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      Incremental diagnostic value of [ 18F]tetrafluoroborate PET-CT compared to [ 131I]iodine scintigraphy in recurrent differentiated thyroid cancer

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          Abstract

          Introduction

          Efficient therapy of recurrent differentiated thyroid cancer (DTC) is dependent on precise molecular imaging techniques targeting the human sodium iodide symporter (hNIS), which is a marker both of thyroid and DTC cells. Various iodine isotopes have been utilized for detecting DTC; however, these come with unfavorable radiation exposure and image quality ([ 131I]iodine) or limited availability ([ 124I]iodine). In contrast, [ 18F]tetrafluoroborate (TFB) is a novel radiolabeled PET substrate of hNIS, results in PET images with high-quality and low radiation doses, and should therefore be suited for imaging of DTC. The aim of the present study was to compare the diagnostic performance of [ 18F]TFB-PET to the clinical reference standard [ 131I]iodine scintigraphy in patients with recurrent DTC.

          Methods

          Twenty-five patients with recurrent DTC were included in this retrospective analysis. All patients underwent [ 18F]TFB-PET combined with either CT or MRI due to newly discovered elevated TG levels, antiTG levels, sonographically suspicious cervical lymph nodes, or combinations of these findings. Correlative [ 131I]iodine whole-body scintigraphy (dxWBS) including SPECT-CT was present for all patients; correlative [ 18F]FDG-PET-CT was present for 21 patients. Histological verification of [ 18F]TFB positive findings was available in 4 patients.

          Results

          [ 18F]TFB-PET detected local recurrence or metastases of DTC in significantly more patients than conventional [ 131I]iodine dxWBS and SPECT-CT (13/25 = 52% vs. 3/25 = 12%, p = 0.002). The diagnosis of 6 patients with cervical lymph node metastases that showed mildly increased FDG metabolism but negative [ 131I]iodine scintigraphy was changed: [ 18F]TFB-PET revealed hNIS expression in the metastases, which were therefore reclassified as only partly de-differentiated (histological confirmation present in two patients). Highest sensitivity for detecting recurrent DTC had the combination of [ 18F]TFB-PET-CT/MRI with [ 18F]FDG-PET-CT (64%).

          Conclusion

          In the present cohort, [ 18F]TFB-PET shows higher sensitivity and accuracy than [ 131I]iodine WBS and SPECT-CT in detecting recurrent DTC. The combination of [ 18F]TFB-PET with [ 18F]FDG-PET-CT seems a reasonable strategy to characterize DTC tumor manifestations with respect to their differentiation and thereby also individually plan and monitor treatment. Future prospective studies evaluating the potential of [ 18F]TFB-PET in recurrent DTC are warranted.

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          Most cited references15

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          CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer

          Although various chemokines have pro-tumorigenic actions in cancers, the effects of CXCL16 remain controversial. The aim of this study was to investigate the molecular characteristics of CXCL16-expressing papillary thyroid cancers (PTCs). CXCL16 expressions were significantly higher in PTCs than benign or normal thyroid tissues. In the TCGA dataset for PTCs, a higher CXCL16 expression was associated with M2 macrophage- and angiogenesis-related genes and poor prognostic factors including a higher TNM staging and the BRAF V600E mutation. PTCs with a higher expression of 3-gene panel including CXCL16, AHNAK2, and THBS2 showed poor recurrence-free survivals than that of the lower expression group. Next, shCXCL16 was introduced into BHP10-3SCp cells to deplete the endogenous CXCL16, and then, the cells were subcutaneously injected to athymic mice. Tumors from the BHP10-3SCpshCXCL16 exhibited a delayed tumor growth with decreased numbers of ERG+ endothelial cells and F4/80+ macrophages than those from the BHP10-3SCpcontrol. CXCL16-related genes including AHNAK2 and THBS2 were downregulated in the tumors from the BHP10-3SCpshCXCL16 compared with that from the BHP10-3SCpcontrol. In conclusion, a higher CXCL16 expression was associated with macrophage- and angiogenesis-related genes and aggressive phenotypes in PTC. Targeting CXCL16 may be a good therapeutic strategy for advanced thyroid cancer.
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            (18)F-Tetrafluoroborate, a PET Probe for Imaging Sodium/Iodide Symporter Expression: Whole-Body Biodistribution, Safety, and Radiation Dosimetry in Thyroid Cancer Patients.

            We report the safety, biodistribution, and internal radiation dosimetry, in humans with thyroid cancer, of (18)F-tetrafluoroborate ((18)F-TFB), a novel PET radioligand for imaging the human sodium/iodide symporter (hNIS). Methods: Serial whole-body PET scans of 5 subjects with recently diagnosed thyroid cancer were acquired before surgery for up to 4 h after injection of 184 ± 15 MBq of (18)F-TFB. Activity was determined in whole blood, plasma, and urine. Mean organ-absorbed doses and effective doses were calculated via quantitative image analysis and using OLINDA/EXM software. Results: Images showed a high uptake of (18)F-TFB in known areas of high hNIS expression (thyroid, salivary glands, and stomach). Excretion was predominantly renal. No adverse effects in relation to safety of the radiopharmaceutical were observed. The effective dose was 0.0326 ± 0.0018 mSv/MBq. The critical tissues/organs receiving the highest mean sex-averaged absorbed doses were the thyroid (0.135 ± 0.079 mSv/MBq), stomach (0.069 ± 0.022 mSv/MBq), and salivary glands (parotids, 0.031 ± 0.011 mSv/MBq; submandibular, 0.061 ± 0.031 mSv/MBq). Other organs of interest were the bladder (0.102 ± 0.046 mSv/MBq) and kidneys (0.029 ± 0.009 mSv/MBq). Conclusion: Imaging using (18)F-TFB imparts a radiation exposure similar in magnitude to many other (18)F-labeled radiotracers. (18)F-TFB shows a biodistribution similar to (99m)Tc-pertechnetate, a known nonorganified hNIS tracer, and is pharmacologically and radiobiologically safe in humans. Phase 2 trials for (18)F-TFB as an hNIS imaging agent are warranted.
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              [ 18 F]Tetrafluoroborate ([ 18 F]TFB) and its analogs for PET imaging of the sodium/iodide symporter

              Sodium/iodide symporter (NIS)-mediated iodide uptake in thyroid follicular cells is the basis of clinical utilization of radioiodines. The cloning of the NIS gene enabled applications of NIS as a reporter gene in both preclinical and translational research. Non-invasive NIS imaging with radioactive iodides and iodide analogs has gained much interest in recent years for evaluation of thyroid cancer and NIS reporter expression. Although radioiodines and [99mTc]pertechnetate ([99mTc]TcO4 -) have been utilized in positron emission tomography (PET) and single photon emission computed tomography (SPECT), they may suffer from limitations of availability, undesirable decay properties or imaging sensitivity (SPECT versus PET). Recently, [18F]tetrafluoroborate ([18F]TFB or [18F]BF4 -) and other fluorine-18 labeled iodide analogs have emerged as a promising iodide analog for PET imaging. These fluorine-18 labeled probes have practical radiosyntheses and biochemical properties that allow them to closely mimic iodide transport by NIS in thyroid, as well as in other NIS-expressing tissues. Unlike radioiodides, they do not undergo organification in thyroid cells, which results in an advantage of relatively lower uptake in normal thyroid tissue. Initial clinical trials of [18F]TFB have been completed in healthy human subjects and thyroid cancer patients. The excellent imaging properties of [18F]TFB for evaluation of NIS-expressing tissues indicate its bright future in PET NIS imaging. This review focuses on the recent evolution of [18F]TFB and other iodide analogs and their potential value in research and clinical practice.

                Author and article information

                Contributors
                robert.seifert@uni-muenster.de
                Journal
                Eur J Nucl Med Mol Imaging
                Eur. J. Nucl. Med. Mol. Imaging
                European Journal of Nuclear Medicine and Molecular Imaging
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1619-7070
                1619-7089
                4 April 2020
                4 April 2020
                2020
                : 47
                : 11
                : 2639-2646
                Affiliations
                [1 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Nuclear Medicine, , University Hospital Münster, ; Albert-Schweitzer-Campus 1, 48149 Münster, Germany
                [2 ]GRID grid.5949.1, ISNI 0000 0001 2172 9288, European Institute for Molecular Imaging (EIMI), , University of Münster, ; Münster, Germany
                [3 ]GRID grid.5949.1, ISNI 0000 0001 2172 9288, Cells in Motion Interfaculty Centre (CiM), , University of Münster, ; Münster, Germany
                Author information
                http://orcid.org/0000-0001-5985-7701
                Article
                4727
                10.1007/s00259-020-04727-9
                7515952
                32248325
                520cb7ce-052f-46f7-9a8f-2cf4c473d7c2
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 January 2020
                : 14 February 2020
                Funding
                Funded by: Universitätsklinikum Münster (8918)
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                Radiology & Imaging
                thyroid cancer,tetrafluoroborate,iodine,pet-ct,spect,wbs
                Radiology & Imaging
                thyroid cancer, tetrafluoroborate, iodine, pet-ct, spect, wbs

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