Background. Although glioblastomas are heterogeneous brain-infiltrating tumors, their treatment is mostly focused on the contrast-enhancing tumor mass. In this study, we combined conventional MRI, diffusion-weighted imaging (DWI), and amino acid PET to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value. Methods. Contrast-enhanced T1, T2/fluid attenuated inversion recovery (FLAIR) MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[ 11 C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients with newly diagnosed glioblastoma. Five tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were correlated, and their prognostic value was determined. Results. A total of 115 MRI/PET-defined subregions were analyzed. Most tumors showed not only a high-AMT uptake (T/N ratio > 1.65, N = 27) but also a low-uptake subregion (N = 21) within the contrast-enhancing tumor mass. High AMT uptake extending beyond contrast enhancement was also common (N = 25) and was associated with low ADC (r = −0.40, P = 0.05). Higher AMT uptake in the contrast-enhancing tumor subregions was strongly prognostic for overall survival (hazard ratio: 7.83; 95% CI: 1.98-31.02, P = 0.003), independent of clinical and molecular genetic prognostic variables. Nonresected high-AMT uptake subregions predicted the sites of tumor progression on posttreatment PET performed in 10 patients. Conclusions. Glioblastomas show heterogeneous amino acid uptake with high-uptake regions often extending into non-enhancing brain with high cellularity; nonresection of these predict the site of posttreatment progression. High tryptophan uptake values in MRI contrast-enhancing tumor subregions are a strong, independent imaging marker for longer overall survival. Key Points1. Regions with high tryptophan uptake in peritumoral brain show high cellularity on diffusion MRI.2. Nonresection of such regions predicts the site of posttreatment tumor progression.3. High tryptophan uptake in contrast-enhancing tumor regions is prognostic for longer survival. 265John et al. Multimodal imaging-defined glioblastoma subregions Neuro-OncologyDespite aggressive multimodal treatment with surgery and chemoradiation therapy, glioblastomas continue to have extremely poor prognosis, with a median overall survival of 15 months. 1,2 Clinical prognostic factors for glioblastoma include age, performance status, tumor radiologic features, and extent of initial tumor resection. 3,4 Among molecular features, high Ki-67 nuclear labeling index carries unfavorable prognosis, 5 whereas isocitrate dehydrogenase 1 (IDH1) mutation is associated with prolonged survival. 6,7 O 6methylguanine-DNA methyltransferase (MGMT) promoter methylation is associated with a favorable response to the alkylating chemotherapeutic agent temozolomide. 8,9 In clinical practice, conventi...

Tumor-treating fields (TTFields) therapy is a relatively new treatment approach for malignant gliomas. We evaluated if amino acid PET can detect an objective metabolic response to TTFields therapy in recurrent glioblastomas. PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) before and 2 to 3 months after the start of TTFields treatment showed an interval decrease of tryptophan uptake in the whole tumor (2 patients) or in a portion of the tumor (1 patient). These data demonstrate that TTFields therapy can induce an early metabolic response in recurrent glioblastoma, and this treatment response can be detected by amino acid PET.

Background: Clinical glioblastoma treatment mostly focuses on the contrast-enhancing tumor mass. Amino acid positron emission tomography (PET) can detect additional, nonenhancing glioblastoma-infiltrated brain regions that are difficult to distinguish on conventional magnetic resonance imaging (MRI). We combined MRI with perfusion imaging and amino acid PET to evaluate such nonenhancing glioblastoma regions. Methods: Structural MRI, relative cerebral blood volume (rCBV) maps from perfusion MRI, and α-[11C]-methyl-l-tryptophan (AMT)-PET images were analyzed in 20 patients with glioblastoma. The AMT uptake and rCBV (expressed as tumor to normal [T/N] ratios) were compared in nonenhancing tumor portions showing increased signal on T2/fluid-attenuated inversion recovery (T2/FLAIR) images. Results: Thirteen (65%) tumors showed robust heterogeneity in nonenhancing T2/FLAIR hyperintense areas on AMT-PET, whereas the nonenhancing regions in the remaining 7 cases had homogeneous AMT uptake (low in 6, high in 1). AMT and rCBV T/N ratios showed only a moderate correlation in the nonenhancing regions ( r = 0.41, P = .017), but regions with very low rCBV (<0.79 T/N ratio) had invariably low AMT uptake. Conclusions: The findings demonstrate the metabolic and perfusion heterogeneity of nonenhancing T2/FLAIR hyperintense glioblastoma regions. Amino acid PET imaging of such regions can detect glioma-infiltrated brain for treatment targeting; however, very low rCBV values outside the contrast-enhancing tumor mass make increased AMT uptake in nonenhancing glioblastoma regions unlikely.

In the latest World Health Organization classification of brain tumors, gliomatosis cerebri has been redefined to varying subsets of diffuse gliomas; however, the term is still used to describe gliomas with infiltrative growth into three or more cerebral lobes. These tumors are frequently misdiagnosed and difficult to treat due to their atypical presentation using structural imaging modalities including computed tomography and T1/T2-weighted magnetic resonance imaging (MRI). In this retrospective case series, we compared clinical MRI to amino acid positron emission tomography (PET) to assess the potential value of PET in the assessment of the extent of tumor involvement and in monitoring disease progression. We report the clinical course and serial multimodal imaging findings of four patients. Each patient presented at varying points in disease progression with widespread glioma brain involvement and was evaluated at least once by amino acid PET using alpha-[11C]methyl-L-tryptophan ([11C]-AMT). Increased uptake of [11C]-AMT was detected in a subset of non-enhancing brain lesions and detected tumor invasion before MRI signs of tumor in some regions. Increased uptake of [11C]-AMT was also detected in tumorous regions not detected by perfusion MRI or MR spectroscopy. Metabolic response to treatment was also observed in two patients. Overall, these data are consistent with and expand upon previous reports using other amino acid PET tracers in gliomatosis and show the potential added value of this imaging modality to clinical MRI in the detection and monitoring of these diffusely infiltrative tumors.