Net Influx Rate Research Articles

Tumor-to-Blood Ratio for Assessment of Somatostatin Receptor Density in Neuroendocrine Tumors Using 68Ga-DOTATOC and 68Ga-DOTATATE.

PET/CT with 68Ga-DOTA-somatostatin analogs has been tested for therapy monitoring in patients with neuroendocrine tumors (NETs). However, SUVs in tumors do not correlate with the net influx rate (Ki), as a representation of the somatostatin receptor expression. In this study, tumor-to-blood ratio (TBR) was evaluated as an alternative tool for semiquantitative assessment of 68Ga-DOTATOC and 68Ga-DOTATATE tumor uptake and as a therapy monitoring tool for patients with NETs. Methods: Twenty-two NET patients underwent a 45-min dynamic PET/CT scan after injection of 68Ga-DOTATOC or 68Ga-DOTATATE. Ki was determined using the Patlak method, and TBR was calculated for the 40- to 45-min interval. Results: A linear relation was found between Ki and TBR, with a square of Pearson correlation of 0.98 and 0.93 for 68Ga-DOTATOC and 68Ga-DOTATATE, respectively. Conclusion: A high correlation was found between Ki and TBR. Hence, TBR reflects somatostatin receptor density more accurately than SUV and is suggested as the preferred metric for semiquantitative assessment of 68Ga-DOTATOC and 68Ga-DOTATATE tumor uptake.

Attenuation of epileptogenesis by 2-deoxy-d-glucose is accompanied by increased cerebral glucose supply, microglial activation and reduced astrocytosis

RationaleNeuronal excitability and brain energy homeostasis are strongly interconnected and evidence suggests that both become altered during epileptogenesis. Pharmacologic modulation of cerebral glucose metabolism might therefore exert anti-epileptogenic effects. Here we provide mechanistic insights into effects of the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) on experimental epileptogenesis by longitudinal 2-deoxy-2[18F]fluoro-d-glucose positron emission tomography ([18F]FDG PET) and histology. MethodsTo imitate epileptogenesis, 6 Hz-corneal kindling was performed in male NMRI mice by twice daily electrical stimulation for 21 days. Kindling groups were treated i.p. 1 min after each stimulation with either 250 mg/kg 2-DG (CoKi_2-DG) or saline (CoKi_vehicle). A separate group of unstimulated mice was treated with 2-DG (2-DG_only). Dynamic 60-min [18F]FDG PET/CT scans were acquired at baseline and interictally on days 10 and 17 of kindling. [18F]FDG uptake (%injected dose/cc) was quantified in predefined regions of interest (ROI) using a MRI-based brain atlas, and kinetic modelling was performed to evaluate glucose net influx rate Ki and glucose metabolic rate MRGlu. Furthermore, statistical parametric mapping (SPM) analysis was applied on kinetic brain maps. For histological evaluation, brain sections were stained for glucose transporter 1 (GLUT1), astrocytes, microglia, as well as dying neurons. ResultsPost-stimulation 2-DG treatment attenuated early kindling progression, indicated by a reduction of fully-kindled mice, and a lower overall percentage of type five seizures. While 2-DG treatment alone led to globally increased Ki and MRGlu values at day 17, kindling progression per se did not influence glucose turnover. Kindling accompanied by 2-DG treatment, however, resulted in regionally elevated [18F]FDG uptake as well as increased Ki at days 10 and 17 compared both to baseline and to the 2-DG_only group. In hippocampus and thalamus, higher MRGlu values were found in the CoKi_2-DG vs. the CoKi_vehicle group at day 17. t maps resulting from SPM analysis generally confirmed the results of the ROI analysis, and additionally revealed increased MRGlu restricted to the ventral hippocampus when comparing the CoKi_2-DG and the 2-DG_only group both at days 10 and, more distinct, day 17. Immunohistochemical staining showed an attenuated kindling-induced regional activation of astrocytes in the CoKi_2-DG group. Interestingly, 2-DG treatment alone (and also in combination with kindling, but not kindling alone) led to increased microglial activation scores, whereas neither staining of GLUT1 nor of dying neurons revealed any differences to untreated controls. ConclusionsPost-stimulation treatment with 2-DG exerts disease-modifying effects in the mouse 6 Hz corneal kindling model. The observed local increase in glucose supply and turnover, the alleviation of astroglial activation and the activation of microglia by 2-DG might contribute separately or in combination to its positive interference with epileptogenesis.

Simplified Methods for Quantification of 18F-DCFPyL Uptake in Patients with Prostate Cancer.

Radiolabeled prostate-specific membrane antigen (PSMA) PET has demonstrated promising results for prostate cancer (PCa) imaging. Quantification of PSMA radiotracer uptake is desired as it enables reliable interpretation of PET images, use of PSMA uptake as an imaging biomarker for tumor characterization, and evaluation of treatment effects. The aim of this study was to perform a full pharmacokinetic analysis of 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL), a second-generation 18F-labeled PSMA ligand. On the basis of the pharmacokinetic analysis (reference method), simplified methods for quantification of 18F-DCFPyL uptake were validated. Methods: Eight patients with metastasized PCa were included. Dynamic PET acquisitions were performed at 0-60 and 90-120 min after injection of a median dose of 313 MBq of 18F-DCFPyL (range, 292-314 MBq). Continuous and manual arterial blood sampling provided calibrated plasma tracer input functions. Time-activity curves were derived for each PCa metastasis, and 18F-DCFPyL kinetics were described using standard plasma input tissue-compartment models. Simplified methods for quantification of 18F-DCFPyL uptake (SUVs; tumor-to-blood ratios [TBRs]) were correlated with kinetic parameter estimates obtained from full pharmacokinetic analysis. Results: In total, 46 metastases were evaluated. A reversible 2-tissue-compartment model was preferred for 18F-DCFPyL kinetics in 59% of the metastases. The observed k4 was small, however, resulting in nearly irreversible kinetics during the course of the PET study. Hence, k4 was fixated (0.015) and net influx rate, Ki, was preferred as the reference kinetic parameter. Whole-blood TBR provided an excellent correlation with Ki from full kinetic analysis (R2 = 0.97). This TBR could be simplified further by replacing the blood samples with an image-based, single measurement of blood activity in the ascending aorta (image-based TBR, R2 = 0.96). SUV correlated poorly with Ki (R2 = 0.47 and R2 = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. Conclusion:18F-DCFPyL kinetics in PCa metastases are best described by a reversible 2-tissue-compartment model. Image-based TBRs were validated as a simplified method to quantify 18F-DCFPyL uptake and might be applied to clinical, whole-body PET scans. SUV does not provide reliable quantification of 18F-DCFPyL uptake.

18F]-sodium fluoride PET-MR imaging reveals bone-cartilage interactions in hip osteoarthritis

18F]-sodium fluoride PET-MR imaging reveals bone-cartilage interactions in hip osteoarthritis

A new methodology to derive 3D kinetic parametric FDG PET images based on a mathematical approach integrating an error model of measurement

BackgroundIn FDG-PET, SUV images are hampered by large potential biases. Our aim was to develop an alternative method (ParaPET) to generate 3D kinetic parametric FDG-PET images easy to perform in clinical oncology.MethodsThe key points of our method are the use of a new error model of PET measurement extracted from a late dynamic PET acquisition of 15 min, centered over the lesion and an image-derived input function (IDIF). The 15-min acquisition is reconstructed to obtain five images of FDG mean activity concentration and images of its variance to model errors of PET measurement. Our approach is carried out on each voxel to derive 3D kinetic parameter images. ParaPET was evaluated and compared to Patlak analysis as a reference. Hunter and Barbolosi methods (Barbolosi-Bl: with blood samples or Barbolosi-Im: with IDIF) were also investigated and compared to Patlak. Our evaluation was carried on Ki index, the net influx rate and its maximum value in the lesion (Ki,max).ResultsThis parameter was obtained from 41 non-small cell lung cancer lesions associated with 4 to 5 blood samples per patient, required for the Patlak analysis. Compare to Patlak, the median relative difference and associated range (median; [min;max]) in Ki,max estimates were not statistically significant (Wilcoxon test) for ParaPET (− 3.0%; [− 31.9%; 47.3%]; p = 0.08) but statistically significant for Barbolosi-Bl (− 8.0%; [− 30.8%; 53.7%]; p = 0.001), Barbolosi-Im (− 7.9%; [− 38.4%; 30.6%]; p = 0.007) or Hunter (32.8%; [− 14.6%; 132.2%]; p < 10− 5). In the Bland-Altman plots, the ratios between the four methods and Patlak are not dependent of the Ki magnitude, except for Hunter. The 95% limits of agreement are comparable for ParaPET (34.7%), Barbolosi-Bl (30.1%) and Barbolosi-Im (30.8%), lower to Hunter (81.1%). In the 25 lesions imaged before and during the radio-chemotherapy, the decrease in the FDG uptake (ΔSUVmax or ΔKi,max) is statistically more important (p < 0.02, Wilcoxon one-tailed test) when estimated from the Ki images than from the SUV images (additional median variation of − 2.3% [− 52.6%; + 19.1%] for ΔKi,max compared to ΔSUVmax).ConclusionNone of the four methodologies is yet ready to replace the Patlak approach, and further improvements are still required. Nevertheless, ParaPET remains a promising approach, offering a non-invasive alternative to methods based on multiple blood samples and only requiring a late PET acquisition. It allows deriving Ki values, highly correlated and presenting the lowest relative bias with Patlak estimates, in comparison to the other methods we evaluated. Moreover, ParaPET gives access to quantitative information at the pixel level, which needs to be evaluated in the perspective of radiomic and tumour response.Trial registrationNCT 02821936; May 2016.

Relative Patlak plot for dynamic PET parametric imaging without the need for early-time input function

The Patlak graphical method is widely used in parametric imaging for modeling irreversible radiotracer kinetics in dynamic PET. The net influx rate of radiotracer can be determined from the slope of the Patlak plot. The implementation of the standard Patlak method requires the knowledge of full-time input function from the injection time until the scan end time, which presents a challenge for use in the clinic. This paper proposes a new relative Patlak plot method that does not require early-time input function and therefore can be more efficient for parametric imaging. Theoretical analysis proves that the effect of early-time input function is a constant scaling factor on the Patlak slope estimation. Thus, the parametric image of the slope of the relative Patlak plot is related to the parametric image of standard Patlak slope by a global scaling factor. This theoretical finding has been further demonstrated by computer simulation and real patient data. The study indicates that parametric imaging of the relative Patlak slope can be used as a substitute of parametric imaging of standard Patlak slope for tasks that do not require absolute quantification, such as lesion detection and tumor volume segmentation.

Role of Various Metabolic Parameters Derived From Baseline 18F-FDG PET/CT as Prognostic Markers in Non-Small Cell Lung Cancer Patients Undergoing Platinum-Based Chemotherapy.

The aim of this study was to prospectively evaluate the role of various quantitative and semiquantitative metabolic parameters derived from dynamic and static baseline F-FDG PET/CT in prediction of overall survival (OS) in non-small cell lung cancer (NSCLC) patients who were planned to undergo platinum-based chemotherapy. Sixty patients (51 male and 9 female patients) with biopsy-proven NSCLC and mean age 59.55 ± 10.06 years who were planned to undergo platinum-based chemotherapy were enrolled in the study. Each patient underwent a baseline regional dynamic and a static whole-body F-FDG PET/CT after injecting 0.21 mCi/kg (5.18-7.77 MBq/kg) of F-FDG intravenously. Two dynamic PET/CT parameters, that is, net influx rate constant and glucose metabolic rate at 30 and 60 minutes, were evaluated. In addition, whole-body PET/CT parameters, that is, SUVmax, average SUV, tumor-to-background ratio, metabolic tumor volume (MTV), total lesion glycolysis (TLG) of the primary tumor, and MTV and TLG of whole-body tumor lesions, were evaluated. Best possible cutoffs for all parameters were calculated using receiver operating characteristic curve analysis. Survival analysis was performed using log-rank test, Kaplan-Meier curves, and Cox proportional hazards model to determine the prognostic markers for OS. The median follow-up period was 4.4 months (range, 8 days to 15.9 months). In univariate analysis, the 4 static whole-body PET/CT parameters, that is, MTV, TLG, and MTV and TLG of whole-body tumor lesions, were found to be significantly associated with OS with cutoff values of 120, 800, 160, and 1350 cm and hazard ratios of 3.64 (P = 0.001), 3.35 (P = 0.002), 2.51 (P = 0.019), and 2.69 (P = 0.008), respectively. In multivariate survival analysis, MTV was found to be an independent prognostic marker for OS. Baseline MTV and TLG evaluated from primary tumor as well as the whole-body tumor lesions are reliable prognostic markers of OS in NSCLC patients undergoing platinum-based chemotherapy. However, other baseline whole-body PET/CT parameters (SUVmax, average SUV, and tumor-to-background ratio) and dynamic PET/CT parameters (net influx rate constant, glucose metabolic rate) have no prognostic value in these patients.

Quantification of the novel N-methyl-d-aspartate receptor ligand [11C]GMOM in man

[11C]GMOM (carbon-11 labeled N-(2-chloro-5-thiomethylphenyl)-N′-(3-[11C]methoxy-phenyl)-N′-methylguanidine) is a PET ligand that binds to the N-methyl-d-aspartate receptor with high specificity and affinity. The purpose of this first in human study was to evaluate kinetics of [11C]GMOM in the healthy human brain and to identify the optimal pharmacokinetic model for quantifying these kinetics, both before and after a pharmacological dose of S-ketamine. Dynamic 90 min [11C]GMOM PET scans were obtained from 10 subjects. In six of the 10 subjects, a second PET scan was performed following an S-ketamine challenge. Metabolite corrected plasma input functions were obtained for all scans. Regional time activity curves were fitted to various single- and two-tissue compartment models. Best fits were obtained using a two-tissue irreversible model with blood volume parameter. The highest net influx rate (Ki) of [11C]GMOM was observed in regions with high N-methyl-d-aspartate receptor density, such as hippocampus and thalamus. A significant reduction in the Ki was observed for the entire brain after administration of ketamine, suggesting specific binding to the N-methyl-d-aspartate receptors. This initial study suggests that the [11C]GMOM could be used for quantification of N-methyl-d-aspartate receptors.

Determination of the unmetabolised 18F-FDG fraction by using an extension of simplified kinetic analysis method: clinical evaluation in paragangliomas

Tumours with high (18)F-FDG uptake values on static late PET images do not always exhibit high proliferation indices. These discrepancies might be related to high proportion of unmetabolised (18)F-FDG components in the tissues. We propose a method that enables to calculate different (18)F-FDG kinetic parameters based on a new mathematical approach that integrates a measurement error model. Six patients with diagnosed non-metastatic paragangliomas (PGLs) and six control patients with different types of lesions were investigated in this pilot study using (18)F-FDG PET/CT. In all cases, a whole-body acquisition was followed by four static acquisitions centred over the target lesions, associated with venous blood samplings. We used an extension of the Hunter's method to calculate the net influx rate constant (K H). The exact net influx rate constant and vascular volume fraction (K i and V, respectively) were subsequently obtained by the method of least squares. Next, we calculated the mean percentages of metabolised (PM) and unmetabolised (PUM) (18)F-FDG components, and the times required to reach 80 % of the amount of metabolised (18)F-FDG (T80%). A test-retest evaluation indicated that the repeatability of our approach was accurate; the coefficients of variation were below 2 % regardless of the kinetic parameters considered. We observed that the PGLs were characterised by high dispersions of the maximum standardised uptake value SUVmax (9.7 ± 11, coefficient of variation CV = 114 %), K i (0.0137 ± 0.0119, CV = 87 %), and V (0.292 ± 0.306, CV = 105 %) values. The PGLs were associated with higher PUM (p = 0.02) and T80% (p = 0.02) values and lower k 3 (p = 0.02) values compared to the malignant lesions despite the similar SUVmax values (p = 0.55). The estimations of these new kinetic parameters are more accurate than SUVmax or K i for in vivo metabolic assessment of PGLs at the molecular level.

Preliminary evaluation of MRI-derived input function for quantitative measurement of glucose metabolism in an integrated PET-MRI.

PET semi-quantitative methods such as relative uptake value can be robust but offer no biological information and do not account for intra-subject variability in tracer administration or clearance. Simultaneous multimodal measurements that combine PET and MRI not only permit crucial multiparametric measurements, it provides means of applying tracer kinetic modelling without the need for serial arterial blood sampling. In this study we adapted an image-derived input function (IDIF) method to improve characterization of glucose metabolism in an ongoing dementia study. Here we present preliminary results in a small group of frontotemporal dementia patients and controls. IDIF was obtained directly from dynamic PET data guided by regions of interest drawn on carotid vessels on high resolution T1-weighted MR Images. IDIF was corrected for contamination of non-arterial voxels. A validation of the method was performed in a porcine model in a PET-CT scanner comparing IDIF to direct arterial blood samples. Metabolic rate of glucose (CMRglc) was measured voxel-by-voxel in gray matter producing maps that were compared between groups. Net influx rate (Ki) and global mean CMRglc are reported. A good correlation (r = 0.9 p<0.0001) was found between corrected IDIF and input function measured from direct arterial blood sampling in the validation study. In 3 FTD and 3 controls, a trend towards hypometabolism was found in frontal, temporal and parietal lobes similar to significant differences previously reported by other groups. The global mean CMRglc and Ki observed in control subjects are in line with previous reports. In general, kinetic modelling of PET-FDG using an MR-IDIF can improve characterization of glucose metabolism in dementia. This method is feasible in multimodal studies that aim to combine PET molecular imaging with MRI as dynamic PET can be acquired along with multiple MRI measurements.

Pharmacokinetic Analysis of (64)Cu-ATSM Dynamic PET in Human Xenograft Tumors in Mice.

The aim of this study was to evaluate the feasibility to perform voxel-wise kinetic modeling on datasets obtained from tumor-bearing mice that underwent dynamic PET scans with 64Cu-ATSM and extract useful physiological parameters. Methods: Tumor-bearing mice underwent 90-min dynamic PET scans with 64Cu-ATSM and CT scans with contrast. Irreversible and reversible two-tissue compartment models were fitted to time activity curves (TACs) obtained from whole tumor volumes and compared using the Akaike information criterion (AIC). Based on voxel-wise pharmacokinetic analysis, parametric maps of model rate constants k1, k3 and Ki were generated and compared to 64Cu-ATSM uptake. Results: Based on the AIC, an irreversible two-tissue compartment model was selected for voxel-wise pharmacokinetic analysis. Of the extracted parameters, k1 (~perfusion) showed a strong correlation with early tracer uptake (mean spearman R = 0.88) 5 min post injection (pi). Moreover, positive relationships were found between late tracer uptake (90 min pi) and both k3 and the net influx rate constant, Ki (mean spearman R = 0.56 and R = 0.86; respectively). Conclusion: This study shows the feasibility to extract relevant parameters from voxel-wise pharmacokinetic analysis to be used for preclinical validation of 64Cu-ATSM as a hypoxia-specific PET tracer.

Methods of collection of plant root exudates in relation to plant metabolism and purpose: A review

AbstractThe aim of this work is to review the current knowledge on the effects of plant metabolism (C3, C4, and CAM) on root exudation and on the methods of exudate collection as well as the use of such exudates for analyses, testing of microbial response, degradation of pollutants, enzymatic activities, and occurrence of allelochemicals. We examine the advantages and disadvantages of each method as related to the downstream use of the exudates. The use of continuous percolation of solid cultivation medium with adjustment of nutrient‐solution strength appears to be a promising methodology for the determination of root exudation rates and qualitative composition of exuded compounds. The method mimics rhizosphere conditions, minimizing the artificial accumulation of compounds, alteration of plasma‐membrane permeability, ATPase activity, and the impacts of inhibitors or stimulators of root enzymes. Of particular significance is the fact that the adjustment of strength of nutrient solution and percolation enables universal and also long‐term use of the method, allowing high exudation yield by minimizing influx and maximizing efflux rates of exuded compounds at high nutrient‐solution strength. Furthermore, it facilitates assessment of the effect on soil microbial populations and their ability to degrade pollutants. Enzymatic activities can be assessed when a low strength of nutrient solution is used, with percolation of the exudates directly into tested soils. Composition of root exudates, regulation of root enzymes, and plant response to nutrient deficiency can be assessed by measuring net efflux or influx rates. The impact of heavy metals and other type of mechanical, chemical, and biological stresses differs according to the type of plant metabolism. This has significant consequences on transformations in plant communities, both structurally and functionally, and impacts upon crop nutrition, with respect to global climate change, and the use of plants for phytoremediation purposes. Understanding the effects of different types of plant metabolism on root exudation with respect to genetic regulation of synthetic pathways through root enzymes and transport systems presents an important direction for future research.

Cadmium uptake kinetics and plants factors of shoot Cd concentration

Accumulation of Cd in the shoots of plants grown on Cd contaminated soils shows considerable variation. A previous preliminary experiment established that one major reason for this variation was the rate of Cd influx into the roots (mol Cd cm−2 root s−1). However, this experiment did not distinguish between solubilization of soil Cd on the one hand and difference in Cd uptake kinetics on the other. The main objectives of the present study were thus to characterize Cd uptake kinetics of plants continuously exposed to Cd concentrations similar to those encountered in soils. Furthermore we determined the factors responsible for differences in shoot Cd concentration such as net Cd influx, root area-shoot dry weight ratio, shoot growth rate and proportion of Cd translocated to the shoot. Maize, sunflower, flax and spinach were grown in nutrient solution with five constant Cd concentrations varying from 0 to 1.0 μmol L−1. Root and shoot parameters as well as Cd uptake were determined at two harvest dates and from these data Cd net influx and shoot growth rates were calculated. Cadmium uptake kinetics, i.e. the net Cd influx vs. Cd solution concentration followed a straight line. Its slope is the root absorbing power, α, $$ \left( {\alpha ={{{\mathrm{Cd}\;\mathrm{net}\;\mathrm{influx}}} \left/ {{\mathrm{Cd}\;\mathrm{solution}\;\mathrm{concentration}}} \right.}} \right) $$ . The α values of spinach and flax were about double that of maize and sunflower (5 × 10−6 cm s−1 vs. 2.5 × 10−6 cm s−1). Spinach and flax had a 3–5 times higher shoot Cd concentration than maize and sunflower. The difference in shoot Cd concentration was partly due to the higher Cd influx but also to a higher translocation of Cd from root to shoot and also to a slower shoot growth rate.

Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy: Implications for Scheduling of Anti-Angiogenic Drugs

Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in cancer patients. It is assumed that anti-angiogenic drugs, such as bevacizumab, transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy. To investigate this concept, a study was performed in non-small cell lung cancer (NSCLC) patients using positron emission tomography (PET) and radiolabeled docetaxel ([(11)C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [(11)C]docetaxel within 5 hr. These effects persisted after 4 days. The clinical relevance of these findings is notable, as there was no evidence for a substantial improvement in drug delivery to tumors. These findings highlight the importance of drug scheduling and advocate further studies to optimize scheduling of anti-angiogenic drugs.

Potential of Early [ 18 F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography for Identifying Hypoperfusion and Predicting Fate of Tissue in a Rat Embolic Stroke Model

Experimental stroke models are essential to study in vivo pathophysiological processes of focal cerebral ischemia. In this study, an embolic stroke model in rats was applied (1) to characterize early development of regional cerebral blood flow and metabolism with positron emission tomography (PET) using [(15)O]H(2)O and [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG); and (2) to identify potential parameters for predicting tissue fate. Remote occlusion of the middle cerebral artery was induced in 10 Wistar rats by injection of 4 TiO(2) macrospheres. Sequential [(15)O]H(2)O-PET (baseline, 5, 30, 60 minutes after middle cerebral artery occlusion) and FDG-PET measurements (75 minutes after middle cerebral artery occlusion) were performed. [(15)O]H(2)O-PET data and FDG kinetic parameters were compared with MRIs and histology at 24 hours. Regional cerebral blood flow decreased substantially within 30 minutes after middle cerebral artery occlusion (41% to 58% of baseline regional cerebral blood flow; P<0.001) with no relevant changes between 30 and 60 minutes. At 60 minutes, regional cerebral blood flow correlated well with the unidirectional transport parameter K1 of FDG in all animals (r=0.86±0.09; P<0.001). Tissue fate could be accurately predicted taking into account K1 and net influx rate constant Ki of FDG. The infarct volume predicted by FDG-PET (375.8±102.3 mm(3)) correlated significantly with the infarct size determined by MRI after 24 hours (360.8±93.7 mm(3); r=0.85). Hypoperfused tissue can be identified by decreased K1 of FDG. Acute ischemic tissue can be well characterized using K1 and Ki allowing for discrimination between infarct core and early viable tissue. Because FDG-PET is widely spread, our findings can be easily translated into clinical application for early diagnoses of ischemia.

Absolute Quantification of [11C]docetaxel Kinetics in Lung Cancer Patients Using Positron Emission Tomography

Tumor resistance to docetaxel may be associated with reduced drug concentrations in tumor tissue. Positron emission tomography (PET) allows for quantification of radiolabeled docetaxel ([(11)C]docetaxel) kinetics and might be useful for predicting response to therapy. The primary objective was to evaluate the feasibility of quantitative [(11)C]docetaxel PET scans in lung cancer patients. The secondary objective was to investigate whether [(11)C]docetaxel kinetics were associated with tumor perfusion, tumor size, and dexamethasone administration. Thirty-four lung cancer patients underwent dynamic PET-computed tomography (CT) scans using [(11)C]docetaxel. Blood flow was measured using oxygen-15 labeled water. The first 24 patients were premedicated with dexamethasone. For quantification of [(11)C]docetaxel kinetics, the optimal tracer kinetic model was developed and a noninvasive procedure was validated. Reproducible quantification of [(11)C]docetaxel kinetics in tumors was possible using a noninvasive approach (image derived input function). Thirty-two lesions (size ≥4 cm(3)) were identified, having a variable net influx rate of [(11)C]docetaxel (range, 0.0023-0.0229 mL·cm(-3)·min(-1)). [(11)C]docetaxel uptake was highly related to tumor perfusion (Spearman's ρ = 0.815;P < 0.001), but not to tumor size (Spearman's ρ = -0.140; P = 0.446). Patients pretreated with dexamethasone showed lower [(11)C]docetaxel uptake in tumors (P = 0.013). Finally, in a subgroup of patients who subsequently received docetaxel therapy, relative high [(11)C]docetaxel uptake was related with improved tumor response. Quantification of [(11)C]docetaxel kinetics in lung cancer was feasible in a clinical setting. Variable [(11)C]docetaxel kinetics in tumors may reflect differential sensitivity to docetaxel therapy. Our findings warrant further studies investigating the predictive value of [(11)C]docetaxel uptake and the effects of comedication on [(11)C]docetaxel kinetics in tumors.

Effects of the antiangiogenic drug bevacizumab on tumor perfusion and drug delivery of 11C-labeled docetaxel in patients with non-small cell lung cancer (NSCLC): Implications for scheduling of antiangiogenic agents.

3059 Background: Current strategies combining anti-angiogenic drugs with chemotherapy provide clinical benefit in patients with advanced-stage NSCLC cancer. It has been hypothesized that pre-treatment with anti-angiogenic drugs may transiently normalize abnormal tumor vasculature and contribute to improved delivery of subsequent chemotherapy (Nat Med 2001;7:987-9). The purpose of the present study was to investigate this concept in NSCLC patients using a perfusion tracer ([15O]H2O), radiolabeled chemotherapy ([11C]docetaxel) and positron emission tomography (PET) before and after a single infusion of bevacizumab. Methods: A total of 70 PET scans were scheduled in 10 NSCLC patients. Patients underwent dynamic PET scans with [15O]H2O and [11C]docetaxel before, and at 5 hours and 4 days after IV administration of bevacizumab (15 mg·kg-1). An additional [15O]H2O scan was performed at 2 hours. Systemic effects of bevacizumab were investigated by assessing: (1) plasma levels of vascular endothelial growth factor (VEGF) using ELISA kits, (2) blood pressure, (3) cardiac output using [15O]H2O, and (4) microcirculation in the skin using capillaroscopy. Results: Two hours after bevacizumab administration, tumor perfusion did not change (Wilcoxon Signed Ranks test , P = 0.89). At 5 hours, however, both tumor perfusion and the net influx rate constant of [11C]docetaxel decreased significantly (P < 0.05 for both). These changes persisted until day 4 (P < 0.01 for both). Changes in tumor parameters were accompanied by a rapid decrease in circulating VEGF at 3 hours (P < 0.05) and a decline in cardiac output at 4 days (P = 0.05). The other systemic parameters remained unchanged. Conclusions: A single dose of bevacizumab induces a rapid and significant decline in tumor perfusion and [11C]docetaxel delivery in NSCLC tumors. These rapid changes in tumor parameters are not due to changes in cardiovascular parameters. The findings of the present study highlight the importance of drug scheduling for enhancing drug delivery to tumors and advocate further studies to optimize scheduling of anti-angiogenic drugs.

Effects of Light Regime, Temperature, and Plant Age on Uptake of Arsenic by Spartina Pectinata and Carex Stricta

We report here on efforts to show that a combination of native wetland plant species might perform better than a monoculture in wetlands designed for arsenic remediation by supplementing weaknesses. Carex stricta and Spartina pectinata were used in hydroponic experiments. (i) Arsenic uptake was first assessed at two ages via exposure to control or arsenic-laden solutions (0 or 1.5 mg As L−1 as Na2HAsO4) for two weeks. Age had no significant effect on arsenic concentrations in roots, but translocation factors were greater in older plants of C. stricta and S. pectinata (0.45 and 0.07, respectively) than in younger plants (0.10 and 0.01, respectively). (ii) Seasonal effects were assessed by determining uptake kinetics for both species in conditions representative of spring temperatures (15/5°C) and light regimes (1050 μmol m−2 s−1, 13 h day−1) and summer temperatures (28/17°C) and light regimes (1300 μmol m−2 s−1, 15 h day−1). Both species had comparable rates of arsenic uptake into roots in summer conditions (44.0 and 46.5 mg As kg−1 dry wt. h−1 in C. stricta and S. pectinata, respectively), but C. stricta had a higher maximum net influx rate in spring conditions (24.5 versus 10.4 mg As kg−1 dry wt. h−1).

PET imaging of [11C]docetaxel uptake and tumor perfusion in lung cancer.

2543 Background: Although docetaxel is an effective treatment of lung cancer, a number of patients do not benefit from this therapy due to tumor resistance. Positron emission tomography (PET) is a noninvasive imaging technique that allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to treatment. The aim of the present study was to determine the feasibility and reproducibility of [11C]docetaxel PET scans in lung cancer and to investigate whether [11C]docetaxel uptake was related to tumor perfusion. Methods: Fourteen patients with advanced lung cancer underwent a dynamic PET-CT scan with [11C]docetaxel (60 min) and H215O (10 min). In addition, patients underwent a second [11C]docetaxel PET scan to assess test-retest reproducibility. Lesions were delineated on the CT scan and projected onto the dynamic PET frames. [11C]docetaxel uptake in tumors was quantified using the net influx rate (Ki). Tumor perfusion was quantified by applying the standard single tissue compartment model to the H215O data. Results: In total, 24 lesions were defined, including both primary tumors and metastases. Clearance of [11C]docetaxel from plasma was rapid and later PET frames suffered from high liver uptake. Therefore, only the first 10 min of data were used for further analysis. The median net influx rate of [11C]docetaxel was 0.009 min-1 (range, 0.000-0.022). [11C]docetaxel PET scans showed good reproducibility (intraclass correlation coefficient, 0.89). The inter- and intra-individual variability of [11C]docetaxel uptake in lesions was high. [11C]docetaxel uptake was correlated with tumor perfusion (r=0.853, p<0.001). Conclusions: Measurement of [11C]docetaxel uptake in lung cancer is feasible with good reproducibility. [11C]docetaxel uptake depends on tumor perfusion. The variability of [11C]docetaxel uptake in lung cancer lesions may reflect differential sensitivity to docetaxel treatment, suggesting that PET scans with [11C]docetaxel may be useful for personalized treatment planning. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Philips Healthcare

Dynamic 18F-Fluoride PET Quantitative Analysis of Bone Grafts

Kinetic modeling in functional imaging can derive quantitative rate constants and macroparameters, which can facilitate clinical evaluation. 18F-fluoride is a suitable tracer for quantifying bone metabolism. This study employed a three-compartment and four-parameter kinetic model for 18F-fluoride to analysis dynamic 18F-fluoride PET studies of eight patients with fibula bone grafts after limb salvage surgery. Kinetic parameters were estimated for bone graft, ilium, rib, femur and lumbar vertebra regions with non-linear least square fitting. Parametric images of the influx rate constant were constructed by the Patlak graphical analysis for comparison. Differences in net influx rate constant between bone graft and normal bone regions could be detected by the technique and the technique shows promise in providing quantitative assessment of the viability of bone grafts.