 20-s injection protocol with a 120-min postinjection PET scan. Changes in K(i) between the 2 PET scans in the same patients also tended to be estimated more accurately and more precisely with ESKA than with SKA. CONCLUSION: ESKA, compared with SKA, significantly improved the accuracy and precision of K(i) estimates in (18)F-FDG PET. ESKA is more robust than SKA with respect to various injection and acquisition protocols.

Can positron emission tomography (PET) or PET/Computed Tomography (CT) acquired in a nontreatment position be accurately registered to a head-and-neck radiotherapy planning CT?

PURPOSE: To quantify the uncertainties associated with incorporating diagnostic positron emission tomography/CT (PET/CT) and PET into the radiotherapy treatment-planning process using different image registration tools, including automated and manual rigid body registration methods, as well as deformable image registration. METHODS AND MATERIALS: The PET/CTs and treatment-planning CTs from 12 patients were used to evaluate image registration accuracy. The PET/CTs also were used without the contemporaneously acquired CTs to evaluate the registration accuracy of stand-alone PET. Registration accuracy for relevant normal structures was quantified using an overlap index and differences in the center of mass (COM) positions. For tumor volumes, the registration accuracy was measured using COM positions only. RESULTS: Registration accuracy was better with PET/CT than with PET alone. The COM displacements ranged from 3.2 +/- 0.6 mm (mean +/- 95% confidence interval, for brain) to 8.4 +/- 2.6 mm (spinal cord) for registration with PET/CT data, compared with 4.8 +/- 1.7 mm (brain) and 9.9 +/- 3.1 mm (spinal cord) with PET alone. Deformable registration improved accuracy, with minimum and maximum errors of 1.1 +/- 0.8 mm (brain) and 5.4 +/- 1.4 mm (mandible), respectively. CONCLUSIONS: It is possible to incorporate PET and/or PET/CT acquired in diagnostic positions into the treatment-planning process through the use of advanced image registration algorithms, but precautions must be taken, particularly when delineating tumor volumes in the neck. Acquisition of PET/CT in the treatment-planning position would be the ideal method to minimize registration errors.

Quantitative accuracy of PET/CT for image-based kinetic analysis.

Accuracy in quantification of activity concentrations (e.g., in Bq/ml) is essential for compartment modeling and kinetic analysis of dynamic reconstructed PET images. Dynamic PET data can be acquired in list-mode, and often are preferred over frame mode acquisitions due to the flexibility of reformatting the list-mode data into different dynamic image sequences after the acquisition is complete. However, most PET data are acquired as static frames. It therefore is important to evaluate the quantitative accuracy of list-mode or dynamic PET acquisitions prior to their use for clinical or research applications. The quantitative accuracy of list-mode acquisitions obtained with a Siemens Biograph 16 PET/CT scanner at our institution was evaluated; the image data were acquired from an anthropomorphic phantom (Data Spectrum, Hillsborough, NC) filled with an aqueous solution of 18F-fluorodeoxyglucose (FDG). PET data were acquired with the phantom for the following three different configurations: (1) with nonradioactive water in the body compartment and aqueous solution of 18F-FDG in only a fillable cylindrical insert to simulate the first several seconds of highly concentrated radioactivity within the field of view such as that in major venous or pulmonary vessels or in the cardiac ventricles, (2) with radioactivity throughout the entire body compartment and imaged with 3 min static frames and 12 min in list-mode that was reformatted into four 3-min frames, and (3) with radioactivity throughout the body compartment and imaged in list-mode and reformatted into sequential time frames having durations of 3, 10, 20, 30, 50, and 67 s, respectively (i.e., total of 180 s). All measured concentration values were compared against values acquired from static images or against the actual activity concentrations calculated from the calibrated activities dispensed into the phantom corrected for physical decay of 18F. These analyses demonstrated that the count rate limitation is minimal or negligible as long as there is no more than 370-440 MBq (10-12 mCi) activity entirely within the axial FOV and that list-mode acquisition yields accurate quantitation of activity concentrations over a clinically realistic range of activities. In addition, reformatting a single list-mode acquisition into frames of different durations retains quantitative accuracy with respect to static frame data and compared to the known radionuclide concentration in the phantom. Within these constraints, the list-mode data acquired with the Biograph 16 PET/CT system are quantitatively accurate for image-based kinetic analysis.

Glucose and insulin variations in patients during the time course of a FDG-PET study and implications for the "glucose-corrected" SUV.

INTRODUCTION: 2-Deoxy-2[(18)F]fluoro-d-glucose (FDG) positron emission tomography (PET) has an established role in the evaluation of cancer. Generally, tumor uptake and response to treatment are evaluated using the standardized uptake value (SUV). Some authors have proposed correcting SUV for glucose levels. Insulin is also thought to influence tumor uptake by changing uptake in other tissues. However, little attention has been paid to understanding the variability of glucose or insulin during a single PET study. METHOD: We studied the biological and instrumental variability of glucose and insulin measurements in 71 nondiabetic patients undergoing FDG-PET studies. Multiple glucose measurements were obtained in all 71 subjects, and in 69 of these 71 subjects, multiple serum insulin measurements were made. We determined the coefficient of observed variation (CV(ow)) and the coefficient of variation attributable to biological variability (CV(bv)) for both glucose and insulin. RESULTS: The mean glucose concentration was 78.9+/-13.5 mg/dl. The mean insulin value was 6.49+/-5.92 microU/ml. The weighted mean CV(ow) and CV(bv) was 5.0% and 3.6%, respectively, for glucose and 14.2% and 8.3%, respectively, for insulin. CONCLUSIONS: Variations in the range of 3.6% are observed in glucose measurements during the time course of an FDG scan even after accounting for analytical error; larger variations of 8.3% are observed in insulin levels. Therefore, corrections of SUV for blood glucose, especially if obtained from single measurements, can introduce additional errors of at least this much.

Intracoronary infusion of autologous mononuclear cells from bone marrow or granulocyte colony-stimulating factor-mobilized apheresis product may not improve remodelling, contractile function, perfusion, or infarct size in a swine model of large myocardial infarction.

AIMS: In a blinded, placebo-controlled study, we investigated whether intracoronary infusion of autologous mononuclear cells from granulocyte colony-stimulating factor (G-CSF)-mobilized apheresis product or bone marrow (BM) improved sensitive outcome measures in a swine model of large myocardial infarction (MI). METHODS AND RESULTS: Four days after left anterior descending (LAD) occlusion and reperfusion, cells from BM or apheresis product of saline- (placebo) or G-CSF-injected animals were infused into the LAD. Large infarcts were created: baseline ejection fraction (EF) by magnetic resonance imaging (MRI) of 35.3 +/- 8.5%, no difference between the placebo, G-CSF, and BM groups (P = 0.16 by ANOVA). At 6 weeks, EF fell to a similar degree in the placebo, G-CSF, and BM groups (-7.9 +/- 6.0, -8.5 +/- 8.8, and -10.9 +/- 7.6%, P = 0.78 by ANOVA). Left ventricular volumes and infarct size by MRI deteriorated similarly in all three groups. Quantitative positron emission tomography (PET) demonstrated significant decline in fluorodeoxyglucose uptake rate in the LAD territory at follow-up, with no histological, angiographic, or PET perfusion evidence of functional neovascularization. Immunofluorescence failed to demonstrate transdifferentiation of infused cells. CONCLUSION: Intracoronary infusion of mononuclear cells from either BM or G-CSF-mobilized apheresis product may not improve or limit deterioration in systolic function, adverse ventricular remodelling, infarct size, or perfusion in a swine model of large MI.

Correcting tumour SUV for enhanced bone marrow uptake: retrospective 18F-FDG PET/CT studies.

PURPOSE: The concentration of F-FDG in the bone marrow is usually low. One common cause of high uptake is due to bone marrow stimulating drugs administered in conjunction with chemotherapy or radiation therapy. It has been hypothesized that the sequestration of F-FDG to the bone marrow may reduce the standardized uptake value (SUV) of a tumour. We tested this hypothesis by quantifying total F-FDG uptake in the bone marrow of patients with visibly enhanced bone marrow uptake and computing its effect on tumour SUV. METHODS: Total F-FDG in bone marrow was measured in two groups of PET/CT studies: one (n=19) with visibly enhanced bone marrow, the other (n=5), a baseline group with 'normal' levels of uptake. To measure the F-FDG in bone marrow, the entire skeleton in the CT was segmented from surrounding tissue, and the resulting volume applied to the PET image. Using kinetic analysis we show that the predicted correction factor to tumour SUV is given by (1-q0/Q)/(1-q/Q), where Q is the injected dose, and q and q0 are enhanced and baseline bone marrow uptake (MBq). RESULTS: The enhanced bone marrow uptake averaged 8.9+/-3.2% of injected dose (15.2% max) vs. 4.2+/-0.4% (4.6% max) at baseline. This resulted in a predicted artificial decrease in tumour SUV of up to 11.5% (4.9+/-4.3%, on average). CONCLUSION: Enhanced bone marrow uptake is predicted to reduce tumour SUVs by as much as 11.5% in our patient group and is a potential confounding factor in using SUV for monitoring tumour response to therapy.

Partial-volume effect in PET tumor imaging.

PET has the invaluable advantage of being intrinsically quantitative, enabling accurate measurements of tracer concentrations in vivo. In PET tumor imaging, indices characterizing tumor uptake, such as standardized uptake values, are becoming increasingly important, especially in the context of monitoring the response to therapy. However, when tracer uptake in small tumors is measured, large biases can be introduced by the partial-volume effect (PVE). The purposes of this article are to explain what PVE is and to describe its consequences in PET tumor imaging. The parameters on which PVE depends are reviewed. Actions that can be taken to reduce the errors attributable to PVE are described. Various PVE correction schemes are presented, and their applicability to PET tumor imaging is discussed.

Partial-volume correction in PET: validation of an iterative postreconstruction method with phantom and patient data.

UNLABELLED: Partial-volume errors (PVEs) in PET can cause incorrect estimation of radiopharmaceutical uptake in small tumors. An iterative postreconstruction method was evaluated that corrects for PVEs without a priori knowledge of tumor size or background. METHODS: Volumes of interest (VOIs) were drawn on uncorrected PET images. PVE-corrected images were produced using an iterative 3-dimensional deconvolution algorithm and a local point spread function. The VOIs were projected on the corrected image to estimate the PVE-corrected mean activity concentration. These corrected mean values were compared with uncorrected maximum and mean values. Simulated data were generated as a first test of the correction algorithm. Phantom measurements were made using (18)F-FDG-filled spheres in a scattering medium. Clinical validation used 154 surrogate tumors from 9 patients. The surrogate tumors were blood-pool images of the descending aorta as well as mesenteric and iliac arteries and veins. Surrogate tumors ranged in diameter from 5 to 25 mm. Analysis used (18)F-FDG and (11)C-CO datasets (both dynamic and static). Values representing "truth" were derived from imaging the blood pool in large structures (e.g., the left ventricle, left atrium, or sections of the aorta) where PVEs were negligible. Surrogate tumor sizes were measured from contrast CT. RESULTS: The PVE-correction technique, when applied to the mean value in spheric phantoms, yielded recovery coefficients of 87% for an 8-mm-diameter sphere and between 100% and 103% for spheres between 13 and 29 mm. For the human studies, PVE-corrected data recovered a large fraction of the true activity concentration (86% +/- 7% for an 8-mm-diameter tumor and 98% +/- 8% for tumors between 10 and 24 mm). For tumors smaller than 18 mm, the PVE-corrected mean values were less biased (P<0.05) than the uncorrected maximum or mean values. CONCLUSION: Iterative postreconstruction PVE correction generated more accurate uptake measurements in subcentimeter tumors for both phantoms and patients than the uncorrected values. The method eliminates the requirement for segmenting anatomic data and estimating tumor metabolic size or tumor background level. This technique applies a PVE correction to the mean voxel value within a VOI, yielding a more accurate estimate of uptake than the maximum voxel value.

The influence of tumor oxygenation on hypoxia imaging in murine squamous cell carcinoma using [64Cu]Cu-ATSM or [18F]Fluoromisonidazole positron emission tomography.

[64Cu]Cu(II)-ATSM (64Cu-ATSM) and [18F]-Fluoromisonidazole (18F-FMiso) tumor binding as assessed by positron emisson topography (PET) was used to determine the responsiveness of each probe to modulation in tumor oxygenation levels in the SCCVII tumor model. Animals bearing the SCCVII tumor were injected with 64Cu-ATSM or 18F-FMiso followed by dynamic small animal PET imaging. Animals were imaged with both agents using different inspired oxygen mixtures (air, 10% oxygen, carbogen) which modulated tumor hypoxia as independently assessed by the hypoxia marker pimonidazole. The extent of hypoxia in the SCCVII tumor as monitored by the pimonidazole hypoxia marker was found to be in the following order: 10% oxygen>air>carbogen. Tumor uptake of 64Cu-ATSM could not be changed if the tumor was oxygenated using carbogen inhalation 90 min post-injection suggesting irreversible cellular uptake of the 64Cu-ATSM complex. A small but significant paradoxical increase in 64Cu-ATSM tumor uptake was observed for animals breathing air or carbogen compared to 10% oxygen. There was a positive trend toward 18F-FMiso tumor uptake as a function of changing hypoxia levels in agreement with the pimonidazole data. 64Cu-ATSM tumor uptake was unable to predictably detect changes in varying amounts of hypoxia when oxygenation levels in SCCVII tumors were modulated. 18F-FMiso tumor uptake was more responsive to changing levels of hypoxia. While the mechanism of nitroimidazole binding to hypoxic cells has been extensively studied, the avid binding of Cu-ATSM to tumors may involve other mechanisms independent of hypoxia that warrant further study.

PET/CT imaging: effect of respiratory motion on apparent myocardial uptake.

BACKGROUND: Positron emission tomography (PET) attenuation correction (AC) using computed tomography (CT) can be affected by respiratory motion: hi-speed CT captures 1 point of the respiratory cycle while PET emission data averages many cycles. We quantified the changes in apparent myocardial uptake due to this respiratory-induced CT attenuation mismatch. METHODS: Twenty-two patients undergoing fluorine-18 fluorodeoxyglucose (FDG) PET/CT received 3 sequential CT scans at normal resting end-inspiration (CT(INSPIR)), ending expiration (CT(EXPIR)), and at midvolume between end-expiration and end-inspiration (CT(MIDVOL)). A pneumotachometer measured absolute changes in lung volume. Seven subjects also underwent a 3-minute transmission scan with a 68Ge rotating rod source (RRS). The PET emission data set was reconstructed up to 4 times using CT(EXPIR), CT(INSPIR), CT(MIDVOL), and RRS AC maps. Relative heart position and cardiac uptake was measured for each CT attenuation correction. RESULTS: Respiratory motion produced marked changes in global and regional myocardial uptake. Changes were large in the lateral and anterior regions at the lung-soft tissue interface (up to 30% using CT(INSPIR) compared to CT(EXPIR) for AC) and smaller in the septal region (10% or less). Data corrected with CT(EXPIR) agreed best with the RRS. CONCLUSION: Respiratory effects can introduce large inhomogeneities in apparent myocardial uptake when CT is used for attenuation correction.