Radiomics in neuro-oncology: Basics, workflow, and applications.

Over the last years, the amount, variety, and complexity of neuroimaging data acquired in patients with brain tumors for routine clinical purposes and the resulting number of imaging parameters have substantially increased. Consequently, a timely and cost-effective evaluation of imaging data is hardly feasible without the support of methods from the field of artificial intelligence (AI). AI can facilitate and shorten various time-consuming steps in the image processing workflow, e.g., tumor segmentation, thereby optimizing productivity. Besides, the automated and computer-based analysis of imaging data may help to increase data comparability as it is independent of the experience level of the evaluating clinician. Importantly, AI offers the potential to extract new features from the routinely acquired neuroimages of brain tumor patients. In combination with patient data such as survival, molecular markers, or genomics, mathematical models can be generated that allow, for example, the prediction of treatment response or prognosis, as well as the noninvasive assessment of molecular markers. The subdiscipline of AI dealing with the computation, identification, and extraction of image features, as well as the generation of prognostic or predictive mathematical models, is termed radiomics. This review article summarizes the basics, the current workflow, and methods used in radiomics with a focus on feature-based radiomics in neuro-oncology and provides selected examples of its clinical application.

Loss of HCN2 in Dorsal Hippocampus of Young Adult Mice Induces Specific Apoptosis of the CA1 Pyramidal Neuron Layer.

Neurons inevitably rely on a proper repertoire and distribution of membrane-bound ion-conducting channels. Among these proteins, the family of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels possesses unique properties giving rise to the corresponding Ih-current that contributes to various aspects of neural signaling. In mammals, four genes (hcn1-4) encode subunits of HCN channels. These subunits can assemble as hetero- or homotetrameric ion-conducting channels. In order to elaborate on the specific role of the HCN2 subunit in shaping electrical properties of neurons, we applied an Adeno-associated virus (AAV)-mediated, RNAi-based knock-down strategy of hcn2 gene expression both in vitro and in vivo. Electrophysiological measurements showed that HCN2 subunit knock-down resulted in specific yet anticipated changes in Ih-current properties in primary hippocampal neurons and, in addition, corroborated that the HCN2 subunit participates in postsynaptic signal integration. To further address the role of the HCN2 subunit in vivo, we injected recombinant (r)AAVs into the dorsal hippocampus of young adult male mice. Behavioral and biochemical analyses were conducted to assess the contribution of HCN2-containing channels in shaping hippocampal network properties. Surprisingly, knock-down of hcn2 expression resulted in a severe degeneration of the CA1 pyramidal cell layer, which did not occur in mice injected with control rAAV constructs. This finding might pinpoint to a vital and yet unknown contribution of HCN2 channels in establishing or maintaining the proper function of CA1 pyramidal neurons of the dorsal hippocampus.

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 blood-brain barrier permeability on O-(2-18F-fluoroethyl)-L-tyrosine uptake in rat gliomas.

PURPOSE: O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) is an established tracer for the diagnosis of brain tumors with PET. This study investigates the influence of blood-brain barrier (BBB) permeability on 18F-FET uptake in two rat glioma models and one human xenograft model. METHODS: F98 glioma, 9L gliosarcoma or human U87 glioblastoma cells were implanted into the striatum of 56 Fischer or RNU rats. Thereafter, animals were divided into a control group and a group receiving injections of the glucocorticoid dexamethasone (Dex). After 12-13 days of tumor growth animals received injection of Evans blue dye (EBD) to visualize BBB disturbance and underwent 18F-FET PET followed by autoradiography. Time activity curves, standardized uptake values (SUV) and Tumor-to-brain ratios (TBR) of 18F-FET uptake [18-61 min post injection (p.i.)] were evaluated using a volume-of-Interest (VOI) analysis. BBB disturbance was quantitatively evaluated by EBD fluorescence. The membrane gaps of blood vessel endothelial tight junctions were measured using electron microscopy to visualize ultrastructural BBB alterations in one untreated and one Dex treated F98 glioma. Data were analyzed by two-way ANOVAs. RESULTS: In Dex treated animals EBD extravasation was significantly reduced in 9L (P < 0.001) and U87 (P = 0.008) models and showed a trend in F98 models (P = 0.053). In contrast, no significant differences of 18F-FET uptake were observed between Dex treated animals and control group except a decrease of the TBR in the 9L tumor model in PET (P < 0.01). Ultrastructural evaluation of tumor blood vessel endothelia revealed significant reduction of the cleft diameter between endothelial cells after Dex treatment in F98 model (P = 0.010). CONCLUSION: Despite a considerable reduction of BBB permeability in rat gliomas after Dex treatment, no relevant changes of 18F-FET uptake were noted in this experimental study. Thus, 18F-FET uptake in gliomas appears to be widely independent of the permeability of the BBB.

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.

Reproducibility of O-(2-(18)F-fluoroethyl)-L-tyrosine uptake kinetics in brain tumors and influence of corticoid therapy: an experimental study in rat gliomas.

PURPOSE: Positron emission tomography (PET) using O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) is a well-established method for the diagnostics of brain tumors. This study investigates reproducibility of (18)F-FET uptake kinetics in rat gliomas and the influence of the frequently used dexamethasone (Dex) therapy. METHODS: F98 glioma or 9L gliosarcoma cells were implanted into the striatum of 31 Fischer rats. After 10-11 days of tumor growth, the animals underwent dynamic PET after injection of (18)F-FET (baseline). Thereafter, animals were divided into a control group and a group receiving Dex injections, and all animals were reinvestigated 2 days later. Tumor-to-brain ratios (TBR) of (18)F-FET uptake (18-61 min p.i.) and the slope of the time-activity-curves (TAC) (18-61 min p.i.) were evaluated using a Volume-of-Interest (VOI) analysis. Data were analyzed by two-way repeated measures ANOVA and reproducibility by the intraclass correlation coefficient (ICC). RESULTS: The slope of the tumor TACs showed high reproducibility with an ICC of 0.93. A systematic increase of the TBR in the repeated scans was noted (3.7 ± 2.8 %; p < 0.01), and appeared to be related to tumor growth as indicated by a significant correlation of TBR and tumor volume (r = 0.77; p < 0.0001). After correction for tumor growth TBR showed high longitudinal stability with an ICC of 0.84. Dex treatment induced a significant decrease of the TBR (-8.2 ± 6.1 %; p < 0.03), but did not influence the slope of the tumor TAC. CONCLUSION: TBR of (18)F-FET uptake and tracer kinetics in brain tumors showed high longitudinal stability. Dex therapy may induce a minor decrease of the TBR; this needs further investigation.

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.

Hybrid PET/MRI in Cerebral Glioma: Current Status and Perspectives.

Advanced MRI methods and PET using radiolabelled amino acids provide valuable information, in addition to conventional MR imaging, for brain tumour diagnostics. These methods are particularly helpful in challenging situations such as the differentiation of malignant processes from benign lesions, the identification of non-enhancing glioma subregions, the differentiation of tumour progression from treatment-related changes, and the early assessment of responses to anticancer therapy. The debate over which of the methods is preferable in which situation is ongoing, and has been addressed in numerous studies. Currently, most radiology and nuclear medicine departments perform these examinations independently of each other, leading to multiple examinations for the patient. The advent of hybrid PET/MRI allowed a convergence of the methods, but to date simultaneous imaging has reached little relevance in clinical neuro-oncology. This is partly due to the limited availability of hybrid PET/MRI scanners, but is also due to the fact that PET is a second-line examination in brain tumours. PET is only required in equivocal situations, and the spatial co-registration of PET examinations of the brain to previous MRI is possible without disadvantage. A key factor for the benefit of PET/MRI in neuro-oncology is a multimodal approach that provides decisive improvements in the diagnostics of brain tumours compared with a single modality. This review focuses on studies investigating the diagnostic value of combined amino acid PET and 'advanced' MRI in patients with cerebral gliomas. Available studies suggest that the combination of amino acid PET and advanced MRI improves grading and the histomolecular characterisation of newly diagnosed tumours. Few data are available concerning the delineation of tumour extent. A clear additive diagnostic value of amino acid PET and advanced MRI can be achieved regarding the differentiation of tumour recurrence from treatment-related changes. Here, the PET-guided evaluation of advanced MR methods seems to be helpful. In summary, there is growing evidence that a multimodal approach can achieve decisive improvements in the diagnostics of cerebral gliomas, for which hybrid PET/MRI offers optimal conditions.

Two Decades of Brain Tumour Imaging with O-(2-[18F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians' rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Current trends in the use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) in neurooncology.

The diagnostic potential of PET using the amino acid analogue O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) in brain tumor diagnostics has been proven in many studies during the last two decades and is still the subject of multiple studies every year. In addition to standard magnetic resonance imaging (MRI), positron emission tomography (PET) using [18F]FET provides important diagnostic data concerning brain tumor delineation, therapy planning, treatment monitoring, and improved differentiation between treatment-related changes and tumor recurrence. The pharmacokinetics, uptake mechanisms and metabolism have been well described in various preclinical studies. The accumulation of [18F]FET in most benign lesions and healthy brain tissue has been shown to be low, thus providing a high contrast between tumor tissue and benign tissue alterations. Based on logistic advantages of F-18 labelling and convincing clinical results, [18F]FET has widely replaced short lived amino acid tracers such as L-[11C]methyl-methionine ([11C]MET) in many centers across Western Europe. This review summarizes the basic knowledge on [18F]FET and its contribution to the care of patients with brain tumors. In particular, recent studies about specificity, possible pitfalls, and the utility of [18F]FET PET in tumor grading and prognostication regarding the revised WHO classification of brain tumors are addressed.

High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of rat gliomas due to activated astrocytes.

BACKGROUND: Recent studies reported on high uptake of the PSMA ligands [68Ga]HBED-CC (68Ga-PSMA) and 18F-DCFPyL in cerebral gliomas. This study explores the regional uptake and cellular targets of 68Ga-PSMA and 18F-DCFPyL in three different rat glioma models. METHODS: F98, 9 L, or U87 rat gliomas were implanted into the brains of 38 rats. After 13 days of tumor growth, 68Ga-PSMA (n = 21) or 18F-DCFPyL (n = 17) was injected intravenously, and animals were sacrificed 40 min later. Five animals for each tracer and tumor model were additionally investigated by micro-PET at 20-40 min post injection. Cryosections of the tumor bearing brains were analyzed by ex vivo autoradiography and immunofluorescence staining for blood vessels, microglia, astrocytes, and presence of PSMA. Blood-brain barrier (BBB) permeability was tested by coinjection of Evans blue dye (EBD). 68Ga-PSMA uptake after restoration of BBB integrity by treatment with dexamethasone (Dex) was evaluated in four animals with U87 gliomas. Competition experiments using the PSMA-receptor inhibitor 2-(phosphonomethyl)pentane-1,5-dioic acid (PMPA) were performed for both tracers in two animals each. RESULTS: Autoradiography demonstrated a strong 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral area and moderate binding in the center of the tumors. PMPA administration led to complete inhibition of 68Ga-PSMA and 18F-DCFPyL binding in the peritumoral region. Restoration of BBB by Dex treatment reduced EBD extravasation but 68Ga-PSMA binding remained unchanged. Expression of activated microglia (CD11b) was low in the intra- and peritumoral area but GFAP staining revealed strong activation of astrocytes in congruency to the tracer binding in the peritumoral area. All tumors were visualized in micro PET, showing a lower tumor/brain contrast with 68Ga-PSMA than with 18F-DCFPyL. CONCLUSIONS: High uptake of 68Ga-PSMA and 18F-DCFPyL in the peritumoral area of all glioma models is presumably caused by activated astrocytes. This may represent a limitation for the clinical application of PSMA ligands in gliomas.

An in vivo multimodal feasibility study in a rat brain tumour model using flexible multinuclear MR and PET systems.

BACKGROUND: In addition to the structural information afforded by 1H MRI, the use of X-nuclei, such as sodium-23 (23Na) or phosphorus-31 (31P), offers important complementary information concerning physiological and biochemical parameters. By then combining this technique with PET, which provides valuable insight into a wide range of metabolic and molecular processes by using of a variety of radioactive tracers, the scope of medical imaging and diagnostics can be significantly increased. While the use of multimodal imaging is undoubtedly advantageous, identifying the optimal combination of these parameters to diagnose a specific dysfunction is very important and is advanced by the use of sophisticated imaging techniques in specific animal models. METHODS: In this pilot study, rats with intracerebral 9L gliosarcomas were used to explore a combination of sequential multinuclear MRI using a sophisticated switchable coil set in a small animal 9.4 T MRI scanner and, subsequently, a small animal PET with the tumour tracer O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET). This made it possible for in vivo multinuclear MR-PET experiments to be conducted without compromising the performance of either multinuclear MR or PET. RESULTS: High-quality in vivo images and spectra including high-resolution 1H imaging, 23Na-weighted imaging, detection of 31P metabolites and [18F]FET uptake were obtained, allowing the characterisation of tumour tissues in comparison to a healthy brain. It has been reported in the literature that these parameters are useful in the identification of the genetic profile of gliomas, particularly concerning the mutation of the isocitrate hydrogenase gene, which is highly relevant for treatment strategy. CONCLUSIONS: The combination of multinuclear MR and PET in, for example, brain tumour models with specific genetic mutations will enable the physiological background of signal alterations to be explored and the identification of the optimal combination of imaging parameters for the non-invasive characterisation of the molecular profile of tumours.

Investigation of Cerebral O-(2-[18F]Fluoroethyl)-L-Tyrosine Uptake in Rat Epilepsy Models.

PURPOSE: A recent study reported on high, longer lasting and finally reversible cerebral uptake of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) induced by epileptic activity. Therefore, we examined cerebral [18F]FET uptake in two chemically induced rat epilepsy models and in patients with focal epilepsy to further investigate whether this phenomenon represents a major pitfall in brain tumor diagnostics and whether [18F]FET may be a potential marker to localize epileptic foci. PROCEDURES: Five rats underwent kainic acid titration to exhibit 3 to 3.5 h of class IV-V motor seizures (status epilepticus, SE). Rats underwent 4× [18F]FET PET and 4× MRI on the following 25 days. Six rats underwent kindling with pentylenetetrazol (PTZ) 3 to 8×/week over 10 weeks, and hence, seizures increased from class I to class IV. [18F]FET PET and MRI were performed regularly on days with and without seizures. Four rats served as healthy controls. Additionally, five patients with focal epilepsy underwent [18F]FET PET within 12 days after the last documented seizure. RESULTS: No abnormalities in [18F]FET PET or MRI were detected in the kindling model. The SE model showed significantly decreased [18F]FET uptake 3 days after SE in all examined brain regions, and especially in the amygdala region, which normalized within 2 weeks. Corresponding signal alterations in T2-weighted MRI were noted in the amygdala and hippocampus, which recovered 24 days post-SE. No abnormality of cerebral [18F]FET uptake was noted in the epilepsy patients. CONCLUSIONS: There was no evidence for increased cerebral [18F]FET uptake after epileptic seizures neither in the rat models nor in patients. The SE model even showed decreased [18F]FET uptake throughout the brain. We conclude that epileptic seizures per se do not cause a longer lasting increased [18F]FET accumulation and are unlikely to be a major cause of pitfall for brain tumor diagnostics.

Flare Phenomenon in O-(2-18F-Fluoroethyl)-l-Tyrosine PET After Resection of Gliomas.

PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) is useful to detect residual tumor tissue after glioma resection. Recent animal experiments detected reactive changes in 18F-FET uptake at the rim of the resection cavity within the first 2 wk after resection of gliomas. In the present study, we evaluated pre- and postoperative 18F-FET PET scans of glioma patients with particular emphasis on the identification of reactive changes after surgery. Methods: Forty-three patients with cerebral gliomas (9 low-grade, 34 high-grade; 9 primary tumors, 34 recurrent tumors) who had preoperative (time before surgery: median, 23 d; range, 6-44 d) and postoperative 18F-FET PET (time after surgery: median, 14 d; range, 5-28 d) were included. PET scans (20-40 min after injection) were evaluated visually for complete or incomplete resection and compared with MRI. Changes in 18F-FET uptake were evaluated by tumor-to-brain ratios in residual tumor and by maximum lesion-to-brain ratios near the resection cavity. Results: Visual analysis of 18F-FET PET scans revealed complete resection in 16 of 43 patients and incomplete resection in the remaining patients. PET results were concordant with MRI in 69% of the patients. The maximum lesion-to-brain ratio for 18F-FET uptake near the resection cavity was significantly higher than preoperative values (1.59 ± 0.36 vs. 1.14 ± 0.17; n = 43; P < 0.001). In 11 patients (26%), a flare phenomenon was observed, with a considerable increase in 18F-FET uptake compared with preoperative values in either the residual tumor (n = 5) or areas remote from the tumor on the preoperative PET scan (n = 6) (2.92 ± 1.24 vs. 1.62 ± 0.75; P < 0.001). Further follow-up in 5 patients showed decreasing 18F-FET uptake in the flare areas in 4 patients and progress in 1 patient. Conclusion: Our study confirmed that 18F-FET PET provides valuable information for assessing the success of glioma resection. Postoperative reactive changes at the rim of the resection cavity appear to be mild. However, in 23% of the patients, a postoperative flare phenomenon was observed that warrants further investigation.

O-(2-[18F]-Fluoroethyl)-L-Tyrosine (FET) in Neurooncology: A Review of Experimental Results.

In recent years, PET using radiolabelled amino acids has gained considerable interest as an additional tool besides MRI to improve the diagnosis of cerebral gliomas and brain metastases. A very successful tracer in this field is O-(2-[18F]fluoroethyl)-L-tyrosine (FET) which in recent years has replaced short-lived tracers such as [11C]-methyl-L-methionine in many neuro-oncological centers in Western Europe. FET can be produced with high efficiency and distributed in a satellite concept like 2- [18F]fluoro-2-deoxy-D-glucose. Many clinical studies have demonstrated that FET PET provides important diagnostic information regarding the delineation of cerebral gliomas for therapy planning, an improved differentiation of tumor recurrence from treatment-related changes and sensitive treatment monitoring. In parallel, a considerable number of experimental studies have investigated the uptake mechanisms of FET on the cellular level and the behavior of the tracer in various benign lesions in order to clarify the specificity of FET uptake for tumor tissue. Further studies have explored the effects of treatment related tissue alterations on tracer uptake such as surgery, radiation and drug therapy. Finally, the role of blood-brain barrier integrity for FET uptake which presents an important aspect for PET tracers targeting neoplastic lesions in the brain has been investigated in several studies. Based on a literature research regarding experimental FET studies and corresponding clinical applications this article summarizes the knowledge on the uptake behavior of FET, which has been collected in more than 30 experimental studies during the last two decades and discusses the role of these results in the clinical context.

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

PURPOSE: O-(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. RESULTS: SUVbrain 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. CONCLUSION: Dexamethasone 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.

Treatment-Related Uptake of O-(2-18F-Fluoroethyl)-l-Tyrosine and l-[Methyl-3H]-Methionine After Tumor Resection in Rat Glioma Models.

Assessment of residual tumor after resection of cerebral gliomas can be difficult with MRI and may be improved by amino acid PET. The aim of this experimental study was to investigate uptake of 2-18F-fluoroethyl-l-tyrosine (18F-FET) and l-[methyl-3H]-methionine (3H-MET) in residual tumor after surgery and possible false-positive uptake in treatment-related changes. Methods: F98 or GS-9L rat gliomas were implanted into the brain of 64 rats. Tumors were resected after 1 wk of tumor growth, and sham surgery was performed in an additional 10 animals. At different time points after surgery (1, 2, 3, 7, and 14-16 d), rats underwent ex vivo dual-tracer autoradiography using 18F-FET and 3H-MET. Histologic slices were evaluated by immunostaining for cell density and astrogliosis. Tracer uptake was quantified by lesion-to-brain ratios (L/B) at the rim of the resection cavity (considered treatment-related uptake) and in residual or recurrent tumor tissue. Four animals showing no residual tumor underwent PET 3 d after surgery to examine time-activity curves of 18F-FET uptake in treatment-related changes. Results: Treatment-related uptake with a mean L/B of 2.0 ± 0.3 for 18F-FET and a mean L/B of 1.7 ± 0.2 for 3H-MET was noted at the rim of the resection cavity in the first week after surgery, decreasing significantly by 14-16 d (P < 0.01). Treatment-related tracer uptake was significantly higher for 18F-FET than for 3H-MET (P < 0.001). Tracer uptake in rat gliomas exceeded treatment-related tracer uptake at all time points (P < 0.001), but the latter was in the range of human gliomas. Reactive astrogliosis was noted near the resection cavity from the second day after surgery. Time-activity curves of 18F-FET uptake in those areas revealed constantly increasing uptake. Conclusion: Surgery may induce significant treatment-related 18F-FET and 3H-MET uptake near the resection cavity in the first week after surgery, presumably caused by reactive astrogliosis. Treatment-related tracer uptake was less pronounced for 3H-MET, indicating that 11C-MET may be better suited for assessing the postoperative situation than 18F-FET. Assessment of residual tumor after surgery by amino acid PET seems to be more reliable after an interval of 14 d.

Evaluation of factors influencing 18F-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.

Predicting IDH genotype in gliomas using FET PET radiomics.

Mutations in the isocitrate dehydrogenase (IDH mut) gene have gained paramount importance for the prognosis of glioma patients. To date, reliable techniques for a preoperative evaluation of IDH genotype remain scarce. Therefore, we investigated the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics using textural features combined with static and dynamic parameters of FET uptake for noninvasive prediction of IDH genotype. Prior to surgery, 84 patients with newly diagnosed and untreated gliomas underwent FET PET using a standard scanner (15 of 56 patients with IDH mut) or a dedicated high-resolution hybrid PET/MR scanner (11 of 28 patients with IDH mut). Static, dynamic and textural parameters of FET uptake in the tumor area were evaluated. Diagnostic accuracy of the parameters was evaluated using the neuropathological result as reference. Additionally, FET PET and textural parameters were combined to further increase the diagnostic accuracy. The resulting models were validated using cross-validation. Independent of scanner type, the combination of standard PET parameters with textural features increased significantly diagnostic accuracy. The highest diagnostic accuracy of 93% for prediction of IDH genotype was achieved with the hybrid PET/MR scanner. Our findings suggest that the combination of conventional FET PET parameters with textural features provides important diagnostic information for the non-invasive prediction of the IDH genotype.

Influence of Bevacizumab on Blood-Brain Barrier Permeability and O-(2-18F-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.