Accurately defining glioma infiltration is crucial for optimizing radiotherapy and surgery, but glioma infiltration is heterogeneous and MRI imperfectly defines the tumor extent. Currently, it is impossible to determine the tumor infiltration gradient within a FLAIR signal. O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET often reveals high-grade glioma infiltration beyond contrast-enhancing areas on MRI. Here, we studied FET uptake dynamics in tumor and normal brain structures by dual-timepoint (10 min and 40-60 min post-injection) acquisition to optimize analysis protocols for defining glioma infiltration. Over 300 serial stereotactic biopsies from 23 patients (mean age 47, 12 female/11 male) of diffuse contrast-enhancing gliomas were taken from areas inside and outside contrast enhancement or outside the FET hotspot but inside FLAIR. The final diagnosis was G4 in 11, grade 3 in 10, and grade 2 in 2 patients. The target-to-background (TBRs) ratios and standardized uptake values (SUVs) were calculated in areas used for biopsy planning and in background structures. The optimal method and threshold values were determined to find a preferred strategy for defining glioma infiltration. Standard thresholding (1.6× uptake in the contralateral brain) in standard acquisition PET images differentiated a tumor of any grade from astrogliosis, although the uptake in astrogliosis and grade 2 glioma was similar. Analyzing an optimal strategy for infiltration volume definition astrogliosis could be accurately differentiated from tumor samples using a choroid plexus as a background. Early acquisition improved the AUC in many cases, especially within FLAIR, from 56% to 90% sensitivity and 41% to 61% specificity (standard TBR 1.6 vs. early TBR plexus). The current FET-PET evaluation protocols for contrast-enhancing gliomas are limited, especially at the tumor border where grade 2 tumor and astrogliosis have similar uptake, but using choroid plexus uptake in early acquisitions as a background, we can precisely define a tumor within FLAIR that was outside of the scope of current FET-PET protocols.

For precise delineation of glioma extent, amino acid PET is superior to conventional MR imaging. Since metabolic MR sequences such as chemical exchange saturation transfer (CEST) imaging and MR spectroscopy (MRS) were developed, we aimed to evaluate the diagnostic accuracy of combined CEST and MRS to predict glioma infiltration. Eighteen glioma patients of different tumor grades were enrolled in this study; 18F-fluoroethyltyrosine (FET)-PET, amide proton transfer CEST at 7 Tesla(T), MRS and conventional MR at 3T were conducted preoperatively. Multi modalities and their association were evaluated using Pearson correlation analysis patient-wise and voxel-wise. Both CEST (R = 0.736, p < 0.001) and MRS (R = 0.495, p = 0.037) correlated with FET-PET, while the correlation between CEST and MRS was weaker. In subgroup analysis, APT values were significantly higher in high grade glioma (3.923 ± 1.239) and IDH wildtype group (3.932 ± 1.264) than low grade glioma (3.317 ± 0.868, p < 0.001) or IDH mutant group (3.358 ± 0.847, p < 0.001). Using high FET uptake as the standard, the CEST/MRS combination (AUC, 95% CI: 0.910, 0.907−0.913) predicted tumor infiltration better than CEST (0.812, 0.808−0.815) or MRS (0.888, 0.885−0.891) alone, consistent with contrast-enhancing and T2-hyperintense areas. Probability maps of tumor presence constructed from the CEST/MRS combination were preliminarily verified by multi-region biopsies. The combination of 7T CEST/MRS might serve as a promising non-radioactive alternative to delineate glioma infiltration, thus reshaping the guidance for tumor resection and irradiation.

Neuroimaging based on O-[2-(18F)fluoroethyl]-l-tyrosine (FET)-PET provides additional information on tumor grade and extent compared with MRI. Dynamic PET for biopsy target selection further improves results but is often clinically impractical. Static FET-PET performed at two time-points may be a good compromise, but data on this approach are limited. The aim of this study was to compare the histology of lesions obtained from two challenging glioma patients with targets selected based on hybrid dual time-point FET-PET/MRI. Five neuronavigated tumor biopsies were performed in two difficult cases of suspected glioma. Lesions with (T1-CE) and without contrast enhancement (T1 and T2-FLAIR) on MRI were selected. Dual time-point FET-PET imaging was performed 5-15 min (PET10) and 45-60 min (PET60) after radionuclide injection. The most informative FET-PET/MRI images were coregistered with MRI in time of biopsy planning. Five biopsy targets (three from high uptake and two from moderate uptake FET areas) thought to represent the most malignant sites and tumor extent were selected. Histopathological findings were compared with FET-PET and MRI images. Increased FET uptake in the area of non-CE locations on MRI correlated well with high-grade gliomas localized as far as 3 cm from T1-CE foci. Selecting a target in the motor cortex based on FET kinetics defined by dual time-point PET resulted in a grade IV diagnosis after previous negative biopsies based on MRI. An additional grade III diagnosis was obtained from an area of glioma infiltration with moderate FET uptake (between 1 and 1.25 SUV). These findings seem to show that dual time-point FET-PET-based biopsies can provide additional and clinically useful information for glioma diagnosis. Selection of targets based on dual time-point images may be useful for determining the most malignant tumor areas and may therefore be useful for resection and radiotherapy planning.

Positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) improves the diagnostics of cerebral gliomas compared with conventional magnetic resonance imaging (MRI). Sodium MRI is an evolving method to assess tumor metabolism. In this pilot study, we explored the relationship of [18F]FET-PET and sodium MRI in patients with cerebral gliomas in relation to the mutational status of the enzyme isocitrate dehydrogenase (IDH).
Ten patients with untreated cerebral gliomas and one patient with a recurrent glioblastoma (GBM) were investigated by dynamic [18F]FET-PET and sodium MRI using an enhanced simultaneous single-quantum- and triple-quantum-filtered imaging of 23Na (SISTINA) sequence to estimate total (NaT), weighted non-restricted (NaNR, mainly extracellular), and restricted (NaR, mainly intracellular) sodium in tumors and normal brain tissue. [18F]FET uptake and sodium parameters in tumors with a different IDH mutational status were compared. After biopsy or resection, histology and the IDH mutational status were determined neuropathologically.
NaT (p = 0.05), tumor-to-brain ratios (TBR) of NaT (p = 0.02), NaNR (p = 0.003), and the ratio of NaT/NaR (p < 0.001) were significantly higher in IDH-mutated than in IDH-wild-type gliomas (n = 5 patients each) while NaR was significantly lower in IDH-mutated gliomas (p = 0.01). [18F]FET parameters (TBR, time-to-peak) were not predictive of IDH status in this small cohort of patients. There was no obvious relationship between sodium distribution and [18F]FET uptake. The patient with a recurrent GBM exhibited an additional radiation injury with strong abnormalities in sodium MRI.
Sodium MRI appears to be more strongly related to the IDH mutational status than are [18F]FET-PET parameters. A further evaluation of the combination of the two methods in a larger group of high- and low-grade gliomas seems promising.

The diagnostic accuracy of magnetic resonance imaging (MRI) for glioblastoma multiforme (GBM) is suboptimal. We analysed pre-treatment MRI- and dual time-point 18F-fluoroethylthyrosine-PET (FET-PET)-based target volumes and GBM recurrence patterns following radiotherapy with temozolomide.
Thirty-four patients with primary GBM were treated according to MRI-based treatment volumes (GTVRM). Patients underwent dual time-point FET-PET scans prior to treatment, and biological tumour volumes (GTVPET) were contoured but not used for target definition. Progressions were classified based on location of primary GTVs. Volume and uniformity of MRI- vs. FET-PET/CT-derived GTVs and progression patterns assessed by MRI were analysed.
FET-based GTVs measured 10min after radionuclide injection (a.r.i.; median 37.3cm(3)) were larger than GTVs measured 60min a.r.i. (median 27.7cm(3)). GTVPET volumes were significantly larger than corresponding MRI-based GTVs. MRI and PET concordance for the identification of glioblastoma GTVs was poor (mean uniformity index 0.4). 74% of failures were inside primary GTVPET volumes, with no solitary progressions inside the MRI-defined margin +20mm but outside the GTVPET detected.
The size and geometry of GTVs differed in the majority of patients. The GTVPET volume depends on time after radionuclide injection. FET-PET better defined failure site than MRI alone.