Estimation of Tumor Volumes by ¹¹C-MeAIB and ¹⁸F-FDG PET in an Orthotopic Glioblastoma Rat Model

Abstract

Brain tumor volume assessment is a major challenge. Molecular imaging using PET may be a promising option because it reflects the biologically active cells. We compared the agreement between PETand histology-derived tumor volumes in an orthotopic glioblastoma rat model with a noninfiltrating (U87MG) and an infiltrating (T87) tumor phenotype using 2 different radiotracers, 2 different image reconstruction algorithms, parametric imaging, and 2 different image segmentation techniques. Methods: Rats with U87MG-and T87-derived glioblastomas were continuously scanned with PET for 1 h starting immediately after the injection of 11 C-methylaminoisobutyric acid ( 11 C-MeAIB). One hour later, 18 F-FDG was injected, followed by a 3-h dynamic PET scan. Images were reconstructed using 2-dimensional ordered-subsets expectation maximization and 3-dimensional maximum a posteriori probability (MAP3D) algorithms. In addition, a parametric image, encompassing the entire tumor kinetics in a single image, was calculated on the basis of the 11 C-MeAIB images. All reconstructed images were segmented by fixed thresholding of maximum voxel intensity (VImax) and mean background intensity. The agreement between PET-and histology-derived tumor volumes and intra-and interobserver agreement of the PET-derived volumes were evaluated using Bland-Altman plots. Results: By PET, the mean U87MG tumor volume was 35.0 mm 3 using 18 F-FDG and 34.1 mm 3 with 11 C-MeAIB, compared with 33.7 mm 3 by histology. Corresponding T87 tumor volumes were 122.1 mm 3 using 18 F-FDG, 118.3 mm 3 with 11 C-MeAIB, and 125.4 mm 3 by histology. None of these volumes were significantly different. The best agreement between PET-and histology-derived U87MG tumor volumes was achieved with 11 C-MeAIB, MAP3D reconstruction, and fixed thresholding of VImax. The intra-and interobserver agreement was high using this method. For T87 tumors, the best agreement between PET-and histology-derived volumes was obtained using 18 F-FDG, MAP3D reconstruction, and fixed thresholding of mean background intensity. The agreement using 11 C-MeAIB, parametric imaging, and fixed thresholding of VImax was slightly inferior, but the intra-and interobserver agreement was clearly superior. Conclusion: Estimation of tumor volume by PET of noninfiltrating brain tumors was accurate and reproducible. In contrast, tumor volume estimation by PET of infiltrating brain tumors was difficult and hard to reproduce. On the basis of our results, PET evaluation of highly infiltrating brain tumors should be further developed.

Migrating glioma cells express stem cell markers and give rise to new tumors upon xenografting

“…In line with the well-known migration for GBMs in the brain, pronounced migration was observed for all investigated GBM spheroid cultures. Supporting the in vivo-like features and translational potential of our model, migration was not observed for the standard U87MG cell line, thereby confirming the growth pattern for U87MG earlier found in the orthotopic xenograft model, where U87MG cells form a circumscribed tumor with a sharp border between tumor and parenchyma [ 17 ]. Our major novel finding in vitro was that not only the five GBM spheroid cultures but also the corresponding in vitro isolated migrating cells had the capacity to form spheroids.…”

Monitoring of Tumor Growth with [18F]-FET PET in a Mouse Model of Glioblastoma: SUV Measurements and Volumetric Approaches

“…Although [ 18 F]-FET is the most established tracer for molecular glioma imaging in the clinical field, other tracers have shown promising results for delineation of BTV in the pre-clinical field as well: 11 C-methylaminoisobutyric acid ([ 11 C]-MeAIB) has for example been used in a double tracer study together with [ 18 F]-FDG to estimate tumor volumes in two phenotypically different orthotopic GBM rat models. [ 11 C]-MeAIB PET was accurate for volume estimation in non-infiltrating brain tumors when compared to histologic findings, proved however to be hardly reproducible in highly infiltrating brain tumors (Halle et al, 2015 ).…”

Heterogenic expression of stem cell markers in patient-derived glioblastoma spheroid cultures exposed to long-term hypoxia

“…In this study, the spheroid cultures T78 (mesenchymal subtype), T86 (classical subtype), T87 (proneural subtype) and T111 (mesenchymal subtype) were used. They are all glioblastoma short-term cultures with tumor stem cell properties established in serum-free medium in our laboratory as previously described [ 20 , 48 , 49 ]. These cultures showed repeated spheroid formation in vitro in serum-free medium, differentiation into cells expressing glial and neuronal markers in serum containing medium as well as formation of infiltrative tumors in immunodeficient mice upon orthotopic implantation.…”