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Prognostic value of subventricular zone involvement in relation to tumor volumes defined by fused MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET imaging in glioblastoma multiforme.

ABSTRACT: BACKGROUND:Subventricular zone (SVZ) involvement is associated with a dismal prognosis in patients with glioblastoma multiforme (GBM). Dual-time point (dtp) O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/CT (PET) may be a time- and cost-effective alternative to dynamic FET PET, but its prognostic value, particularly with respect to SVZ involvement, is unknown. METHODS:Thirty-five patients had two scans 5-15 and 50-60?min after i.v. FET injection to define tumor volumes and SVZ involvement before starting radiotherapy. Associations between clinical progression markers, MRI- and dtp FET PET-based tumor volumes, or SVZ involvement and progression-free (PFS) and overall survival (OS) were assessed in univariable and multivariable analyses. RESULTS:The extent of resection was not related to outcomes. Albeit non-significant, dtp FET PET detected more SVZ infiltration than MRI (60% vs. 51%, p?=?0.25) and was significantly associated with poor survival (p?

SUBMITTER: Harat M

PROVIDER: S-EPMC6398237 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Prognostic value of subventricular zone involvement in relation to tumor volumes defined by fused MRI and O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine (FET) PET imaging in glioblastoma multiforme.

Harat Maciej M Małkowski Bogdan B Roszkowski Krzysztof K

Radiation oncology (London, England) 20190304 1

<h4>Background</h4>Subventricular zone (SVZ) involvement is associated with a dismal prognosis in patients with glioblastoma multiforme (GBM). Dual-time point (dtp) O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine (FET) PET/CT (PET) may be a time- and cost-effective alternative to dynamic FET PET, but its prognostic value, particularly with respect to SVZ involvement, is unknown.<h4>Methods</h4>Thirty-five patients had two scans 5-15 and 50-60 min after i.v. FET injection to define tumor volumes and ...[more]

PMID: 30832691

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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: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.

Project description:Current equipment and methods for preparation of radiopharmaceuticals for positron emission tomography (PET) are expensive and best suited for large-scale multi-doses batches. Microfluidic radiosynthesizers have been shown to provide an economic approach to synthesize these compounds in smaller quantities, but can also be scaled to clinically-relevant levels. Batch microfluidic approaches, in particular, offer significant reduction in system size and reagent consumption. Here we show a simple and rapid technique to concentrate the radioisotope, prior to synthesis in a droplet-based radiosynthesizer, enabling production of clinically-relevant batches of [18F]FET and [18F]FBB. The synthesis was carried out with an automated synthesizer platform based on a disposable Teflon-silicon surface-tension trap chip. Up to 0.1 mL (4 GBq) of radioactivity was used per synthesis by drying cyclotron-produced aqueous [18F]fluoride in small increments directly inside the reaction site. Precursor solution (10 µL) was added to the dried [18F]fluoride, the reaction chip was heated for 5 min to perform radiofluorination, and then a deprotection step was performed with addition of acid solution and heating. The product was recovered in 80 µL volume and transferred to analytical HPLC for purification. Purified product was formulated via evaporation and resuspension or a micro-SPE formulation system. Quality control testing was performed on 3 sequential batches of each tracer. The method afforded production of up to 0.8 GBq of [18F]FET and [18F]FBB. Each production was completed within an hour. All batches passed quality control testing, confirming suitability for human use. In summary, we present a simple and efficient synthesis of clinically-relevant batches of [18F]FET and [18F]FBB using a microfluidic radiosynthesizer. This work demonstrates that the droplet-based micro-radiosynthesizer has a potential for batch-on-demand synthesis of 18F-labeled radiopharmaceuticals for human use.

Project description:PurposeGlioblastoma multiforme (GBM) is the most common glioma and standard therapies can only slightly prolong the survival. Neo-vascularization is a potential target to image tumor microenvironment, as it defines its brain invasion. We investigate [18F]rhPSMA-7.3 with PET/MRI for quantitative imaging of neo-vascularization in GBM bearing mice and human tumor tissue and compare it to [18F]FET and [18F]fluciclovine using PET pharmacokinetic modeling (PKM).Methods[18F]rhPSMA-7.3, [18F]FET, and [18F]fluciclovine were i.v. injected with 10.5 ± 3.1 MBq, 8.0 ± 2.2 MBq, 11.5 ± 1.9 MBq (n = 28, GL261-luc2) and up to 90 min PET/MR imaged 21/28 days after surgery. Regions of interest were delineated on T2-weighted MRI for (i) tumor, (ii) brain, and (iii) the inferior vena cava. Time-activity curves were expressed as SUV mean, SUVR and PKM performed using 1-/2-tissue-compartment models (1TCM, 2TCM), Patlak and Logan analysis (LA). Immunofluorescent staining (IFS), western blotting, and autoradiography of tumor tissue were performed for result validation.Results[18F]rhPSMA-7.3 showed a tumor uptake with a tumor-to-background-ratio (TBR) = 2.1-2.5, in 15-60 min. PKM (2TCM) confirmed higher K1 (0.34/0.08, p = 0.0012) and volume of distribution VT (0.24/0.1, p = 0.0017) in the tumor region compared to the brain. Linearity in LA and similar k3 = 0.6 and k4 = 0.47 (2TCM, tumor, p = ns) indicated reversible binding. K1, an indicator for vascularization, increased (0.1/0.34, 21 to 28 days, p < 0.005). IFS confirmed co-expression of PSMA and tumor vascularization. [18F]fluciclovine showed higher TBR (2.5/1.8, p < 0.001, 60 min) and VS (1.3/0.7, p < 0.05, tumor) compared to [18F]FET and LA indicated reversible binding. VT increased (p < 0.001, tumor, 21 to 28 days) for [18F]FET (0.5-1.4) and [18F]fluciclovine (0.84-1.5).Conclusion[18F]rhPSMA-7.3 showed to be a potential candidate to investigate the tumor microenvironment of GBM. Following PKM, this uptake was associated with tumor vascularization. In contrast to what is known from PSMA-PET in prostate cancer, reversible binding was found for [18F]rhPSMA-7.3 in GBM, contradicting cellular trapping. Finally, [18F]fluciclovine was superior to [18F]FET rendering it more suitable for PET imaging of GBM.

Dataset Information

Prognostic value of subventricular zone involvement in relation to tumor volumes defined by fused MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET imaging in glioblastoma multiforme.

Publications

Prognostic value of subventricular zone involvement in relation to tumor volumes defined by fused MRI and O-(2-[<sup>18</sup>F]fluoroethyl)-L-tyrosine (FET) PET imaging in glioblastoma multiforme.

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