Dataset Information

Quantitative parametric maps of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.

ABSTRACT: Quantitative parametric images of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine kinetics in diffuse gliomas could be used to improve glioma grading, tumour delineation or the assessment of the uptake distribution of this positron emission tomography tracer. In this study, several parametric images and tumour-to-normal maps were compared in terms of accuracy of region averages (when compared to results from nonlinear regression of a reversible two-tissue compartment plasma input model) and image noise using 90 min of dynamic scan data acquired in seven patients with diffuse glioma. We included plasma input methods (the basis function implementation of the single-tissue compartment model, spectral analysis and Logan graphical analysis) and reference tissue methods (basis function implementations of the simplified reference tissue model, variations of the multilinear reference tissue model and non-invasive Logan graphical analysis) as well as tumour-to-normal ratio maps at three intervals. (Non-invasive) Logan graphical analysis provided volume of distribution maps and distribution volume ratio maps with the lowest level of noise, while the basis function implementations provided the best accuracy. Tumour-to-normal ratio maps provided better results if later interval times were used, i.e. 60-90 min instead of 20-40 min, leading to lower bias (2.9% vs. 10.8%, respectively) and less noise (12.8% vs. 14.4%).

SUBMITTER: Koopman T

PROVIDER: S-EPMC7074601 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Quantitative parametric maps of O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.

Koopman Thomas T Verburg Niels N Pouwels Petra Jw PJ Wesseling Pieter P Hoekstra Otto S OS De Witt Hamer Philip C PC Lammertsma Adriaan A AA Yaqub Maqsood M Boellaard Ronald R

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190524 4

Quantitative parametric images of O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine kinetics in diffuse gliomas could be used to improve glioma grading, tumour delineation or the assessment of the uptake distribution of this positron emission tomography tracer. In this study, several parametric images and tumour-to-normal maps were compared in terms of accuracy of region averages (when compared to results from nonlinear regression of a reversible two-tissue compartment plasma input model) and image n ...[more]

PMID: 31122112

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Project description:BackgroundThis study identified the optimal tracer kinetic model for quantification of dynamic O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) positron emission tomography (PET) studies in seven patients with diffuse glioma (four glioblastoma, three lower grade glioma). The performance of more simplified approaches was evaluated by comparison with the optimal compartment model. Additionally, the relationship with cerebral blood flow-determined by [15O]H2O PET-was investigated.ResultsThe optimal tracer kinetic model was the reversible two-tissue compartment model. Agreement analysis of binding potential estimates derived from reference tissue input models with the distribution volume ratio (DVR)-1 derived from the plasma input model showed no significant average difference and limits of agreement of - 0.39 and 0.37. Given the range of DVR-1 (- 0.25 to 1.5), these limits are wide. For the simplified methods, the 60-90 min tumour-to-blood ratio to parent plasma concentration yielded the highest correlation with volume of distribution VT as calculated by the plasma input model (r = 0.97). The 60-90 min standardized uptake value (SUV) showed better correlation with VT (r = 0.77) than SUV based on earlier intervals. The 60-90 min SUV ratio to contralateral healthy brain tissue showed moderate agreement with DVR with no significant average difference and limits of agreement of - 0.24 and 0.30. A significant but low correlation was found between VT and CBF in the tumour regions (r = 0.61, p = 0.007).ConclusionUptake of [18F]FET was best modelled by a reversible two-tissue compartment model. Reference tissue input models yielded estimates of binding potential which did not correspond well with plasma input-derived DVR-1. In comparison, SUV ratio to contralateral healthy brain tissue showed slightly better performance, if measured at the 60-90 min interval. SUV showed only moderate correlation with VT. VT shows correlation with CBF in tumour.

Project description:Background and Purpose: Glioblastomas are the most aggressive of all gliomas. The prognosis of these gliomas, which are classified as grade IV tumors by the World Health Organization (WHO), is poor. Combination therapy, including surgery, radiotherapy, and chemotherapy has variable outcomes and is expensive. In light of rising healthcare costs, there are societal demands for the justification of medical expenses. Therefore, we calculated the cost-effectiveness of follow-up [18F] fluoroethyl-L-tyrosine ([18F] FET) positron emission tomography (PET) scans performed on patients with glioblastoma after surgery and before commencing temozolomide maintenance treatment. Materials and Methods: To determine the cost-effectiveness of follow-up [18F] FET PET procedures, we examined published clinical data and calculated the associated costs in the context of Belgian healthcare. We subsequently performed one-way deterministic sensitivity analysis and Monte Carlo analysis on the calculated ratios. Results: The decision tree based on overall survival rates showed that the number of non-responders identified using PET was 57.14% higher than the number of non-responders identified using conventional MRI. Further, the decision tree based on progression-free survival rates revealed a comparable increase of 57.50% non-responders identified. The calculated cost of two required PET scans per patient during the follow-up treatment phase was 780.50 euros. Two cost-effectiveness ratios were determined for overall survival and progression-free survival rates. Both of these calculations yielded very similar results: incremental cost-effectiveness ratios of 1,365.86 and 1,357.38 euros, respectively, for each identified non-responder. The findings of the sensitivity analysis supported the calculated results, confirming that the obtained data were robust. Conclusion: Our comparative study of conventional MRI and [18F] FET PET revealed that the latter is a valuable tool for predicting the treatment responses of patients with glioblastomas to follow-up temozolomide maintenance treatment while considering its cost-effectiveness. Thus, [18F] FET PET scans enable clinical outcomes to be predicted accurately and at a low cost. Moreover, given the robustness of the data in the sensitivity analyses, the level of certainty of this outcome is acceptable.

Project description:BackgroundConventional scale production of small batches of PET tracers (e.g. for preclinical imaging) is an inefficient use of resources. Using O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET), we demonstrate that simple microvolume radiosynthesis techniques can improve the efficiency of production by consuming tiny amounts of precursor, and maintaining high molar activity of the tracers even with low starting activity.ProceduresThe synthesis was carried out in microvolume droplets manipulated on a disposable patterned silicon "chip" affixed to a heater. A droplet of [18F]fluoride containing TBAHCO3 was first deposited onto a chip and dried at 100 °C. Subsequently, a droplet containing 60 nmol of precursor was added to the chip and the fluorination reaction was performed at 90 °C for 5 min. Removal of protecting groups was accomplished with a droplet of HCl heated at 90 °C for 3 min. Finally, the crude product was collected in a methanol-water mixture, purified via analytical-scale radio-HPLC and formulated in saline. As a demonstration, using [18F]FET produced on the chip, we prepared aliquots with different molar activities to explore the impact on preclinical PET imaging of tumor-bearing mice.ResultsThe microdroplet synthesis exhibited an overall decay-corrected radiochemical yield of 55 ± 7% (n = 4) after purification and formulation. When automated, the synthesis could be completed in 35 min. Starting with < 370 MBq of activity, ~ 150 MBq of [18F]FET could be produced, sufficient for multiple in vivo experiments, with high molar activities (48-119 GBq/μmol). The demonstration imaging study revealed the uptake of [18F]FET in subcutaneous tumors, but no significant differences in tumor uptake as a result of molar activity differences (ranging 0.37-48 GBq/μmol) were observed.ConclusionsA microdroplet synthesis of [18F]FET was developed demonstrating low reagent consumption, high yield, and high molar activity. The approach can be expanded to tracers other than [18F]FET, and adapted to produce higher quantities of the tracer sufficient for clinical PET imaging.

Project description: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.

Project description:IntroductionGlioblastoma is the most common aggressive primary central nervous system cancer in adults characterised by uniformly poor survival. Despite maximal safe resection and postoperative radiotherapy with concurrent and adjuvant temozolomide-based chemotherapy, tumours inevitably recur. Imaging with O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) has the potential to impact adjuvant radiotherapy (RT) planning, distinguish between treatment-induced pseudoprogression versus tumour progression as well as prognostication.Methods and analysisThe FET-PET in Glioblastoma (FIG) study is a prospective, multicentre, non-randomised, phase II study across 10 Australian sites and will enrol up to 210 adults aged ≥18 years with newly diagnosed glioblastoma. FET-PET will be performed at up to three time points: (1) following initial surgery and prior to commencement of chemoradiation (FET-PET1); (2) 4 weeks following concurrent chemoradiation (FET-PET2); and (3) within 14 days of suspected clinical and/or radiological progression on MRI (performed at the time of clinical suspicion of tumour recurrence) (FET-PET3). The co-primary outcomes are: (1) to investigate how FET-PET versus standard MRI impacts RT volume delineation and (2) to determine the accuracy and management impact of FET-PET in distinguishing pseudoprogression from true tumour progression. The secondary outcomes are: (1) to investigate the relationships between FET-PET parameters (including dynamic uptake, tumour to background ratio, metabolic tumour volume) and progression-free survival and overall survival; (2) to assess the change in blood and tissue biomarkers determined by serum assay when comparing FET-PET data acquired prior to chemoradiation with other prognostic markers, looking at the relationships of FET-PET versus MRI-determined site/s of progressive disease post chemotherapy treatment with MRI and FET-PET imaging; and (3) to estimate the health economic impact of incorporating FET-PET into glioblastoma management and in the assessment of post-treatment pseudoprogression or recurrence/true progression. Exploratory outcomes include the correlation of multimodal imaging, blood and tumour biomarker analyses with patterns of failure and survival.Ethics and disseminationThe study protocol V.2.0 dated 20 November 2020 has been approved by a lead Human Research Ethics Committee (Austin Health, Victoria). Other clinical sites will provide oversight through local governance processes, including obtaining informed consent from suitable participants. The study will be conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. Results of the FIG study (TROG 18.06) will be disseminated via relevant scientific and consumer forums and peer-reviewed publications.Trial registration numberANZCTR ACTRN12619001735145.

Project description:PurposeThere is currently no ideal radiotracer for imaging bacterial infections. Radiolabelled D-amino acids are promising candidates because they are actively incorporated into the peptidoglycan of the bacterial cell wall, a structural feature which is absent in human cells. This work describes fluorine-18 labelled analogues of D-tyrosine and D-methionine, O-(2-[18F]fluoroethyl)-D-tyrosine (D-[18F]FET) and S-(3-[18F]fluoropropyl)-D-homocysteine (D-[18F]FPHCys), and their pilot evaluation studies as potential radiotracers for imaging bacterial infection.ProceduresD-[18F]FET and D-[18F]FPHCys were prepared in classical fluorination-deprotection reactions, and their uptake in Staphylococcus aureus and Pseudomonas aeruginosa was evaluated over 2 h. Heat killed bacteria were used as controls. A clinically-relevant foreign body model of S. aureus infection was established in Balb/c mice, as well as a sterile foreign body to mimic inflammation. The ex vivo biodistribution of D-[18F]FPHCys in the infected and inflamed mice was evaluated after 1 h, by dissection and gamma counting. The uptake was compared to that of [18F]FDG.ResultsIn vitro uptake of both D-[18F]FET and D-[18F]FPHCys was specific to live bacteria. Uptake was higher in S. aureus than in P. aeruginosa for both radiotracers, and of the two, higher for D-[18F]FPHCys than D-[18F]FET. Blocking experiments with non-radioactive D-[19F]FPHCys confirmed specificity of uptake. In vivo, D-[18F]FPHCys had greater accumulation in S. aureus infection compared with sterile inflammation, which was statistically significant. As anticipated, [18F]FDG showed no significant difference in uptake between infection and inflammation.ConclusionsD-[18F]FPHCys uptake was higher in infected tissues than inflammation, and represents a fluorine-18 labelled D-AA with potential to detect a S. aureus reference strain (Xen29) in vivo. Additional studies are needed to evaluate uptake of this radiotracer in clinical isolates.

Project description:Aim: Positron emission tomography (PET) imaging is a useful tool for assisting in correct differentiation of tumor progression from reactive changes, and the radiolabeled amino acid analog tracer O-(2-18F-fluoroethyl)-L-tyrosine (FET)-PET is amongst the most frequently used. The FET-PET images need to be quantitatively correct in order to be used clinically, which require accurate attenuation correction (AC) in PET/MRI. The aim of this study was to evaluate the use of the subject-specific MR-derived AC method RESOLUTE in post-operative brain tumor patients. Methods: We analyzed 51 post-operative brain tumor patients (68 examinations, 200 MBq [18F]-FET) investigated in a PET/MRI scanner. MR-AC maps were acquired using: (1) the Dixon water fat separation sequence, (2) the ultra short echo time (UTE) sequences, (3) calculated using our new RESOLUTE methodology, and (4) a same day low-dose CT used as reference "gold standard." For each subject and each AC method the tumor was delineated by isocontouring tracer uptake above a tumor(T)-to-brain background (B) activity ratio of 1.6. We measured B, tumor mean and maximal activity (TMEAN, TMAX), biological tumor volume (BTV), and calculated the clinical metrics TMEAN/B and TMAX/B. Results: When using RESOLUTE 5/68 studies did not meet our predefined acceptance criteria of TMAX/B difference to CT-AC < ±0.1 or 5%, TMEAN/B < ±0.05 or 5%, and BTV < ±2 mL or 10%. In total, 46/68 studies failed our acceptance criteria using Dixon, and 26/68 using UTE. The 95% limits of agreement for TMAX/B was for RESOLUTE (-3%; 4%), Dixon (-9%; 16%), and UTE (-7%; 10%). The absolute error when measuring BTV was 0.7 ± 1.9 mL (N.S) with RESOLUTE, 5.3 ± 10 mL using Dixon, and 1.7 ± 3.7 mL using UTE. RESOLUTE performed best in the identification of the location of peak activity and in brain tumor follow-up monitoring using clinical FET PET metrics. Conclusions: Overall, we found RESOLUTE to be the AC method that most robustly reproduced the CT-AC clinical metrics per se, during follow-up, and when interpreted into defined clinical use cut-off criteria and into the patient history. RESOLUTE is especially suitable for brain tumor patients, as these often present with distorted anatomy where other methods based on atlas/template information might fail.

Dataset Information

Quantitative parametric maps of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.

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Quantitative parametric maps of O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.

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Quantitative parametric maps of O-(2-[18F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.

Publications

Quantitative parametric maps of O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.

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OmicsDI is part of the ELIXIR infrastructure

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Quantitative parametric maps of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine kinetics in diffuse glioma.