| 1. |
- Bahce, Idris, et al.
(författare)
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Development of [11C]erlotinib Positron Emission Tomography for In Vivo Evaluation of EGF Receptor Mutational Status
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 183-193
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To evaluate whether, in patients with non-small cell lung carcinoma (NSCLC), tumor uptake of [(11)C]erlotinib can be quantified and imaged using positron emission tomography and to assess whether the level of tracer uptake corresponds with the presence of activating tumor EGF receptor (EGFR) mutations.EXPERIMENTAL DESIGN: Ten patients with NSCLCs, five with an EGFR exon 19 deletion, and five without were scanned twice (test retest) on the same day with an interval of at least 4 hours. Each scanning procedure included a low-dose computed tomographic scan, a 10-minute dynamic [(15)O]H(2)O scan, and a 1-hour dynamic [(11)C]erlotinib scan. Data were analyzed using full tracer kinetic modeling. EGFR expression was evaluated using immunohistochemistry.RESULTS: The quantitative measure of [(11)C]erlotinib uptake, that is, volume of distribution (V(T)), was significantly higher in tumors with activating mutations, that is, all with exon 19 deletions (median V(T), 1.76; range, 1.25-2.93), than in those without activating mutations (median V(T), 1.06; range, 0.67-1.22) for both test and retest data (P = 0.014 and P = 0.009, respectively). Good reproducibility of [(11)C]erlotinib V(T) was seen (intraclass correlation coefficient = 0.88). Intergroup differences in [(11)C]erlotinib uptake were not correlated with EGFR expression levels, nor tumor blood flow.CONCLUSION: [(11)C]erlotinib V(T) was significantly higher in NSCLCs tumors with EGFR exon 19 deletions.
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| 2. |
- Harms, Hendrik J, et al.
(författare)
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Quantification of [(11)C]-meta-hydroxyephedrine uptake in human myocardium
- 2014
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aims of this study were to determine the optimal tracer kinetic model for [(11)C]-meta-hydroxyephedrine ([(11)C]HED) and to evaluate the performance of several simplified methods.METHODS: Thirty patients underwent dynamic 60-min [(11)C]HED scans with online arterial blood sampling. Single-tissue and both reversible and irreversible two-tissue models were fitted to the data using the metabolite-corrected arterial input function. For each model, reliable fits were defined as those yielding outcome parameters with a coefficient of variation (CoV) <25%. The optimal model was determined using Akaike and Schwarz criteria and the F-test, together with the number of reliable fits. Simulations were performed to study accuracy and precision of each model. Finally, quantitative results obtained using a population-averaged metabolite correction were evaluated, and simplified retention index (RI) and standardized uptake value (SUV) results were compared with quantitative volume of distribution (V T) data.RESULTS: The reversible two-tissue model was preferred in 75.8% of all segments, based on the Akaike information criterion. However, V T derived using the single-tissue model correlated highly with that of the two-tissue model (r (2) = 0.94, intraclass correlation coefficient (ICC) = 0.96) and showed higher precision (CoV of 24.6% and 89.2% for single- and two-tissue models, respectively, at 20% noise). In addition, the single-tissue model yielded reliable fits in 94.6% of all segments as compared with 77.1% for the reversible two-tissue model. A population-averaged metabolite correction could not be used in approximately 20% of the patients because of large biases in V T. RI and SUV can provide misleading results because of non-linear relationships with V T.CONCLUSIONS: Although the reversible two-tissue model provided the best fits, the single-tissue model was more robust and results obtained were similar. Therefore, the single-tissue model was preferred. RI showed a non-linear correlation with V T, and therefore, care has to be taken when using RI as a quantitative measure.
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| 3. |
- Harms, Hendrik J, et al.
(författare)
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Use of a Single 11C-Meta-Hydroxyephedrine Scan for Assessing Flow-Innervation Mismatches in Patients with Ischemic Cardiomyopathy
- 2015
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 56:11, s. 1706-1711
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Mismatch between areas of reduced myocardial blood flow (MBF) and reduced myocardial innervation (defect areas) may be used to estimate the risk for ventricular arrhythmias. The presence of a mismatch zone can be derived using a combined protocol consisting of both an MBF scan and an (11)C-meta-hydroxyephedrine ((11)C-HED) scan. The rate of influx from blood to myocardium (K1) of (11)C-HED is proportional to MBF and can potentially be used as an index for defining MBF defects. The aim of this study was to assess whether K1 derived from an (11)C-HED scan can be used as an index of MBF, potentially allowing for an assessment of MBF-innervation mismatch areas from a single (11)C-HED scan.METHODS: Seventeen patients with known ischemic cardiomyopathy underwent dynamic (15)O-water and (11)C-HED scans. Discrete arterial blood samples were taken during (11)C-HED scans for metabolite correction of the image-derived input function. (11)C-HED influx rate was obtained using a single-tissue-compartment model and compared with transmural MBF (MBFT), defined as MBF as measured with (15)O-water multiplied by perfusable tissue fraction. Defect sizes were obtained from parametric K1 and MBFT images, using 50% of a remote control segment as the cutoff value.RESULTS: There was a significant correlation between MBFT and K1 (y = 0.40x + 0.05 mL·g(-1)·min(-1), r = 0.80, P < 0.001), although K1 was significantly lower than MBFT (slope of the regression line significantly different from 1, P < 0.001). Correlation between MBFT and K1 defect sizes was high (y = 0.89x + 1.38%, r = 0.95, P < 0.001), with no significant difference in mean defect size based on K1 or MBFT (20.9% ± 11.3% and 20.1% ± 10.7% for MBFT and K1, respectively, P = 0.41).CONCLUSION: (11)C-HED influx rate K1 can be used as an alternative to a separate MBF scan for assessing mismatch areas between MBF and myocardial innervation.
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| 4. |
- van Assema, Danielle M. E., et al.
(författare)
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Blood-brain barrier P-glycoprotein function in Alzheimer's disease
- 2012
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135, s. 181-189
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Tidskriftsartikel (refereegranskat)abstract
- A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-beta from the brain may lead to these elevated amyloid-beta levels. One of the clearance pathways of amyloid-beta is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-beta. P-glycoprotein function can be assessed in vivo using (R)-[C-11]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[C-11]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 +/- 7 years, Mini-Mental State Examination 23 +/- 3), global (R)-[C-11]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 +/- 4 years, Mini-Mental State Examination 30 +/- 1). Global (R)-[C-11]verapamil binding potential values were 2.18 +/- 0.25 for patients with Alzheimer's disease and 1.77 +/- 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[C-11]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[C-11]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic Alzheimer's disease and suggests that decreased P-glycoprotein function may be involved in the pathogenesis of Alzheimer's disease.
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| 5. |
- van Assema, Danielle M. E., et al.
(författare)
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No evidence for additional blood-brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds
- 2012
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 32:8, s. 1468-1471
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Tidskriftsartikel (refereegranskat)abstract
- Decreased blood-brain barrier P-glycoprotein (Pgp) function has been shown in Alzheimer's disease (AD) patients using positron emission tomography (PET) with the radiotracer (R)-[C-11] verapamil. Decreased Pgp function has also been hypothesized to promote cerebral amyloid angiopathy (CAA) development. Here, we used PET and (R)-[C-11] verapamil to assess Pgp function in eighteen AD patients, of which six had microbleeds (MBs), presumably reflecting underlying CAA. No differences were found in binding potential and nonspecific volume of distribution of (R)-[C-11] verapamil between patient groups. These results provide no evidence for additional Pgp dysfunction in AD patients with MBs.
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| 6. |
- van Assema, Danielle M. E., et al.
(författare)
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P-Glycoprotein Function at the Blood-Brain Barrier : Effects of Age and Gender
- 2012
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Ingår i: Molecular Imaging and Biology. - : Springer Science and Business Media LLC. - 1536-1632 .- 1860-2002. ; 14:6, s. 771-776
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Tidskriftsartikel (refereegranskat)abstract
- PurposeP-glycoprotein (Pgp) is an efflux transporter involved in transport of several compounds across the blood–brain barrier (BBB). Loss of Pgp function with increasing age may be involved in the development of age-related disorders, but this may differ between males and females. Pgp function can be quantified in vivo using (R)-[11C]verapamil and positron emission tomography. The purpose of this study was to assess global and regional effects of both age and gender on BBB Pgp function.ProceduresThirty-five healthy men and women in three different age groups were included. Sixty minutes dynamic (R)-[11C]verapamil scans with metabolite-corrected arterial plasma input curves were acquired. Grey matter time–activity curves were fitted to a validated constrained two-tissue compartment plasma input model, providing the volume of distribution (V T) of (R)-[11C]verapamil as outcome measure.ResultsIncreased V T of (R)-[11C]verapamil with aging was found in several large brain regions in men. Young and elderly women showed comparable V T values. Young women had higher V T compared with young men.ConclusionsDecreased BBB Pgp is found with aging; however, effects of age on BBB Pgp function differ between men and women.
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| 7. |
- van Assema, Daniëlle Me, et al.
(författare)
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Reproducibility of quantitative (R)-[11C]verapamil studies
- 2012
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Ingår i: EJNMMI Research. - 2191-219X. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundP-glycoprotein [Pgp] dysfunction may be involved in neurodegenerative diseases, such as Alzheimer's disease, and in drug resistant epilepsy. Positron emission tomography using the Pgp substrate tracer (R)-[11C]verapamil enables in vivo quantification of Pgp function at the human blood-brain barrier. Knowledge of test-retest variability is important for assessing changes over time or after treatment with disease-modifying drugs. The purpose of this study was to assess reproducibility of several tracer kinetic models used for analysis of (R)-[11C]verapamil data.MethodsDynamic (R)-[11C]verapamil scans with arterial sampling were performed twice on the same day in 13 healthy controls. Data were reconstructed using both filtered back projection [FBP] and partial volume corrected ordered subset expectation maximization [PVC OSEM]. All data were analysed using single-tissue and two-tissue compartment models. Global and regional test-retest variability was determined for various outcome measures.ResultsAnalysis using the Akaike information criterion showed that a constrained two-tissue compartment model provided the best fits to the data. Global test-retest variability of the volume of distribution was comparable for single-tissue (6%) and constrained two-tissue (9%) compartment models. Using a single-tissue compartment model covering the first 10 min of data yielded acceptable global test-retest variability (9%) for the outcome measure K1. Test-retest variability of binding potential derived from the constrained two-tissue compartment model was less robust, but still acceptable (22%). Test-retest variability was comparable for PVC OSEM and FBP reconstructed data.ConclusionThe model of choice for analysing (R)-[11C]verapamil data is a constrained two-tissue compartment model.
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| 8. |
- van der Veldt, Astrid A M, et al.
(författare)
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Absolute Quantification of [11C]docetaxel Kinetics in Lung Cancer Patients Using Positron Emission Tomography
- 2011
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 17:14, s. 4814-4824
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Tumor resistance to docetaxel may be associated with reduced drug concentrations in tumor tissue. Positron emission tomography (PET) allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to therapy. The primary objective was to evaluate the feasibility of quantitative [11C]docetaxel PET scans in lung cancer patients. The secondary objective was to investigate whether [11C]docetaxel kinetics were associated with tumor perfusion, tumor size, and dexamethasone administration.Experimental Design:Thirty-four lung cancer patients underwent dynamic PET–computed tomography (CT) scans using [11C]docetaxel. Blood flow was measured using oxygen-15 labeled water. The first 24 patients were premedicated with dexamethasone. For quantification of [11C]docetaxel kinetics, the optimal tracer kinetic model was developed and a noninvasive procedure was validated.Results:Reproducible quantification of [11C]docetaxel kinetics in tumors was possible using a noninvasive approach (image derived input function). Thirty-two lesions (size ≥4 cm3) were identified, having a variable net influx rate of [11C]docetaxel (range, 0.0023–0.0229 mL·cm−3·min−1). [11C]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 [11C]docetaxel uptake in tumors (P = 0.013). Finally, in a subgroup of patients who subsequently received docetaxel therapy, relative high [11C]docetaxel uptake was related with improved tumor response.Conclusions:Quantification of [11C]docetaxel kinetics in lung cancer was feasible in a clinical setting. Variable [11C]docetaxel kinetics in tumors may reflect differential sensitivity to docetaxel therapy. Our findings warrant further studies investigating the predictive value of [11C]docetaxel uptake and the effects of comedication on [11C]docetaxel kinetics in tumors.
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| 9. |
- van der Veldt, Astrid A. M., et al.
(författare)
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Rapid Decrease in Delivery of Chemotherapy to Tumors after Anti-VEGF Therapy : Implications for Scheduling of Anti-Angiogenic Drugs
- 2012
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 21:1, s. 82-91
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Tidskriftsartikel (refereegranskat)abstract
- 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 ([11C]docetaxel). In NSCLC, bevacizumab reduced both perfusion and net influx rate of [11C]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.
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| 10. |
- van der Veldt, Astrid A. M., et al.
(författare)
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Toward Prediction of Efficacy of Chemotherapy : A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography
- 2013
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:15, s. 4163-4173
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([11C]docetaxel). The objective of this study was to investigate whether a [11C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel.Experimental Design:Docetaxel-naïve lung cancer patients underwent 2 [11C]docetaxel PET scans; one after bolus injection of [11C]docetaxel and another during combined infusion of [11C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2). Compartmental and spectral analyses were used to quantify [11C]docetaxel tumor kinetics. [11C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans.Results:Net rates of influx (Ki) of [11C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [11C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [11C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [11C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = −0.800; P = 0.010).Conclusions:Microdosing data of [11C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.
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