Publications by authors named "Martin Schlumberger"

281 Publications

Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid Cancer.

J Clin Oncol 2021 May 7:JCO2003093. Epub 2021 May 7.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Anaplastic thyroid cancer (ATC), an aggressive malignancy, is associated with a poor prognosis and an unmet need for effective treatment, especially for patients without mutations or or fusions. Lenvatinib is US Food and Drug Administration-approved for radioiodine-refractory differentiated thyroid cancer and has previously demonstrated activity in a small study of patients with ATC (n = 17). We aimed to further evaluate lenvatinib in ATC.

Methods: This open-label, multicenter, international, phase II study enrolled patients with ATC, who had ≥ 1 measurable target lesion, to receive lenvatinib 24 mg once daily. The primary end points were objective response rate (ORR) by investigator assessment per RECIST v1.1 and safety. Responses were confirmed ≥ 4 weeks after the initial response. Additional end points included progression-free survival and overall survival (OS).

Results: The study was halted for futility as the minimum ORR threshold of 15% was not met upon interim analysis. The interim analysis set included the first 20 patients. The full analysis set includes all 34 enrolled and treated patients. In the full analysis set, one patient achieved a partial response (ORR, 2.9%; 95% CI, 0.1 to 15.3). More than half of the evaluable patients experienced tumor shrinkage; three patients experienced a > 30% tumor reduction. The median progression-free survival was 2.6 months (95% CI, 1.4 to 2.8); the median overall survival was 3.2 months (95% CI, 2.8 to 8.2). The most common treatment-related adverse events (AEs) were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). No major treatment-related bleeding events or grade 5 treatment-related AEs occurred.

Conclusion: The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.
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http://dx.doi.org/10.1200/JCO.20.03093DOI Listing
May 2021

Role of DNA Repair Variants and Diagnostic Radiology Exams in Differentiated Thyroid Cancer Risk: A Pooled Analysis of Two Case-Control Studies.

Cancer Epidemiol Biomarkers Prev 2021 Jun 7;30(6):1208-1217. Epub 2021 Apr 7.

INSERM, Centre for Research in Epidemiology and Population Health (CESP), 94800 Villejuif, France.

Background: Given the increased use and diversity of diagnostic procedures, it is important to understand genetic susceptibility to radiation-induced thyroid cancer.

Methods: On the basis of self-declared diagnostic radiology examination records in addition to existing literature, we estimated the radiation dose delivered to the thyroid gland from diagnostic procedures during childhood and adulthood in two case-control studies conducted in France. A total of 1,071 differentiated thyroid cancer (DTC) cases and 1,188 controls from the combined studies were genotyped using a custom-made Illumina OncoArray DNA chip. We focused our analysis on variants in genes involved in DNA damage response and repair pathways, representing a total of 5,817 SNPs in 571 genes. We estimated the OR per milli-Gray (OR/mGy) of the radiation dose delivered to the thyroid gland using conditional logistic regression. We then used an unconditional logistic regression model to assess the association between DNA repair gene variants and DTC risk. We performed a meta-analysis of the two studies.

Results: The OR/mGy was 1.02 (95% confidence interval, 1.00-1.03). We found significant associations between DTC and rs7164173 in CHD2 ( = 5.79 × 10), rs6067822 in NFATc2 ( = 9.26 × 10), rs1059394 and rs699517 both in ENOSF1/THYS, rs12702628 in RPA3, and an interaction between rs7068306 in MGMT and thyroid radiation doses ( = 3.40 × 10).

Conclusions: Our results suggest a role for variants in CDH2, NFATc2, ENOSF1/THYS, RPA3, and MGMT in DTC risk.

Impact: CDH2, NFATc2, ENOSF1/THYS, and RPA3 have not previously been shown to be associated with DTC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1142DOI Listing
June 2021

Redifferentiation-facilitated radioiodine therapy in thyroid cancer.

Endocr Relat Cancer 2021 Mar 1. Epub 2021 Mar 1.

M Schlumberger, Endocrine oncology and nuclear medicine, Gustave Roussy, Villejuif, France.

Based on experimental data, the inhibition of the MAPkinase pathway in patients with radioiodine refractory thyroid cancer was capable to induce a redifferentiation. Preliminary data obtained on small series of patients are encouraging and this strategy might become an alternative treatment in those patients with a druggable mutation that induces a stimulation of the MAP kinase pathway. This is an active field of research to answer many still unresolved questions.
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http://dx.doi.org/10.1530/ERC-21-0024DOI Listing
March 2021

RADTHYR: an open-label, single-arm, prospective multicenter phase II trial of Radium-223 for the treatment of bone metastases from radioactive iodine refractory differentiated thyroid cancer.

Eur J Nucl Med Mol Imaging 2021 Feb 23. Epub 2021 Feb 23.

Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Paris Saclay University, 114 Rue Edouard Vaillant, Villejuif, France.

Purpose: This is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer.

Methods: RADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by F-FDG PET/CT, Tc-HMDP bone scan and FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety.

Results: Ten patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4-35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2). F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, Tc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3-4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related.

Conclusion: The trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation.

Trial Registration Number: NCT02390934. Registration date 18.03.2015.
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http://dx.doi.org/10.1007/s00259-021-05229-yDOI Listing
February 2021

The importance of the RET gene in thyroid cancer and therapeutic implications.

Nat Rev Endocrinol 2021 05 18;17(5):296-306. Epub 2021 Feb 18.

Département de Médecine Nucléaire et Cancérologie Endocrinienne, Gustave Roussy, Université Paris-Saclay, Villejuif, France.

Since the discovery of the RET receptor tyrosine kinase in 1985, alterations of this protein have been found in diverse thyroid cancer subtypes. RET gene rearrangements are observed in papillary thyroid carcinoma, which result in RET fusion products. By contrast, single amino acid substitutions and small insertions and/or deletions are typical of hereditary and sporadic medullary thyroid carcinoma. RET rearrangements and mutations of extracellular cysteines facilitate dimerization and kinase activation, whereas mutations in the RET kinase coding domain drive dimerization-independent kinase activation. Thus, RET kinase inhibition is an attractive therapeutic target in patients with RET alterations. This approach was initially achieved using multikinase inhibitors, which affect multiple deregulated pathways that include RET kinase. In clinical practice, use of multikinase inhibitors in patients with advanced thyroid cancer resulted in therapeutic efficacy, which was associated with frequent and sometimes severe adverse effects. However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers.
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http://dx.doi.org/10.1038/s41574-021-00470-9DOI Listing
May 2021

Long-term management of lenvatinib-treated thyroid cancer patients: a real-life experience at a single institution.

Endocrine 2021 Feb 3. Epub 2021 Feb 3.

Department of Public Health, University of Naples "Federico II", 80131, Naples, Italy.

Purpose: The efficacy of lenvatinib for advanced and progressive radioactive iodine refractory differentiated thyroid cancer is well established. Herein, we retrospectively evaluated the long-term safety and efficacy of lenvatinib in 23 patients treated at a single Institution.

Methods: Clinical data of all patients treated for a differentiated thyroid cancer with lenvatinib from April 2015 to September 2020 were retrospectively analyzed.

Results: A total of 23 patients were included. In all, 21 patients received lenvatinib as first-line systemic therapy. Median age at initiation of lenvatinib treatment was 68 (44-90) years. Median duration of the study from initiation of lenvatinib to study end was 23 (2-65) months. The indication for lenvatinib treatment was documented progression of distant metastases in 20 patients and of locally advanced disease in the other 3 and median duration of lenvatinib therapy was 15 (2-64) months. Best treatment responses were: partial response in 6 patients, stable disease in 14, progressive disease in 1, and not evaluable in 2. Median progression-free survival was 25 months (95% CI: 12-40) and median overall survival was 46 months (95% CI: 28-65). Three patients had to discontinue lenvatinib treatment due to serious adverse events and no drug-related death was observed. Ten patients continued lenvatinib for more than 24 months and the only newly registered adverse event after this period of time was one case of G2 proteinuria. Six patients continued lenvatinib treatment beyond documented tumor progression due to oligoprogression or slowly progressive disease (median time 18.5 months, 8-42 months). A total of 14 patients were alive at the end of the study: 11 showed partial response/stable disease on lenvatinib, including 3 who had a stable disease after local ablative therapy for oligoprogressive metastases; 3 had to change treatment, including 2 for lenvatinib-related serious adverse events and 1 for progressive disease.

Conclusions: Long-term lenvatinib treatment is safe and some patients may experience persistent long-term control of the disease. Late treatment-related AEs rarely occurred. Oligoprogressive and slowly progressive disease can be managed without treatment withdrawal as long as there are some clinical benefits.
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http://dx.doi.org/10.1007/s12020-021-02634-zDOI Listing
February 2021

Thyroid cancer incidence in children and adolescents.

Lancet Diabetes Endocrinol 2021 03 19;9(3):128-129. Epub 2021 Jan 19.

Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy and University Paris-Saclay, Villejuif 94800, France. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30430-7DOI Listing
March 2021

Current practice in patients with differentiated thyroid cancer.

Nat Rev Endocrinol 2021 03 18;17(3):176-188. Epub 2020 Dec 18.

Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy and Université Paris Saclay, Villejuif, France.

Considerable changes have occurred in the management of differentiated thyroid cancer (DTC) during the past four decades, based on improved knowledge of the biology of DTC and on advances in therapy, including surgery, the use of radioactive iodine (radioiodine), thyroid hormone treatment and availability of recombinant human TSH. Improved diagnostic tools are available, including determining serum levels of thyroglobulin, neck ultrasonography, imaging (CT, MRI, SPECT-CT and PET-CT), and prognostic classifications have been improved. Patients with low-risk DTC, in whom the risk of thyroid cancer death is <1% and most recurrences can be cured, currently represent the majority of patients. By contrast, patients with high-risk DTC represent 5-10% of all patients. Most thyroid cancer-related deaths occur in this group of patients and recurrences are frequent. Patients with high-risk DTC require more aggressive treatment and follow-up than patients with low-risk DTC. Finally, the strategy for treating patients with intermediate-risk DTC is frequently defined on a case-by-case basis. Prospective trials are needed in well-selected patients with DTC to demonstrate the extent to which treatment and follow-up can be limited without increasing the risk of recurrence and thyroid cancer-related death.
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http://dx.doi.org/10.1038/s41574-020-00448-zDOI Listing
March 2021

Impact of expert review of histological diagnosis of papillary and follicular thyroid cancer.

Endocrine 2021 Jun 31;72(3):791-797. Epub 2020 Oct 31.

Department of Endocrine Oncology and Nuclear Medicine, Gustave Roussy and Paris Saclay University, 114 Rue Edouard Vaillant, 94805, Villejuif, France.

Purpose: Histologic and pTNM classification of differentiated thyroid cancer (DTC) is mandatory to assess risk of relapse, risk of death, and radioactive iodine administration. The impact of an expert central review of external pathology reports has not yet been reported.

Methods: Monocentric retrospective study to evaluate the difference between initial and second-opinion histopathologic diagnosis for DTC patients referred for post-operative radioactive iodine administration between January 2014 and December 2016. We evaluated major discordance (change of diagnosis from malignant to benign or in main histological subtype or a description of aggressive pathological subtypes), minor discordance (change in histological subtype or description of an aggressive component, multifocality or extrathyroidal extension), and change in ATA classification.

Results: A second-opinion histological diagnosis was available for 199 patients. A major discordance was observed in 42 (21%) cases (changes in malignancy in 4 cases, changes in main histological subtype in 22, changes in aggressive pathology variants of PTC in 16). One hundred and four minor discordances were observed regarding 92 patients. These histopathological changes led to changes in the ATA 2015 risk stratification classification in 61 (31%) of cases. There were no predictive factors of major/minor histologic changes or ATA risk stratification changes.

Conclusion: Expert central review of pathology has an impact on the 2015 ATA risk stratification classification that can lead to changes in the management of patients with differentiated thyroid cancer.
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http://dx.doi.org/10.1007/s12020-020-02531-xDOI Listing
June 2021

Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview.

Endocr Relat Cancer 2021 Jan;28(1):15-26

Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Université Paris Saclay, Villejuif, France.

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9-3.5) and median OS was 3.1 months (95% CI; 0.6-5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.
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http://dx.doi.org/10.1530/ERC-20-0106DOI Listing
January 2021

Management of differentiated thyroid cancer through nuclear medicine facilities during Covid-19 emergency: the telemedicine challenge.

Eur J Nucl Med Mol Imaging 2021 03 23;48(3):831-836. Epub 2020 Sep 23.

Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy.

Purpose: To investigate whether a telemedicine service (TMS) carried out during the Covid-19 pandemic impacted on management of patients with differentiated thyroid cancer (DTC).

Methods: We retrospectively reviewed the number and the findings of outpatient visits in DTC subjects referred between March 11, 2020, and May 31, 2020, during the Covid-19 pandemic at the Radiometabolic Unit of the University of Naples Federico II. Office visits scheduled in March and May 2020 were converted in teleconsultation reaching all patients planned for an in-ward access to advise them to use the TMS for all clinical necessity. The number and the findings of DTC patients evaluated by in-ward access in the corresponding period of 2019 were also assessed for direct comparison.

Results: The number of outpatient visits performed by TMS during the pandemic (n = 445) and by in-ward access in the corresponding period of 2019 (n = 525) was comparable with only 15% of outpatient evaluations missed.

Conclusions: Our findings demonstrate the utility of telemedicine tools to avoid the potential negative impact of interruption or postponement of diagnostic and/or therapeutic procedures. Therefore, investments in medical network system development, including the implementation of telehealth approaches, should be encouraged at national and international levels.
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http://dx.doi.org/10.1007/s00259-020-05041-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509822PMC
March 2021

DNA FISH Diagnostic Assay on Cytological Samples of Thyroid Follicular Neoplasms.

Cancers (Basel) 2020 Sep 6;12(9). Epub 2020 Sep 6.

Department of Endocrinology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.

Although fine-needle aspiration cytology (FNAC) is helpful in determining whether thyroid nodules are benign or malignant, this distinction remains a cytological challenge in follicular neoplasms. Identification of genomic alterations in cytological specimens with direct and routine techniques would therefore have great clinical value. A series of 153 cases consisting of 72 and 81 histopathologically confirmed classic follicular adenomas (cFAs) and classic follicular thyroid carcinomas (cFTCs), respectively, was studied by means of different molecular techniques in three different cohorts of patients (pts). In the first cohort (training set) of 66 pts, three specific alterations characterized by array comparative genomic hybridization (aCGH) were exclusively found in half of cFTCs. These structural abnormalities corresponded to losses of 1p36.33-35.1 and 22q13.2-13.31, and gain of whole chromosome X. The second independent cohort (validation set) of 60 pts confirmed these data on touch preparations of frozen follicular neoplasms by triple DNA fluorescent in situ hybridization using selected commercially available probes. The third cohort, consisting of 27 archived cytological samples from an equal number of pts that had been obtained for preoperative FNAC and morphologically classified as and histologically verified to be follicular neoplasms, confirmed our previous findings and showed the feasibility of the DNA FISH (DNA fluorescent in situ hybridization) assay. All together, these data suggest that our triple DNA FISH diagnostic assay may detect 50% of cFTCs with a specificity higher than 98% and be useful as a low-cost adjunct to cytomorphology to help further classify follicular neoplasms on already routinely stained cytological specimens.
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http://dx.doi.org/10.3390/cancers12092529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564487PMC
September 2020

Salivary and lacrimal dysfunction after radioactive iodine for differentiated thyroid cancer: American Head and Neck Society Endocrine Surgery Section and Salivary Gland Section joint multidisciplinary clinical consensus statement of otolaryngology, ophthalmology, nuclear medicine and endocrinology.

Head Neck 2020 11 19;42(11):3446-3459. Epub 2020 Aug 19.

Department of Otolaryngology - Head and Neck Surgery, Harvard Medical School, Boston, Massachusetts, USA.

Background: Postoperative radioactive iodine (RAI) administration is widely utilized in patients with differentiated thyroid cancer. While beneficial in select patients, it is critical to recognize the potential negative sequelae of this treatment. The prevention, diagnosis, and management of the salivary and lacrimal complications of RAI exposure are addressed in this consensus statement.

Methods: A multidisciplinary panel of experts was convened under the auspices of the American Head and Neck Society Endocrine Surgery and Salivary Gland Sections. Following a comprehensive literature review to assess the current best evidence, this group developed six relevant consensus recommendations.

Results: Consensus recommendations on RAI were made in the areas of patient assessment, optimal utilization, complication prevention, and complication management.

Conclusion: Salivary and lacrimal complications secondary to RAI exposure are common and need to be weighed when considering its use. The recommendations included in this statement provide direction for approaches to minimize and manage these complications.
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http://dx.doi.org/10.1002/hed.26417DOI Listing
November 2020

Long-term follow-up and safety of vandetanib for advanced medullary thyroid cancer.

Endocrine 2021 Feb 20;71(2):434-442. Epub 2020 Jul 20.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Villejuif, France.

Introduction: Vandetanib is indicated for adults with advanced medullary thyroid cancer (MTC).

Objectives: To describe the efficacy and toxicity profile of vandetanib treatment with a maximal follow-up of 11 years at Institut Gustave Roussy/France.

Methods: A review of the clinical files of the 76 MTC patients treated with vandetanib. Efficacy was estimated by markers and imaging.

Results: A total of 76 patients received vandetanib. Nine were excluded from efficacy analysis because lack of morphological data. The overall (N = 76) median treatment duration was 17.6 (range: 0.7-130.6) months and the median progression-free survival (PFS) was 22.7 (95% CI, 13.9-37.3) months. In total, 21/76 (27.6%) patients were classified as long-term users because have received vandetanib for more than 48 months, with a median treatment duration of 68.1 (range: 49.1-130.6) months. For long-term vandetanib users, the objective response rate was 85.7%, the median time to best response was 27.8 (11.6.1-110) months and the median duration of response was 70.4 (38.3-127.5) (95% CI 49.5-102.8) months with a median PFS of 73.2 (95% CI, 53.1-105.6) months. Duration of response had a significant negative correlation with patient age at diagnosis (p = 0.03) and was significantly higher in patients that did not have confirmed tumor progression before treatment onset (p = 0.007). After 48 months of vandetanib use, renal failure took place in two patients and heart failure, cholecystitis, acute pancreatitis, posterior encephalopathy, and skin cancer first occurred in one patient, each.

Conclusions: Our findings suggest that a substantial number of patients receiving first-/second-line vandetanib may sustain long clinical benefit and that a younger age at diagnosis and the absence of progression before treatment could be considered as predictors of durable response.
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http://dx.doi.org/10.1007/s12020-020-02426-xDOI Listing
February 2021

Comparison of simultaneous F-2-[18F] FDG PET/MR and PET/CT in the follow-up of patients with differentiated thyroid cancer.

Eur J Nucl Med Mol Imaging 2020 12 30;47(13):3066-3073. Epub 2020 Jun 30.

Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy.

Aims: F-FDG PET/CT is the most accurate imaging modality in differentiated thyroid cancer (DTC) patients with either an aggressive histology, an absence of radioiodine uptake in neoplastic foci, or in the absence of imaging abnormalities in patients with an elevated serum thyroglobulin (Tg) level that progresses with time. We evaluated the diagnostic performance of FDG PET/MR in comparison with that of PET/CT.

Methods And Results: Following the injection of a single F-FDG activity, PET/MR and PET/CT were sequentially performed in 40 consecutive patients with DTC previously treated with total thyroidectomy and radioiodine ablation. All patients were then followed up for at least 6 months. PET/MR was positive in 11 patients and PET/CT in 10. PET/MR detected 33 tumor foci and PET/CT 30. During the follow-up of the 12 patients with negative initial PET studies and with a detectable serum Tg, only one patient had a neck recurrence and the administration of an empiric high activity of I in the other 11 patients did not reveal any tumor focus. In the 17 patients with an initial serum Tg level < 2 ng/mL, no recurrence occurred.

Conclusion: This study confirms the high diagnostic accuracy of FDG PET studies in DTC patients with elevated serum Tg levels and shows that PET/MR brings similar information as compared to PET/CT imaging.
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http://dx.doi.org/10.1007/s00259-020-04938-0DOI Listing
December 2020

Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial.

J Clin Oncol 2020 08 25;38(24):2773-2781. Epub 2020 Jun 25.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Université Paris Saclay, Villejuif, France.

Purpose: We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients.

Patients And Methods: Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated.

Results: Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm.

Conclusion: Vandetanib demonstrated clinical benefit-specifically, increased PFS-in patients with symptomatic and progressive MTC.
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http://dx.doi.org/10.1200/JCO.19.02790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430220PMC
August 2020

Risk of structural persistent disease in pediatric patients with low or intermediate risk differentiated thyroid cancer.

Endocrine 2021 Feb 11;71(2):378-384. Epub 2020 Jun 11.

Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy.

Purpose: In pediatric patients with differentiated thyroid cancer (DTC), the risk of recurrence is high and the indication for postoperative I administration is still debated. The aim of this study was to assess the outcome in low and intermediate risk pediatric DTC patients.

Methods: We retrospectively evaluated 45 pediatric patients with low or intermediate risk DTC, treated with surgery and I between 1992 and 2002 and with no detectable antithyroglobulin (Tg) antibodies. Follow-up was performed every 6-12 months with Tg blood level determination and imaging procedures.

Results: During follow-up (64 ± 53 months), 15 events occurred (33% cumulative event rate, with an annual event rate of 5% person years). Five of these patients were submitted to additional surgery and all these 15 patients underwent a second I treatment course. All patients were alive at the end of the follow-up. Structural persistent disease occurred more frequently in patients at intermediate risk (p < 0.01) and in those with Tg values after thyroid hormone withdrawal >10 ng/ml before I therapy (p < 0.01). At multivariate analysis, only a postoperative thyroid stimulating hormone-stimulated Tg level >10 ng/ml was an independent predictor of persistent disease.

Conclusions: In pediatric patients with DTC, postoperative high stimulated Tg values (>10 ng/ml) should be taken into account for deciding the extent of both initial treatment and follow-up.
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http://dx.doi.org/10.1007/s12020-020-02379-1DOI Listing
February 2021

Concurrent BRAF V600E mutated papillary thyroid carcinoma and Erdheim-Chester disease.

Endocrine 2020 12 21;70(3):655-656. Epub 2020 Apr 21.

Department of Advanced Biomedical Sciences, University Federico II, Naples, Italy.

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http://dx.doi.org/10.1007/s12020-020-02317-1DOI Listing
December 2020

[Are the two formulas of Levothyrox bioequivalent?]

Rev Prat 2019 Oct;69(8):831-837

Médecin généraliste, Aubusson.

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October 2019

Body Composition in Patients with Radioactive Iodine-Refractory, Advanced Differentiated Thyroid Cancer Treated with Sorafenib or Placebo: A Retrospective Analysis of the Phase III DECISION Trial.

Thyroid 2019 12;29(12):1820-1827

Department of Medical Oncology, Cochin Hospital, AP-HP, Paris, France.

Rates of adverse events with sorafenib were higher in the DECISION trial in radioactive iodine-refractory, advanced differentiated thyroid cancer (DTC) than in trials of sorafenib for other tumor types. One possible explanation is that sarcopenia, a known predictive factor of toxicity in patients with cancer, is more common in patients with DTC due to hormone suppressive therapy. This retrospective exploratory analysis was performed to assess whether the risk of early toxicity leading to dose modification (DMT) with sorafenib was higher in patients with sarcopenia compared with those without sarcopenia. The data set comprised patients from the phase III DECISION trial with a computed tomography scan available to determine muscle mass. The skeletal muscle (SM) cross-sectional area was used to determine the SM index and define sarcopenia. The end points were changes in body composition, DMT, early DMT (within 1 month), severe toxic events (STEs), and early STEs. Overall, 365 patients were eligible for this analysis; baseline characteristics were well balanced between patients receiving sorafenib ( = 180) versus placebo ( = 185). Using a sarcopenia definition of an SM index less than the median sex-specific SM index, approximately half of the patients receiving sorafenib were at risk of sarcopenia (89/180; 49.4%), with wide geographical variation. At 6 months, the mean weight, body mass index, and lean body mass of patients receiving sorafenib were lower than at baseline and significantly lower than for patients receiving placebo (all  < 0.0001). Most DMTs and STEs occurred in the first month of treatment. There was a nonsignificant trend for more early DMTs in patients with sarcopenia compared with those without sarcopenia (55.3% vs. 44.7%, respectively;  = 0.2273). These results show a significant effect of sorafenib on muscle mass. However, there was no association between sarcopenia and DMT or early DMT, in contrast to observations in hepatocellular and renal cell carcinoma.
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http://dx.doi.org/10.1089/thy.2018.0784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918875PMC
December 2019

[Both formulas of Levothyrox are not bioequivalent].

Rev Prat 2019 Jun;69(6):599-601

Institut Gustave-Roussy, Villejuif, France.

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June 2019

Surgery in the context of kinase inhibitor therapy for locally invasive thyroid cancer.

Eur J Surg Oncol 2020 04 25;46(4 Pt A):650-655. Epub 2019 Sep 25.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Paris Saclay University, Villejuif, France.

Kinase inhibitors (KI) for advanced and aggressive forms of differentiated, medullary and anaplastic thyroid carcinoma have been shown to provide significant tumor response, locally and in distant metastases. Their use, however, may also increase the risk for local complications such as fistula formation and bleeding, and head and neck surgeons may be solicited to palliatively remove potentially dangerous lesions before initiating these systemic treatments. During KI therapy for progressive metastatic and/or locally invasive disease, surgery may be urgently necessary to secure the airway or for symptomatic neck lesions. Finally, there are more and more reports of surgery following KI therapy that suggest a new neoadjuvant paradigm for extensive lesions. In this review, we aim to discuss the literature regarding surgery before, during and after KI therapy in the context of progressive metastatic and/or locally invasive thyroid cancer.
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http://dx.doi.org/10.1016/j.ejso.2019.09.184DOI Listing
April 2020

Identification of Expression Profiles Defining Distinct Prognostic Subsets of Radioactive-Iodine Refractory Differentiated Thyroid Cancer from the DECISION Trial.

Mol Cancer Ther 2020 01 20;19(1):312-317. Epub 2019 Sep 20.

Cancer Genomic Group, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Several biomarkers have been suggested to have prognostic value in differentiated thyroid carcinomas (DTC) with no validation in the refractory setting, including all tumor subtypes. We aim to correlate RNA expression profiles with survival based on patients included in the DECISION trial. We obtained 247 samples from the 417 patients included in the DECISION study and performed RNAseq analysis (77 million paired-end reads for each sample on HiSeq2000). After quality control, 125 samples were included in the secondary analysis and mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameter. Survival analysis was calculated using the Kaplan-Meier method and log-rank test was used for statistical comparison. In this analysis, we identified three groups of tumors based on their gene expression profile: BRAF-like, RAS-like, and non-BRAF-non-RAS-like (NoBRaL). No significant correlation with sorafenib responders was observed. However, we identified a statistically significant correlation between the RNA-expression profiles and progression-free survival. The BRAF-like profile had a significantly better outcome compared with RAS-like and NoBRaL (11.8, 6.2, and 5.5 months, respectively) [HR: 0.31, 95% confidence interval (CI), 0.17-0.60; < 0.001 and HR: 0.36 (95% CI, 0.21-0.63); < 0.001] and HR: 0.36 (95% CI, 0.21-0.63; < 0.001) and maintained significance as an independent prognostic factor for overall survival in the multivariate analysis for papillary thyroid cancers. To our knowledge, this is the first comprehensive RNA-seq analysis of all histologic subtypes of DTC. The RNA expression profiles identified may suggest a new prognostic parameter to be considered before recommendation of systemic therapies or the design of stratification factors for future clinical trials.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0211DOI Listing
January 2020

F-18-Dopa Positron Emission Tomography/Computed Tomography Is More Sensitive Than Whole-Body Magnetic Resonance Imaging for the Localization of Persistent/Recurrent Disease of Medullary Thyroid Cancer Patients.

Thyroid 2019 10;29(10):1457-1464

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy and Université Paris Saclay, Villejuif, France.

Elevated postoperative serum calcitonin (Ctn) level indicates persistent/recurrent disease in patients with medullary thyroid carcinoma (MTC). Its location is a challenge. The aim of our study was to compare the disease detection rates of F-18-Dopa (fluoro dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT), whole-body (WB) magnetic resonance imaging (MRI), F-18-FDG (fluorodeoxyglucose) PET/CT, WB CT scanning, neck ultrasonography, and bone scintigraphy in MTC patients with increased Ctn levels and unknown localization of the source. We compared the independent reading of each imaging procedure with a reference assessment for structural disease defined by pathology or concordance between two imagings or with subsequent follow-up. The detection rate of each imaging modality was determined in per patient, per organ, and per lesion analysis. Thirty-six consecutive patients (21 females, mean age: 57 years, sporadic MTC in 26 cases, median serum Ctn level: 760 pg/mL; range: 21-10,121) were analyzed. The reference assessment localized disease in 24 (64%) patients with 74 lesions detected in the thyroid bed (8), in neck lymph nodes (15), mediastinal lymph nodes (6), lungs (1), liver (2), bones (3), and other site (1). At the patient level, the detection rates were 64% (CI 0.48-0.80) for F-18-Dopa PET/CT with early acquisitions, 40% (CI 0.24-0.56) for F-18-FDG PET/CT, 40% (CI 0.24-0.56) for WB MRI, and 48% (CI 0.31-0.66) for WB CT scan. In MTC patients with increased Ctn and no known distant metastases, F-18-Dopa PET/CT is more sensitive to detect structural disease than any other imaging modality, including WB MRI.
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http://dx.doi.org/10.1089/thy.2018.0351DOI Listing
October 2019

An update on the management of low-risk differentiated thyroid cancer.

Endocr Relat Cancer 2019 11;26(11):R597-R610

Gustave Roussy Cancer Campus and University Paris-Saclay, Villejuif, Cedex, France.

Low-risk papillary cancers, which represent the vast majority of thyroid cancers diagnosed today, do not require aggressive treatment or follow-up. Initial treatment consists of a total thyroidectomy without prophylactic lymph node dissection. A hemithyroidectomy is an alternative in some patients with an intrathyroidal tumor and with a normal contralateral lobe at pre-operative neck ultrasonography. The use of post-operative radioiodine should be restricted to selected patients. Follow-up at 6-18 months is based on serum thyroglobulin (Tg), Tg-antibody determination and neck ultrasonography. In the absence of any abnormality (excellent response to treatment), the risk of recurrence is extremely low and follow-up may consist of serum TSH monitoring that is maintained in the normal range, and a Tg and Tg-antibody titer determination every year. There is no need for referral to a specialized center. In patients with detectable serum Tg or detectable Tg antibodies, the trend over time of these markers on levothyroxine treatment will dictate subsequent follow-up: a decreasing trend is reassuring, but an increasing trend should lead to imaging, starting with neck ultrasonography.
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http://dx.doi.org/10.1530/ERC-19-0294DOI Listing
November 2019

Genetic susceptibility to radiation-related differentiated thyroid cancers: a systematic review of literature.

Endocr Relat Cancer 2019 10;26(10):R583-R596

INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Radiation Epidemiology Group, Villejuif, France.

The first study establishing exposure to ionizing radiations (IRs) as a risk factor for differentiated thyroid cancer (DTC) was published 70 years ago. Given that radiation exposure causes direct DNA damage, genetic alterations in the different DNA repair mechanisms are assumed to play an important role in long-term IR-induced DNA damage prevention. Individual variations in DNA repair capacity may cause different reactions to damage made by IR exposure. The aim of this review is to recapitulate current knowledge about constitutional genetic polymorphisms found to be significantly associated with DTC occurring after IR exposure. Studies were screened online using electronic databases - only fully available articles, and studies performed among irradiated population or taking radiation exposure as adjustment factors and showing significant results are included. Nine articles were identified. Ten variants in/near to genes in six biological pathways, namely thyroid activity regulations, generic transcription, RET signaling, ATM signaling and DNA repair pathways were found to be associated with radiation-related DTC in these studies. Only seven variants were found to be in interaction with IR exposure in DTC risk. Most of these variants are also associated to sporadic DTC and are not specific to IR-related DTC. In the published studies, no data on children treated with radiotherapy is described. In conclusion, more studies carried out on larger cohorts or on case-control studies with well-documented individual radiation dose estimations are needed to get a comprehensive picture of genetic susceptibility factors involved in radiation-related DTC.
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http://dx.doi.org/10.1530/ERC-19-0321DOI Listing
October 2019

Thyroid Cancer Patients With No Evidence of Disease: The Need for Repeat Neck Ultrasound.

J Clin Endocrinol Metab 2019 11;104(11):4981-4989

Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

Context: Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck.

Objective: To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy.

Design: Retrospective analysis of prospectively recorded data.

Setting: Academic center.

Patients: Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable (<0.20 ng/mL) or low (0.21 to 0.99 ng/mL) at the 1-year evaluation.

Interventions: Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes.

Main Outcome Measures: Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits.

Results: In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment.

Conclusions: Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels <1 ng/mL at the 1-year evaluation can be safely followed with clinical assessments and unstimulated serum Tg determinations. Neck US might be repeated if TgAb titers rise, or unstimulated Tg levels exceed 1 ng/mL.
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http://dx.doi.org/10.1210/jc.2019-00962DOI Listing
November 2019

Increased bone marrow SUVmax on 18F-FDG PET is associated with higher pelvic treatment failure in patients with cervical cancer treated by chemoradiotherapy and brachytherapy.

Oncoimmunology 2019;8(5):e1574197. Epub 2019 Mar 6.

INSERM, Villejuif, France.

The aim of this study was to evaluate if bone marrow (BM) SUVmax measured on pre-treatment 18F-FDG PET/CT predicts the clinical outcome of locally advanced cervical cancer (LACC). We recruited retrospectively patients with LACC who underwent staging 18F-FDG PET/CT and had baseline blood tests, then treated by chemoradiation therapy (CRT), followed by image-guided adaptive brachytherapy (IGABT). BM SUVmax was calculated and correlated to inflammatory blood markers. Tumor size and pelvic lymph node involvement were evaluated on baseline MRI. Prognostic value of SUV uptake and blood markers regarding overall survival (OS), pelvic and extra-pelvic recurrence-free survival (PRFS and EPRFS respectively) was assessed using Cox models with adjusted p-values. 116 patients with FIGO stage Ib-IVa cervical cancer, treated between 2005 and 2014, were analyzed. The median follow-up was 75.5 months. BM SUVmax was significantly correlated to tumor SUVmax. In multivariate analysis, PRFS was significantly poorer in patients with high BM SUVmax (>2.8) and neutrophilia (p < .05). Tumor size (>5 vs ≤5 cm) could predict PRFS, EPRFS and OS (p < .05). In our cohort, FIGO stage (I-II vs III-IV), pelvic lymph node involvement and tumor SUVmax (>12 vs ≤12) were not prognostic for OS or pelvic and extra-pelvic relapses. Patients with LACC and high BM SUVmax on 18F-FDG PET have worse PFRS following CRT plus IGABT. These results can be potentially explained by the pro-inflammatory role of the tumor microenvironment and G-CSF expressed by tumor cells. These data support the role of PET as a potential indicator of disease aggressiveness beyond tumor staging.
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http://dx.doi.org/10.1080/2162402X.2019.1574197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492982PMC
March 2019

Exposure-Response Modeling and Simulation of Progression-Free Survival and Adverse Events of Sorafenib Treatment in Patients With Advanced Thyroid Cancer.

Clin Transl Sci 2019 09 12;12(5):459-469. Epub 2019 Apr 12.

Bayer AG, Berlin, Germany.

Sorafenib is an oral multikinase inhibitor approved for the treatment of differentiated thyroid carcinoma (DTC), renal cell carcinoma, and hepatocellular carcinoma. In the phase III DECISION trial in patients with DTC, sorafenib exposure and the incidence of some adverse events (AEs) were higher than in previous trials; therefore, we analyzed exposure-response relationships, including progression-free survival (PFS) and selected AEs in patients with DTC. A novel, stratified prediction-corrected visual predictive check (pc-VPC) was developed to show robustness of the exposure-response relationships. Time-to-event simulations confirmed the benefit of the recommended dosing schedule of 800 mg/day: initial doses of 800 mg/day were associated with the highest PFS, whereas lower doses (600 or 400 mg/day) were associated with improved tolerability but reduced PFS. A simulated dose-reduction strategy of 800 mg/day for an initial two cycles followed by dose reductions seemed likely to maintain efficacy while possibly mitigating selected AEs (e.g., diarrhea and hand-foot skin reactions).
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http://dx.doi.org/10.1111/cts.12634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742948PMC
September 2019

Redifferentiation of a -Mutated Poorly Differentiated Thyroid Cancer Patient with Dabrafenib and Trametinib Treatment.

Thyroid 2019 05;29(5):735-742

3 Department of Medical Biology and Pathology, Gustave Roussy and Paris Saclay University, Villejuif, France.

A 59-year-old woman with locally invasive poorly differentiated thyroid cancer with synchronous lung, mediastinal, and bone metastases and a somatic mutation with contraindication for antiangiogenic drugs was treated with dabrafenib and trametinib. During treatment, serum levels of thyroglobulin increased as early as day 7 up to 10-fold over baseline at week 4. Concurrently, clinical hyperthyroidism occurred, with free triiodothyronine and free thyroxine levels increasing to 6.6 and 4.4 times their upper reference limit. Fludeoxyglucose positron emission tomography/computed tomography at one and two months after treatment initiation showed a PERCIST metabolic response with a 82% decrease in fludeoxyglucose uptake, whereas disease remained morphologically stable according to RECIST criteria. A diagnostic radioactive iodine whole-body scan performed when the patient was thyrotoxic with an undetectable serum thyrotropin level, in the absence of any exogenous thyrotropin stimulation, showed high radioactive iodine uptake in the lung, mediastinum, and skull metastases. A biopsy performed two months after treatment initiation showed a more differentiated growth pattern and a decrease in the mitotic activity compared to baseline. An increase of thyroglobulin and thyroid peroxidase was observed at both the protein and mRNA levels. Sodium-iodide symporter mRNA expression increased by >750 times over its initial level, and sodium-iodide symporter protein expression became detectable under treatment. A decrease in general status due to thyrotoxicosis led to treatment discontinuation. Thyrotoxicosis resolved rapidly and radioactive iodine uptake decreased by >90%. This clinical case shows that redifferentiation itself is not necessarily associated with an antitumor effect.
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http://dx.doi.org/10.1089/thy.2018.0457DOI Listing
May 2019