Nagara Tamaki

Reduction of coronary flow reserve in areas with and without ischemia on stress perfusion imaging in patients with coronary artery disease: a study using oxygen 15–labeled water PET

BackgroundMyocardial perfusion single photon emission computed tomography (SPECT) occasionally fails to detect coronary stenosis in patients with coronary artery disease (CAD). We evaluated coronary flow reserve (CFR) using oxygen 15-labeled water in areas with and without ischemia on technetium 99m tetrofosmin stress perfusion SPECT in patients with angiographically documented CAD.Methods and ResultsTwenty-seven patients with CAD and eleven age-matched normal subjects were studied. Baseline myocardial blood flow (MBF) and MBF during hyperemia induced by intravenous adenosine triphosphate infusion (0.16 mg · kg-1 · min-1) were determined with the use of O-15-labeled water positron emission tomography, and the CFR was calculated. Tc-99m tetrofosmin stress/rest SPECT was performed for comparison. On the basis of the results of coronary angiography and SPECT, coronary segments were divided into 3 types: segments with coronary stenosis and a perfusion abnormality on stress SPECT imaging (group A, n = 16), segments with coronary stenosis without a perfusion abnormality (group B, n = 42), and remote segments with no coronary stenosis or perfusion abnormality (group C, n = 18). Baseline MBF values were similar among the 3 groups. CFR in group A was lower (1.82 ± 0.54) than in group B (2.22 ± 0.87, P < .05), in group C (2.92 ± 1.21, P < .01), and in normal segments (3.86 ± 1.24, P < .001). CFR in group B was lower than in group C (P < .02) and in normal segments (P < .001). CFR in group C was lower than in normal segments (P < .02).ConclusionsAreas with a perfusion abnormality on stress SPECT had reduced CFR. In the areas without a perfusion abnormality and with coronary stenosis, lowering of CFR was intermediate between the areas with a perfusion abnormality and remote segments. Moreover, CFR was slightly, but significantly, lower in remote segments in patients with CAD compared with normal segments.

Performance characterization of the Inveon preclinical small-animal PET/SPECT/CT system for multimodality imaging

PurposeWe investigated the performance of the Inveon small-animal PET/SPECT/CT system and compared the imaging capabilities of the SPECT and PET components.MethodsFor SPECT, the energy resolution, tomographic spatial resolution and system sensitivity were evaluated with a 99mTc solution using a single pinhole collimator. For PET, the spatial resolution, absolute sensitivity, scatter fraction and peak noise equivalent count were evaluated. Phantoms and a normal rat were scanned to compare the imaging capabilities of SPECT and PET.ResultsThe SPECT spatial resolution was 0.84xa0mm full-width at half-maximum (FWHM) at a radius of rotation of 25xa0mm using a 0.5-mm pinhole aperture collimator, while the PET spatial resolution was 1.63xa0mm FWHM at the centre. The SPECT system sensitivity at a radius of rotation of 25xa0mm was 35.3xa0cps/MBq (4u2009×u200910−3%) using the 0.5-mm pinhole aperture, while the PET absolute sensitivity was 3.2% for 350–650xa0keV and 3.432xa0ns. Accordingly, the volume sensitivity of PET was three orders of magnitude higher than that of SPECT.ConclusionThis integrated PET/SPECT/CT system showed high performance with excellent spatial resolution for SPECT and sensitivity for PET. Based on the tracer availability and system performance, SPECT and PET have complementary roles in multimodality small-animal imaging.

Repeatability of Rest and Hyperemic Myocardial Blood Flow Measurements with 82Rb Dynamic PET

The repeatability of rest and hyperemic myocardial blood flow (MBF) measurements using 82Rb PET has not been evaluated. The aim of this study was to investigate the short-term repeatability of such measurements. Methods: Fifteen healthy volunteers underwent rest and pharmacologic stress 82Rb PET, repeated 60 min apart. Results: There was no significant difference in repeated rest MBF (0.77 ± 0.25 vs. 0.82 ± 0.25 mL/min/g, P = 0.31; mean difference, 6.18% ± 12.22%) or repeated hyperemic MBF (3.35 ± 1.37 vs. 3.39 ± 1.37 mL/min/g, P = 0.81; mean difference, 1.17% ± 13.64%). The repeatability coefficients were 0.19 mL/min/g for rest MBF and 0.92 mL/min/g for hyperemia. Conclusion: MBF using 82Rb is highly reproducible using a same-day short-term repeatability protocol. Serial MBF measurements with 82Rb PET should have the ability to quantify the acute effects of therapeutic interventions on MBF.

All-trans Retinoic Acid Enhances Murine Dendritic Cell Migration to Draining Lymph Nodes via the Balance of Matrix Metalloproteinases and Their Inhibitors

Cancers escape immune surveillance through the manipulation of the host’s immune system. Sequestration of dendritic cells (DCs) within tumor tissues and the subsequent inhibition of their migration is one of the several mechanisms by which tumors induce immunosuppression. In view of recent findings depicting the improvement of tumor immune responses in cancer patients following all-trans retinoic acid (ATRA) treatment, we sought to identify the effects of ATRA on DC mobility in the context of tumor immunotherapy. Our results demonstrate that ATRA, added to differentiating murine bone marrow progenitor cells, enhances the invasive capacity of the resulting DCs. Immature DCs injected intratumorally in mice show increased accumulation in draining lymph nodes, but not in nondraining lymph nodes and spleens, when differentiated in the presence of ATRA. The in vitro migration of mature DCs through the basement membrane matrix toward the lymphoid chemokines CCL19 and CCL21 is enhanced in these cells, albeit not in the presence of a matrix metalloproteinase (MMP) inhibitor. An increase in MMP production with a simultaneous decrease in the production of their inhibitors (tissue inhibitors of matrix metalloproteinase or TIMPs) is provoked by ATRA. This affects the MMP/TIMP balance in DCs, in particular that of MMP-9 and TIMP-1, favoring protease activity and thus allowing for enhanced DC mobilization. In conclusion, this study demonstrates that ATRA is capable of improving DC trafficking in a tumor milieu and, in view of the encouraging results obtained in the clinic, further supports the notion that ATRA might be a valuable chemical adjuvant to current immunotherapeutic strategies for cancer.

Myocardial beta-Adrenergic Receptor Density Assessed by 11C-CGP12177 PET Predicts Improvement of Cardiac Function After Carvedilol Treatment in Patients with Idiopathic Dilated Cardiomyopathy

We evaluated whether myocardial β-adrenergic receptor (β-AR) density, as determined by 11C-CGP12177 PET, could predict improvement of cardiac function by β-blocker carvedilol treatment in patients with idiopathic dilated cardiomyopathy (IDC). Methods: Ten patients with IDC (left ventricular ejection fraction [LVEF] < 45%) were studied. Myocardial β-AR density was estimated using 11C-CGP12177 PET before treatment with carvedilol. Changes of LVEF in response to dobutamine infusion (ΔLVEF-dobutamine) were also measured by echocardiography. Changes of LVEF (ΔLVEF-carvedilol) were evaluated after 20 mo of carvedilol treatment. Results: Baseline myocardial β-AR density significantly correlated with ΔLVEF-carvedilol (r = −0.88, P < 0.001). In contrast, ΔLVEF-dobutamine did not correlate with ΔLVEF-carvedilol (P = 0.65). Myocardial β-AR density was the significant multivariate independent predictor of ΔLVEF-carvedilol (β = −0.88, P < 0.001) among univariate predictors, including functional class (r = 0.76, P < 0.05), plasma norepinephrine (r = 0.85, P < 0.01), LVEF (r = −0.64, P < 0.05), and age as confounding factors. Furthermore, myocardial β-AR density was significantly correlated with plasma norepinephrine (r = −0.79, P < 0.01) and LVEF (r = 0.70, P < 0.05). Conclusion: Myocardial β-AR density is more tightly related to improvement of LVEF-carvedilol than is cardiac contractile reserve in patients with IDC. Patients with decreased myocardial β-AR have higher resting adrenergic drive, as reflected by plasma norepinephrine, and may receive greater benefit from being treated by antiadrenergic drugs.

Usefulness of 11C-Methionine for Differentiating Tumors from Granulomas in Experimental Rat Models: A Comparison with 18F-FDG and 18F-FLT

Many clinical PET studies have shown that increased 18F-FDG uptake is not specific to malignant tumors. 18F-FDG is also taken up in inflammatory lesions, particularly in granulomatous lesions such as sarcoidosis or active inflammatory processes after chemoradiotherapy, making it difficult to differentiate malignant tumors from benign lesions, and is the main source of false-positive 18F-FDG PET findings in oncology. These problems may be overcome by multitracer studies using 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) or l-11C-methionine. However, 18F-FLT or 11C-methionine uptake in granulomatous lesions remains unclarified. In this study, the potentials of 18F-FLT and 11C-methionine in differentiating malignant tumors from granulomas were compared with 18F-FDG using experimental rat models. Methods: Dual-tracer tissue distribution studies using 18F-FDG and 3H-FLT (groups I and III) or 18F-FDG and 14C-methionine (groups II and IV) were performed on rats bearing both granulomas (Mycobacterium bovis bacillus Calmette-Guérin [BCG]–induced) and hepatomas (KDH-8–induced) (groups I and II) or on rats bearing both turpentine oil–induced inflammation and hepatomas (groups III and IV). One hour after the injection of a mixture of 18F-FDG and 3H-FLT or of 18F-FDG and 14C-methionine, tissues were excised to determine the radioactivities of 18F-FDG, 3H-FLT, and 14C-methionine (differential uptake ratio). Results: Mature epithelioid cell granuloma formation and massive lymphocyte infiltration were observed in the granuloma tissue induced by BCG, histologically similar to sarcoidosis. The granulomas showed high 18F-FDG uptake comparable to that in the hepatomas (group I, 8.18 ± 2.40 vs. 9.13 ± 1.52, P = NS; group II, 8.43 ± 1.45 vs. 8.91 ± 2.32, P = NS). 14C-Methionine uptake in the granuloma was significantly lower than that in the hepatoma (1.31 ± 0.22 vs. 2.47 ± 0.60, P < 0.01), whereas 3H-FLT uptake in the granuloma was comparable to that in the hepatoma (1.98 ± 0.70 vs. 2.30 ± 0.67, P = NS). Mean uptake of 18F-FDG, 3H-FLT, and 14C-methionine was markedly lower in the turpentine oil–induced inflammation than in the tumor. Conclusion: 14C-Methionine uptake was significantly lower in the granuloma than in the tumor, whereas 18F-FDG and 3H-FLT were not able to differentiate granulomas from tumors. These results suggest that 14C-methionine has the potential to accurately differentiate malignant tumors from benign lesions, particularly granulomatous lesions, providing a biologic basis for clinical PET studies.

Evaluating performance of a pixel array semiconductor SPECT system for small animal imaging

ObjectivesSmall animal imaging has recently been focused on basic nuclear medicine. We have designed and built a small animal SPECT imaging system using a semiconductor camera and a newly designed collimator. We assess the performance of this system for small object imaging.MethodsWe employed an MGC1500 (Acrorad Co.) camera including a CdTe semiconductor. The pixel size was 1.4 mm/pixel. We designed and produced a parallel-hole collimator with 20-mm hole length. Our SPECT system consisted of a semiconductor camera with the subject holder set on an electric rotating stage controlled by a computer. We compared this system with a conventional small animal SPECT system comprising a SPECT-2000H scanner with four Anger type cameras and pinhole collimators. The count rate linearity for estimation of the scatter was evaluated for a pie-chart phantom containing different concentrations of99mTc. We measured the FWHM of the99mTc SPECT line source along with scatter. The system volume sensitivity was examined using a flood source phantom which was 35 mm long with a 32-mm inside diameter. Additionally, anin vivo myocardial perfusion SPECT study was performed with a rat.ResultsWith regards to energy resolution, the semiconductor camera (5.6%) was superior to the conventional Anger type camera (9.8%). In the count rate linearity evaluation, the regression lines of the SPECT values werey = 0.0 9x+ 0.031 (r2 = 0.999) for our system andy = 0.018* + 0.060 (r2 = 0.997) for the conventional system. Thus, the scatter count using the semiconductor camera was less than that using the conventional camera. FWHMs of our system and the conventional system were 2.9 ± 0.1 and 2.0 ± 0.1 mm, respectively. Moreover, the system volume sensitivity of our system [0.51 kcps/(MBq/ ml)/cm] was superior to that of the conventional system [0.44 kcps/(MBq/m/)/cm]. Our system provided clear images of the rat myocardium, sufficient for practical use in small animal imaging.ConclusionsOur SPECT system, utilizing a semiconductor camera, permits high quantitative analysis by virtue of its low scatter radiation and high sensitivity. Therefore, this system may contribute to molecular imaging of small animals and basic medical research. Key words: semiconductor detectors, small animal imaging, single photon emission computed tomography

A New PET Scanner with Semiconductor Detectors Enables Better Identification of Intratumoral Inhomogeneity

An autoradiography method revealed intratumoral inhomogeneity in various solid tumors. It is becoming increasingly important to estimate intratumoral inhomogeneity. However, with low spatial resolution and high scatter noise, it is difficult to detect intratumoral inhomogeneity in clinical settings. We developed a new PET system with CdTe semiconductor detectors to provide images with high spatial resolution and low scatter noise. Both phantom images and patients images were analyzed to evaluate intratumoral inhomogeneity. Methods: This study was performed with a cold spot phantom that had 6-mm-diameter cold sphenoid defects, a dual-cylinder phantom with an adjusted concentration of 1:2, and an “H”-shaped hot phantom. These were surrounded with water. Phantom images and 18F-FDG PET images of patients with nasopharyngeal cancer were compared with conventional bismuth germanate PET images. Profile curves for the phantoms were measured as peak-to-valley ratios to define contrast. Intratumoral inhomogeneity and tumor edge sharpness were evaluated on the images of the patients. Results: The contrast obtained with the semiconductor PET scanner (1.53) was 28% higher than that obtained with the conventional scanner (1.20) for the 6-mm-diameter cold sphenoid phantom. The contrast obtained with the semiconductor PET scanner (1.43) was 27% higher than that obtained with the conventional scanner (1.13) for the dual-cylinder phantom. Similarly, the 2-mm cold region between 1-mm hot rods was identified only by the new PET scanner and not by the conventional scanner. The new PET scanner identified intratumoral inhomogeneity in more detail than the conventional scanner in 6 of 10 patients. The tumor edge was sharper on the images obtained with the new PET scanner than on those obtained with the conventional scanner. Conclusion: These phantom and clinical studies suggested that this new PET scanner has the potential for better identification of intratumoral inhomogeneity, probably because of its high spatial resolution and low scatter noise.

Semiquantitative analysis of C-11 methionine PET may distinguish brain tumor recurrence from radiation necrosis even in small lesions

Objective11C-Methionine positron emission tomography (MET-PET) has been used to distinguish brain tumor recurrence from radiation necrosis. Because the spatial resolution of conventional PET scanners is low, partial volume effect (PVE) may decrease the detectability of small tumor recurrence. The aim of this study is to investigate the diagnostic value of MET-PET upon semiquantitative analyses in particular PVE-affected small lesions.MethodsFirst, we performed a phantom experiment to investigate what size lesion is affected by PVE. This study included 29 patients (33 lesions) suspected of recurrent brain tumors by magnetic resonance imaging (MRI) after radiation therapy. All of them received MET-PET. Semiquantitative analysis was performed using maximum standardized uptake value (SUVmax) and lesion-versus-normal ratio (L/N ratio). ROC analysis was also assessed about the diagnostic value of MET-PET.ResultsFrom the result of the phantom experiment, lesions smaller than 20xa0mm in brain mode or smaller than 30xa0mm in whole-body mode were defined as PVE-affected lesions. Histological analysis or clinical follow-up confirmed the diagnosis of tumor recurrence in 22 lesions, and radiation necrosis in 11 lesions. L/N ratios of recurrence and necrosis for overall lesions were 1.98xa0±xa00.62 and 1.27xa0±xa00.28, respectively (pxa0<xa00.01). In the PVE-affected lesions, L/N ratio for recurrence (1.72xa0±xa00.44) was also significantly higher than that for necrosis (1.20xa0±xa00.11) (pxa0<xa00.01). On the ROC analysis for the PVE-affected lesions, the area under the curve for L/N ratio (0.897) was significantly higher than that for SUVmax (0.718) (pxa0<xa00.05). These areas under the curve were almost equal to that of overall lesions for L/N ratio (0.886) and for SUVmax (0.738).ConclusionsSemiquantitative analysis of MET provided high diagnostic value even for PVE-affected small lesions. MET-PET enables early diagnosis of recurrence of brain tumor in the follow-up after the radiation therapy.

Quantification of regional myocardial blood flow estimation with three-dimensional dynamic rubidium-82 PET and modified spillover correction model.

PurposeMyocardial blood flow (MBF) estimation with 82Rubidium (82Rb) positron emission tomography (PET) is technically difficult because of the high spillover between regions of interest, especially due to the long positron range. We sought to develop a new algorithm to reduce the spillover in image-derived blood activity curves, using non-uniform weighted least-squares fitting.MethodsFourteen volunteers underwent imaging with both 3-dimensional (3D) 82Rb and 15O-water PET at rest and during pharmacological stress. Whole left ventricular (LV) 82Rb MBF was estimated using a one-compartment model, including a myocardium-to-blood spillover correction to estimate the corresponding blood input function Ca(t)whole. Regional K1 values were calculated using this uniform global input function, which simplifies equations and enables robust estimation of MBF. To assess the robustness of the modified algorithm, inter-operator repeatability of 3D 82Rb MBF was compared with a previously established method.ResultsWhole LV correlation of 82Rb MBF with 15O-water MBF was better (Pxa0<xa0.01) with the modified spillover correction method (rxa0=xa00.92 vs rxa0=xa00.60). The modified method also yielded significantly improved inter-operator repeatability of regional MBF quantification (rxa0=xa00.89) versus the established method (rxa0=xa00.82) (Pxa0<xa0.01).ConclusionA uniform global input function can suppress LV spillover into the image-derived blood input function, resulting in improved precision for MBF quantification with 3D 82Rb PET.