Abstract
Noninvasive tumor growth monitoring is of particular interest for the evaluation of experimental glioma therapies. This study investigates the potential of positron emission tomography (PET) using O-(2-18F-fluoroethyl)-L-tyrosine ([18F]-FET) to determine tumor growth in a murine glioblastoma (GBM) model—including estimation of the biological tumor volume (BTV), which has hitherto not been investigated in the pre-clinical context. Fifteen GBM-bearing mice (GL261) and six control mice (shams) were investigated during 5 weeks by PET followed by autoradiographic and histological assessments. [18F]-FET PET was quantitated by calculation of maximum and mean standardized uptake values within a universal volume-of-interest (VOI) corrected for healthy background (SUVmax/BG, SUVmean/BG). A partial volume effect correction (PVEC) was applied in comparison to ex vivo autoradiography. BTVs obtained by predefined thresholds for VOI definition (SUV/BG: ≥1.4; ≥1.6; ≥1.8; ≥2.0) were compared to the histologically assessed tumor volume (n = 8). Finally, individual “optimal” thresholds for BTV definition best reflecting the histology were determined. In GBM mice SUVmax/BG and SUVmean/BG clearly increased with time, however at high inter-animal variability. No relevant [18F]-FET uptake was observed in shams. PVEC recovered signal loss of SUVmean/BG assessment in relation to autoradiography. BTV as estimated by predefined thresholds strongly differed from the histology volume. Strikingly, the individual “optimal” thresholds for BTV assessment correlated highly with SUVmax/BG (ρ = 0.97, p < 0.001), allowing SUVmax/BG-based calculation of individual thresholds. The method was verified by a subsequent validation study (n = 15, ρ = 0.88, p < 0.01) leading to extensively higher agreement of BTV estimations when compared to histology in contrast to predefined thresholds. [18F]-FET PET with standard SUV measurements is feasible for glioma imaging in the GBM mouse model. PVEC is beneficial to improve accuracy of [18F]-FET PET SUV quantification. Although SUVmax/BG and SUVmean/BG increase during the disease course, these parameters do not correlate with the respective tumor size. For the first time, we propose a histology-verified method allowing appropriate individual BTV estimation for volumetric in vivo monitoring of tumor growth with [18F]-FET PET and show that standardized thresholds from routine clinical practice seem to be inappropriate for BTV estimation in the GBM mouse model.
Highlights
The last decade has seen a considerable range of studies emphasizing the increasing importance of positron emission tomography (PET) using the radiolabeled amino acid analog O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]-FET) for clinical neuro-oncology (La Fougere et al, 2011; Dunet et al, 2012; Galldiks et al, 2015b)
[18F]-FET PET for GBM Growth Monitoring set of animal experiments was performed to analyze standard PET parameters and to determine optimal parameters for biological tumor volume (BTV) measurements: At day 0, the mice were inoculated either with 50,000 GL261 cells suspended in 1 μL of saline (GBM mice, n = 15) or with 1 μL of saline for control
In the present multimodal study, we tested different approaches to perform in vivo imaging with small animal [18F]-FET PET in an orthotopic glioblastoma mouse model
Summary
The last decade has seen a considerable range of studies emphasizing the increasing importance of positron emission tomography (PET) using the radiolabeled amino acid analog O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]-FET) for clinical neuro-oncology (La Fougere et al, 2011; Dunet et al, 2012; Galldiks et al, 2015b). With precision medicine in mind, [18F]-FET PET has become of crucial interest especially for individual therapy management in glioma patients, since it visualizes the metabolic activity of the glioma-affected brain tissue and thereby broadens neuroimaging to the molecular level (Pauleit et al, 2005; Rachinger et al, 2005; Langen et al, 2006; Dhermain et al, 2010; Galldiks et al, 2012a). Whereas conventional imaging techniques like structural magnetic resonance imaging (MRI)—as the current clinical standard for neuro-oncological imaging—focus on morphologic information, [18F]-FET PET is a tool to visualize the altered biology of the tumoral lesion (as compared to non-neoplastic parenchyma) and promotes a personalized therapy management. While [18F]-FET PET has the potential to play a more and more important role for neuro-oncology in the clinical setting, its pre-clinical potential is not yet fully appreciated. Pre-clinical glioma imaging in mouse models is challenging due to relatively small tumor sizes (of barely a few cubic millimeters), which require special diligence to precision imaging and encourage technically sophisticated methods of image correction
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