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The positron emission tomography (PET) with the amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) is becoming increasingly important in the diagnosis of brain tumors. Due to many logistical advantages such as long half-life (109 min) and synthesis with relatively high yields (Wester et al., 1999; Long et al, 2006; Herholz et al, 2012; Galldiks & Langen, 2015) as well as diagnostic advantages like determining the extent of the tumor, biopsy and treatment planning, relapse diagnosis, prognosis and treatment monitoring, the 18F-FET PET is superior to other radiopharmaceuticals (Popperl et al, 2004; Pauleit et al, 2005a; Floeth et al, 2007; Pauleit et . al, 2009; Pichler et al, 2010a; Galldiks et al, 2012b; Jansen et al, 2015). Furthermore, the dynamic 18F-FET PET provides important additional information about the malignancy of tumors based upon the curve form of 18F-FET accumulation kinetics (Weckesser et al., 2005; Popperl et al, 2006; Popperl et al, 2007; Calcagni et al, 2011).Up to now, there are no studies on the reproducibility of 18F-FET accumulation kinetics. Alterations of that accumulation kinetics are of great importance in therapy monitoring. Supportive therapy with glucocorticoids and antiangiogenic treatment improve the pathologically increased permeability of tumor vessels and affect medical imaging with magnetic resonance imaging (MRI). Thus, the objectives of this experimental work was, first, to determine the reproducibility of 18F-FET uptake kinetics in rat glioma models with different kinetics and, furthermore, to test the influence of therapy with glucocorticoids (dexamethasone) and antiangiogenic treatment (Avastin) on the accumulation kinetics with particular attention to determine the blood-brain barrier permeability. Finally, the data were compared to the also frequently used radiopharmaceutical 3'-desoxy -3 '-[18F]fluorothymidine (18F-FLT) .Within the reproducibility study, two 18F-FET PET scans were performed in animal models at intervals of 48 hours and the most important clinical parameters were evaluated by Volume of Interest (VOI) analysis. The results were compared within the tumor models as well as between the tumor models. The standardized uptake value (SUV) and the slope of the tracer kinetics were reproducible in three of the four models. Only a slight increase in tumor/brain ratio (TBR) was observed, which could be attributed to the increase in size of tumors within the 48 hour interval. The fourth model showed nonspecific 18F-FET uptake around the tumor, which was most likely caused by an immune response. Pretests with healthy animals provided important additional information regarding effects of dexamethasone and blood-amino acid level on tracer accumulation in healthy brain tissue.Within the dexamethasone study, also two scans were performed in 48 h interval in which the rats were treated with three injections of dexamethasone. After treatment, the SUV and the slope of the tracer kinetics remained unchanged, but the TBR showed a slight decrease. This could be attributed to an increased 18F-FET uptake in the contralateral healthy brain tissue. The reason for that effect needs further investigation and has to be validated in patient data. The 18F-FLT uptake showed neither changes in the tumor parameters nor in contralateral normal tissue by dexamethasone treatment.In the Avastin study, the long-term effect of antiangiogenic treatment was tested with two injections of Avastin over a period of ten days. A short-term effect of this therapeutic antibody was tested with a single high dose 48 h before the final PET scan. Compared to a control group, the SUV, the TBR and the slope remained unchanged. Only the area under the curve (AUC) of the time activity curve was slightly reduced in the long-term study compared to the control group.Furthermore, the permeability of the BBB was tested without treatment and after dexamethasone and Avastin intervention by extravasation of Evans blue dye. After all tested treatments, a decrease in BBB permeability was observed, which was not accompanied by a change in tracer uptake.In this experimental work, the accumulation kinetics of the tracer 18F-FET was tested in rat glioma models with and without pharmacological interventions. The reproducibility of the kinetics was shown and its independence on the tested interventions as well as on BBB permeability were demonstrated. Thus, this work provides important information for tumor diagnosis and therapy monitoring in patients with brain tumors.
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Dissertation RWTH Aachen 2016
Language:
English
Keywords:
Hochschulschrift
URN:
urn:nbn:de:hbz:82-rwth-2016-011817
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