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- Silins, Isabella, 1983-, et al.
(författare)
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First-in-human evaluation of [18F]CETO : a novel tracer for adrenocortical tumours
- 2023
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Nature. - 1619-7070 .- 1619-7089. ; 50:2, s. 398-409
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Tidskriftsartikel (refereegranskat)abstract
- Purpose[11C]Metomidate positron emission tomography (PET) is currently used for staging of adrenocortical carcinoma and for lateralization in primary aldosteronism (PA). Due to the short half-life of carbon-11 and a high non-specific liver uptake of [11C]metomidate there is a need for improved adrenal imaging methods. In a previous pre-clinical study para-chloro-2-[18F]fluoroethyletomidate has been proven to be a specific adrenal tracer. The objective is to perform a first evaluation of para-chloro-2-[18F]fluoroethyletomidate positron emission computed tomography ([18F]CETO-PET/CT) in patients with adrenal tumours and healthy volunteers.MethodsFifteen patients underwent [18F]CETO-PET/CT. Five healthy volunteers were recruited for test-retest analysis and three out of the five underwent additional [15O]water PET/CT to measure adrenal blood flow. Arterial blood sampling and tracer metabolite analysis was performed. The kinetics of [18F]CETO were assessed and simplified quantitative methods were validated by comparison to outcome measures of tracer kinetic analysis.ResultsUptake of [18F]CETO was low in the liver and high in adrenals. Initial metabolization was rapid, followed by a plateau. The kinetics of [18F]CETO in healthy adrenals and all adrenal pathologies, except for adrenocortical carcinoma, were best described by an irreversible single-tissue compartment model. Standardized uptake values (SUV) correlated well with the uptake rate constant K1. Both K1 and SUV were highly correlated to adrenal blood flow in healthy controls. Repeatability coefficients of K1, SUV65–70, and SUV120 were 25, 22, and 17%.ConclusionsHigh adrenal uptake combined with a low unspecific liver uptake suggests that 18F]CETO is a suitable tracer for adrenal imaging. Adrenal SUV, based on a whole-body scan at 1 h p.i., correlated well with the net uptake rate Ki.Trial registrationClinicalTrials.gov, NCT05361083 Retrospectively registered 29 April 2022. at, https://clinicaltrials.gov/ct2/show/NCT05361083
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| 2. |
- Silins, Isabella, 1983-
(författare)
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Improved adrenocortical PET imaging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Adrenal tumours can either be benign or malignant, hormone secreting or not, and they can be discovered through clinical examination of the patient or by pure chance. Increased knowledge in the area, plus the widespread use of imaging techniques, have resulted in a rising number of patients with adrenal tumours that subsequently need to be diagnosed. Improved imaging is needed for primary aldosteronism (PA) and adrenocortical carcinoma (ACC) but the positron emission tomography (PET) tracer currently in use, [11C]metomidate (MTO), has many important limitations. This thesis aims to improve adrenocortical PET imaging.Methods: Paper 1 investigated the pre-clinical properties of Para-Chloro-2-[18F]fluoroethyl-etomidate (CETO), by autoradiography, binding studies, ex vivo biodistribution on rats and in vivo imaging using mice and one non-human primate (NHP). Paper II investigated the clinical properties of [18F]CETO and included patients with various kinds of adrenocortical tumours, and healthy volunteers. Metabolic and kinetic analyses were performed and three out of five healthy volunteers also underwent [15O]water PET/CT to measure adrenal blood flow. Test-retest was performed on all healthy volunteers. Paper III assessed the in vivo and in-human radiation dosimetry of [18F]CETO. Ex vivo uptake data from rats and in vivo PET/CT from NHP and humans were used to calculate residence times. Paper IV evaluated the use of the block-sequential regularized expectation maximization (BSREM) reconstruction algorithm (Q.Clear, GE Healthcare, Milwaukee, USA) for [11C]MTO PET/CT in patients with PA.Results: Papers I and II demonstrated that [18F]CETO is highly specific to the adrenal cortex both in vitro and in vivo. The non-specific binding of [18F]CETO in the liver was significantly lower than that of [11C]MTO. [18F]CETO metabolizes rapidly and the single tissue irreversible (1T1k) kinetic model provided the best fit. [15O]water PET/CT results indicated that the adrenal [18F]CETO uptake was flow limited. Several retest values, including adrenal blood flow, were lower than the test values. Paper III found that the effective dose based on human data was 18.2 μSv/MBq and that the adrenal glands were the limiting organ regardless of species used. Paper IV showed that the BSREM reconstruction algorithm improves image quality, without compromising SUVmax quantification, and a β-value between 70 and 130 was found optimal.Conclusion: [18F]CETO PET/CT is a promising method for adrenocortical imaging and is safe for clinical imaging in terms of radiation dose. [18F]CETO PET/CT should be further investigated in patients with PA or ACC, preferably in conjunction with BSREM reconstruction.
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| 3. |
- Silins, Isabella, 1983-, et al.
(författare)
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Para-chloro-2-[18F]fluoroethyl-etomidate : A promising new PET radiotracer for adrenocortical imaging
- 2021
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Ingår i: International Journal of Medical Sciences. - : Ivyspring International Publisher. - 1449-1907. ; 18:10, s. 2187-2196
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting.Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer.Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO.Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO.Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.
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| 4. |
- Silins, Isabella, 1983-, et al.
(författare)
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Penalized-likelihood reconstruction of [11C]metomidate PET in patients with primary aldosteronism
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective[11C]metomidate PET/CT is used for adrenocortical cancer imaging and is currently evaluated as an adjunct to adrenal vein sampling (AVS) for lateralization of aldosterone-producing adenomas (APA) in patients with primary aldosteronism (PA). This study assessed the image quality of a block-sequential regularized expectation maximization (BSREM) reconstruction algorithm (Q.Clear, GE Healthcare, Milwaukee, USA), to determine the optimal penalization factor (expressed as beta values) for clinical [11C]metomidate PET/CT. The time-of-flight coupled ordered subset expectation maximization (TOF OSEM) algorithm was used as the reference reconstruction. MethodsRetrospectively, seven patients with primary aldosteronism were assessed, for whom raw data and TOF OSEM reconstructions of [11C]metomidate PET were available. Raw data were reconstructed applying BSREM with β-values 70-800. Tumour SUVmax in the APAs was measured and image quality was assessed mainly in terms of signal-to-background ratio (SBR) and signal-to-noise ratio (SNR) in comparison with TOF OSEM, applying a two-tailed Wilcoxon matched-pairs signed rank test. In addition, we addressed the effect of BSREM on lateralization. ResultsWith the BSREM algorithm, and as compared to TOF OSEM reconstruction, the average lesion SUVmax increased for β-values 70 and 130 (p=0.0156).SBR increased for β-values 130 or higher (p=0.0156) and SNR increased only for β-value 130 (p=0.0156). By using an adenoma-to-normal-adrenal gland ratio of 1.25 as the cut-off, one additional patient was lateralized by [11C]metomidate PET reconstructed with the BSREM (β 70 and 130, p=0.0156 and p=0.0312) as compared to TOF OSEM. ConclusionsThe BSREM reconstruction algorithm improves image quality, without compromising SUVmax quantification. In this study, a β-value between 70 and 130 was found optimal. BSREM may therefore improve lateralization by [11C]metomidate PET/CT in primary aldosteronism, with the expectation of the greatest impact on small adenomas.
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| 5. |
- Silins, Isabella, 1983-, et al.
(författare)
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Radiation dosimetry of para-chloro-2-[18F]fluoroethyl-etomidate:a PET tracer for adrenocortical imaging
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Introduction[11C]metomidate, a methyl ester analogue of etomidate, is used for positron emission tomography of adrenocortical cancer, and has been tested in recent clinical trials for lateralization in primary aldosteronism (PA). However, in PA, visualization as well as uptake quantification are hampered by the tracer’s rather high non-specific liver uptake, and its overall clinical usefulness is also limited by the short 20-minute half-life of carbon-11. Therefore, we evaluated para-chloro-2-[18F]fluoroethyl-etomidate, [18F]CETO, a fluorine-18 (T1/2=109.8 min) analogue, as a potential new adrenocortical PET tracer.ObjectivesThe aim of this study was to assess in vivo and in-human radiation dosimetry of [18F]CETO.Methods: Residence times were calculated based on uptake data from rats (n=30, biodistribution study with ex vivo measurements) as well as in vivo PET/CT in cynomolgus (n=1) and humans (n=9). OLINDA 1.1 was used to obtain absorbed doses in human organs (mGy/MBq) and effective dose (mSv/MBq).Results[18F]CETO showed a high uptake in human adrenal glands, still increasing at 90 minutes post injection. Regardless of species used for input data (rat, cynomolgus or human), adrenal glands (absorbed dose 0.093 ± 0.038 mGy/MBq based on human data) were confirmed as the dose-limiting organs. The effective dose based on human data was 18.2 μSv/MBq and varied little when using rat (18.4 μSv/MBq) or cynomolgus data (16.1 μSv/MBq). Conclusions[18F]CETO has a favourable biodistribution in humans for adrenal imaging. The effective dose for a typical clinical PET/CT examination with 200 MBq [18F]CETO is 3.6 mSv.
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