Search

Purpose and Methods: Regional overexpression of the multidrug transporter P-glycoprotein (P-gp) in epileptic brain tissue may lower target site concentrations of antiepileptic drugs and thus contribute to pharmacoresistance in epilepsy. We used the P-gp substrate R-[11C]verapamil and positron emission tomography (PET) to test for differences in P-gp activity between epileptogenic and nonepileptogenic brain regions of patients with drug-resistant unilateral temporal lobe epilepsy (n = 7). We compared R-[11C]verapamil kinetics in homologous brain volumes of interest (VOIs) located ipsilateral and contralateral to the seizure focus. Results: Among different VOIs, radioactivity was highest in the choroid plexus. The hippocampal VOI could not be used for data analysis because it was contaminated by spill-in of radioactivity from the adjacent choroid plexus. In several other temporal lobe regions that are known to be involved in seizure generation and propagation ipsilateral influx rate constants K1 and efflux rate constants k2 of R-[11C]verapamil were descriptively increased as compared to the contralateral side. Parameter asymmetries were most prominent in parahippocampal and ambient gyrus ( K1, range: −3.8% to +22.3%; k2, range: −2.3% to +43.9%), amygdala ( K1, range: −20.6% to +31.3%; k2, range: −18.0% to +38.9%), medial anterior temporal lobe ( K1, range: −8.3% to +14.5%; k2, range: −14.5% to +31.0%) and lateral anterior temporal lobe ( K1, range: −20.7% to +16.8%; k2, range: −24.4% to +22.6%). In contrast to temporal lobe VOIs, asymmetries were minimal in a region presumably not involved in epileptogenesis located outside the temporal lobe (superior parietal gyrus, K1, range: −3.7% to +4.5%; k2, range: −4.2% to +5.8%). In 5 of 7 patients, ipsilateral efflux ( k2) increases were more pronounced than ipsilateral influx ( K1) increases, which resulted in ipsilateral reductions (10%–26%) of R-[11C]verapamil distribution volumes (DV). However, for none of the examined brain regions, any of the differences in K1, k2 and DV between the epileptogenic and the nonepileptogenic hemisphere reached statistical significance (p > 0.05, Wilcoxon matched pairs test). Conclusions: Even though we failed to detect statistically significant differences in R-[11C]verapamil model parameters between epileptogenic and nonepileptogenic brain regions, it cannot be excluded from our pilot data in a small sample size of patients that regionally enhanced P-gp activity might contribute to drug resistance in some patients with temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

The article to which this erratum refers was published in Hum Brain Mapp 2008, DOI: . © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Introduction Inhibition of the multidrug efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier (BBB) is considered a promising strategy in order to increase intracerebral penetration of therapeutics, such as antiepileptic and anticancer drugs. The aim of this study was to evaluate the usefulness of (R)-[11C]verapamil (VPM) and small-animal positron emission tomography (µPET) to measure P-gp inhibition at the BBB following administration of the third-generation P-gp inhibitor tariquidar (TQD, Xenova, UK). Methods Five Wistar Unilever rats underwent paired VPM µPET scans, one baseline scan followed by i.v. administration of TQD (15 mg/kg) and a second PET scan at 2 hour after TQD administration. Arterial blood sampling was performed along with analysis of metabolism and plasma protein binding of VPM. Results Following TQD administration, the brain-to-plasma ratio of radioactivity was increased by a factor of 11-16 as compared to baseline scans, whereas VPM metabolism and plasma protein binding were left unaffected. Conclusion Our pilot data suggest that VPM PET is a sensitive tool to quantitatively visualize P-gp inhibition at the animal and human BBB. [ABSTRACT FROM AUTHOR]

Introduction (R)-[11C]Verapamil (VPM) is a new positron emission tomography (PET) tracer to measure P-glycoprotein (Pgp)-mediated transport at the blood-brain barrier (BBB). Owing to the lack of a suitable reference region in brain that is devoid of P-gp, a metabolite-corrected arterial input function is required for quantitative analysis of VPM PET data [1]. The aim of this study was to compare metabolism of VPM in epilepsy patients and healthy volunteers. Methods Selected arterial blood samples from 9 patients, who underwent VPM PET, were analyzed for radio-labeled metabolites by a previously described combined solid-phase extraction/HPLC assay [2]. Results VPM metabolism was significantly faster in patients as compared to healthy volunteers [1] (unchanged VPM at 60 min after injection: 26.1 ± 6.4 vs. 49.0 ± 13.4%, p < 0.05, t-test). Conclusion Faster metabolism of VPM in epilepsy patients may be caused by CyP450 enzyme induction by antiepileptic drugs. Based on these data caution is warranted when using an averaged arterial input function derived from healthy volunteers for the analysis of patient data. As radio-labeled metabolites of VPM are known to cross the BBB [1], different kinetic modeling parameters obtained in patients and healthy volunteers might be at least partly attributed to different rates of tracer metabolism rather than to differences in cerebral P-gp activity. [ABSTRACT FROM AUTHOR]

Introduction Tariquidar (TQD, Xenova, UK) is a third-generation inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) with potential applications in neurology and oncology in order to increase drug exposure of tissues targeted for treatment. We used small-animal positron emission tomography (µPET) with the P-gp substrate (R)-[11C]verapamil (VPM) in order to measure in vivo the degree of P-gp inhibition at the rat blood-brain barrier (BBB) after administration of different doses of TQD. Methods Wistar Unilever rats received intravenous doses of 0, 1, 3, 5, 7.5 and 15 mg/kg of TQD followed by a 1-hour VPM µPET scan recorded at 2 hours after TQD administration. Brain-to-plasma radioactivity ratios were fitted to a sigmoidal dose-response curve. Results TQD inhibited P-gp-mediated efflux of VPM across the BBB with an apparent half-maximum effective dose (ED50) of 6.6 mg/kg (95% confidence interval: 4.9-8.2 mg/kg) which was in good agreement with previous data reported in mice for another P-gp substrate (loperamide, ED50: 5.7 mg/kg) [1]. Brain-to-plasma radioactivity ratios after 0 and 15 mg/kg of TQD were 0.23 and 3.15, respectively. Conclusion Our data suggest that TQD is a potent inhibitor of P-gp at the rat BBB. Moreover, VPM PET appears to be a useful tool for in vivo dose finding of novel P-gp inhibitors in animals and humans. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the possible changes in CD4+ and CD8+ T-cell cytokine production patterns in Hashimoto's thyroiditis (HT) with elevated calcitonin (CT). Fourteen consecutive patients with verified HT were included in the present study. Patients were divided into two groups. Group I: 7 HT patients with elevated CT levels (>10 pg/ml); Group II: 7 HT patients with CT levels <10 pg/ml). All patients underwent intracellular cytokine detection in CD4+ and CD8+ T-cells of peripheral blood mononuclear cells (PBMC) by flow cytometry. Patients with elevated CT levels (group I) had significantly higher percentages of CD8+ cells producing IFN-gamma compared to healthy donors. A detailed analysis of cytokine production patterns revealed that this was accompanied by an increased frequency of single IFN-gamma positive cells, i.e., cells not expressing most of the other cytokines tested. Similarly, patients in group I also showed higher percentages of CD8+ TNF-alpha positive cells than healthy donors. In this case, cells co-expressing TNF-alpha and IFN-gamma were found at significantly higher frequencies. No increase in Th1 type cytokines, such as IFN-gamma or TNF-alpha, was detectable in CD4+ T-cells. In contrast, CD4+ T-cells from group I patients showed significantly higher percentages of cells producing Th2 cytokines, such as IL-4 or IL-13. The lack of increased Th1 cytokine production accompanied by an increased Th2 cytokine production seems to be a special feature of HT patients with elevated CT levels that may reflect a pathogenetic mechanism for tumor initiation.

The measurement of basal serum calcitonin (CT) in patients with evidence of Hashimoto's thyroiditis (HT) has been proposed in a recent study demonstrating an increased prevalence of elevated basal and stimulated CT. The aim of this study was to evaluate the frequency and relevance of elevated CT levels in HT. The basal sera CT were measured in 568 consecutive HT patients using a chemiluminescent immuno-assay. Whenever the serum CT was > 10 pg/ml, a pentagastrin (PG) stimulation test was performed. Two patients with abnormal/pathological PG tests were identified. Total thyroidectomy and lymph node dissection revealed for the first patient medullary thyroid carcinoma (MTC) and for the second patient C cell hyperplasia (CCH), together with papillary thyroid carcinoma. Our data showed a low prevalence of MTC and its premalignant condition CCH in HT patients; nevertheless, the patient with MTC presented lymph node metastasis. The fact that both cases presented without evidence of nodular thyroid disease highlights the persistent diagnostic dilemma of CT screening programs.

Unlabelled: The purpose of this study was to evaluate myocardial electrocardiography (ECG)-gated 13N-ammonia (13N-NH3) PET for the assessment of cardiac end-diastolic volume (EDV), cardiac end-systolic volume (ESV), left ventricular (LV) myocardial mass (LVMM), and LV ejection fraction (LVEF) with gated 18F-FDG PET as a reference method., Methods: ECG-gated 13N-NH3 and 18F-FDG scans were performed for 27 patients (23 men and 4 women; mean+/-SD age, 55+/-15 y) for the evaluation of myocardial perfusion and viability. For both 13N-NH3 and 18F-FDG studies, a model-based image analysis tool was used to estimate endocardial and epicardial borders of the left ventricle on a set of short-axis images and to calculate values for EDV, ESV, LVEF, and LVMM., Results: The LV volumes determined by 13N-NH3 and 18F-FDG were 108+/-60 mL and 106+/-63 mL for ESV and 175+/-71 mL and 169+/-73 mL for EDV, respectively. The LVEFs determined by 13N-NH3 and 18F-FDG were 42%+/-13% and 41%+/-13%, respectively. The LVMMs determined by 13N-NH3 and 18F-FDG were 179+/-40 g and 183+/-43 g, respectively. All P values were not significant, as determined by paired t tests. A significant correlation was observed between 13N-NH3 imaging and 18F-FDG imaging for the calculation of ESV (r=0.97, SEE=14.1, P<0.0001), EDV (r=0.98, SEE=15.4, P<0.0001), LVEF (r=0.9, SEE=5.6, P<0.0001), and LVMM (r=0.93, SEE=15.5, P<0.0001)., Conclusion: Model-based analysis of ECG-gated 13N-NH3 PET images is accurate in determining LV volumes, LVMM, and LVEF. Therefore, ECG-gated 13N-NH3 can be used for the simultaneous assessment of myocardial perfusion, LV geometry, and contractile function.

Unlabelled: The aim of this study was to compare nonfluoroscopic electroanatomic mapping (NOGA), SPECT perfusion imaging, and PET metabolic imaging for assessment of myocardial viability. In particular, we sought to elucidate differences of electromechanical properties between the perfusion/metabolism mismatch as an indicator of a potentially reversible ischemic injury and the perfusion/metabolism match indicating irreversibly damaged myocardial tissue., Methods: Twenty-one patients with coronary artery disease underwent NOGA mapping of endocardial unipolar voltage, cardiac 18F-FDG PET of glucose utilization, and resting 201Tl SPECT of myocardial perfusion., Results: Electrical activity was 10.8 +/- 4.6 mV (mean +/- SD) in normal myocardium and was unchanged in hypoperfused segments with maintained glucose metabolism (perfusion/metabolism mismatch), 9.3 +/- 3.4 mV (P = not significant). In contrast, hypoperfused segments with a perfusion/metabolism match and nonviable segments showed significantly lower voltage (6.9 +/- 3.1 mV, P < 0.0001 and 4.1 +/- 1.1 mV, P < 0.0001 vs. normal). In hypoperfused segments, metabolic activity was more closely related to endocardial voltage than was myocardial perfusion (201Tl vs. voltage: r = 0.38, SEE = 3.2, P < 0.001; 18F-FDG PET vs. voltage: r = 0.6, SEE = 2.8, P < 0.0001)., Conclusion: In hypoperfused myocardium, electrical activity by NOGA mapping is more closely related to PET metabolic activity than to SPECT myocardial perfusion. As NOGA mapping does not differentiate hypoperfused myocardium with enhanced glucose utilization from normal myocardium, results from NOGA mapping need to be correlated with results from perfusion imaging to identify hypoperfused, yet viable, myocardium and to stratify patients for revascularization procedures.

Unlabelled: Nuclear medicine plays an important role in the imaging of neuroendocrine tumors (NETs). Somatostatin receptor scintigraphy (SRS) with (111)In-labeled somatostatin receptor analogs is a standard procedure for the detection and staging of NET. Based on the ability of NETs to store biogenic amines, this study evaluated whether 6-(18)F-fluoro-L-DOPA ((18)F-FDOPA) is a suitable PET tracer for NETs., Methods: Twenty-three patients with histologically verified NETs in advanced stages were consecutively enrolled in the study. All patients underwent PET with (18)F-FDOPA, CT, and SRS within 6 wk. In patients with discrepancies between nuclear medicine and radiologic methods, follow-up investigations were performed by CT, MRI, and ultrasound. (18)F-FDOPA PET with attenuation correction was done 30 and 90 min after injection from the neck to the upper legs. SRS was performed with (111)In-DOTA-D-Phe(1)-Tyr(3)-octreotide at 6 and 24 h. All images were read without knowledge of the results of the other modalities. In every patient, the following regions were evaluated separately: bones, mediastinum, lungs, liver, pancreas, and others, including the abdominal and supraclavicular lymph nodes, spleen, and soft- tissue lesions. The findings were confirmed by clinical examination. The nuclear medicine methods were compared against morphologic imaging, which was considered as gold standard., Results: The most frequently involved organs or regions were the liver (prevalence, 70%) and bone (52%), followed by mediastinal foci (31%), the lungs (22%), and the pancreas (13%). Fifty-two percent of patients had various lymphatic lesions. (18)F-FDOPA was most accurate in detecting skeletal lesions (sensitivity, 100%; specificity, 91%) but was insufficient in the lung (sensitivity, 20%; specificity, 94%); SRS yielded its best results in the liver (sensitivity, 75%; specificity, 100%); however, it was less accurate than PET in all organs. In about 40%, initial CT failed to detect bone metastases shown by PET that were later on verified by radiologic follow-up., Conclusion: (18)F-FDOPA PET performs better than SRS in visualizing NETs and may even do better than CT for bone lesions. SRS is essential to establish the usefulness of therapy with somatostatin analogs, yet is less accurate than (18)F-FDOPA PET for staging.

Unlabelled: This study presents and evaluates a model-based image analysis method to calculate from gated cardiac (18)F-FDG PET images diastolic and systolic volumes, ejection fraction, and myocardial mass of the left ventricle. The accuracy of these estimates was delineated using measurements obtained by MRI, which was considered the reference standard because of its high spatial resolution., Methods: Twenty patients (18 men, 2 women; mean age +/- SD, 59 +/- 12 y) underwent electrocardiography-gated cardiac PET and MRI to acquire a set of systolic and diastolic short-axis images covering the heart from apex to base. For PET images, left ventricular radius and wall thickness were estimated by model-based nonlinear regression analysis applied to the observed tracer concentration along radial rays. Endocardial and epicardial contours were derived from these estimates, and left ventricular volumes, ejection fraction, and myocardial mass were calculated. For MR images, an expert manually drew contours., Results: Left ventricular volumes by PET and MRI were 101 +/- 60 mL and 112 +/- 93 mL, respectively, for end-systolic volume and 170 +/- 68 mL and 189 +/- 99 mL, respectively, for end-diastolic volume. Ejection fraction was 44% +/- 13% by PET and 46% +/- 18% by MRI. The left ventricular mass by PET and MRI was 196 +/- 44 g and 200 +/- 46 g, respectively. PET and MRI measurements were not statistically significant. A significant correlation was observed between PET and MRI for calculation of end-systolic volumes (r = 0.93, SEE = 23.4, P < 0.0001), end-diastolic volumes (r = 0.92, SEE = 26.7, P < 0.0001), ejection fraction (r = 0.85, SEE = 7.4, P < 0.0001), and left ventricular mass (r = 0.75, SEE = 29.6, P < 0.001)., Conclusion: Model-based analysis of gated cardiac PET images permits an accurate assessment of left ventricular volumes, ejection fraction, and myocardial mass. Cardiac PET may thus offer a near-simultaneous assessment of myocardial perfusion, metabolism, and contractile function.