18F-FET Positron Emission Tomography Research Articles

Diagnostic accuracy of glioma pseudoprogression identification with positron emission tomography imaging: a systematic review and meta-analysis.

Positron emission tomography (PET) imaging is a promising molecular neuroimaging technique and has been proposed as one of the criteria for glioma management. However, there is some controversy concerning the diagnostic accuracy of PET using different radiotracers to differentiate between glioma pseudoprogression (PsP) and true progression (TPR). The purpose of this meta-analysis was to systematically evaluate the methodological quality and clinical value of original studies for distinguishing PsP from TPR in glioma. The Medline, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov were searched from inception until September 1, 2022. Retrieved clinical studies only investigated the PsP cases but did not include the cases of radiation necrosis or other treatment-related changes. Eligible studies were screened for data extraction and evaluated by 2 independent reviewers using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. A random effects model was used to describe summary receiver operating characteristics. Meta-regression and subgroup analyses were applied to identify any sources of heterogeneity. The meta-analysis included 20 studies, comprising 317 (30.9%) patients with PsP and 708 (69.1%) with TPR. The summary sensitivity and specificity of general PET for identifying PsP were 0.86 [95% confidence interval (CI): 0.77-0.91] and 0.84 (95% CI: 0.79-0.88), respectively. The statistical heterogeneity was explained by sample size, study design, World Health Organization (WHO) grade, gold standard, and radiotracer type. The summary sensitivity and specificity of O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET PET) were 0.80 (95% CI: 0.68-0.88) and 0.81 (95% CI: 0.75-0.85), respectively. The maximum tumor-to-brain ratio (TBRmax) and the mean tumor-to-brain ratio (TBRmean) both showed excellent diagnostic performance in 18F-FET studies, the summary sensitivity was 0.83 (95% CI: 0.72-0.91) and 0.79 (95% CI: 0.65-0.98), respectively, and the specificity was 0.76 (95% CI: 0.68-0.84) and 0.78 (95% CI: 0.64-0.88), respectively. PET imaging is generally accurate in identifying glioma PsP. Considering the credibility of meta-evidence and the practicability of using radiotracer, 18F-FET PET holds the highest clinical value, while TBRmax and TBRmean should be regarded as reliable parameters. PET used with the radiotracers and multiple-parameter combinations of PET with magnetic resonance imaging (MRI) and radiomics analysis have broad research and application prospects, whose diagnostic values for identifying glioma PsP warrant further investigation.

Radiotherapy Target Volume Definition in Newly Diagnosed High-Grade Glioma Using 18F-FET PET Imaging and Multiparametric MRI: An Inter Observer Agreement Study.

Background: The aim of this prospective monocentric study was to assess the inter-observer agreement for tumor volume delineations by multiparametric MRI and 18-F-FET-PET/CT in newly diagnosed, untreated high-grade glioma (HGG) patients. Methods: Thirty patients HGG underwent O-(2-[18F]-fluoroethyl)-l-tyrosine(18F-FET) positron emission tomography (PET), and multiparametric MRI with computation of rCBV map and K2 map. Three nuclear physicians and three radiologists with different levels of experience delineated the 18-F-FET-PET/CT and 6 MRI sequences, respectively. Spatial similarity (Dice and Jaccard: DSC and JSC) and overlap (Overlap: OV) coefficients were calculated between the readers for each sequence. Results: DSC, JSC, and OV were high for 18F-FET PET/CT, T1-GD, and T2-FLAIR (>0.67). The Spearman correlation coefficient between readers was ≥0.6 for these sequences. Cross-comparison of similarity and overlap parameters showed significant differences for DSC and JSC between 18F-FET PET/CT and T2-FLAIR and for JSC between 18F-FET PET/CT and T1-GD with higher values for 18F-FET PET/CT. No significant difference was found between T1-GD and T2-FLAIR. rCBV, K2, b1000, and ADC showed correlation coefficients between readers <0.6. Conclusion: The interobserver agreements for tumor volume delineations were high for 18-F-FET-PET/CT, T1-GD, and T2-FLAIR. The DWI (b1000, ADC), rCBV, and K2-based sequences, as performed, did not seem sufficiently reproducible to be used in daily practice.

The Value of FET PET/CT in Recurrent Glioma with a Different IDH Mutation Status: The Relationship between Imaging and Molecular Biomarkers

The evaluation of treatment response remains a challenge in glioma cases because the neuro oncological therapy can lead to the development of treatment-related changes (TRC) that mimic true progression (TP). Positron emission tomography (PET) using O-(2-[18F] fluoroethyl-)-L-tyrosine (18F-FET) has been shown to be a useful tool for detecting TRC and TP. We assessed the diagnostic performance of different 18F-FET PET segmentation approaches and different imaging biomarkers for differentiation between late TRC and TP in glioma patients. Isocitrate dehydrogenase (IDH) status was evaluated as a predictor of disease outcome. In our study, the proportion of TRC in IDH wild type (IDHwt) and IDH mutant (IDHm) subgroups was without significant difference. We found that the diagnostic value of static and dynamic biomarkers of 18F-FET PET for discrimination between TRC and TP depends on the IDH mutation status of the tumor. Dynamic 18F-FET PET acquisition proved helpful in the IDH wild type (IDHwt) subgroup, as opposed to the IDH mutant (IDHm) subgroup, providing an early indication to discontinue dynamic imaging in the IDHm subgroup.

Negative 18F-FET PET/CT in brain metastasis recurrence: a teaching case report

Positron emission tomography (PET) using O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET has been shown to be a useful tool for differentiating radiation therapy outcomes, such as brain metastasis recurrence or radiation necrosis. We present the case of a female patient with brain metastases from pulmonary mucinous adenocarcinoma with suspicion of tumor recurrence on follow-up magnetic resonance imaging (MRI) after radiosurgery. 18F-FET PET/computed tomography (CT) was indicative of radiation necrosis. Due to the patient's medical history and the discrepancy between the brain MRI and PET/CT results, surgical biopsies were decided, which were positive for brain metastasis recurrence. The diagnosis of metastasis recurrence may also be challenging on 18F-FET PET/CT. In case of discrepancies between MRI and PET/CT results, false-negative 18F-FET PET/CT remains a possibility and requires careful follow-up or biopsy.

18 F-FET PET maximum standard uptake value and WHO tumour classification grade in glioma.

In the area of oncology, molecular imaging techniques are becoming increasingly utilised. In neuro-oncology imaging, 18 Fluoro-O-(2) fluoroethyl-L-tyrosine (18 F-FET) is one of the molecular tracers used in positron-emission tomography (PET). Here, we investigated the correlation between maximum standard uptake value (SUV) of 18 F-FET PET and histologically determined World Health Organization (WHO) grade in glioma. This was a retrospective review of all 18 F-FET PET studies conducted between August 2014 and August 2019. Review was conducted to identify imaging studies performed on patients who had a glioma with histopathology results from surgical resection or biopsy available. A total of 31 18 F-FET PET studies of histologically confirmed glioma were included. WHO grades ranged from II-IV. A positive correlation between maximum SUV uptake on 18 F-FET PET and WHO grade was observed. There was a correlation identified between WHO glioma grade and maximum SUV on 18 F-FET PET. Further studies are recommended to explore this relationship.

18F-FET and 18F-choline PET-CT in patients with MRI-suspected low-grade gliomas: a pilot study

AimTo investigate the diagnostic accuracy of O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) and fluoromethyl-(18F)-dimethyl-2-hydroxyethyl-ammonium chloride (18F-FCH) computed tomography (CT) in patients with primary low-grade gliomas (LGG).MethodsThe study enrolled patients with magnetic resonance imaging (MRI)-suspected LGG. Patients underwent both 18F-FET and 18F-FCH positron emission tomography (PET)-CT. Brain PET-CT was performed according to standard protocol – 20 minutes after intravenous injection of 185 MBq of 18F-FET and 185 MBq of 18F-FCH PET. Surgery and pathohistological diagnosis were performed in the next two weeks.ResultsWe observed significantly better concordance between tumor histology and 18F-FET PET (weighted Kappa 0.74) compared with both 18F-FCH (weighted Kappa 0.15) and MRI (weighted Kappa 0.00). Tumor histology was significantly associated with 18F-FET (odds ratio 12.87; 95% confidence interval [CI], 0.49-333.70; P = 0.013, logistic regression analysis). Receiver operating characteristic curve analysis comparing 18F-FCH (area under the curve [AUC] 0.625, 95% CI 0.298-0.884) and 18F-FET (AUC 0.833, 95% CI 0.499-0.982) showed better diagnostic properties of 18F-FET (AUC difference 0.208, 95% CI -0.145 to 0.562, P = 0.248).ConclusionPerforming PET-CT in patients with newly diagnosed LGG should be preceded by a selection of an appropriate radiopharmaceutical. 18F-FET seems to be more accurate than 18F-FCH in the LGG diagnosis.

Heterogeneous parameters based on 18F-FET PET imaging can non-invasively predict tumor grade and isocitrate dehydrogenase gene 1 mutation in untreated gliomas.

The present study aimed to explore the efficacy of easily obtained intratumoral heterogeneous parameters, other than regular semi-quantitative parameters, based on static O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) positron emission tomography (PET) imaging in glioma grade and isocitrate dehydrogenase (IDH) gene 1 mutation prediction. Fifty-eight adult patients with untreated glioma (grades II-IV) who underwent preoperative 18F-FET PET/computed tomography (CT) imaging were enrolled in the present study. Eight semi-automatically obtained static PET imaging parameters after lesion delineation were chosen for analysis. These were: maximal tumor-to-background ratio (TBRmax), peak tumor-to-background ratio (TBRpeak), mean tumor-to-background ratio (TBRmean), coefficient of variation (COV), heterogeneity index (HI), the standard deviation of lesion standardized uptake value (SUVsd), metabolic tumor volume (MTV), and total lesion tracer standardized uptake (TLU). Pathological and immunohistochemical results were used as a reference. The receiver-operating characteristic analysis was used to investigate the predictive efficacy of these parameters in glioma grade and IDH1 mutation status. TLU [area under the curve (AUC): 0.841, P<0.0001], TBRpeak (AUC: 0.832, P<0.0001), and HI (AUC: 0.826, P<0.0001) had the top 3 single-parameter predictive performance between grade II or III and grade IV glioma patients. Combinations of TBRmax, SUVsd, and TBRmean (AUC: 0.850, P<0.0001); HI, SUVsd, and MTV (AUC: 0.848, P<0.0001); and HI, SUVsd, and TLU (AUC: 0.848, P<0.0001) had the top 3 multiple-parameter predictive performance. SUVsd (AUC: 0.710, P=0.0028), TLU (AUC: 0.698, P=0.0074), and HI (AUC: 0.676, P=0.0159) had the top 3 single-parameter predictive performance in the IDH1 genotype. Combinations of TBRmax, SUVsd, and TBRmean (AUC: 0.821, P<0.0001); SUVsd and TBRmean (AUC: 0.804, P<0.0001); and SUVsd, HI, and TBRmean (AUC: 0.799, P<0.0001) had the top 3 multiple-parameter predictive performance. These easily obtained and highly repetitive heterogeneous parameters based on static 18F-FET PET/CT imaging can non-invasively predict glioma grade and IDH1 mutation, crucial in treatment planning, and prognostic evaluation.

Radiotherapy target volume definition in newly diagnosed high grade glioma using 18F-FET PET imaging and multiparametric perfusion MRI: A prospective study (IMAGG)

PurposeThe aim of this study was to prospectively investigate tumor volume delineation by amino acid PET and multiparametric perfusion magnetic resonance imaging (MRI) in patients with newly diagnosed, untreated high grade glioma (HGG). Materials and methodsThirty patients with histologically confirmed HGG underwent O-(2-[18F]-fluoroethyl)-l-tyrosine (18F-FET) positron emission tomography (PET), conventional Magnetic Resonance Imaging (MRI) as contrast-enhanced (CE) and fluid-attenuated inversion recovery (FLAIR) and multiparametric MRI as relative cerebral blood volume (rCBV) and permeability estimation map (K2). Areas of MRI volumes were semi-automatically segmented. The percentage overlap volumes, Dice and Jaccard spatial similarity coefficients (OV, DSC, JSC) were calculated. ResultsThe 18F-FET tumor volume was significantly larger than the CE volume (median 43.5 mL (2.5–124.9) vs. 23.8 mL (1.4–80.3), p = 0.005). The OV between 18F-FET uptake and CE volume was low (median OV 0.59 (0.10–1)), as well as spatial similarity (median DSC 0.52 (0.07–0.78); median JSC 0.35 (0.03–0.64)). Twenty-five patients demonstrated both rCBV and CE on MRI: The median rCBV tumor volume was significantly smaller than the median CE volume (p < 0.001). The OV was high (median 0.83 (0.54–1)), but the spatial similarity was low (median DSC 0.45 (0.04–0.83); median JSC 0.29 (0.07–0.71)). Twenty-eight patients demonstrated both K2 and CE on MRI. The median K2 tumor volume was not significantly larger than the median CE volume. The OV was high (median OV 0.90 (0.61–1)), and the spatial similarity was moderate (median DSC 0.75 (0.01–0.83); median JSC 0.60 (0.11–0.89)). ConclusionWe demonstrated that multiparametric perfusion MRI volumes (rCBV, K2) were highly correlated with CE T1 gadolinium volumes whereas 18F-FET PET provided complementary information, suggesting that the metabolically active tumor volume in patients with newly diagnosed untreated HGG is critically underestimated by contrast enhanced MRI. 18F-FET PET imaging may help to improve target volume delineation accuracy for radiotherapy planning.

Dynamic 18F-Fluoro-Ethyl-Tyrosine Positron Emission Tomography/ Computed Tomography: A Better Predictor of Isocitrate Dehydrogenase Mutation in Presurgical Evaluations of Glioma.

The recent WHO classification of gliomas has incorporated molecular markers such as isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion into the ambit of morphological diagnosis, and 18F-fluoro-ethyl-tyrosine (18F-FET) positron emission tomography (PET) has shown its utility in noninvasive glioma grading and prognosis. Both dynamic and static FET PET parameters may assist in predicting the IDH mutational status, but time to peak derived from dynamic data may be a better predictor for IDH status. We present a case of left frontal lobe lesion suggestive of high-grade glioma on magnetic resonance imaging and static 18F-FET PET images, however, dynamic FET image was suggestive of low-grade IDH1-mutated glioma which was later confirmed on histology and immunohistochemistry.

P04.07 Correlation of 18F-fluorethyl-L-tyrosine (18F-FET) uptake in positron emission tomography (PET) and MRI growth rate in low-grade glioma

Abstract BACKGROUND Low-grade gliomas (LGGs, WHO grade II) are a heterogeneous group of tumors of the central nervous system with diverse behavior in histopathology, genetics and growth patterns. Therefore, different therapeutic strategies are discussed ranging from watchful waiting to radical resection and adjuvant radio-/chemotherapy. For a better evaluation of tumor progression or malignant transformation, the O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) uptake in PET or the tumor growth rate assessed on MRI are used depending on the neurooncological center. Here, we correlated both methods. MATERIAL AND METHODS Inclusion criteria for this retrospective study were (1) newly diagnosed and neuropathologically confirmed low-grade glioma; (2) at least two MRIs at initial diagnosis and follow-up for calculation of the tumor growth rate (using IDS7 by Sectra AB, Sweden, 2018); (3) and an additional preoperative 18F-FET PET scan. RESULTS From 2008 to 2018, 34 patients were identified (mean age 39.7 years; 68% diffuse astrocytoma). The mean tumor growth rate on MRI was 0.091 cm3/d. The average mean 18F-FET uptake was 1.42; the average maximum 18F-FET uptake was 2.18. The Pearson correlation coefficient between the tumor growth rate and the mean and maximum 18F-FET uptake was r=0.19, and r=0.10. In the group of diffuse astrocytomas, the mean growth rate in tumors with a mean 18F-FET uptake of &gt;1.5 was significantly higher than the mean growth rate of those with a mean 18F-FET uptake of ≤1.5 (p&lt;0.1). CONCLUSION Data suggest that astrocytic LGGs with increased 18F-FET uptake may show a more aggressive behaviour, with a potentially higher risk for an earlier tumor progression or malignant transformation. For further elucidation of a correlation between the tumor growth rate and the 18F-FET uptake, larger prospective studies are needed. In the future, the combination of both methods in the management of low-grade gliomas could help to detect tumor progression as well as tumor malignization more precisely.

Value of 18F-FET PET in Patients With Suspected Tumefactive Demyelinating Disease-Preliminary Experience From a Retrospective Analysis.

To investigate the diagnostic value of F-fluoroethyl-L-tyrosine (FET) positron emission tomography (PET) in patients with suspected tumefactive demyelinating disease. We retrospectively examined FET-PET and MR imaging of 21 patients (12 female, 9 male) with known demyelinating disease and newly diagnosed tumefactive lesions. The maximum standardized uptake value (SUVmax), time activity curves (TAC) and lesion-to-background ratio (TBR) of these lesions were calculated. The standard of reference consisted of biopsy and/or follow-up imaging. FET parameters of true neoplastic lesions and tumefactive demyelinating lesions were compared using Mann-Whitney U-test and receiver operating characteristic (ROC) analysis. Nine patients (42.9%) had neoplastic lesions, 12 patients (57.1%) had tumefactive demyelinating lesions. TBRmax, SUVmax and TAC were significantly different between demyelinating lesions and neoplastic lesions: Tumors had a higher TBRmax (3.53 ± 1.09 vs. 1.48 ± 0.31, respectively; P < 0.001) and SUVmax (3.95 ± 1.59 vs. 1.86 ± 0.50, respectively; P < 0.001) than tumefactive demyelinating lesions. The TAC of tumors was significantly higher compared to tumefactive demyelinating lesions at all time points (P < 0.05). ROC analysis revealed that a TBRmax threshold of 2.2 and a SUVmax threshold of 2.5 could reliably differentiate tumor and tumefactive demyelination (area under the curve, 1.000 and 0.958, respectively). In patients with demyelinating disease, FET-PET parameters TBRmax (cut-off 2.2) and SUVmax (cut-off 2.5) are able to distinguish tumefactive demyelinations from true neoplastic lesions.

Recent Developments of 18F-FET PET in Neuro-oncology.

From the past decade to date, several studies related to O-(2- [18F]fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography (PET) in brain tumours have been published in the literature. The aim of this narrative review is to summarize the recent developments and the current role of 18F-FET PET in brain tumours according to recent literature data. Main findings from selected recently published and relevant articles on the role of 18F-FET PET in neuro-oncology are described. 18F-FET PET may be useful in the differential diagnosis between brain tumours and non-neoplastic lesions and between low-grade and high-grade gliomas. Integration of 18F-FET PET into surgical planning allows better delineation of the extent of resection beyond margins visible with standard MRI. For biopsy planning, 18F-FET PET is particularly useful in identifying malignant foci within non-contrast-enhancing gliomas. 18F-FET PET may improve the radiation therapy planning in patients with gliomas. This metabolic imaging method may be useful to evaluate treatment response in patients with gliomas and it improves the differential diagnosis between brain tumours recurrence and posttreatment changes. 18F-FET PET may provide useful prognostic information in high-grade gliomas. Based on recent literature data 18F-FET PET may provide additional diagnostic information compared to standard MRI in neuro-oncology.

Automatic lesion detection and segmentation of 18F-FET PET in gliomas: A full 3D U-Net convolutional neural network study.

IntroductionAmino-acids positron emission tomography (PET) is increasingly used in the diagnostic workup of patients with gliomas, including differential diagnosis, evaluation of tumor extension, treatment planning and follow-up. Recently, progresses of computer vision and machine learning have been translated for medical imaging. Aim was to demonstrate the feasibility of an automated 18F-fluoro-ethyl-tyrosine (18F-FET) PET lesion detection and segmentation relying on a full 3D U-Net Convolutional Neural Network (CNN).MethodsAll dynamic 18F-FET PET brain image volumes were temporally realigned to the first dynamic acquisition, coregistered and spatially normalized onto the Montreal Neurological Institute template. Ground truth segmentations were obtained using manual delineation and thresholding (1.3 x background). The volumetric CNN was implemented based on a modified Keras implementation of a U-Net library with 3 layers for the encoding and decoding paths. Dice similarity coefficient (DSC) was used as an accuracy measure of segmentation.ResultsThirty-seven patients were included (26 [70%] in the training set and 11 [30%] in the validation set). All 11 lesions were accurately detected with no false positive, resulting in a sensitivity and a specificity for the detection at the tumor level of 100%. After 150 epochs, DSC reached 0.7924 in the training set and 0.7911 in the validation set. After morphological dilatation and fixed thresholding of the predicted U-Net mask a substantial improvement of the DSC to 0.8231 (+ 4.1%) was noted. At the voxel level, this segmentation led to a 0.88 sensitivity [95% CI, 87.1 to, 88.2%] a 0.99 specificity [99.9 to 99.9%], a 0.78 positive predictive value: [76.9 to 78.3%], and a 0.99 negative predictive value [99.9 to 99.9%].ConclusionsWith relatively high performance, it was proposed the first full 3D automated procedure for segmentation of 18F-FET PET brain images of patients with different gliomas using a U-Net CNN architecture.

NIMG-42. EXPERIENCE WITH 18F-FET PET/MRI FOR CNS-TUMORS IN CHILDREN AND ADOLESCENTS

Positron Emission Tomography (PET) with 18F-fluoro-ethyltyrosine (18F-FET) improves diagnostic accuracy in adult patients with gliomas but the literature in pediatric neuro-oncology is still scarce. We aimed 1) to collect a material of various pediatric brain tumors 2) to determine sensitivity and specificity for tumor using 18F-FET PET versus MRI alone 3) to test the clinical impact of the scans. Eighty patients with primary pediatric CNS-tumors was included and a total of 121 hybrid 18F-FET PET/MRI or PET/CT scans have been performed. Clinical impact was assessed as minor (change of diagnosis) or major (change of treatment plan). Minor impact was seen in 28% of all scans and major impact in 9%. In the 27 cases, when a PET scan had beforehand been regarded clinically indicated, 38% showed minor impact and 35% showed major impact. A high uptake was seen in pilocytic astrocytoma and in high grade gliomas, while lower uptake was seen in e.g. AT/RT (atypical teratoid/rhabdoid tumor), ependymoma, germinomas. No increased uptake was seen in e.g. non-contrast enhancing low grade glioma. In 24 early postoperative 18F-FET PET scans conducted primarily within 72 hours after surgery, minor impact was seen in 42% and major impact in 4% of cases. Based on a consensus reading for residual tumor of follow-up scans (up to 24 months), we found the following lesion-based sensitivity/specificity/accuracy for diagnosing residual tumor: MRI alone: 80%/64%/72%. PET/MRI: 73%/100%/86%. The addition of 18F-FET PET to MRI for imaging of pediatric CNS-tumors has a major impact on the clinical management in 9% of all scans and in 35% of the clinically indicated scans. The addition of 18F-FET PET for early postoperative imaging seems to increase the specificity for residual tumor and should be considered when radical surgery is of high priority, especially if MRI is equivocal.

18F-fluoroethyl-L-tyrosine positron emission tomography-guided diagnosis of a malignant intramedullary spinal cord tumor.

Diagnosis in patients with a suspected malignant intramedullary lesion that requires biopsy for definitive diagnosis may be challenging, as spinal cord surgery carries the risk of irreversible neurological deficits. The current study presents the first case of 18F-fluoroethyl-L-tyrosine (18F-FET) positron emission tomography (PET) imaging in a patient with a spinal cord tumor. The patient was unsuitable for magnetic resonance imaging due to his implanted cardiac defibrillator. 18F-FET PET indicated a high-grade malignancy of the spinal cord, justifying tumor biopsy. Histological analysis was compatible with a malignant melanoma. This is also the first report demonstrating the FET-PET appearance/metabolic phenotype of a malignant melanoma of the spinal cord.

Kinetic Modeling and Graphical Analysis of 18F-Fluoromethylcholine (FCho), 18F-Fluoroethyltyrosine (FET) and 18F-Fluorodeoxyglucose (FDG) PET for the Fiscrimination between High-Grade Glioma and Radiation Necrosis in Rats.

BackgroundDiscrimination between glioblastoma (GB) and radiation necrosis (RN) post-irradiation remains challenging but has a large impact on further treatment and prognosis. In this study, the uptake mechanisms of 18F-fluorodeoxyglucose (18F-FDG), 18F-fluoroethyltyrosine (18F-FET) and 18F-fluoromethylcholine (18F-FCho) positron emission tomography (PET) tracers were investigated in a F98 GB and RN rat model applying kinetic modeling (KM) and graphical analysis (GA) to clarify our previous results.MethodsDynamic 18F-FDG (GB n = 6 and RN n = 5), 18F-FET (GB n = 5 and RN n = 5) and 18F-FCho PET (GB n = 5 and RN n = 5) were acquired with continuous arterial blood sampling. Arterial input function (AIF) corrections, KM and GA were performed.ResultsThe influx rate (Ki) of 18F-FDG uptake described by a 2-compartmental model (CM) or using Patlak GA, showed more trapping (k3) in GB (0.07 min-1) compared to RN (0.04 min-1) (p = 0.017). K1 of 18F-FET was significantly higher in GB (0.06 ml/ccm/min) compared to RN (0.02 ml/ccm/min), quantified using a 1-CM and Logan GA (p = 0.036). 18F-FCho was rapidly oxidized complicating data interpretation. Using a 1-CM and Logan GA no clear differences were found to discriminate GB from RN.ConclusionsBased on our results we concluded that using KM and GA both 18F-FDG and 18F-FET were able to discriminate GB from RN. Using a 2-CM model more trapping of 18F-FDG was found in GB compared to RN. Secondly, the influx of 18F-FET was higher in GB compared to RN using a 1-CM model. Important correlations were found between SUV and kinetic or graphical measures for 18F-FDG and 18F-FET. 18F-FCho PET did not allow discrimination between GB and RN.

Abstract P3-03-01: Intracranial PDX models of breast cancer metastasis

Abstract Background: Overexpression of the human epidermal growth factor receptor 2 (HER2) in breast cancer is an independent factor for development of brain metastases. Up to 37% of patients with HER2 positive disease relapse intracranially despite control of extra-cranial metastatic disease. Inability of anti-cancer agents to cross an intact blood-brain barrier (BBB) is a possible explanation for the increased incidence of brain metastases. Subcutaneous (SQ) patient-derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, orthotopic PDX models may confer a translational advantage as the patient tumor microenvironment is more closely mimicked. Especially when targeting brain tumors, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to develop a panel of intracranial PDX models of breast cancer brain metastases for pre-clinical efficacy studies of new anticancer drugs. Methods: SQ tumors from three different HER2 positive PDX breast cancer models designated ST340, ST1339 and ST1616B were enzymatically digested and used for intracranial stereotactic injection in nude mice. Contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) were used to determine tumor take. Intracranial tumor growth was monitored using MRI and positron emission tomography (PET) in conjunction with the amino acid radio tracer 18F-FET. Results: MRI confirmed tumor take in one model as early as 2 weeks after intracranial implantation. Increased 18F-FET uptake was detected in all models. MRI could be effectively used to monitor tumor growth and the corresponding 18F-FET PET images demonstrated increased 18F-FET uptake over time. Conclusion: Three different HER2 positive intracranial PDX breast metastases models were established from low passage SQ PDX models. We suggest, that using these intracranial PDX models of brain metastases, new drugs for advanced breast cancer can be evaluated in preclinical models that more closely mimic the microenvironment and the BBB in patients. In addition, translational imaging techniques can be evaluated during preclinical testing and the potential of tracers like 18F-FET as imaging biomarkers of therapeutic response can be assessed. Together, the established SQ and orthotopic PDX models of breast cancer and brain metastases can be used as a relevant translational platform for testing of new drugs. Citation Format: Nielsen CH, Nedergaard MK, Wick MJ, Papadopoulos K, Tolcher AW, Kjaer A. Intracranial PDX models of breast cancer metastasis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-01.

Comparison of 18F-FET and 18F-FLT small animal PET for the assessment of anti-VEGF treatment response in an orthotopic model of glioblastoma

BackgroundThe radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (FET) and thymidine analogue 3′-deoxy-3′-18F-fluorothymidine (FLT) are widely used for positron emission tomography (PET) brain tumor imaging; however, comparative studies are scarce. The aim of this study therefore was to compare FLT and FET PET for the assessment of anti-VEGF response in glioblastoma xenografts. MethodsXenografts with confirmed intracranial glioblastoma were treated with anti-VEGF therapy (B20-4.1) or saline as control. Weekly bioluminescence imaging (BLI), FLT and FET PET/CT were used to follow treatment response. Tracer uptake of FLT and FET was quantified using maximum standardized uptake (SUVmax) values and tumor-to-background ratios (TBRs). Survival, the Ki67 proliferation index and micro-vessel density (MVD) were evaluated. ResultsIn contrast to FLT TBRs, FET TBRs were significantly lower as early as one week after treatment initiation in the anti-VEGF group as compared to the control group. Following two weeks of treatment, both FLT and FET TBRs were significantly lower in the anti-VEGF group. In contrast, no significant difference between the treatment groups was detected using BLI. Furthermore, we found a significantly lower MVD in the anti-VEGF group as compared to the control group. However, we found no difference in the Ki67 proliferation index or mean survival time. ConclusionFET appears to be a more sensitive tracer than FLT to measure early response to anti-VEGF therapy with PET.Advances in knowledge and implications for patient care FET PET appears to be an early predictor of anti-VEGF efficacy. Confirmation of these results in clinical studies is needed.

Correlation of 18F-fluoroethyl tyrosine positron-emission tomography uptake values and histomorphological findings by stereotactic serial biopsy in newly diagnosed brain tumors using a refined software tool

BackgroundMagnetic resonance imaging (MRI) is the standard neuroimaging method to diagnose neoplastic brain lesions, as well as to perform stereotactic biopsy surgical planning. MRI has the advantage of providing structural anatomical details with high sensitivity, though histological specificity is limited. Although combining MRI with other imaging modalities, such as positron-emission tomography (PET), has proven to increment specificity, exact correlation between PET threshold uptake ratios (URs) and histological diagnosis and grading has not yet been described.ObjectivesThe aim of this study was to correlate exactly the histopathological criteria of the biopsy site to its PET uptake value with high spatial resolution (mm3), and to analyze the diagnostic value of PET using the amino acid O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET in patients with newly diagnosed brain lesions in comparison to histological findings obtained from stereotactic serial biopsy.Patients and methodsA total of 23 adult patients with newly diagnosed brain tumors on MRI were enrolled in this study. Subsequently to diagnoses, all patients underwent a 18F-FET PET-guided stereotactic biopsy, using an original newly developed software module, which is presented here. Conventional MRI, stereotactic computed tomography series, and 18F-FET PET images were semiautomatically fused, and hot-spot detection was performed for target planning. UR was determined using the uptake value from the biopsy sites in relation to the contralateral frontal white matter. UR values ≥1.6 were considered positive for glioma. High-grade glioma (HGG) was suspected with URs ≥3.0, while low-grade glioma (LGG) was suspected with URs between 1.6 and 3.0. Stereotactic serial biopsies along the trajectory at multiple sites were performed in millimeter steps, and the FET URs for each site were correlated exactly with a panel of 27 different histopathological markers. Comparisons between FET URs along the biopsy trajectories and the histological diagnoses were made with Pearson product-moment correlation coefficients. Analysis of variance was performed to test for significant differences in maximum UR between different tumor grades.ResultsA total of 363 biopsy specimens were taken from 23 patients by stereotactic serial biopsies. Histological examination revealed eight patients (35%) with an LGG: one with a World Health Organization (WHO)-I lesion and seven with a WHO-II lesion. Thirteen (57%) patients revealed an HGG (two with a WHO-III and three with a WHO-IV tumor), and two patients (9%) showed a process that was neither HGG nor LGG (group X or no-grade group). The correlation matrix between histological findings and the UR revealed five strong correlations. Low cell density in tissue samples was found to have a significant negative correlation with the measured cortical uptake rate (r=−0.43, P=0.02), as well as moderate cell density (r=−0.48, P=0.02). Pathological patterns of proliferation (r=0.37, P=0.04), GFAP (r=0.37, P=0.04), and Olig2 (r=0.36, P=0.05) showed a significant positive correlation with cortical URs. Analysis of variance tests showed a significant difference between the LGG and the HGG groups (F=8.27, P<0.002), but no significant differences when differentiating between the X group and the HGG (P=0.2)/LGG (P=0.8) groups, nor between the no-grade group and the WHO-I group.Conclusion18F-FET PET is a valuable tool, as it allows the differentiation of HGGs from LGGs. Its use is not limited to preoperative evaluation; it may also refine biopsy targeting and improve tumor delimitation for radiotherapy. Histology is still necessary, and remains the gold standard for definitive diagnosis of brain lesions.

The Sum of Tumour-to-Brain Ratios Improves the Accuracy of Diagnosing Gliomas Using 18F-FET PET.

Gliomas are common brain tumours, but obtaining tissue for definitive diagnosis can be difficult. There is, therefore, interest in the use of non-invasive methods to diagnose and grade the disease. Although positron emission tomography (PET) with 18F-fluorethyltyrosine (18F-FET) can be used to differentiate between low-grade (LGG) and high-grade (HGG) gliomas, the optimal parameters to measure and their cut-points have yet to be established. We therefore assessed the value of single and dual time-point acquisition of 18F-FET PET parameters to differentiate between primary LGGs (n = 22) and HGGs (n = 24). PET examination was considered positive for glioma if the metabolic activity was 1.6-times higher than that of background (contralateral) brain, and maximum tissue-brain ratios (TBRmax) were calculated 10 and 60 min after isotope administration with their sums and differences calculated from individual time-point values. Using a threshold-based method, the overall sensitivity of PET was 97%. Several analysed parameters were significantly different between LGGs and HGGs. However, in a receiver operating characteristics analysis, TBR sum had the best diagnostic accuracy of 87% and sensitivity, specificity, and positive and negative predictive values of 100%, 72.7%, 80%, and 100%, respectively. 18F-FET PET is valuable for the non-invasive determination of glioma grade, especially when dual time-point metrics are used. TBR sum shows the greatest accuracy, sensitivity, and negative predictive value for tumour grade differentiation and is a simple method to implement. However, the cut-off may differ between institutions and calibration strategies would be useful.