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      MET-receptor targeted fluorescent imaging and spectroscopy to detect multifocal papillary thyroid cancer

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          Abstract

          Purpose

          Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection.

          Methods

          A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy.

          Results

          Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg ( n = 1), 0.13 mg/kg ( n = 8), or 0.18 mg/kg ( n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound.

          Conclusion

          EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease.

          Trial registration

          NCT03470259

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s00259-023-06525-5.

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          Most cited references35

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          2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

          Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer.
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            Gene expression in papillary thyroid carcinoma reveals highly consistent profiles.

            Papillary thyroid carcinoma (PTC) is clinically heterogeneous. Apart from an association with ionizing radiation, the etiology and molecular biology of PTC is poorly understood. We used oligo-based DNA arrays to study the expression profiles of eight matched pairs of normal thyroid and PTC tissues. Additional PTC tumors and other tissues were studied by reverse transcriptase-PCR and immunohistochemistry. The PTCs showed concordant expression of many genes and distinct clustered profiles. Genes with increased expression in PTC included many encoding adhesion and extracellular matrix proteins. Expression was increased in 8/8 tumors for 24 genes and in 7/8 tumors for 22 genes. Among these genes were several previously known to be overexpressed in PTC, such as MET, LGALS3, KRT19, DPP4, MDK, TIMP1, and FN1. The numerous additional genes include CITED1, CHI3L1, ODZ1, N33, SFTPB, and SCEL. Reverse transcriptase-PCR showed high expression of CITED1, CHI3L1, ODZ1, and SCEL in 6/6 additional PTCs. Immunohistochemical analysis detected CITED1 and SFTPB in 49/52 and 39/52 PTCs, respectively, but not in follicular thyroid carcinoma and normal thyroid tissue. Genes underexpressed in PTC included tumor suppressors, thyroid function-related proteins, and fatty acid binding proteins. Expression was decreased in 7/8 tumors for eight genes and decreased in 6/8 tumors for 19 genes. We conclude that, despite its clinical heterogeneity, PTC is characterized by consistent and specific molecular changes. These findings reveal clues to the molecular pathways involved in PTC and may provide biomarkers for clinical use.
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              Health-Related Quality of Life After Diagnosis and Treatment of Differentiated Thyroid Cancer and Association With Type of Surgical Treatment

              What health-related quality of life outcomes are associated with diagnosis and treatment of differentiated thyroid cancer and do they vary by type of surgery received? In this content analysis of survey responses of 1005 patients with differentiated thyroid cancer, 775 (77.1%) reported issues in their health-related quality of life after diagnosis and current treatment regimens for differentiated thyroid cancer. These issues are more prevalent in those who received a total thyroidectomy (without neck dissection) compared with those who received a hemithyroidectomy. Given the recent concerns regarding overdiagnosis and overtreatment in thyroid cancer, hemithyroidectomies offer fewer adverse effects of treatment and better health-related quality of life outcomes than total thyroidectomies for patients with differentiated thyroid cancer. This content analysis assesses health-related quality of life outcomes and adverse effects of different types of surgical treatment of differentiated thyroid cancer among patients in an Australian case-control study. Concerns around possible overdiagnosis and overtreatment of differentiated thyroid cancer (DTC) have been raised. Issues concerning health-related quality of life (HRQOL) after diagnosis and treatment of DTC are understudied in this patient group. To better understand the range of HRQOL outcomes, including possible adverse effects of treatment, associated with diagnosis and treatment of DTC and whether these outcomes vary by type of surgery received. This content analysis assessed responses to an open-ended question about outcomes and concerns after DTC diagnosis and treatment among patients ascertained from the major postsurgical thyroid cancer treatment center and the population-based Cancer Registry in Queensland, Australia. Participants were aged 18 to 79 years and recently diagnosed with throid cancer. Responses underwent analysis to identify and code emergent themes to describe HRQOL issues and adverse effects of treatment experienced. Quantitative analysis was used to explore whether surgery type was associated with HRQOL issues and/or adverse effects of treatment. Of 1416 eligible patients, 1005 (71.0%) participated. Data were collected from July 1, 2013, through August 31, 2016, and analyzed from January 11 through April 9, 2018. Issues concerning HRQOL. The analysis included 1005 patients (72.2% female [n = 726]; mean [SD] age, 52 [14.0 years) with DTC. Most patients were diagnosed with papillary thyroid cancer (889 of 1003 [88.6%]), had tumors smaller than 2 cm in size (564 of 1000 [56.4%]), and received a total thyroidectomy (791 of 1005 [78.7%]). Overall, 775 patients (77.1%) reported HRQOL issues after diagnosis and treatment of DTC. The following 4 main themes emerged from content analysis of patient responses: physical (663 [66.0%]), psychological (187 [18.6%]), lifestyle (82 [8.2%]), and no issue or adverse effect (246 [24.5%]). Patients who had a total thyroidectomy (without neck dissection) were 1.5 times (odds ratio, 1.49; 95% CI, 1.04-2.12) more likely to report an HRQOL issue or an adverse effect of treatment compared with patients who underwent a hemithyroidectomy. According to results of this study, patients diagnosed with DTC report wide-ranging HRQOL issues; these are more prevalent among patients who have total thyroidectomies rather than hemithyroidectomies. For patients with small, localized DTCs, hemithyroidectomy may offer fewer adverse effects of treatment and better HRQOL outcomes than total thyroidectomy. It appears that issues with HRQOL should be considered by patients and physicians when deciding on the best treatment approach after a diagnosis of DTC.
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                Author and article information

                Contributors
                s.kruijff@umcg.nl
                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
                29 November 2023
                29 November 2023
                2024
                : 51
                : 8
                : 2384-2394
                Affiliations
                [1 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Department of Surgery, , University Medical Center Groningen, University of Groningen, ; Hanzeplein 1, 9713 GZ Groningen, the Netherlands
                [2 ]Department of Endocrine Surgery and Surgical Oncology, Royal North Shore Hospital, ( https://ror.org/02gs2e959) St Leonards, Australia
                [3 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Department of Biomedical Sciences of Cell & Systems – Section Molecular Cell Biology, University Medical Center Groningen, , University of Groningen, ; Groningen, the Netherlands
                [4 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Pathology, , University Medical Center Groningen, University of Groningen, ; Groningen, the Netherlands
                [5 ]NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, ( https://ror.org/02gs2e959) St Leonards, Australia
                [6 ]Sydney Medical School, University of Sydney, ( https://ror.org/0384j8v12) Sydney, Australia
                [7 ]Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital, ( https://ror.org/02gs2e959) St Leonards, Australia
                [8 ]Department of Pathology, University Medical Center Utrecht, ( https://ror.org/0575yy874) Utrecht, the Netherlands
                [9 ]Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, ( https://ror.org/05m5b8x20) Baltimore, USA
                [10 ]Department of Surgery, Erasmus MC Cancer Institute, ( https://ror.org/03r4m3349) Rotterdam, the Netherlands
                [11 ]Department of Radiology and Nuclear Medicine, Erasmus MC, ( https://ror.org/018906e22) Rotterdam, the Netherlands
                [12 ]Department of Pathology, Erasmus MC, ( https://ror.org/018906e22) Rotterdam, the Netherlands
                [13 ]Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC Cancer Institute, ( https://ror.org/03r4m3349) Rotterdam, the Netherlands
                [14 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Nuclear Medicine and Molecular Imaging, , University Medical Center Groningen, University of Groningen, ; Groningen, the Netherlands
                [15 ]AxelaRx/TRACER B.V, Groningen, the Netherlands
                [16 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Department of Endocrinology, , University Medical Center Groningen, University of Groningen, ; Groningen, the Netherlands
                [17 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Radiation Oncology, , University Medical Center Groningen, University of Groningen, ; Groningen, the Netherlands
                [18 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Medical Oncology, , University Medical Center Groningen, University of Groningen, ; Groningen, the Netherlands
                Author information
                http://orcid.org/0000-0002-5151-7320
                Article
                6525
                10.1007/s00259-023-06525-5
                11178647
                38017325
                ba6f69cf-1d76-4ef8-992f-3ad14be65094
                © The Author(s) 2023

                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
                : 26 September 2023
                : 14 November 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004622, KWF Kankerbestrijding;
                Award ID: project number 10851
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2024

                Radiology & Imaging
                papillary thyroid cancer,multifocality,molecular fluorescence–guided imaging,spectroscopy

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