Philipp Lohmann

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.

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.

Influence of bevacizumab on blood-brain barrier permeability and O-(2- 18 F-fluoroethyl)-L-tyrosine uptake in rat gliomas

Restoration of the blood–brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and 18F-FET uptake in a human xenograft model. Methods: Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. 18F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; n = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; n = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment (n = 8). Time–activity curves, slope, and tumor-to-brain ratios of 18F-FET uptake (18–61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Results: Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration (P = 0.055) and long-term therapy resulted in a significant decrease (P = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of 18F-FET uptake were observed in PET and autoradiography (P > 0.05). Conclusion: 8F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.

Evaluation of factors influencing 18 F-FET uptake in the brain

PET using the amino-acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) is gaining increasing interest for brain tumour management. Semi-quantitative analysis of tracer uptake in brain tumours is based on the standardized uptake value (SUV) and the tumour-to-brain ratio (TBR). The aim of this study was to explore physiological factors that might influence the relationship of SUV of 18F-FET uptake in various brain areas, and thus affect quantification of 18F-FET uptake in brain tumours. Negative 18F-FET PET scans of 107 subjects, showing an inconspicuous brain distribution of 18F-FET, were evaluated retrospectively. Whole-brain quantitative analysis with Statistical Parametric Mapping (SPM) using parametric SUV PET images, and volumes of interest (VOIs) analysis with fronto-parietal, temporal, occipital, and cerebellar SUV background areas were performed to study the effect of age, gender, height, weight, injected activity, body mass index (BMI), and body surface area (BSA). After multivariate analysis, female gender and high BMI were found to be two independent factors associated with increased SUV of 18F-FET uptake in the brain. In women, SUVmean of 18F-FET uptake in the brain was 23% higher than in men (p < 0.01). SUVmean of 18F-FET uptake in the brain was positively correlated with BMI (r = 0.29; p < 0.01). The influence of these factors on SUV of 18F-FET was similar in all brain areas. In conclusion, SUV of 18F-FET in the normal brain is influenced by gender and weakly by BMI, but changes are similar in all brain areas.

High-resolution, quantitative 3D PET image reconstruction for the Siemens hybrid 3T MR/BrainPET scanner using the PET reconstruction software toolkit (PRESTO).

The Siemens 3T MR-BrainPET scanner allows us to simultaneously acquire high-resolution MR and PET images thus giving a strong asset for studies of the human brain. Meanwhile, the system is routinely used for MR-PET studies with a variety of radiotracers, e.g. 18F-FDG, 18F-FET, 11C-Raclopride, 11C-Flumazenil, 15O-Water. Based on the vendors’ sinogram-based reconstruction, quantitative dynamic images are obtained. However, this reconstruction uses compressed data in terms of span (axial) and mash (transaxial). Avoiding such data reduction strategies is desirable to improve the image quality. In this context, the PET Reconstruction Software Toolkit (PRESTO) provides better image quality in terms of resolution and noise at the expense of increased computational effort. For the first time, an accurate quantification with PRESTO has been achieved by integrating all mandatory data corrections. All data corrections are calculated for LORs individually and passed to the OP-OSEM implementation of PRESTO. The corrections comprise: component-based normalisation, template-based attenuation correction, variance-reduced random correction, scatter correction based on Single Scatter Simulation, dead time/pile up correction, decay correction and system calibration. In this way, the reconstructed images provide calibrated time-activity (TA) values (Bq/cc). Comparisons between TA curves (TAC) from the sinogram-based reconstruction and PRESTO show reproducible values within a few percent for all available tracers. Exemplarily, Figure ​Figure11 compares the brain tumor dynamics for a scan with FET. No significant deviations are observed in the TACs. However, the better SNR becomes evident for PRESTO (Figure ​(Figure2).2). Consequently, the hybrid 3T MR-BrainPET has emerged as an excellent tool for a wide spectrum of PET studies of the human brain due to the continuous improvements, which have successfully addressed the issues of quantification, optimising image quality and workflow. Figure 1 Comparison of TAC of a dynamic FET human brain tumor measurement. Figure 2 Image quality of a FET brain tumor measurement; PRESTO (top) vendors’ reconstruction (bottom).

Influence of Dexamethasone on O-(2-[18F]-Fluoroethyl)-l-Tyrosine Uptake in the Human Brain and Quantification of Tumor Uptake

PurposeO-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) is an established positron emission tomography (PET) tracer for brain tumor imaging. This study explores the influence of dexamethasone therapy on [18F]FET uptake in the normal brain and its influence on the maximum and mean tumor-to-brain ratio (TBR).Procedures[18F]FET PET scans of 160 brain tumor patients were evaluated (80 dexamethasone treated, 80 untreated; each group with 40 men/40 women). The standardized uptake value of [18F]FET uptake in the normal brain (SUVbrain) in the different groups was compared. Nine patients were examined repeatedly with and without dexamethasone therapy.ResultsSUVbrain of [18F]FET uptake was significantly higher in dexamethasone-treated patients than in untreated patients (SUVbrain 1.33 ± 0.1 versus 1.06 ± 0.16 in male and 1.45 ± 0.25 versus 1.31 ± 0.28 in female patients). Similar results were observed in patients with serial PET scans. Furthermore, compared to men, a significantly higher SUVbrain was found in women, both with and without dexamethasone treatment. There were no significant differences between the different groups for TBRmax and TBRmean, which could have been masked by the high standard deviation. In a patient with a stable brain metastasis investigated twice with and without dexamethasone, the TBRmax and the biological tumor volume (BTV) decreased considerably after dexamethasone due to an increased SUVbrain.ConclusionDexamethasone treatment appears to increase the [18F]FET uptake in the normal brain. An effect on TBRmax, TBRmean, and BTV cannot be excluded which should be considered especially for treatment monitoring and the estimation of BTV using [18F]FET PET.

Investigation of cis-4-[ 18 F]Fluoro-D-Proline Uptake in Human Brain Tumors After Multimodal Treatment

PurposeCis-4-[18F]fluoro-D-proline (D-cis-[18F]FPro) has been shown to pass the intact blood-brain barrier and to accumulate in areas of secondary neurodegeneration and necrosis in the rat brain while uptake in experimental brain tumors is low. This pilot study explores the uptake behavior of D-cis-[18F]FPro in human brain tumors after multimodal treatment.ProceduresIn a prospective study, 27 patients with suspected recurrent brain tumor after treatment with surgery, radiotherapy, and/or chemotherapy (SRC) were investigated by dynamic positron emission tomography (PET) using D-cis-[18F]FPro (22 high-grade gliomas, one unspecified glioma, and 4 metastases). Furthermore, two patients with untreated lesions were included (one glioblastoma, one reactive astrogliosis). Data were compared with the results of PET using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) which detects viable tumor tissue. Tracer distribution, mean and maximum lesion-to-brain ratios (LBRmean, LBRmax), and time-to-peak (TTP) of the time activity curve (TAC) of tracer uptake were evaluated. Final diagnosis was determined by histology (n = 9), clinical follow-up (n = 10), or by [18F]FET PET (n = 10).ResultsD-cis-[18F]FPro showed high uptake in both recurrent brain tumors (n = 11) and lesions classified as treatment-related changes (TRC) only (n = 16) (LBRmean 2.2 ± 0.7 and 2.1 ± 0.6, n.s.; LBRmax 3.4 ± 1.2 and 3.2 ± 1.3, n.s.). The untreated glioblastoma and the lesion showing reactive astrogliosis exhibited low D-cis-[18F]FPro uptake. Distribution of [18F]FET and D-cis-[18F]FPro uptake was discordant in 21/29 cases indicating that the uptake mechanisms are different.ConclusionThe high accumulation of D-cis-[18F]FPro in pretreated brain tumors and TRC supports the hypothesis that tracer uptake is related to cell death. Further studies before and after therapy are needed to assess the potential of D-cis-[18F]FPro for treatment monitoring.

Spatial Relationship of Glioma Volume Derived from FET PET and Volumetric MRSI: a hybrid PET-MRI study

PET imaging of amino acid transport using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) and proton MR spectroscopy (MRS) imaging of cell turnover measured by the ratio of choline to N-acetyl-aspartate (Cho/NAA) may provide additional information on tumor extent of cerebral gliomas compared with anatomic imaging; however, comparative studies are rare. Methods: In this prospective study, 41 patients (16 women, 25 men; mean age ± SD, 48 ± 14 y) with cerebral gliomas (World Health Organization [WHO] grade II: 10 [including 1 patient with 2 lesions], WHO III: 17, WHO IV: 13, without biopsy low-grade: 1, high-grade: 1) were investigated with a hybrid PET/MR scanner. Tumor extent, spatial overlap, and the distance between the corresponding centers of mass in 18F-FET PET and MRS imaging of Cho/NAA, determined by simultaneously acquired, 3-dimensional spatially resolved MRS imaging data, were compared. Results: The average tumor volumes for 18F-FET uptake and increased Cho/NAA were 19 ± 20 cm3 (mean ± SD) and 22 ± 24 cm3, respectively, with an overlap of 40% ± 25% and separation of the centers of mass by 9 ± 8 mm. None of the parameters showed a significant correlation with tumor grade. Conclusion: 18F-FET uptake and increased Cho/NAA ratio are not always congruent and may represent different properties of glioma metabolism. The relationship to histologic tumor extent needs to be further analyzed.

Adapting MR-BrainPET scans for comparison with conventional PET: experiences with dynamic FET-PET in brain tumours

Imaging results from subsequent measurements (preclinical 3T MR-BrainPET, HR+) are compared. O-(2-[18F]fluoroethyl)-L-tyrosine (FET) may exhibit non-uniform tracer uptake in gliomas. The aim was to analyse and adapt the physical properties of the scanners and study variations of biological tumour volume (BTV) in early and late FET-PET. Spatial resolution of the BrainPET and HR+ was measured according to NEMA standard. For evaluation of a threshold-based volume determination -as used for BTV- volumes of an 18F-filled spheres phantom were evaluated. Influence of different filter kernels for correction of differences in spatial resolution hereon was compared. Differences in BTV between early and late FET-PET of 45 patients were analysed. BTV was determined using a tumour-to-brain ratio ≥1.6 [1]. Spatial resolution (FWHM) of the BrainPET was 2.63mm–3.47mm and 4.39mm–5.10mm for the HR+ (10mm off-centre) [2]. 3D-filtered backprojection was used for reconstruction [3]. BTV of largest sphere was 22.8ml in HR+ and between 23.2ml (unfiltered) and 24.5ml (3D-Gaussian 3.5mm) in the BrainPET. BTV of smallest sphere was 0.1 ml in HR+ and between 0.2ml (unfiltered) and 0.06ml (3D-Gaussian 3.5mm) in the BrainPET. A 2.5mm filter showed the smallest deviation for all spheres and was applied to the BrainPET data for cross-scanner comparison. Changes in BTV >10% were considered significant and not related to physical differences between scanners. 41% of patients showed a considerable deviation between early and late FET-PET. BTV increased in 14 patients. Four patients showed a FET positive region only in late FET-PET. Taking into account the physical differences of PET scanners is important for cross-scanner studies. It was shown in a patient study that BTV may vary between early and late FET-PET, which is important for patient management and needs further investigation. Figure 1 MRI and FET-PET scan of a patient with oligodendroglioma WHO grade II. T1-weighted MR image (MPRAGE) acquired simultaneously to the early PET scan with the 3T MR-BrainPET (top). Summation scan 20-40 min post-injection (BrainPET, middle), summation scan ...