The impact of brain lesions on health-related quality of life in patients with WHO CNS grade 3 or 4 glioma: a lesion-function and resting-state fMRI analysis.

PURPOSE: In glioma patients, tumor development and multimodality therapy are associated with changes in health-related quality of life (HRQoL). It is largely unknown how different types and locations of tumor- and treatment-related brain lesions, as well as their relationship to white matter tracts and functional brain networks, affect HRQoL. METHODS: In 121 patients with pretreated gliomas of WHO CNS grades 3 or 4, structural MRI, O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET, resting-state functional MRI (rs-fMRI) and self-reported HRQoL questionnaires (EORTC QLQ-C30/BN20) were obtained. Resection cavities, T1-enhancing lesions, T2/FLAIR hyperintensities, and lesions with pathologically increased FET uptake were delineated. Effects of tumor lateralization, involvement of white matter tracts or resting-state network nodes by different types of lesions and within-network rs-fMRI connectivity were analyzed in terms of their interaction with HRQoL scores. RESULTS: Right hemisphere gliomas were associated with significantly less favorable outcomes in physical, role, emotional and social functioning, compared with left-sided tumors. Most functional HRQoL scores correlated significantly with right-sided white-matter tracts involvement by T2/FLAIR hyperintensities and with loss of within-network functional connectivity of right-sided nodes. Tumors of the left hemisphere caused significantly more communication deficits. CONCLUSION: In pretreated high-grade gliomas, right hemisphere lesions are associated with reduced HRQoL scores in most functional domains except communication ability, compared to tumors of the left hemisphere. These relationships are mainly observed for T2/FLAIR lesions involving structural and functional networks in the right hemisphere. The data suggest that sparing the right hemisphere from treatment-related tissue damage may improve HRQoL in glioma patients.

Static FET PET radiomics for the differentiation of treatment-related changes from glioma progression.

PURPOSE: To investigate the potential of radiomics applied to static clinical PET data using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine (FET) to differentiate treatment-related changes (TRC) from tumor progression (TP) in patients with gliomas. PATIENTS AND METHODS: One hundred fifty-one (151) patients with histologically confirmed gliomas and post-therapeutic progressive MRI findings according to the response assessment in neuro-oncology criteria underwent a dynamic amino acid PET scan using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine (FET). Thereof, 124 patients were investigated on a stand-alone PET scanner (data used for model development and validation), and 27 patients on a hybrid PET/MRI scanner (data used for model testing). Mean and maximum tumor to brain ratios (TBRmean, TBRmax) were calculated using the PET data from 20 to 40 min after tracer injection. Logistic regression models were evaluated for the FET PET parameters TBRmean, TBRmax, and for radiomics features of the tumor areas as well as combinations thereof to differentiate between TP and TRC. The best performing models in the validation dataset were finally applied to the test dataset. The diagnostic performance was assessed by receiver operating characteristic analysis. RESULTS: Thirty-seven patients (25%) were diagnosed with TRC, and 114 (75%) with TP. The logistic regression model comprising the conventional FET PET parameters TBRmean and TBRmax resulted in an AUC of 0.78 in both the validation (sensitivity, 64%; specificity, 80%) and the test dataset (sensitivity, 64%; specificity, 80%). The model combining the conventional FET PET parameters and two radiomics features yielded the best diagnostic performance in the validation dataset (AUC, 0.92; sensitivity, 91%; specificity, 80%) and demonstrated its generalizability in the independent test dataset (AUC, 0.85; sensitivity, 81%; specificity, 70%). CONCLUSION: The developed radiomics classifier allows the differentiation between TRC and TP in pretreated gliomas based on routinely acquired static FET PET scans with a high diagnostic accuracy.

Diagnostic impact of additional O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET following immunotherapy with dendritic cell vaccination in glioblastoma patients.

OBJECTIVE: Vaccination therapy using tumour antigen-loaded, autologous dendritic cells (DC) is a promising therapeutic approach alongside standard treatment for glioblastoma (GBM). However, reliable diagnostic criteria regarding therapy monitoring are not established. Here, we analysed the impact of additional 18F-fluoroethyl-tyrosine positron emission tomography (18F-FET PET) imaging following DC vaccination therapy. METHODS: We analysed data of GBM patients who received DC vaccination therapy. Following MRI diagnosis of tumour recurrence, additional static and dynamic 18F-FET PET imaging was performed. Vaccination was performed five times by intradermal injections, either weekly between concomitant radio/-chemotherapy and intermittent chemotherapy or after tumour recurrence, before re-radiation therapy. MRI and 18F-FET PET results were compared and correlated with clinical data. RESULTS: Between 2003 and 2016, 5 patients were identified who received DC vaccination and 18F-FET PET imaging (1 female/4 males; mean age: 44 ± 14 y). 3/5 patients showed congruent results of tumour progression. In three patients 18F-FET PET indicated treatment related changes, which was in contrast to MRI findings that indicated tumour progression. In these patients 18F-FET PET results could be confirmed by either neuropathological diagnosis or according to the RANO criteria. CONCLUSIONS: Despite the small patients number our results indicate an additional impact of 18F-FET PET for monitoring outcome following vaccination therapy.

Invasive versus non-invasive mapping of the motor cortex.

Precise and comprehensive mapping of somatotopic representations in the motor cortex is clinically essential to achieve maximum resection of brain tumours whilst preserving motor function, especially since the current gold standard, that is, intraoperative direct cortical stimulation (DCS), holds limitations linked to the intraoperative setting such as time constraints or anatomical restrictions. Non-invasive techniques are increasingly relevant with regard to pre-operative risk-assessment. Here, we assessed the congruency of neuronavigated transcranial magnetic stimulation (nTMS) and functional magnetic resonance imaging (fMRI) with DCS. The motor representations of the hand, the foot and the tongue regions of 36 patients with intracranial tumours were mapped pre-operatively using nTMS and fMRI and by intraoperative DCS. Euclidean distances (ED) between hotspots/centres of gravity and (relative) overlaps of the maps were compared. We found significantly smaller EDs (11.4 ± 8.3 vs. 16.8 ± 7.0 mm) and better spatial overlaps (64 ± 38% vs. 37 ± 37%) between DCS and nTMS compared with DCS and fMRI. In contrast to DCS, fMRI and nTMS mappings were feasible for all regions and patients without complications. In summary, nTMS seems to be the more promising non-invasive motor cortex mapping technique to approximate the gold standard DCS results.

Prediction of survival in patients with IDH-wildtype astrocytic gliomas using dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET.

PURPOSE: Integrated histomolecular diagnostics of gliomas according to the World Health Organization (WHO) classification of 2016 has refined diagnostic accuracy and prediction of prognosis. This study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in newly diagnosed, histomolecularly classified astrocytic gliomas of WHO grades III or IV. METHODS: Before initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumour/brain ratios (TBRmax/mean), the metabolic tumour volume (MTV) as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated concerning the progression-free and overall survival (PFS, OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess the predictive power of these parameters for survival. RESULTS: Sixty patients (45 GBM and 15 AA patients) of two university centres were retrospectively identified. Patients with isocitrate dehydrogenase (IDH)-mutant or O6-methylguanine-DNA-methyltransferase (MGMT) promoter-methylated tumours had a significantly longer PFS and OS (both P < 0.001). Furthermore, ROC analysis of IDH-wildtype glioma patients (n = 45) revealed that a TTP > 25 min (AUC, 0.90; sensitivity, 90%; specificity, 87%; P < 0.001) was highly prognostic for longer PFS (13 vs. 7 months; P = 0.005) and OS (29 vs. 12 months; P < 0.001). In contrast, at a lower level of significance, TBRmax, TBRmean, and MTV were only prognostic for longer OS (P = 0.004, P = 0.038, and P = 0.048, respectively). Besides complete resection and a methylated MGMT promoter, TTP remained significant in multivariate survival analysis (all P ≤ 0.02), indicating an independent predictor for OS. CONCLUSIONS: Our data suggest that dynamic FET PET allows the identification of patients with longer OS among patients with newly diagnosed IDH-wildtype GBM and AA.

Differentiation of treatment-related changes from tumour progression: a direct comparison between dynamic FET PET and ADC values obtained from DWI MRI.

BACKGROUND: Following brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumour progression. PATIENTS AND METHODS: Forty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment was 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI coregistered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher's exact test for a combinational approach. RESULTS: Ten of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89 ± 0.05; P < 0.001) than that of ADC values (threshold ADC, 1.09 × 10-3 mm2/s; accuracy, 69%; AUC, 0.73 ± 0.09; P = 0.13). The addition of static FET PET parameters to ADC values increased the latter's accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%). Moreover, in contrast to ADC values, TBRs <1.95 at suspected progression predicted a significantly longer survival (P = 0.01). CONCLUSIONS: Data suggest that static and dynamic FET PET provide valuable information concerning the differentiation of early treatment-related changes from tumour progression and outperform ADC measurement for this highly relevant clinical question.

Use of FET PET in glioblastoma patients undergoing neurooncological treatment including tumour-treating fields: initial experience.

PURPOSE: We present our first clinical experience with O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET in patients with high-grade glioma treated with various neurooncological therapies including tumour-treating fields (TTFields) for the differentiation of tumour progression from treatment-related changes. METHODS: We retrospectively assessed 12 patients (mean age 51 ± 12 years, range 33-72 years) with high-grade glioma (11 glioblastomas, 1 gliosarcoma) in whom the treatment regimen included TTFields and who had undergone FET PET scans for differentiation of tumour progression from treatment-related changes. Mean and maximum tumour-to-brain ratios (TBRmean, TBRmax) were calculated. The definitive diagnosis (tumour progression or posttherapeutic changes) was confirmed either by histopathology (4 of 12 patients) or on clinical follow-up. RESULTS: In all nine patients with confirmed tumour progression, the corresponding FET PET showed increased uptake (TBRmax 3.5 ± 0.6, TBRmean 2.7 ± 0.7). In one of these nine patients, FET PET was consistent with treatment-related changes, whereas standard MRI showed a newly diagnosed contrast-enhancing lesion. In two patients treated solely with TTFields without any other concurrent neurooncological therapy, serial FET PET revealed a decrease in metabolic activity over a follow-up of 6 months or no FET uptake without any signs of tumour progression or residual tumour on conventional MRI. CONCLUSION: FET PET may add valuable information in monitoring therapy in individual patients with high-grade glioma undergoing neurooncological treatment including TTFields.

Static and dynamic 18F-FET PET for the characterization of gliomas defined by IDH and 1p/19q status.

PURPOSE: The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion. METHODS: Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic 18F-FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBRmean/max), as well as dynamic parameters (time-to-peak and slope) of 18F-FET uptake were calculated. RESULTS: Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBRmean, TBRmax, TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (P < 0.01). TBRmean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBRmean, TBRmax, TTP, and slope discriminated between gliomas with and without IDH mutation (p < 0.01). The best diagnostic performance was obtained for the combination of TTP with TBRmax or slope (accuracy, 73%). CONCLUSION: Data suggest that static and dynamic 18F-FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by 18F-FET PET.

Early treatment response evaluation using FET PET compared to MRI in glioblastoma patients at first progression treated with bevacizumab plus lomustine.

BACKGROUND: The goal of this prospective study was to compare the value of both conventional MRI and O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET for response evaluation in glioblastoma patients treated with bevacizumab plus lomustine (BEV/LOM) at first progression. METHODS: After chemoradiation with concomitant and adjuvant temozolomide, 21 IDH wild-type glioblastoma patients at first progression (age range, 33-75 years; MGMT promoter unmethylated, 81%) were treated with BEV/LOM. Contrast-enhanced MRI and FET-PET scans were performed at baseline and after 8-10 weeks. We obtained FET metabolic tumor volumes (MTV) and tumor/brain ratios. Threshold values of FET-PET parameters for treatment response were established by ROC analyses using the post-progression overall survival (OS) ≤/>9 months as the reference. MRI response assessment was based on RANO criteria. The predictive ability of FET-PET thresholds and MRI changes on early response assessment was evaluated subsequently concerning OS using uni- and multivariate survival estimates. RESULTS: Early treatment response as assessed by RANO criteria was not predictive for an OS>9 months (P = 0.203), whereas relative reductions of all FET-PET parameters significantly predicted an OS>9 months (P < 0.05). The absolute MTV at follow-up enabled the most significant OS prediction (sensitivity, 85%; specificity, 88%; P = 0.001). Patients with an absolute MTV below 5 ml at follow-up survived significantly longer (12 vs. 6 months, P < 0.001), whereas early responders defined by RANO criteria lived only insignificantly longer (9 vs. 6 months; P = 0.072). The absolute MTV at follow-up remained significant in the multivariate survival analysis (P = 0.006). CONCLUSIONS: FET-PET appears to be useful for identifying responders to BEV/LOM early after treatment initiation.

Imaging of amino acid transport in brain tumours: Positron emission tomography with O-(2-[18F]fluoroethyl)-L-tyrosine (FET).

The assessment of cerebral gliomas using magnetic resonance imaging (MRI) provides excellent structural images but cannot solve all diagnostic problems satisfactorily. The differentiation of tumour tissue from non-neoplastic changes may be difficult especially in the post-treatment phase. In recent years, positron emission tomography (PET) using radiolabelled amino acids has gained considerable interest as an additional tool to improve the diagnosis of cerebral gliomas and brain metastases. A key step for this advancement was the development of the F-18 labelled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) which has spread rapidly in the last decade and replaced carbon-11 labelled amino acid tracers such as 11C-methyl-L-methionine (MET) in many centres in Europe. FET can be produced with high efficiency and distributed in a satellite concept like 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Furthermore, FET exhibits favourable properties such as high in vivo stability, high tumour to background contrast and tissue specific tracer kinetics, which provides additional information for tumour grading or differential diagnosis. The Response Assessment in Neuro-Oncology (RANO) working group - an international effort to develop new standardized response criteria for clinical trials in brain tumours - has recently recommended the additional use of amino acid PET imaging for brain tumour management. FET PET can provide important diagnostic information in crucial situations such as the definition of biopsy site, the delineation of cerebral gliomas for therapy planning, sensitive monitoring of treatment response and an improved differentiation of tumour recurrence from treatment-related changes. In this article the basic information, methodological aspects and the actual status of clinical application of FET PET are reviewed.

Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation.

Novel therapeutic targets in malignant glioma patients are urgently needed. Point mutations of the v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene occur predominantly in melanoma patients, but may also occur in gliomas. Thus, this is a target of great interest for this group of patients. In a nine-year-old male patient, an anaplastic astrocytoma in the left temporoparietal region was diagnosed histologically. After first- and second-line treatment, a malignant progression to a secondary glioblastoma was observed ten years after the initial diagnosis. Within the following seven years, all other conventional treatment options were exhausted. At this time point, recurrent tumor histology revealed an epithelioid glioblastoma, without a mutation in the isocitrate dehydrogenase gene (IDH wild-type). In order to identify a potential target for an experimental salvage therapy, mutational tumor analysis showed a BRAF V600E mutation. Consecutively, dabrafenib treatment was initiated. The patient remained clinically stable, and follow-up magnetic resonance images (MRI) were consistent with "Stable Disease" according to the Response Assessment in Neuro-Oncology Working Group (RANO) criteria for the following ten months until tumor progression was detected. The patient died 16 months after dabrafenib treatment initiation. Particularly in younger glioma patients as well as in patients with an epithelioid glioblastoma, screening for a V600E BRAF mutation is promising since, in these cases, targeted therapy with BRAF inhibitors seems to be a useful salvage treatment option.

Comparison of 18F-FET PET and perfusion-weighted MRI for glioma grading: a hybrid PET/MR study.

PURPOSE: Both perfusion-weighted MR imaging (PWI) and O-(2-18F-fluoroethyl)-L-tyrosine PET (18F-FET) provide grading information in cerebral gliomas. The aim of this study was to compare the diagnostic value of 18F-FET PET and PWI for tumor grading in a series of patients with newly diagnosed, untreated gliomas using an integrated PET/MR scanner. METHODS: Seventy-two patients with untreated gliomas [22 low-grade gliomas (LGG), and 50 high-grade gliomas (HGG)] were investigated with 18F-FET PET and PWI using a hybrid PET/MR scanner. After visual inspection of PET and PWI maps (rCBV, rCBF, MTT), volumes of interest (VOIs) with a diameter of 16 mm were centered upon the maximum of abnormality in the tumor area in each modality and the contralateral unaffected hemisphere. Mean and maximum tumor-to-brain ratios (TBRmean, TBRmax) were calculated. In addition, Time-to-Peak (TTP) and slopes of time-activity curves were calculated for 18F-FET PET. Diagnostic accuracies of 18F-FET PET and PWI for differentiating low-grade glioma (LGG) from high-grade glioma (HGG) were evaluated by receiver operating characteristic analyses (area under the curve; AUC). RESULTS: The diagnostic accuracy of 18F-FET PET and PWI to discriminate LGG from HGG was similar with highest AUC values for TBRmean and TBRmax of 18F-FET PET uptake (0.80, 0.83) and for TBRmean and TBRmax of rCBV (0.80, 0.81). In case of increased signal in the tumor area with both methods (n = 32), local hot-spots were incongruent in 25 patients (78%) with a mean distance of 10.6 ± 9.5 mm. Dynamic FET PET and combination of different parameters did not further improve diagnostic accuracy. CONCLUSIONS: Both 18F-FET PET and PWI discriminate LGG from HGG with similar diagnostic performance. Regional abnormalities in the tumor area are usually not congruent indicating that tumor grading by 18F-FET PET and PWI is based on different pathophysiological phenomena.

Radiation injury vs. recurrent brain metastasis: combining textural feature radiomics analysis and standard parameters may increase 18F-FET PET accuracy without dynamic scans.

OBJECTIVES: We investigated the potential of textural feature analysis of O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET to differentiate radiation injury from brain metastasis recurrence. METHODS: Forty-seven patients with contrast-enhancing brain lesions (n = 54) on MRI after radiotherapy of brain metastases underwent dynamic 18F-FET PET. Tumour-to-brain ratios (TBRs) of 18F-FET uptake and 62 textural parameters were determined on summed images 20-40 min post-injection. Tracer uptake kinetics, i.e., time-to-peak (TTP) and patterns of time-activity curves (TAC) were evaluated on dynamic PET data from 0-50 min post-injection. Diagnostic accuracy of investigated parameters and combinations thereof to discriminate between brain metastasis recurrence and radiation injury was compared. RESULTS: Diagnostic accuracy increased from 81 % for TBRmean alone to 85 % when combined with the textural parameter Coarseness or Short-zone emphasis. The accuracy of TBRmax alone was 83 % and increased to 85 % after combination with the textural parameters Coarseness, Short-zone emphasis, or Correlation. Analysis of TACs resulted in an accuracy of 70 % for kinetic pattern alone and increased to 83 % when combined with TBRmax. CONCLUSIONS: Textural feature analysis in combination with TBRs may have the potential to increase diagnostic accuracy for discrimination between brain metastasis recurrence and radiation injury, without the need for dynamic 18F-FET PET scans. KEY POINTS: • Textural feature analysis provides quantitative information about tumour heterogeneity • Textural features help improve discrimination between brain metastasis recurrence and radiation injury • Textural features might be helpful to further understand tumour heterogeneity • Analysis does not require a more time consuming dynamic PET acquisition.

Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-L-tyrosine PET.

PURPOSE: The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood-brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma. METHODS: A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with (18)F-FET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) were determined. (18)F-FET uptake kinetic parameters (i.e. patterns of time-activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS). RESULTS: PsP was confirmed in 11 of the 22 patients. In patients with PsP, (18)F-FET uptake was significantly lower than in patients with EP (TBRmax 1.9 ± 0.4 vs. 2.8 ± 0.5, TBRmean 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal (18)F-FET TBRmax cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBRmax <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046). CONCLUSION: (18)F-FET PET may facilitate the diagnosis of PsP following radiochemotherapy of glioblastoma.

Uptake and tracer kinetics of O-(2-(18)F-fluoroethyl)-L-tyrosine in meningiomas: preliminary results.

PURPOSE: O-(2-[(18)F]Fluoroethyl)-L-tyrosine ((18)F-FET) is a well-established PET tracer for the imaging of cerebral gliomas, but little is known about (18)F-FET uptake in meningiomas. The aim of this study was to explore (18)F-FET kinetics and tumour-to-background contrast in meningiomas of various histologies. METHODS: A group of 24 patients with suspected cerebral meningioma on MRI/CT had an additional dynamic (18)F-FET PET scan prior to surgery. Time-activity curves (TAC) of (18)F-FET uptake in the tumours and tumour-to-brain ratios (TBR) for early (3 - 14 min after injection) and late (18)F-FET uptake (20 - 40 min after injection) were analysed and compared with histological subtypes and WHO grade. (18)F-FET uptake in critical structures in the skull base was also evaluated in terms of tumour-to-tissue (T/Tis) ratio. RESULTS: TBR of (18)F-FET uptake in meningiomas was significantly higher in the early phase than in the late phase (3.5 ± 0.8 vs. 2.2 ± 0.3; P < 0.001). The difference in TBR between low-grade meningiomas (WHO grade I, 18 patients) and high-grade meningiomas (WHO grade II or III, 6 patients) was significant in the late phase of (18)F-FET uptake (2.1 ± 0.2 vs. 2.5 ± 0.2, P = 0.003) while there was no significant difference in the early phase. ROC analysis showed that TBR of (18)F-FET uptake in the late phase had significant power to differentiate low-grade from high-grade meningiomas (AUC 0.87 ± 0.18, sensitivity 83 %, specificity 83 %, optimal cut-off 2.3; P < 0.01). Evaluation of TAC yielded three different curve patterns of (18)F-FET PET uptake. Combination of TBR (cut-off value 2.3) and TAC pattern slightly improved the differentiation of high-grade from low-grade meningiomas (accuracy 92 %; P = 0.001). Analysis of background radioactivity in the skull base indicated that (18)F-FET uptake may be helpful in distinguishing meningioma tissue in the late phase. T/Tis ratios were >1.2 in all patients for the periorbita, sphenoidal sinus, pituitary gland, tentorium, bone and brain, in more than 90 % of patients for the mucosa and dura, but in only 63 % of patients for the cavernous sinus. CONCLUSION: (18)F-FET PET may provide additional information for noninvasive grading of meningiomas and possibly for the discrimination of tumour in critical areas of the skull base. A further evaluation of (18)F-FET PET in meningiomas appears to be justified.

Dual-time-point O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for grading of cerebral gliomas.

OBJECTIVE: We aimed to evaluate the diagnostic potential of dual-time-point imaging with positron emission tomography (PET) using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) for non-invasive grading of cerebral gliomas compared with a dynamic approach. METHODS: Thirty-six patients with histologically confirmed cerebral gliomas (21 primary, 15 recurrent; 24 high-grade, 12 low-grade) underwent dynamic PET from 0 to 50 min post-injection (p.i.) of (18)F-FET, and additionally from 70 to 90 min p.i. Mean tumour-to-brain ratios (TBRmean) of (18)F-FET uptake were determined in early (20-40 min p.i.) and late (70-90 min p.i.) examinations. Time-activity curves (TAC) of the tumours from 0 to 50 min after injection were assigned to different patterns. The diagnostic accuracy of changes of (18)F-FET uptake between early and late examinations for tumour grading was compared to that of curve pattern analysis from 0 to 50 min p.i. of (18)F-FET. RESULTS: The diagnostic accuracy of changes of the TBRmean of (18)F-FET PET uptake between early and late examinations for the identification of HGG was 81% (sensitivity 83%; specificity 75%; cutoff - 8%; p < 0.001), and 83% for curve pattern analysis (sensitivity 88%; specificity 75%; p < 0.001). CONCLUSION: Dual-time-point imaging of (18)F-FET uptake in gliomas achieves diagnostic accuracy for tumour grading that is similar to the more time-consuming dynamic data acquisition protocol. KEY POINTS: • Dual-time-point imaging is equivalent to dynamic FET PET for grading of gliomas. • Dual-time-point imaging is less time consuming than dynamic FET PET. • Costs can be reduced due to higher patient throughput. • Reduced imaging time increases patient comfort and sedation might be avoided. • Quicker image interpretation is possible, as no curve evaluation is necessary.

Structural connectome-based predictive modeling of cognitive deficits in treated glioma patients.

Background: In glioma patients, tumor growth and subsequent treatments are associated with various types of brain lesions. We hypothesized that cognitive functioning in these patients critically depends on the maintained structural connectivity of multiple brain networks. Methods: The study included 121 glioma patients (median age, 52 years; median Eastern Cooperative Oncology Group performance score 1; CNS-WHO Grade 3 or 4) after multimodal therapy. Cognitive performance was assessed by 10 tests in 5 cognitive domains at a median of 14 months after treatment initiation. Hybrid amino acid PET/MRI using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine, a network-based cortical parcellation, and advanced tractography were used to generate whole-brain fiber count-weighted connectivity matrices. The matrices were applied to a cross-validated machine-learning model to identify predictive fiber connections (edges), critical cortical regions (nodes), and the networks underlying cognitive performance. Results: Compared to healthy controls (n = 121), patients' cognitive scores were significantly lower in 9 cognitive tests. The models predicted the scores of 7/10 tests (median correlation coefficient, 0.47; range, 0.39-0.57) from 0.6% to 5.4% of the matrix entries; 84% of the predictive edges were between nodes of different networks. Critically involved cortical regions (≥10 adjacent edges) included predominantly left-sided nodes of the visual, somatomotor, dorsal/ventral attention, and default mode networks. Highly critical nodes (≥15 edges) included the default mode network's left temporal and bilateral posterior cingulate cortex. Conclusions: These results suggest that the cognitive performance of pretreated glioma patients is strongly related to structural connectivity between multiple brain networks and depends on the integrity of known network hubs also involved in other neurological disorders.

Assessment of Brain Tumour Perfusion Using Early-Phase 18F-FET PET: Comparison with Perfusion-Weighted MRI.

PURPOSE: Morphological imaging using MRI is essential for brain tumour diagnostics. Dynamic susceptibility contrast (DSC) perfusion-weighted MRI (PWI), as well as amino acid PET, may provide additional information in ambiguous cases. Since PWI is often unavailable in patients referred for amino acid PET, we explored whether maps of relative cerebral blood volume (rCBV) in brain tumours can be extracted from the early phase of PET using O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). PROCEDURE: Using a hybrid brain PET/MRI scanner, PWI and dynamic 18F-FET PET were performed in 33 patients with cerebral glioma and four patients with highly vascularized meningioma. The time interval from 0 to 2 min p.i. was selected to best reflect the blood pool phase in 18F-FET PET. For each patient, maps of MR-rCBV, early 18F-FET PET (0-2 min p.i.) and late 18F-FET PET (20-40 min p.i.) were generated and coregistered. Volumes of interest were placed on the tumour (VOI-TU) and normal-appearing brain (VOI-REF). The correlation between tumour-to-brain ratios (TBR) of the different parameters was analysed. In addition, three independent observers evaluated MR-rCBV and early 18F-FET maps (18F-FET-rCBV) for concordance in signal intensity, tumour extent and intratumoural distribution. RESULTS: TBRs calculated from MR-rCBV and 18F-FET-rCBV showed a significant correlation (r = 0.89, p < 0.001), while there was no correlation between late 18F-FET PET and MR-rCBV (r = 0.24, p = 0.16) and 18F-FET-rCBV (r = 0.27, p = 0.11). Visual rating yielded widely agreeing findings or only minor differences between MR-rCBV maps and 18F-FET-rCBV maps in 93 % of the tumours (range of three independent raters 91-94%, kappa among raters 0.78-1.0). CONCLUSION: Early 18F-FET maps (0-2 min p.i.) in gliomas provide similar information to MR-rCBV maps and may be helpful when PWI is not possible or available. Further studies in gliomas are needed to evaluate whether 18F-FET-rCBV provides the same clinical information as MR-rCBV.

Diagnostic Accuracy of MR Spectroscopic Imaging and 18F-FET PET for Identifying Glioma: A Biopsy-Controlled Hybrid PET/MRI Study.

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18F-FET uptake and the MRSI signals choline (Cho), N-acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18F-FET PET.

Earlier diagnosis of progressive disease during bevacizumab treatment using O-(2-18F-fluorethyl)-L-tyrosine positron emission tomography in comparison with magnetic resonance imaging.

Antiangiogenic treatment using bevacizumab in brain tumor patients may cause difficulties in the diagnosis of tumor progression (ie, nonenhancing tumor progression). Newly defined criteria for treatment assessment and diagnosis of tumor progression (ie, RANO [Response Assessment in Neuro-Oncology] criteria) have implemented signal alterations on T2/fluid-attenuated inversion recovery (FLAIR) sequences to changes in contrast enhancement. However, T2/FLAIR hyperintensity may be influenced by other causes (eg, radiation-induced leukoencephalopathy, peritumoral edema, gliosis). Positron emission tomography using the radiolabeled amino acid O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET-PET) may help detect the metabolically active tumor extent. We present 18F-FET-PET imaging findings in a glioblastoma patient during bevacizumab treatment suggesting an earlier diagnosis of tumor progression than magnetic resonance imaging changes, which are based on the RANO criteria.