carbon-11-methionine and Glioblastoma

Response criteria of glioblastoma after chemoradiation do not account for metabolic changes that occur after treatment. The purpose of this study is to evaluate the utility of positron emission tomography (PET) imaging with C11 methionine (MET) (MET-PET) for detecting changes that occur after chemoradiation therapy and the value of molecular biomarkers for predicting the magnitude of metabolic response.. Patients with newly diagnosed glioblastoma undergoing standard chemoradiation treatment were enrolled in this prospective imaging study, with MET-PET scan performed within 3 days after surgical resection and again at 4 weeks after completion of chemoradiation. Near contemporaneous contrast-enhanced magnetic resonance imaging was performed within 2 weeks of each MET-PET scan. MET-PET imaging was analyzed for maximum standardized uptake value (SUV), SUVmean, and SUVvolume on a multimodality workstation.. A total of 18 patients underwent baseline postoperative MET-PET imaging, 14 of whom underwent postchemoradiation MET-PET imaging. Among those who showed residual MET-avid disease on immediate postoperative MET-PET scans and underwent postchemoradiation MET-PET imaging (n = 10), mean ΔSUVmax was -40% (range -100% to 0%), mean ΔSUVmean was -35% (range -100% to 0%), and mean ΔSUV volume was -64% (range -100% to 0%). The Δtumor/brain reference was -40% (range -100% to 0%) using SUVmax and -35% (range -100% to 0%) using SUVmean. In contrast, none of the T2-weighted images on contrast-enhanced magnetic resonance imaging showed a >25% reduction in abnormal T2/fluid-attenuated inversion recovery signal on visual assessment. ΔSUVmax, ΔSUVmean, and ΔSUVvolume correlated with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status (P = .01), but not with epidermal growth factor receptor or c-MET amplification status. All patients were IDH-1 wildtype.. MET-PET scanning shows a significant decrease in metabolic signal at 1 month after chemoradiation compared with the immediate postoperative period, even when T2/fluid-attenuated inversion recovery changed little. MGMT promoter methylation status further predicts differential metabolic responses. MET-PET may be a useful tool for delineation of radiation targets and assessment of response.

Topics: Aged; Chemoradiotherapy; Female; Glioblastoma; Humans; Male; Methionine; Middle Aged; Neoplasm, Residual; Positron-Emission Tomography; Postoperative Period; Treatment Outcome

Glioblastoma multiforme (GBM) is characterized by tissue hypoxia associated with resistance to radiotherapy and chemotherapy. To clarify the biological link between hypoxia and tumour-induced neovascularization and tumour aggressiveness, we analysed detailed volumetric and spatial information of viable hypoxic tissue assessed by (18)F-fluoromisonidazole (FMISO) PET relative to neovascularization in Gd-enhanced MRI and tumour aggressiveness by L-methyl-(11)C-methionine (MET) PET in newly diagnosed GBMs.. Ten patients with newly diagnosed GBMs were investigated with FMISO PET, MET PET and Gd-enhanced MRI before surgery. Tumour volumes were calculated by performing a three-dimensional threshold-based volume of interest (VOI) analysis for metabolically active volume on MET PET (MET uptake indices of ≥1.3 and ≥1.5) and Gd-enhanced volume on MRI. FMISO PET was scaled to the blood FMISO activity to create tumour to blood (T/B) images. The hypoxic volume (HV) was defined as the region with T/B greater than 1.2. PET and MR images of each patient were coregistered to analyse the spatial location of viable hypoxic tissue relative to neovascularization and active tumour extension.. Metabolically active tumour volumes defined using MET uptake indices of ≥1.3 and ≥1.5 and the volumes of Gd enhancement showed a strong correlation (r = 0.86, p < 0.01 for an index of ≥1.3 and r = 0.77, p < 0.05 for an index of ≥1.5). The HVs were also excellently correlated with the volumes of Gd enhancement (r = 0.94, p < 0.01). The metabolically active tumour volumes as defined by a MET uptake index of ≥1.3 and the HVs exhibited a strong correlation (r = 0.87, p < 0.01). On superimposed images, the metabolically active area on MET PET defined by a MET uptake index of ≥1.3 was usually larger than the area of the Gd enhancement and about 20-30% of the MET area extended outside the area of the enhancement. On the other hand, the surface area of viable hypoxic tissue with a T/B cutoff of ≥1.2 on FMISO PET did not substantially differ from the area of the Gd enhancement.. The volumetric analysis demonstrates that the viable hypoxic tissue assessed by FMISO PET is related to the neovascularization in Gd-enhanced MRI and the tumour aggressiveness by MET PET in newly diagnosed GBMs. The spatial analysis shows that the metabolically active tumour may be substantially underestimated by Gd-enhanced MRI. Complementary use of MET and FMISO to Gd-enhanced MRI may improve the understanding of tumour biology and lead to the most efficient delineation of tumour volume and treatment strategy.

Topics: Adult; Aged; Brain Neoplasms; Cell Hypoxia; Female; Glioblastoma; Humans; Male; Methionine; Middle Aged; Misonidazole; Positron-Emission Tomography; Tumor Burden

To determine whether increased uptake on 11C-methionine-PET (MET-PET) imaging obtained before radiation therapy and temozolomide is associated with the site of subsequent failure in newly diagnosed glioblastoma multiforme (GBM).. Patients with primary GBM were treated on a prospective trial with dose- escalated radiation and concurrent temozolomide. As part of the study, MET-PET was obtained before treatment but was not used for target volume definition. Using automated image registration, we assessed whether the area of increased MET-PET activity (PET gross target volume [GTV]) was fully encompassed within the high-dose region and compared the patterns of failure for those with and without adequate high-dose coverage of the PET-GTV.. Twenty-six patients were evaluated with a median follow-up of 15 months. Nineteen of 26 had appreciable (>1 cm(3)) volumes of increased MET-PET activity before treatment. Five of 19 patients had PET-GTV that was not fully encompassed within the high-dose region, and all five patients had noncentral failures. Among the 14 patients with adequately covered PET-GTV, only two had noncentral treatment failures. Three of 14 patients had no evidence of recurrence more than 1 year after radiation therapy. Inadequate PET-GTV coverage was associated with increased risk of noncentral failures. (p < 0.01).. Pretreatment MET-PET appears to identify areas at highest risk for recurrence for patients with GBM. It would be reasonable to test a strategy of incorporating MET-PET into radiation treatment planning, particularly for identifying areas for conformal boost.

Topics: Adult; Aged; Algorithms; Antineoplastic Agents, Alkylating; Biopsy; Brain; Brain Neoplasms; Combined Modality Therapy; Dacarbazine; Disease Progression; Glioblastoma; Humans; Magnetic Resonance Imaging; Methionine; Middle Aged; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Retreatment; Software; Temozolomide; Treatment Failure; Young Adult

Nowadays, the quantitative analysis of PET/CT data in patients with glioblastoma is not strictly standardized in the clinic and does not exclude the human factor. This study aimed to evaluate the relationship between the radiomic features of glioblastoma 11C-methionine PET images and the tumor-to-normal brain (T/N) ratio determined by radiologists in clinical routine. PET/CT data were obtained for 40 patients (mean age 55 ± 12 years; 77.5% men) with a histologically confirmed diagnosis of glioblastoma. Radiomic features were calculated for the whole brain and tumor-containing regions of interest using the RIA package for R. We redesigned the original RIA functions for GLCM and GLRLM calculation to reduce computation time significantly. Machine learning over radiomic features was applied to predict T/N with the best median correlation between the true and predicted values of 0.73 (p = 0.01). The present study showed a reproducible linear relationship between 11C-methionine PET radiomic features and a T/N indicator routinely assessed in brain tumors. Radiomics enabled utilizing texture properties of PET/CT neuroimaging that may reflect the biological activity of glioblastoma and can potentially augment the radiological assessment.

Topics: Adult; Aged; Carbon Radioisotopes; Female; Glioblastoma; Humans; Male; Methionine; Middle Aged; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Retrospective Studies

11C-Methionine (11C-MET) PET prognostication of isocitrate dehydrogenase (IDH) wild type glioblastomas is inadequate as conventional parameters such as standardized uptake value (SUV) do not adequately reflect tumor heterogeneity. We retrospectively evaluated whether volume-based parameters such as metabolic tumor volume (MTV) and total lesion methionine metabolism (TLMM) outperformed SUV for survival correlation in patients with IDH wild type glioblastomas.. Thirteen IDH wild type glioblastoma patients underwent preoperative 11C-MET PET. Both SUV-based parameters and volume-based parameters were calculated for each lesion. Kaplan-Meier curves with log-rank testing and Cox regression analysis were used for correlation between PET parameters and overall survival.. Median overall survival for the entire cohort was 393 days. MTV (HR 1.136, p = 0.007) and TLMM (HR 1.022, p = 0.030) were inversely correlated with overall survival. SUV-based 11C-MET PET parameters did not show a correlation with survival. In a paired analysis with other clinical parameters including age and radiotherapy dose, MTV and TLMM were found to be independent factors.. MTV and TLMM, and not SUV, significantly correlate with overall survival in patients with IDH wild type glioblastomas. The incorporation of volume-based 11C-MET PET parameters may lead to a better outcome prediction for this heterogeneous patient population.

Topics: Adult; Aged; Disease-Free Survival; Female; Glioblastoma; Humans; Isocitrate Dehydrogenase; Male; Methionine; Middle Aged; Neoplasm Proteins; Positron Emission Tomography Computed Tomography; Survival Rate; Tumor Burden

We previously reported that glioma stemlike cells (GSCs) exist in the area of the tumor periphery showing no gadolinium enhancement on magnetic resonance imaging. In the present work, we analyzed glucose metabolism to investigate whether lactate could be predictive of tumor invasiveness and of use in detection of the tumor invasion area in glioblastoma multiforme (GBM).. The expression of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase (PDH) was investigated in 20 patients. In GSC lines, LDH-A and PDH expression also was examined in parallel to assessments of mitochondrial respiration. We then investigated the relationship between lactate/creatine ratios in the tumor periphery measured by magnetic resonance spectroscopy, using learning-compression-model algorithms and phenotypes of GBMs.. In 20 GBMs, high-invasive GBM expressed LDH-A at significantly higher expression than did low-invasive GBM, whereas low-invasive GBM showed significantly higher expression of PDH than did high-invasive GBM. The highly invasive GSC line showed higher expression of LDH-A and lower expression of PDH compared with low-invasive GSC lines. The highly invasive GSC line also showed the lowest consumption of oxygen and the lowest production of adenosine triphosphate. Lactate levels, as measured by magnetic resonance spectroscopy, showed a significant positive correlation with LDH-A transcript levels, permitting classification of the GBMs into high-invasive and low-invasive phenotypes based on a cutoff value of 0.66 in the lactate/creatine ratio.. In the tumor periphery area of the highly invasive GBM, aerobic glycolysis was the predominant pathway for glucose metabolism, resulting in the accumulation of lactate. The level of lactate may facilitate prediction of the tumor-infiltrating area on GBM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Brain Neoplasms; Chemoradiotherapy, Adjuvant; Energy Metabolism; Female; Glioblastoma; Humans; Lactate Dehydrogenase 5; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Methionine; Middle Aged; Mitochondria; Neoplastic Stem Cells; Neurosurgical Procedures; Positron-Emission Tomography; Pyruvate Dehydrogenase (Lipoamide); Radiopharmaceuticals; RNA, Messenger; Temozolomide; Young Adult

The purpose of this work was to define the optimal margins for gadolinium-enhanced T(1)-weighted magnetic resonance imaging (Gd-MRI) and T(2)-weighted MRI (T(2)-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([(11)C]MET-PET) findings.. Computed tomography (CT), MRI, and [(11)C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T(2)-MRI of the CTV (CTV-T(2)) were compared with the extent of [(11)C]MET-PET (CTV--[(11)C]MET-PET) uptake by using CT--MRI or CT--[(11)C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T(2) (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T(2), respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [(11)C]MET-PET and the relationship between CTV-T(2) (x mm) and CTV-- [(11)C]MET-PET.. The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T(2) (20 mm) (96.4%) was significantly higher than that of the other CTV-T(2) (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T(2) (x = 20 mm).. It is necessary to use a margin of at least 2 cm for CTV-T(2) for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T(2)-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Contrast Media; Female; Gadolinium; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Methionine; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy Planning, Computer-Assisted; Sensitivity and Specificity; Tomography, Spiral Computed; Tumor Burden; Young Adult

To determine the maximum-tolerated dose (MTD) of radiation (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma (GBM), to estimate their progression-free (PFS) and overall survival (OS), and to assess the role of (11)C methionine PET (MET-PET) imaging in predicting recurrence.. Intensity-modulated RT (IMRT) doses of 66 to 81 Gy, assigned to patients by the time-to-event continual reassessment method, were delivered over 6 weeks with concurrent daily temozolomide (75 mg/m(2)) followed by adjuvant cyclic temozolomide (200 mg/m(2) d1-5 q28d ×6 cycles). Treatment was based on gadolinium-enhanced MRI. Pretreatment MET-PET scans were obtained for correlation with eventual sites of failure.. A total of 38 patients were analyzed with a median follow-up of 54 months for patients who remain alive. Late CNS grade ≥III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). None of 22 patients receiving 75 or less Gy developed RT necrosis. Median OS and PFS were 20.1 (14.0-32.5) and 9.0 (6.0-11.7) months, respectively. Twenty-two of 32 patients with pretreatment MET-PET uptake showed uptake beyond the contrast-enhanced MRI. Patients whose treatment did not include the region of increased MET-PET uptake showed an increased risk of noncentral failure (P < 0.001).. Patients with GBM can safely receive standard temozolomide with 75 Gy in 30 fractions, delivered using IMRT. The median OS of 20.1 months is promising. Furthermore, MET-PET appears to predict regions of high risk of recurrence not defined by MRI, suggesting that further improvements may be possible by targeting metabolically active regions.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Chemoradiotherapy; Dacarbazine; Dose Fractionation, Radiation; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Methionine; Middle Aged; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Radiotherapy, Intensity-Modulated; Salvage Therapy; Survival Rate; Temozolomide; Tissue Distribution; Young Adult

The aim of our study was to examine the usefulness of PET with C-methionine (MET) and F-fluorodeoxyglucose (FDG) in the differentiation of glioblastoma multiforme (GBM) and intracranial diffuse large B-cell lymphoma (DLBCL).. We evaluated 22 patients retrospectively with an enhancing brain tumor on MRI, including 15 GBM and 7 DLBCL, which was confirmed by histopathology. Dynamic PET scans with MET and FDG were performed for preoperative differential diagnosis. We assessed the images qualitatively and quantitatively. In quantitative assessment, the SUVmax was used on FDG PET and both late and early phases on MET PET. In addition, the ratio of SUVmax in the late and early phases on MET-PET was evaluated (ΔSUVmax).. SUVmax on FDG PET of DLBCL was significantly higher than that of GBM. Setting an SUVmax of 12.0 as the cutoff for differentiating DLBCL from GBM, 1 GBM and 1 DLBCL were found to be false-positive and false-negative, respectively.SUVmax in the late and early phases of MET-PET was not significantly different between DLBCL and GBM; however, we also found significant differences in ΔSUVmax on MET-PET. Using ΔSUVmax 1.17 as the cutoff, we could differentiate DLBCL from GBM completely. In the present study, ΔSUVmax on MET-PET was slightly superior to SUVmax on FDG PET.. Both SUVmax on FDG PET and ΔSUVmax on MET-PET were considered to be good diagnostic tests when encountering difficulties in this differential diagnosis.

Topics: Adult; Aged; Aged, 80 and over; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Glioblastoma; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Methionine; Middle Aged; Positron-Emission Tomography; Quality Control; Retrospective Studies; Young Adult

We have investigated dual-time-point (18)F-FDG PET for the detection and delineation of high-grade brain tumors using quantitative criteria applied on a voxel basis.. Twenty-five patients with suspected high-grade brain tumors and inconclusive MRI findings underwent (11)C-methionine PET and dual-time-point (18)F-FDG PET. Images from each subject were registered and spatially normalized. Parametric maps of standardized uptake value (SUV) and tumor-to-normal gray matter (TN) ratio for each PET image were obtained. Tumor diagnosis was evaluated according to 4 criteria comparing standard and delayed (18)F-FDG PET images: any SUV increase, SUV increase greater than 10%, any TN increase, and TN increase greater than 10%. Voxel-based analysis sensitivity was assessed using (11)C-methionine as a reference and compared with visual and volume-of-interest analysis for dual-time-point PET images. Additionally, volumetric assessment of the tumor extent that fulfills each criterion was compared with the volume defined for (11)C-methionine PET.. The greatest sensitivity for tumor identification was obtained with any increase of TN ratio (100%), followed by a TN increase greater than 10% (96%), any SUV increase (80%), and an SUV increase greater than 10% (60%). These values were superior to visual analysis of standard (18)F-FDG (sensitivity, 40%) and delayed (18)F-FDG PET (sensitivity, 52%). Volume-of-interest analysis of dual-time-point PET reached a sensitivity of only 64% using the TN increase criterion. Regarding volumetry, voxel-based analysis with the TN ratio increase as a criterion, compared with (11)C-methionine PET, detected 55.4% of the tumor volume, with the other criteria detecting volumes lower than 20%. Nevertheless, volume detection presented great variability, being better for metastasis (78%) and glioblastomas (56%) than for anaplastic tumors (12%). A positive correlation was observed between the volume detected and the time of acquisition of the delayed PET image (r = 0.66, P < 0.001), showing volumes greater than 75% when the delayed image was obtained at least 6 h after (18)F-FDG injection.. Compared with standard (18)F-FDG PET studies, quantitative dual-time-point (18)F-FDG PET can improve sensitivity for the identification and volume delineation of high-grade brain tumors.

Topics: Adolescent; Adult; Aged; Brain; Brain Neoplasms; Child; Female; Fluorodeoxyglucose F18; Glioblastoma; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Methionine; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Young Adult

Thallium-201, carbon-11 methionine (MET) and fluorine-18 fluorodeoxyglucose (FDG) have all been used to assess brain tumours. The aim of this study was to determine which of these tracers are of use for evaluating the histological grade and the extent of astrocytoma. 201Tl single-photon emission tomography (SPET), MET positron emission tomography (PET) and FDG PET were all performed in 23 patients (13 men, 10 women) with newly diagnosed astrocytic tumours [seven with astrocytoma (grade II), ten with anaplastic astrocytoma (grade III) and six with glioblastoma (grade IV)]. The 201Tl uptake of the tumours was evaluated by a lesion-to-normal region count ratio. Both MET and FDG uptake of the tumours was evaluated by a semiquantitative analysis using the standardized uptake value. 201Tl uptake was found to increase in rank order with histological grade and was significantly different among the three groups (grade II: 1.51+/-0.36; grade III: 2.58+/-1.50; grade IV: 7. 65+/-3.84). MET uptake in grade II (1.49+/-0.44) was also significantly lower than that in both grade III (3.29+/-1.44) and grade IV (3.20+/-0.92). FDG uptake was not significantly different among the three groups (grade II: 2.90+/-0.45; grade III: 3.86+/-1. 56; grade IV: 3.57+/-0.83). No significant correlation was observed between 201Tl uptake and either MET uptake or FDG uptake. In most patients, the extent of the increased MET uptake was the largest while that of the increased FDG uptake was the smallest. In patients with positive 201Tl uptake, the extent of the 201Tl uptake was equal to or smaller than that of gadolinium enhancement. For evaluation of histological grade of astrocytic tumours. 201Tl is therefore considered to be useful though the 201Tl uptake in some grade III astrocytomas was not different from that in grade II astrocytomas. MET was found to be highly useful for detecting astrocytomas, for differentiating between benign and malignant astrocytomas, and for evaluating the extent of astrocytomas; however, it was not sufficiently useful permit evaluation of the histological grade. FDG was not found to be useful either for evaluating the histological grade or for differentiating between benign and malignant astrocytomas.

Topics: Astrocytoma; Brain; Brain Neoplasms; Carbon Radioisotopes; Diagnosis, Differential; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Methionine; Middle Aged; Radiopharmaceuticals; Thallium Radioisotopes; Tomography, Emission-Computed; Tomography, Emission-Computed, Single-Photon

Topics: Aged; Brain Neoplasms; Deoxyglucose; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glioblastoma; Humans; Male; Meningeal Neoplasms; Meningioma; Methionine; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Parietal Lobe; Tomography, Emission-Computed