Christian Filss

Role of O-(2-18 F-Fluoroethyl)-L-Tyrosine PET for differentiation of local recurrent brain metastasis from radiation necrosis

The aim of this study was to investigate the potential of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation necrosis after radiation therapy because the use of contrast-enhanced MRI for this issue is often difficult. Methods: Thirty-one patients (mean age ± SD, 53 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 40) on MRI after radiation therapy of brain metastases were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively; 20–40 min after injection) of 18F-FET uptake were determined. Time–activity curves were generated, and the time to peak (TTP) was calculated. Furthermore, time–activity curves of each lesion were assigned to one of the following curve patterns: (I) constantly increasing 18F-FET uptake, (II) 18F-FET uptake peaking early (TTP ≤ 20 min) followed by a plateau, and (III) 18F-FET uptake peaking early (TTP ≤ 20 min) followed by a constant descent. The diagnostic accuracy of the TBRmax and TBRmean of 18F-FET uptake and the curve patterns for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or Fisher exact test for 2 × 2 contingency tables using subsequent histologic analysis (11 lesions in 11 patients) or clinical course and MRI findings (29 lesions in 20 patients) as reference. Results: Both TBRmax and TBRmean were significantly higher in patients with recurrent metastasis (n = 19) than in patients with radiation necrosis (n = 21) (TBRmax, 3.2 ± 0.9 vs. 2.3 ± 0.5, P < 0.001; TBRmean, 2.1 ± 0.4 vs. 1.8 ± 0.2, P < 0.001). The diagnostic accuracy of 18F-FET PET for the correct identification of recurrent brain metastases reached 78% using TBRmax (area under the ROC curve [AUC], 0.822 ± 0.07; sensitivity, 79%; specificity, 76%; cutoff, 2.55; P = 0.001), 83% using TBRmean (AUC, 0.851 ± 0.07; sensitivity, 74%; specificity, 90%; cutoff, 1.95; P < 0.001), and 92% for curve patterns II and III versus curve pattern I (sensitivity, 84%; specificity, 100%; P < 0.0001). The highest accuracy (93%) to diagnose local recurrent metastasis was obtained when both a TBRmean greater than 1.9 and curve pattern II or III were present (AUC, 0.959 ± 0.03; sensitivity, 95%; specificity, 91%; P < 0.001). Conclusion: Our findings suggest that the combined evaluation of the TBRmean of 18F-FET uptake and the pattern of the time–activity curve can differentiate local brain metastasis recurrence from radionecrosis with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.

Comparison of cerebral blood flow acquired by simultaneous [15O]water positron emission tomography and arterial spin labeling magnetic resonance imaging.

Until recently, no direct comparison between [15O]water positron emission tomography (PET) and arterial spin labeling (ASL) for measuring cerebral blood flow (CBF) was possible. With the introduction of integrated, hybrid magnetic resonance (MR)-PET scanners, such a comparison becomes feasible. This study presents results of CBF measurements recorded simultaneously with [15O]water and ASL. A 3T MR-BrainPET scanner was used for the simultaneous acquisition of pseudo-continuous ASL (pCASL) magnetic resonance imaging (MRI) and [15O]water PET. Quantitative CBF values were compared in 10 young healthy male volunteers at baseline conditions. A statistically significant (P<0.05) correlation was observed between the two modalities; the whole-brain CBF values determined with PET and pCASL were 43.3 ±6.1 mL and 51.9 ± 7.1 mL per 100 g per minute, respectively. The gray/white matter (GM/WM) ratio of CBF was 3.0 for PET and 3.4 for pCASL. A paired t-test revealed differences in regional CBF between ASL and PET with higher ASL-CBF than PET-CBF values in cortical areas. Using an integrated, hybrid MR-PET a direct simultaneous comparison between ASL and [15O]water PET became possible for the first time so that temporal, physiologic, and functional variations were avoided. Regional and individual differences were found despite the overall similarity between ASL and PET, requiring further detailed investigations.

The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma

BACKGROUND We evaluated the diagnostic value of static and dynamic O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET) PET parameters in patients with progressive or recurrent glioma. METHODS We retrospectively analyzed 132 dynamic (18)F-FET PET and conventional MRI scans of 124 glioma patients (primary World Health Organization grade II, n = 55; grade III, n = 19; grade IV, n = 50; mean age, 52 ± 14 y). Patients had been referred for PET assessment with clinical signs and/or MRI findings suggestive of tumor progression or recurrence based on Response Assessment in Neuro-Oncology criteria. Maximum and mean tumor/brain ratios of (18)F-FET uptake were determined (20-40 min post-injection) as well as tracer uptake kinetics (ie, time to peak and patterns of the time-activity curves). Diagnoses were confirmed histologically (95%) or by clinical follow-up (5%). Diagnostic accuracies of PET and MR parameters for the detection of tumor progression or recurrence were evaluated by receiver operating characteristic analyses/chi-square test. RESULTS Tumor progression or recurrence could be diagnosed in 121 of 132 cases (92%). MRI and (18)F-FET PET findings were concordant in 84% and discordant in 16%. Compared with the diagnostic accuracy of conventional MRI to diagnose tumor progression or recurrence (85%), a higher accuracy (93%) was achieved by (18)F-FET PET when a mean tumor/brain ratio ≥2.0 or time to peak <45 min was present (sensitivity, 93%; specificity, 100%; accuracy, 93%; positive predictive value, 100%; P < .001). CONCLUSION Static and dynamic (18)F-FET PET parameters differentiate progressive or recurrent glioma from treatment-related nonneoplastic changes with higher accuracy than conventional MRI.

Comparison of 18F-FET PET and Perfusion-Weighted MR Imaging: A PET/MR Imaging Hybrid Study in Patients with Brain Tumors

PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) provides important diagnostic information in addition to that from conventional MR imaging on tumor extent and activity of cerebral gliomas. Recent studies suggest that perfusion-weighted MR imaging (PWI), especially maps of regional cerebral blood volume (rCBV), may provide similar diagnostic information. In this study, we directly compared 18F-FET PET and PWI in patients with brain tumors. Methods: Fifty-six patients with gliomas were investigated using static 18F-FET PET and PWI. For comparison, 8 patients with meningiomas were included. We generated a set of tumor and reference volumes of interest (VOIs) based on morphologic MR imaging and transferred these VOIs to the corresponding 18F-FET PET scans and PWI maps. From these VOIs, tumor-to-brain ratios (TBR) were calculated, and normalized histograms were generated for 18F-FET PET and rCBV maps. Furthermore, in rCBV maps and in 18F-FET PET scans, tumor volumes, their spatial congruence, and the distance between the local hot spots were assessed. Results: For patients with glioma, TBR was significantly higher in 18F-FET PET than in rCBV maps (TBR, 2.28 ± 0.99 vs. 1.62 ± 1.13; P < 0.001). Histogram analysis of the VOIs revealed that 18F-FET scans could clearly separate tumor from background. In contrast, deriving this information from rCBV maps was difficult. Tumor volumes were significantly larger in 18F-FET PET than in rCBV maps (tumor volume, 24.3 ± 26.5 cm3 vs. 8.9 ± 13.9 cm3; P < 0.001). Accordingly, spatial overlap of both imaging parameters was poor (congruence, 11.0%), and mean distance between the local hot spots was 25.4 ± 16.1 mm. In meningioma patients, TBR was higher in rCBV maps than in 18F-FET PET (TBR, 5.33 ± 2.63 vs. 2.37 ± 0.32; P < 0.001) whereas tumor volumes were comparable. Conclusion: In patients with cerebral glioma, tumor imaging with 18F-FET PET and rCBV yields different information. 18F-FET PET shows considerably higher TBRs and larger tumor volumes than rCBV maps. The spatial congruence of both parameters is poor. The locations of the local hot spots differ considerably. Taken together, our data show that metabolically active tumor tissue of gliomas as depicted by amino acid PET is not reflected by rCBV as measured with PWI.

Dynamic O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography differentiates brain metastasis recurrence from radiation injury after radiotherapy.

Background The aim of this study was to investigate the potential of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating local recurrent brain metastasis from radiation injury after radiotherapy since contrast-enhanced MRI often remains inconclusive. Methods Sixty-two patients (mean age, 55 ± 11 y) with single or multiple contrast-enhancing brain lesions (n = 76) on MRI after radiotherapy of brain metastases (predominantly stereotactic radiosurgery) were investigated with dynamic 18F-FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) of 18F-FET uptake were determined (20-40 min postinjection) as well as tracer uptake kinetics (ie, time-to-peak and slope of time-activity curves). Diagnoses were confirmed histologically (34%; 26 lesions in 25 patients) or by clinical follow-up (66%; 50 lesions in 37 patients). Diagnostic accuracies of PET parameters for the correct identification of recurrent brain metastasis were evaluated by receiver-operating-characteristic analyses or the chi-square test. Results TBRs were significantly higher in recurrent metastases (n = 36) than in radiation injuries (n = 40) (TBRmax 3.3 ± 1.0 vs 2.2 ± 0.4, P < .001; TBRmean 2.2 ± 0.4 vs 1.7 ± 0.3, P < .001). The highest accuracy (88%) for diagnosing local recurrent metastasis could be obtained with TBRs in combination with the slope of time-activity curves (P < .001). Conclusions The results of this study confirm previous preliminary observations that the combined evaluation of the TBRs of 18F-FET uptake and the slope of time-activity curves can differentiate local brain metastasis recurrence from radiation-induced changes with high accuracy. 18F-FET PET may thus contribute significantly to the management of patients with brain metastases.

Relationship of Regional Cerebral Blood Flow and Kinetic Behaviour of O-(2-18F- Fluoroethyl)-L-Tyrosine Uptake in Cerebral Gliomas.

ObjectivesO-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) is an established tracer for brain tumour imaging. 18F-FET kinetics in gliomas appear to have potential for tumour grading, but the mechanisms remain unclear. The aim of this study was to explore the relationship between regional cerebral blood flow (rCBF) as measured by arterial spin labelling MRI and the kinetic behaviour of 18F-FET PET in cerebral gliomas. Materials and methodsTwenty patients with cerebral gliomas were investigated using arterial spin labelling MRI and dynamic 18F-FET PET. Time–activity curves (TACs) of 18F-FET uptake were analysed in 33 different tumour regions. The slopes of TAC during the early (0–5 min; slopeup) and late phases of tracer uptake (17–50 min; slopedown) were fitted using linear regression lines. In addition, TACs of each lesion were assigned to different curve patterns. Furthermore, we calculated tumour-to-brain ratios of 18F-FET uptake. The relationship between 18F-FET parameters and rCBF was determined. Results18F-FET uptake in the early phase (slopeup) showed a significant correlation with rCBF (r=0.4; P=0.02). In contrast, both slopedown and TAC patterns showed no significant correlation with rCBF. Furthermore, a significant correlation was found between rCBF and tumour-to-brain ratio (r=0.53; P=0.002). ConclusionThere is a relationship between rCBF and 18F-FET uptake in cerebral gliomas in the initial uptake phase, but the kinetic behaviour of 18F-FET uptake in the late phase is not significantly influenced by rCBF. Thus, the differential kinetic pattern of 18F-FET uptake in high-grade and low-grade gliomas appears to be determined by factors other than rCBF.

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.

Amino acid PET and MR perfusion imaging in brain tumours

PurposeDespite the excellent capacity of the conventional MRI to image brain tumours, problems remain in answering a number of critical diagnostic questions. To overcome these diagnostic shortcomings, PET using radiolabeled amino acids and perfusion-weighted imaging (PWI) are currently under clinical evaluation. The role of amino acid PET and PWI in different diagnostic challenges in brain tumours is controversial.MethodsBased on the literature and experience of our centres in correlative imaging with PWI and PET using O-(2-[18F]fluoroethyl)-l-tyrosine or 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine, the current role and shortcomings of amino acid PET and PWI in different diagnostic challenges in brain tumours are reviewed. Literature searches were performed on PubMed, and additional literature was retrieved from the reference lists of identified articles. In particular, all studies in which amino acid PET was directly compared with PWI were included.ResultsPWI is more readily available, but requires substantial expertise and is more sensitive to artifacts than amino acid PET. At initial diagnosis, PWI and amino acid PET can help to define a site for biopsy but amino acid PET appears to be more powerful to define the tumor extent. Both methods are helpful to differentiate progression or recurrence from unspecific posttherapeutic changes. Assessment of therapeutic efficacy can be achieved especially with amino acid PET, while the data with PWI are sparse.ConclusionBoth PWI and amino acid PET add valuable diagnostic information to the conventional MRI in the assessment of patients with brain tumours, but further studies are necessary to explore the complementary nature of these two methods.

Discrepant MR and [18F]Fluoroethyl-l-Tyrosine PET Imaging Findings in a Patient with Bevacizumab Failure

Antiangiogenic treatment using bevacizumab may cause difficulties in distinguishing between antivascular and true antitumor effects when using MRI response criteria based on changes of contrast enhancement (i.e., Macdonald criteria). Furthermore, more precise tumor response assessment criteria (i.e., RANO criteria), which incorporate nonenhancing T2/FLAIR sequences into Macdonald criteria, may be influenced by other causes of T2/FLAIR hyperintensity (e.g., radiation-induced gliosis). The authors present discrepant MR and [18F]fluoroethyl-l-tyrosine PET imaging findings in a patient with bevacizumab treatment failure.

Congruency of tumour volume delineated by FET PET and MRSI.

In addition to MR imaging, PET imaging of O-(2-[18F]Fluorethyl)-L-Tyrosine (FET) uptake provides information on brain tumour extent and metabolic activity. Similarly, MRS has been shown to be of value for distinguishing high- from low-grade gliomas. Based on 2D spatially resolved MRSI, an overlap between 18FET uptake and the choline/N-acetyl-aspartate (Cho/NAA) ratio of more than 75 % has been reported.