Raymond F. Muzic

The Dynamic in vivo Distribution of Bone Marrow-Derived Mesenchymal Stem Cells after Infusion

Bone marrow-derived mesenchymal stem cells (MSCs) have the potential to differentiate along different mesenchymal lineages including those forming bone, cartilage, tendon, fat, muscle and marrow stroma that supports hematopoiesis. This differentiation potential makes MSCs candidates for cell-based therapeutic strategies for mesenchymal tissue injuries and for hematopoietic disorders by both local and systemic application. In the present study, rat marrow-derived MSCs were ex vivo culture-expanded, labeled with 111In-oxine, and infused into syngeneic rats via intra-artery (i.a.), intravenous (i.v.) and intraperitoneal cavity (i.p.) infusions. In addition, for i.a. and i.v. infusions, a vasodilator, sodium nitroprusside, was administered prior to the cell infusion and examined for its effect on MSC circulation. The dynamic distribution of infused MSCs was monitored by real-time imaging using a gamma camera immediately after infusion and at 48 h postinfusion. After 48 h, radioactivity in excised organs, including liver, lungs, kidneys, spleen and long bones, was measured in a gamma well counter and expressed as a percentage of injected doses. After both i.a. and i.v. infusion, radioactivity associated with MSCs was detected primarily in the lungs and then secondarily in the liver and other organs. When sodium nitroprusside was used, more labeled MSCs cleared the lungs resulting in a larger proportion detected in the liver. Most importantly, the homing of labeled MSCs to the marrow of long bones was significantly increased by the pretreatment with vasodilator. These results indicate multiple homing sites for injected MSCs and that the distribution of MSCs can be influenced by administration of vasodilator.

Spillover and Partial-Volume Correction for Image-Derived Input Functions for Small-Animal 18F-FDG PET Studies

We present and validate a method to obtain an input function from dynamic image data and 0 or 1 blood sample for small-animal 18F-FDG PET studies. The method accounts for spillover and partial-volume effects via a physiologic model to yield a model-corrected input function (MCIF). Methods: Image-derived input functions (IDIFs) from heart ventricles and myocardial time–activity curves were obtained from 14 Sprague–Dawley rats and 17 C57BL/6 mice. Each MCIF was expressed as a mathematic equation with 7 parameters, which were estimated simultaneously with the myocardial model parameters by fitting the IDIFs and myocardium curves to a dual-output compartment model. Zero or 1 late blood sample was used in the simultaneous estimation. MCIF was validated by comparison with input measured from blood samples. Validation included computing errors in the areas under the curves (AUCs) and in the 18F-FDG influx constant Ki in 3 types of tissue. Results: For the rat data, the AUC error was 5.3% ± 19.0% in the 0-sample MCIF and −2.3% ± 14.8% in the 1-sample MCIF. When the MCIF was used to calculate the Ki of the myocardium, brain, and muscle, the overall errors were −6.3% ± 27.0% in the 0-sample method (correlation coefficient r = 0.967) and 3.1% ± 20.6% in the 1-sample method (r = 0.970). The t test failed to detect a significant difference (P > 0.05) in the Ki estimates from both the 0-sample and the 1-sample MCIF. For the mouse data, AUC errors were 4.3% ± 25.5% in the 0-sample MCIF and −1.7% ± 20.9% in the 1-sample MCIF. Ki errors averaged −8.0% ± 27.6% for the 0-sample method (r = 0.955) and −2.8% ± 22.7% for the 1-sample method (r = 0.971). The t test detected significant differences in the brain and muscle in the Ki for the 0-sample method but no significant differences with the 1-sample method. In both rat and mouse, 0-sample and 1-sample MCIFs both showed at least a 10-fold reduction in AUC and Ki errors compared with uncorrected IDIFs. Conclusion: MCIF provides a reliable, noninvasive estimate of the input function that can be used to accurately quantify the glucose metabolic rate in small-animal 18F-FDG PET studies.

Loss of D2 receptor binding with age in rhesus monkeys: Importance of correction for differences in striatal size

The relation between striatal dopamine D2 receptor binding and aging was investigated in rhesus monkeys with PET. Monkeys (n = 18, 39 to 360 months of age) were scanned with 11C-raclopride; binding potential in the striatum was estimated graphically. Because our magnetic resonance imaging analysis revealed a concomitant relation between size of striatum and age, the dynamic positron emission tomography (PET) data were corrected for possible partial volume (PV) artifacts before parameter estimation. The age-related decline in binding potential was 1% per year and was smaller than the apparent effect if the age-related change in size was ignored. This is the first in vivo demonstration of a decline in dopamine receptor binding in nonhuman primates. The rate of decline in binding potential is consistent with in vitro findings in monkeys but smaller than what has been measured previously in humans using PET. Previous PET studies in humans, however, have not corrected for PV error, although a decline in striatal size with age has been demonstrated. The results of this study suggest that PV correction must be applied to PET data to accurately detect small changes in receptor binding that may occur in parallel with structural changes in the brain.

Measurement of Human Cerebral Blood Flow with [15O]Butanol and Positron Emission Tomography

Although H215O is widely used for CBF measurement by positron tomography, it underestimates CBF, especially at elevated flow rates. Several tracers, including butanol, overcome this problem, but the short half-life of 15O provides advantages that cause water to remain the tracer of choice. We report the first use and evaluation of 15O–labeled butanol for CBF measurement. Flow measurements made in a similar fashion with water and butanol at 10-min intervals were compared in normal volunteers under resting and hypercapnic conditions. Regional analysis showed good agreement between the tracers at low flows, and significant underestimation of flow by water relative to butanol in regions of elevated flow. The observed relationship between the tracers and the curve-fitted permeability-surface area product for water (133 ml · 100 g−1 · min−1) follow the known relationship between water and true flow. These observations indicate that [15O]-butanol provided accurate measurements of human regional CBF under conditions of elevated perfusion. We conclude that butanol is a convenient and accurate method for routine CBF determination by positron emission tomography.

18F-FDG PET/CT for Monitoring of Treatment Response in Breast Cancer

Changes in tumor metabolic activity have been shown to be an early indicator of treatment effectiveness for breast cancer, mainly in the neoadjuvant setting. The histopathologic response at the completion of chemotherapy has been used as the reference standard for assessment of the accuracy of 18F-FDG PET in predicting a response during systemic treatment. Although a pathologic complete response (pCR) remains an important positive prognostic factor for an individual patient, a recent metaanalysis could validate pCR as a surrogate marker for patient outcomes only in aggressive breast cancer subtypes. For establishment of the clinical application of metabolic treatment response studies, larger series of specific breast cancer subtypes—including hormone receptor–positive, human epidermal growth factor receptor 2–positive, and triple-negative breast cancers—are necessary. In addition, thresholds for relative changes in 18F-FDG uptake to distinguish between responding and nonresponding tumors need to be validated for different systemic treatment approaches, with progression-free survival and overall survival as references. A PET-based treatment stratification is applicable clinically only if valid alternative therapies are available. Of note, patients who do not achieve a pCR might still benefit from neoadjuvant therapy enabling breast-conserving surgery. In the metastatic setting, residual tumor metabolic activity after the initiation of systemic therapy is an indicator of active disease, whereas a complete resolution of metabolic activity is predictive of a successful treatment response.

Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function

Previous studies have reported that high fat feeding in mild to moderate heart failure (HF) results in the preservation of contractile function. Recent evidence has suggested that preventing the switch from fatty acid to glucose metabolism in HF may ameliorate dysfunction, and insulin resistance is one potential mechanism for regulating substrate utilization. This study was designed to determine whether peripheral and myocardial insulin resistance exists with HF and/or a high-fat diet and whether myocardial insulin signaling was altered accordingly. Rats underwent coronary artery ligation (HF) or sham surgery and were randomized to normal chow (NC; 14% kcal from fat) or a high-fat diet (SAT; 60% kcal from fat) for 8 wk. HF + SAT animals showed preserved systolic (+dP/dt and stroke work) and diastolic (-dP/dt and time constant of relaxation) function compared with HF + NC animals. Glucose tolerance tests revealed peripheral insulin resistance in sham + SAT, HF + NC, and HF + SAT animals compared with sham + NC animals. PET imaging confirmed myocardial insulin resistance only in HF + SAT animals, with an uptake ratio of 2.3 ± 0.3 versus 4.6 ± 0.7, 4.3 ± 0.4, and 4.2 ± 0.6 in sham + NC, sham + SAT, and HF + NC animals, respectively; the myocardial glucose utilization rate was similarly decreased in HF + SAT animals only. Western blot analysis of insulin signaling protein expression was indicative of cardiac insulin resistance in HF + SAT animals. Specifically, alterations in Akt and glycogen synthase kinase-3β protein expression in HF + SAT animals compared with HF + NC animals may be involved in mediating myocardial insulin resistance. In conclusion, HF animals fed a high-saturated fat exhibited preserved myocardial contractile function, peripheral and myocardial insulin resistance, decreased myocardial glucose utilization rates, and alterations in cardiac insulin signaling. These results suggest that myocardial insulin resistance may serve a cardioprotective function with high fat feeding in mild to moderate HF.

A method to correct for scatter, spillover, and partial volume effects in region of interest analysis in PET

Scatter and spatial resolution effects degrade the accuracy of radioactivity concentration estimates obtained from positron emission tomography (PET) data. The authors present and evaluate a methodology for region quantification which accounts for these degradations. The method is based on analysis of sinogram data and does not require dynamic data sequences to be reconstructed. Moreover, estimates of region variance are also produced which may be used to define weights for model analyses that use weighted least squares minimization in order to obtain unbiased parameter estimates. The authors evaluate the method using both simulation and measured data and find that, with an appropriate model of scatter and spatial resolution effects, it is unbiased and capable of quantifying myocardial concentration with no more than a 5% error in accuracy for myocardium as thin as 10 mm.

The Role of Imaging in Radiation Therapy Planning: Past, Present, and Future

The use of ionizing radiation for cancer treatment has undergone extraordinary development during the past hundred years. The advancement of medical imaging has been critical in helping to achieve this change. The invention of computed tomography (CT) was pivotal in the development of treatment planning. Despite some disadvantages, CT remains the only three-dimensional imaging modality used for dose calculation. Newer image modalities, such as magnetic resonance (MR) imaging and positron emission tomography (PET), are also used secondarily in the treatment-planning process. MR, with its better tissue contrast and resolution than those of CT, improves tumor definition compared with CT planning alone. PET also provides metabolic information to supplement the CT and MR anatomical information. With emerging molecular imaging techniques, the ability to visualize and characterize tumors with regard to their metabolic profile, active pathways, and genetic markers, both across different tumors and within individual, heterogeneous tumors, will inform clinicians regarding the treatment options most likely to benefit a patient and to detect at the earliest time possible if and where a chosen therapy is working. In the post-human-genome era, multimodality scanners such as PET/CT and PET/MR will provide optimal tumor targeting information.

Image quality and diagnostic performance of a digital PET prototype in patients with oncologic diseases: Initial experience and comparison with analog PET

We report our initial clinical experience for image quality and diagnostic performance of a digital PET prototype scanner with time-of-flight (DigitalTF), compared with an analog PET scanner with time-of-flight (GeminiTF PET/CT). Methods: Twenty-one oncologic patients, mean age 58 y, first underwent clinical 18F-FDG PET/CT on the GeminiTF. The scanner table was then withdrawn while the patient remained on the table, and the DigitalTF was inserted between the GeminiTF PET and CT scanner. The patients were scanned for a second time using the same PET field of view with CT from the GeminiTF for attenuation correction. Two interpreters reviewed the 2 sets of PET/CT images for overall image quality, lesion conspicuity, and sharpness. They counted the number of suggestive 18F-FDG–avid lesions and provided the TNM staging for the 5 patients referred for initial staging. Standardized uptake values (SUVs) and SUV gradients as a measure of lesion sharpness were obtained. Results: The DigitalTF showed better image quality than the GeminiTF. In a side-by-side comparison using a 5-point scale, lesion conspicuity (4.3 ± 0.6), lesion sharpness (4.3 ± 0.6), and diagnostic confidence (3.4 ± 0.7) were better with DigitalTF than with GeminiTF (P < 0.01). In 52 representative lesions, the lesion maximum SUV was 36% higher with DigitalTF than with GeminiTF, lesion–to–blood-pool SUV ratio was 59% higher, and SUV gradient was 51% higher, with good correlation between the 2 scanners. Lesions less than 1.5 cm showed a greater increase in SUV from GeminiTF to DigitalTF than those lesions 1.5 cm or greater. In 5 of 21 patients, DigitalTF showed an additional 8 suggestive lesions that were not seen using GeminiTF. In the 15 restaging patients, the true-negative rate was 100% and true-positive rate was 78% for both scanners. In the 5 patients for initial staging, DigitalTF led to upstaging in 2 patients and showed the same staging in the other 3 patients, compared with GeminiTF. Conclusion: DigitalTF provides better image quality, diagnostic confidence, and accuracy than GeminiTF. DigitalTF may be the most beneficial in detecting small tumor lesions and disease staging.

A nonlinear spatially variant object-dependent system model for prediction of partial volume effects and scatter in PET

Accurate quantitation of small lesions with positron emission tomography (PET) requires correction for the partial volume effect. Traditional methods that use Gaussian models of the PET system were found to be insufficient. A new approach that models the non-Gaussian object-dependent scatter was developed. The model consists of eight simple functions with a total of 24 parameters. Images of line and disk sources in circular and elliptical cylinders, and an anthropomorphic chest phantom were used to determine the parameter values. Empirical rules to determine these parameter values for various objects based on those for a reference object, a 21.5-cm circular cylinder, were also proposed. For seven spheroids and a 3.4-cm cylinder, pixel values predicted by the model were compared with the measured values. The model-to-measurement-ratio was 1.03/spl plusmn/0.07 near the center of the spheroids and 0.99/spl plusmn/0.03 near the center of the 3.4-cm cylinder. In comparison, the standard single Gaussian model had corresponding ratios of 1.27/spl plusmn/0.09 and 1.24/spl plusmn/0.03, respectively, and the corresponding ratios for a double Gaussian model were 1.13/spl plusmn/0.09 and 1.05/spl plusmn/0.01. Scatter fraction (28.5%) for a line source in the 21.5-cm cylinder was correctly estimated by our model. Because of scatter. The authors found that errors in the measurement of activity in spheroids with diameters from 0.6 to 3.4 cm were more significant than previously appreciated.