Publications by authors named "Claire Bournaud"

37 Publications

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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February 2021

TERT promoter mutations identify a high-risk group in metastasis-free advanced thyroid carcinoma.

Eur J Cancer 2019 02 12;108:41-49. Epub 2019 Jan 12.

Hospices Civils de Lyon, Fédération D'Endocrinologie, Bron Cedex, F-69677, France; Université Lyon 1, HESPER EA 7425, Lyon, F-69008, France.

Background: TERT promoter mutations are associated with adverse clinicopathological characteristics in thyroid carcinomas and considered as a major indicator of poor outcomes. Nevertheless, most studies have pooled heterogeneous types of thyroid carcinomas and have been conducted retrospectively. We investigated the association between TERT promoter mutations and recurrence in a prospective series of 173 intermediate- to high-risk patients with thyroid cancer.

Patients: Patients referred for radioiodine treatment after thyroidectomy for intermediate- to high-risk differentiated thyroid carcinoma were included in a prospective observational study and tested for TERT promoter, BRAF, and RAS mutations of their primary tumours. We analysed the relationship between TERT promoter mutations and outcomes.

Results: The prevalence of TERT promoter mutations was 20.2% (35/173) in the total population. It was significantly higher in tumours harbouring aggressive histological features (poorly differentiated carcinoma, tall cell variant of papillary cancer or widely invasive follicular cancer) than in non-aggressive tumours: 32.7% (16/49) versus 15.3% (19/124; p = 0.020). TERT promoter mutations were also strongly associated with age ≥45 years (p = 0.005), pT4 stage (p = 0.015), metastatic disease (p = 0.014), and extrathyroidal extension (p = 0.002). TERT promoter mutations were associated with poor outcomes in the total population (p < 0.001) but not in the subgroup of non-metastatic patients (p = 0.051). However, they were associated with a worse outcome in patients both free of metastases and devoid of aggressive histological features. Neither BRAF nor RAS mutations were associated with event-free survival in non-metastatic patients.

Conclusion: Although their prognostic value does not seem to overcome that of histology, TERT promoter mutations may help to better define the prognosis of localized thyroid cancer patients without aggressive histology.
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February 2019

Recombinant Thyrotropin vs Levothyroxine Withdrawal in 131I Therapy of N1 Thyroid Cancer: A Large Matched Cohort Study (ThyrNod).

J Clin Endocrinol Metab 2019 04;104(4):1020-1028

Aix-Marseille University, La Timone University Hospital, European Center for Research in Medical Imaging, Marseille, France.

Context: Recombinant human thyrotropin (rhTSH) has been shown to be an effective stimulation method for radioactive iodine (RAI) therapy in differentiated thyroid cancer, including in those with nodal metastases (N1 DTC).

Objectives: To demonstrate the noninferiority of rhTSH vs thyroid hormone withdrawal (THW) in preparation to RAI regarding disease status at the first evaluation in the real-life setting in patients with N1 DTC.

Design: This was a French multicenter retrospective study. Groups were matched according to age (<45/≥45 years), number of N1 nodes (≤5/>5 lymph nodes), and stage (pT1-T2/pT3).

Results: The cohort consisted of 404 patients pT1-T3/N1/M0 DTC treated with rhTSH (n = 205) or THW (n = 199). Pathological characteristics and initially administrated RAI activities (3.27 ± 1.00 GBq) were similar between the two groups. At first evaluation (6 to 18 months post-RAI), disease-free status was defined by thyroglobulin levels below threshold and a normal ultrasound. Disease-free rate was not inferior in the rhTSH group (75.1%) compared with the THW group (71.9%). The observed difference between the success rates was 3.3% (-6.6 to 13.0); rhTSH was therefore considered noninferior to THW because the upper limit of this interval was <15%. At the last evaluation (29.7 ± 20.7 months for rhTSH; 36.7 ± 23.8 months for THW), 83.5% (rhTSH) and 81.5% (THW) of patients achieved a complete response. This result was not influenced by any of the known prognostic factors.

Conclusions: A preparation for initial RAI treatment with rhTSH was noninferior to that with THW in our series of pT1-T3/N1/M0-DTC on disease-free status outcomes at the first evaluation and after 3 years.
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April 2019

Graves' disease and pregnancy.

Ann Endocrinol (Paris) 2018 Dec 16;79(6):636-646. Epub 2018 Aug 16.

Service de médecine nucléaire, hospices civils de lyon, groupement hospitalier Est, 69677 Bron cedex, France.

This section deals with the specificities of managing Graves' disease during pregnancy. Graves' disease incurs risks of fetal, neonatal and maternal complications that are rare but may be severe: fetal hyper- or hypothyroidism, usually first showing as fetal goiter, neonatal dysthyroidism, premature birth and pre-eclampsia. Treatment during pregnancy is based on antithyroid drugs alone, without association to levothyroxine. An history of Graves' disease, whether treated radically or not, with persistent maternal anti-TSH-receptor antibodies must be well identified. Fetal monitoring should be initiated in a multidisciplinary framework that should be continued throughout pregnancy. Neonatal monitoring is also crucial if the mother still shows anti-TSH-receptor antibodies at end of pregnancy or underwent antithyroid treatment. The risk of recurrence of hyperthyroidism in the weeks following delivery requires maternal monitoring. The long-term neuropsychological progression of children of mothers with Graves' disease is poorly known.
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December 2018

Effect of Buparlisib, a Pan-Class I PI3K Inhibitor, in Refractory Follicular and Poorly Differentiated Thyroid Cancer.

Thyroid 2018 09;28(9):1174-1179

8 Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Institut Gustave Roussy , Villejuif et Université Paris Saclay, France .

Background: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is frequent in advanced follicular (FTC) and poorly differentiated thyroid (PDTC) carcinomas and has been implicated in oncogenesis and tumor progression. This study investigated the efficacy and safety of buparlisib, a pan-PI3K inhibitor in radioiodine refractory FTC and PDTC.

Methods: The primary endpoint of this open-label, multicenter, phase 2 pilot study was progression-free survival (PFS) at 6 months. The sample size was determined considering that a PFS ≤50% at 6 months would denote an absence of benefits (null hypothesis). Secondary endpoints were objective response rate, PFS at 12 months, overall survival at 6 and 12 months, and safety based on the frequency and severity of adverse events (AEs).

Results: Forty-three patients (19M/24 F; median age: 67 years) with metastatic, radioiodine refractory, progressive disease received buparlisib, 100 mg, daily. Histology was PDTC in 25 (58%), FTC in 17 (40%), and Hürthle cell carcinoma in 1 (2%). RAS mutation was found in 44% (12/27) and activation of the PI3K pathway in 35% (8/23) of tested tumors. The probability of PFS was 41.7% [95% confidence interval (CI) 7.7-55.5] at 6 months and 20.9% [CI 0-35.7] at 12 months, lower than the 50% expected PFS. At 6 months, 25.6% patients had stable disease, 48.8% were progressive and 25.6% had stopped treatment due to AE. The response to therapy was not influenced by age, sex, histology, or genetic alterations. The overall survivals at 6 and 12 months were 85.9% [CI 76-97] and 78.7 % [CI 67-92], respectively. The mean tumor growth rate decreased from 3.78 mm/month [CI 2.61-4.95] before treatment to 0.8 mm/month [CI -0.2-1.88] during treatment (p < 0.02). Severe grade 3-4 AEs occurred in 27 patients (63%), including hepatitis (25%), hyperglycemia (21%), mood disorders (12%), and skin toxicity (12%), with favorable outcome after temporary or permanent treatment discontinuation or dose reduction.

Conclusions: Buparlisib did not result in significant efficacy in advanced FTC and PDTC. However, the decrease in tumor growth rate may suggest incomplete inhibition of oncogenic pathways and/or escape mechanisms. This should lead to evaluate combined therapy associating inhibitors of both the PI3K and mitogen-activated protein kinase pathways.
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September 2018

Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial.

Lancet Diabetes Endocrinol 2018 08 26;6(8):618-626. Epub 2018 May 26.

Biostatistics and Epidemiology, Gustave Roussy, Paris, France; University Paris-Saclay, Paris, France. Electronic address:

Background: In ESTIMABL1, a randomised phase 3 trial of radioactive iodine (I) administration after complete surgical resection in patients with low-risk thyroid cancer, 92% of patients had complete thyroid ablation at 6-10 months, defined as a recombinant human thyroid-stimulating hormone (rhTSH)-stimulated serum thyroglobulin concentration of 1 ng/mL or less and normal findings on neck ultrasonography. Equivalence was shown between low-activity (1·1 GBq) and high-activity (3·7 GBq) radioactive iodine and also between the use of rhTSH injections and thyroid hormone withdrawal. Here, we report outcomes after 5 years of follow-up.

Methods: This multicentre, randomised, open-label, equivalence trial was done at 24 centres in France. Between March 28, 2007, and Feb 25, 2010, we randomly assigned (1:1:1:1) adults with low-risk differentiated thyroid carcinoma who had undergone total thyroidectomy to one of four strategies, each combining one of two methods of thyrotropin stimulation (rhTSH or thyroid hormone withdrawal) and one of two radioactive iodine activities (1·1 GBq or 3·7 GBq). Randomisation was by computer-generated sequence, with variable block size. Follow-up consisted of a yearly serum thyroglobulin measurement on levothyroxine treatment. Measurement of rhTSH-stimulated thyroglobulin and neck ultrasonography were done at the discretion of the treating physician. No evidence of disease was defined as serum thyroglobulin of 1 ng/mL or less on levothyroxine treatment and normal results on neck ultrasonography, when performed. This study was registered with, number NCT00435851.

Findings: 726 patients (97% of the 752 patients originally randomised) were followed up. At a median follow-up since randomisation of 5·4 years (range 0·5-9·2), 715 (98%) had no evidence of disease. The other 11 had either structural disease (n=4), raised serum thyroglobulin concentration (n=5), or indeterminate findings on neck ultrasonography (n=2). At ablation, six of these patients had received 1·1 GBq radioactive iodine (five after rhTSH and one after withdrawal) and five had received 3·7 GBq (two after rhTSH and three after withdrawal). TSH-stimulated (either after rhTSH injections or thyroid hormone withdrawal according to the treatment group) thyroglobulin concentration measured at the time of ablation was prognostic for structural disease status at ablation, ablation status at 6-10 months, and the final outcome.

Interpretation: Our findings suggest that disease recurrence was not related to the strategy used for ablation. These data validate the use of 1·1 GBq radioactive iodine after rhTSH for postoperative ablation in patients with low-risk thyroid cancer.

Funding: French National Cancer Institute (INCa), French Ministry of Health, and Sanofi Genzyme.
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August 2018

Quantitative analysis of normal and pathologic adrenal glands with 18F-FDOPA PET/CT: focus on pheochromocytomas.

Nucl Med Commun 2017 Sep;38(9):771-779

Departments of aNuclear Medicine bEndocrinology, GHE cEndocrine Surgery, GHS, CHU Lyon dDepartment of Nuclear Medicine eDermatology Unit, CLB Lyon fEA 3637, Lyon 1 University, Lyon, France gDepartment of Nuclear Sciences and Applications, Vienna International Centre, Division of Human Health, Nuclear Medicine and Diagnostic Imaging Section, International Atomic Energy Agency, Vienna, Austria.

Introduction: Many studies have reported the high performance of 6-fluorine-18-fluorodihydroxyphenilalanine (F-FDOPA) PET/CT in the diagnosis of pheochromocytomas but nobody seems to have investigated physiological and pathological adrenal glands from a quantitative point of view. The purpose of the present study was to assess the quantitative F-FDOPA uptake of normal and pathologic adrenal glands and to establish thresholds to characterize pheochromocytomas. We were especially interested in characterizing the remaining adrenal glands captation after an adrenalectomy.

Patients And Methods: We reviewed 112 F-FDOPA PET/CT scans taken for different indications. A total of 212 adrenal glands, of which 17 were pheochromocytomas, were analyzed on the basis of their functional and morphological features. The final diagnosis was based on histologic proof when available (six pheochromocytomas) or after synthesis of clinical, biological, morphological, and functional results. Maximum standardized uptake value (SUVmax), mediastinum, and liver ratios in case of pheochromocytomas, adenomas, and solitary adrenal glands were determined and compared with those of healthy glands. Receiver operating characteristic curves were determined and areas under the curve were compared for different cutoffs of each index.

Results: Pheochromocytomas demonstrated a higher F-FDOPA uptake compared with normal adrenal glands (mean SUVmax: 7.5, SD 4.0, range: 3.5-20.0 vs. mean SUVmax: 2.6, SD: 0.8, range: 1.0-6.9) (P<0.0001). An SUVmax threshold of 4.2 has a sensitivity and specificity of 94 and 98%, respectively. The areas under the curve were 0.988, 0.991, and 0.987 for an SUVmax of 4.2, a mediastinum ratio of 3.0, and a liver ratio of 1.7, respectively. A large number of nonsecreting pheochromocytomas were noticed. On the basis of the SUVmax no statistically significant difference was found between secreting (SUVmax: 8.9, SD: 5.3) and nonsecreting pheochromocytomas (SUVmax: 5.1, SD: 0.9) (P=0.141). After unilateral adrenalectomy, solitary glands presented no increased uptake compared with healthy adrenal glands. An unexpected lower captation was also observed (SUVmax: 2.0, P=0.047).

Conclusion: We confirm the high affinity of F-FDOPA for secreting or nonsecreting pheochromocytoma. Indeed within a series of various adrenal glands, only these tumors presented a significant increased uptake compared with normal adrenal glands. Because of a high rate of nonhypersecreting lesions, F-FDOPA can act as a surrogate to biological assays. After an adrenalectomy, the remaining glands did not demonstrate compensatory accumulation of F-FDOPA. To our knowledge this last point has never been addressed.
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September 2017

Modeling therapeutic response to radioiodine in metastatic thyroid cancer: a proof-of-concept study for individualized medicine.

Oncotarget 2017 Jun;8(24):39167-39176

Service de Médecine Nucléaire, CHU La Timone, Aix-Marseille Université, 13385 Marseille 05, France.

Purpose: Radioiodine therapy (RAI) has traditionally been used as treatment for metastatic thyroid cancer, based on its ability to concentrate iodine. Propositions to maximize tumor response with minimizing toxicity, must recognize the infinite possibilities of empirical tests. Therefore, an approach of this study was to build a mathematical model describing tumor growth with the kinetics of thyroglobulin (Tg) concentrations over time, following RAI for metastatic thyroid cancer.

Experimental Design: Data from 50 patients with metastatic papillary thyroid carcinoma treated within eight French institutions, followed over 3 years after initial RAI treatments, were included in the model. A semi-mechanistic mathematical model that describes the tumor growth under RAI treatment was designed.

Results: Our model was able to separate patients who responded to RAI from those who did not, concordant with the physicians' determination of therapeutic response. The estimated tumor doubling-time (Td was found to be the most informative parameter for the distinction between responders and non-responders. The model was also able to reclassify particular patients in early treatment stages.

Conclusions: The results of the model present classification criteria that could indicate whether patients will respond or not to RAI treatment, and provide the opportunity to perform personalized management plans.
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June 2017

Time course of Graves' orbitopathy after total thyroidectomy and radioiodine therapy for thyroid cancer.

Medicine (Baltimore) 2016 Nov;95(48):e5474

CHU Clermont-Ferrand, Endocrinology Department, Clermont-Ferrand, France Department of Clinical and Experimental Medicine and Surgery "F. Magrassi, A. Lanzara," Second University of Naples, Naples, Italy CHU Clermont-Ferrand, Biostatistics Unit (Clinical Research and Innovation Direction), Clermont-Ferrand Department of nuclear medicine, Hospices civils de Lyon, Groupement hospitalier Est, Bron, France Nuclear Medicine, Jean Perrin Cancer Center, Clermont-Ferrand UMR CNRS 6293, INSERM U1103, Génétique Reproduction et Développement, Université Clermont-Auvergne, Aubiere Department of Endocrinology, Hospices Civils de Lyon, Bron, Université Lyon I Lyon 1 University, CRCL, INSERM U1052, Lyon, France.

The risk of cancer is relatively higher in Graves' patients presenting simultaneously with thyroid nodules. Radioiodine (RAI) therapy recommended in high-risk differentiated thyroid carcinoma may be associated with worsening of a pre-existing Graves' orbitopathy (GO) or developing a new onset. The impact of RAI therapy in patients with differentiated thyroid cancer on the course of a pre-exisiting GO has not been specifically investigated.The aim of this study is to assess the influence of RAI treatment administered for differentiated thyroid cancer on the course of a pre-existing GO.This is a retrospective multicenter study including 35 patients from the University Hospital of Clermont-Ferrand (7 patients) and Lyon-Est (6 patients) in France and from a literature review published as case reports or studies (22 patients).Seven patients exhibited a worsened pre-existing GO after total thyroidectomy followed by RAI treatment for thyroid cancer. Older men, those who initially presented with a lower clinical score of GO before RAI therapy, received higher doses of I especially when prepared with recombinant thyroid-stimulating hormone, and/or not prepared with glucocorticoids during RAI are at a higher risk to worsen their GO.This study is the first and complete study collection. We describe worsening of GO in 20% of patients after RAI treatment for thyroid cancer and determine a pool of predictive factors.
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November 2016

Quality of life, clinical outcomes and safety of early prophylactic levothyroxine administration in patients with Graves' hyperthyroidism undergoing radioiodine therapy: a randomized controlled study.

Eur J Endocrinol 2016 Apr 15;174(4):491-502. Epub 2016 Jan 15.

Department of Nuclear MedicineLa Timone University Hospital, European and Center for Research in Medical Imaging, Aix-Marseille University, 264 rue Saint-Pierre 13385 Marseille Cedex 5, FranceInserm UMR1068 Marseille Cancerology Research CenterInstitut Paoli-Calmettes, Marseille, FranceDepartment of Endocrinology and Nuclear MedicineGHE-Hospices Civils de Lyon and Lyon 1 University, Lyon, FranceDepartment of Nuclear MedicineLapeyronie University Hospital, Montpellier, FranceUniversity Hospital of BordeauxBordeaux, FranceDepartment of Nuclear MedicineJean Godinot Institute, Reims, FranceDepartment of Nuclear MedicineBrest University Hospital, Brest, FranceDepartment of Nuclear MedicineSaint-Antoine Hospital, Paris, FranceDepartment of Nuclear MedicineSaint-Louis Hospital, Paris, FranceDepartment of Nuclear MedicineUniversity of Nice, Nice, FranceDepartment of Endocrinology and Metabolic DiseasesCHU Larrey, Toulouse University Hospital, Toulouse, FranceDepartment of Public HealthEA3279 Self-perceived Health Assessment Research Unit, La Timone University, Aix-Marseille University, Marseille, France.

Objective: While radioiodine therapy is commonly used for treating Graves' disease, a prolonged and clinical hypothyroidism may result in disabling symptoms leading to deterioration of quality of life (QoL) of patients. Introducing levothyroxine (LT4) treatment in the early post-therapeutic period may be an interesting approach to limit this phenomenon.

Methods: A multicenter, prospective, open-label randomized controlled trial enrolled 94 patients with Graves' hyperthyroidism randomly assigned to the experimental group (n=46) (group A: early prophylactic LT4 treatment) or the control group (n=48) (group B: standard follow-up). The primary endpoint was the 6-month QoL. The secondary endpoints were other QoL scores such as Graves' ophthalmopathy (GO) outcomes, thyroid function tests and safety.

Results: The primary endpoint at 6 months was achieved: the mental composite score (MCS) of Short Form 36 (SF-36) was significantly higher in group A compared to group B (P=0.009). Four other dimension scores of the SF-36 and four dimension scores of the thyroid-specific patient-reported outcome (ThyPRO) significantly differed between the two groups, indicating better QoL in group A. After adjustment for variables, the early LT4 administration strategy was found as an independent factor for only two scores of SF-36: the MCS and the general health (GH) score. There were no differences in GO, final thyroid status and changes in the anti-TSH receptor antibodies (TRAbs) levels between the two groups. No adverse cardiovascular event was reported.

Conclusion: Early LT4 administration post-radioactive iodine (RAI) could represent a safe potential benefit for patients with regard to QoL. The optimal strategy taking into account administered RAI activities and LT4 treatment dosage and timing remains to be determined.
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April 2016

Quality of Life and Cost-Effectiveness Assessment of Radioiodine Ablation Strategies in Patients With Thyroid Cancer: Results From the Randomized Phase III ESTIMABL Trial.

J Clin Oncol 2015 Sep 3;33(26):2885-92. Epub 2015 Aug 3.

Isabelle Borget, Julia Bonastre, Désirée Déandréis, Sophie Leboulleux, Florence Journeau, Ellen Benhamou, and Martin Schlumberger, Gustave Roussy, Villejuif; Isabelle Borget, Julia Bonastre, and Ellen Benhamou, Center for Research in Epidemiology and Population Health, L'Institut National de la Santé et de la Recherche Médicale 1018; Isabelle Borget and Martin Schlumberger, University Paris-Sud; Laurence Leenhardt, Hôpital Pitié-Salpétrière; Marie-Elisabeth Toubert, Hôpital Saint-Louis, Paris; Bogdan Catargi, Centre Hospitalier Universitaire (CHU) Bordeaux; Francoise Bonichon, Institut Bergonié, Bordeaux; Slimane Zerdoud, Centre Claudius Regaud; Delphine Bastie, CHU Toulouse, Toulouse; Daniela Rusu, Centre René Gauducheau, Nantes; Stéphane Bardet, Centre François Baclesse, Caen; Claire Schvartz, Institut Jean Godinot, Reims; Pierre Vera, Centre Becquerel, Rouen; Olivier Morel, Institut de Cancérologie de l'Ouest, Paul Papin, Angers; Daniele Benisvy, Centre Lacassagne, Nice; Claire Bournaud, CHU Lyon, Lyon; and Antony Kelly, Centre Jean Perrin, Clermont-Ferrand, France.

Purpose: In the ESTIMABL phase III trial, the thyroid ablation rate was equivalent for the two thyroid-stimulating hormone (TSH) stimulation methods (thyroid hormone withdrawal [THW] and recombinant human TSH [rhTSH]) and the two iodine-131 ((131)I) activities (1.1 or 3.7 GBq). The objectives of this article were to present health-related quality-of-life (HRQoL) results and a cost-effectiveness evaluation performed alongside this trial.

Patients And Methods: HRQoL and utility were longitudinally assessed, from random assignment to the follow-up visit at 8 ± 2 months for the 752 patients with thyroid cancer, using the Short Form-36 and the EuroQoL-5D questionnaires, respectively. A cost-effectiveness analysis was performed from the societal perspective in the French context. Resource use (hospitalization for (131)I administration, rhTSH, sick leaves, and transportation) was collected prospectively. We used the net monetary benefit approach and computed cost-effectiveness acceptability curves for both TSH stimulation methods and (131)I activities. Sensitivity analyses of the costs of rhTSH were performed.

Results: At (131)I administration, THW caused a clinically significant deterioration of HRQoL, whereas HRQoL remained stable with rhTSH. This deterioration was transient with no difference 3 months later. rhTSH was more effective than THW in terms of quality-adjusted life-years (QALYs; +0.013 QALY/patient) but more expensive (+€474/patient). The probability that rhTSH would be cost effective at a €50,000/QALY threshold was 47% in France. The use of 1.1 GBq of (131)I instead of 3.7 GBq reduced per-patient costs by €955 (US$1,018) but with slightly decreased efficacy (-0.007 QALY/patient).

Conclusion: rhTSH avoids the transient THW-induced deterioration of HRQoL but is unlikely to be cost effective at its current price.
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September 2015

PREGO (presentation of Graves' orbitopathy) study: changes in referral patterns to European Group On Graves' Orbitopathy (EUGOGO) centres over the period from 2000 to 2012.

Br J Ophthalmol 2015 Nov 7;99(11):1531-5. Epub 2015 May 7.

Department of Endocrinology and Metabolism, Faculty of Medicine, Gazi University, Ankara, Turkey.

Background/aims: The epidemiology of Graves' orbitopathy (GO) may be changing. The aim of the study was to identify trends in presentation of GO to tertiary centres and initial management over time.

Methods: Prospective observational study of European Group On Graves' Orbitopathy (EUGOGO) centres. All new referrals with a diagnosis of GO over a 4-month period in 2012 were included. Clinical and demographic characteristics, referral timelines and initial decisions about management were recorded. The data were compared with a similar EUGOGO survey performed in 2000.

Results: The demographic characteristics of 269 patients studied in 2012 were similar to those collected in the year 2000, including smoking rates (40.0% vs 40.2%). Mild (60.5% vs 41.2%, p<0.01) and inactive GO (63.2% vs 39.9%, p<0.01) were more prevalent in 2012. The times from diagnosis of thyroid disease to being seen in EUGOGO centres (6 vs 16 months) and from first symptoms of GO (9 vs 16 months) or from diagnosis of GO (6 vs 12 months) to first consultation in EUGOGO centres were shorter in 2012 (p<0.01). The initial management plans for GO were no different except surgical treatments for patients with mild inactive disease were more frequently offered in the 2012 cohort than in 2000 (27.3% vs 17%, p<0.05), and selenium supplements were offered only in the 2012 cohort (21.2% vs 0%, p<0.01).

Conclusions: These findings suggest that the clinical manifestations of patients with GO may be changing over time in Europe.
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November 2015

Predictive value of maternal second-generation thyroid-binding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism.

Eur J Endocrinol 2014 Oct;171(4):451-60

Hospices Civils de LyonLyon, FranceFédération d'EndocrinologieService d'Endocrinologie PédiatriqueService de Médecine NucléaireService de Gynécologie-ObstétriqueService de NéonatalogieService de BiochimieGroupement Hospitalier Est, F-69003 Lyon, FranceService de BiochimieService d'EndocrinologieCentre Hospitalier Lyon Sud, 69310 Lyon, FranceFaculté de Médecine Lyon-EstUniversité Lyon 1, Lyon, FranceFaculté de PharmacieLyon, FranceFaculté de Médecine et de Maïeutique Lyon Sud - Charles MérieuxLyon, FranceCARMEN INSERM U1060Lyon, FranceINSERM U1052Lyon, FranceService de Biostatistiques162 Avenue Lacassagne, 69003 Lyon, France Hospices Civils de LyonLyon, FranceFédération d'EndocrinologieService d'Endocrinologie PédiatriqueService de Médecine NucléaireService de Gynécologie-ObstétriqueService de NéonatalogieService de BiochimieGroupement Hospitalier Est, F-69003 Lyon, FranceService de BiochimieService d'EndocrinologieCentre Hospitalier Lyon Sud, 69310 Lyon, FranceFaculté de Médecine Lyon-EstUniversité Lyon 1, Lyon, FranceFaculté de PharmacieLyon, FranceFaculté de Médecine et de Maïeutique Lyon Sud - Charles MérieuxLyon, FranceCARMEN INSERM U1060Lyon, FranceINSERM U1052Lyon, FranceService de Biostatistiques162 Avenue Lacassagne, 69003 Lyon, France Hospices Civils de LyonLyon, FranceFédération d'EndocrinologieService d'Endocrinologie PédiatriqueService de Médecine NucléaireService de Gynécologie-ObstétriqueService de NéonatalogieService de BiochimieGroupement Hospitalier Est, F-69003 Lyon, FranceService de BiochimieService d'EndocrinologieCentre Hospitalier Lyon Sud, 69310 Lyon, FranceFaculté de Médecine Lyon-EstUniversité Lyon 1, Lyon, FranceFaculté de PharmacieLyon, FranceFaculté de Médecine et de Maïeutique Lyon Sud - Charles MérieuxLyon, FranceCARMEN INSERM U1060Lyon, FranceINSERM U1052Lyon, FranceService de Biostatistiques162 Avenue Lacassagne, 69003 Lyon, France Hospices Civils de LyonLyon, FranceFédération d'Endocr

Context: Hyperthyroidism occurs in 1% of neonates born to mothers with active or past Graves' disease (GD). Current guidelines for the management of GD during pregnancy were based on studies conducted with first-generation thyroid-binding inhibitory immunoglobulin (TBII) assays.

Objective: This retrospective study was conducted in order to specify the second-generation TBII threshold predictive of fetal and neonatal hyperthyroidism, and to identify other factors that may be helpful in predicting neonatal hyperthyroidism.

Methods: We included 47 neonates born in the Lyon area to 42 mothers harboring measurable levels of TBII during pregnancy. TBII measurements were carried out in all mothers; bioassays were carried out in 20 cases.

Results: Nine neonates were born with hyperthyroidism, including five with severe hyperthyroidism requiring treatment. Three neonates were born with hypothyroidism. All hyperthyroid neonates were born to mothers with TBII levels >5 IU/l in the second trimester (sensitivity, 100% and specificity, 43%). No mother with TSH receptor-stimulating antibodies (TSAb measured by bioassay) below 400% gave birth to a hyperthyroid neonate. Among mothers of hyperthyroid neonates, who required antithyroid drugs during pregnancy, none could stop treatment before delivery. Analysis of TBII evolution showed six unexpected cases of increasing TBII values during pregnancy.

Conclusion: Maternal TBII value over 5 IU/l indicates a risk of neonatal hyperthyroidism. Among these mothers, a TSAb measurement contributes to identify more specifically those who require a close fetal thyroid ultrasound follow-up. These results should be confirmed in a larger series.
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October 2014

¹⁸F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

Eur J Nucl Med Mol Imaging 2014 Aug 8;41(8):1501-10. Epub 2014 May 8.

Nuclear Medicine Department, University Hospital, Brest, France.

Purpose: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial.

Methods: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods.

Results: Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis.

Conclusion: (18)F-FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment.
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August 2014

Is thyroid cancer recurrence risk increased after transplantation?

J Clin Endocrinol Metab 2013 Oct 24;98(10):3981-8. Epub 2013 Jul 24.

Fédération d'Endocrinologie, Groupement Hospitalier Est, 59 Boulevard Pinel, 69677 Bron Cedex, France.

Context: An increased cancer mortality is reported in transplanted patients.

Objective: This multicentric study aimed to investigate the rate of thyroid cancer recurrence after transplantation.

Results: Sixty-eight patients (35 male/33 female) with a history of both thyroid cancer and organ transplantation were recruited via two nationwide French networks. Histological analysis identified 58 papillary (88%), 5 follicular (7.5%), and 3 poorly differentiated cancer cases (4.5 %). Thirty-one patients (52%) presented high recurrence risk tumors. In the 36 patients with thyroid cancer diagnosed after transplantation, the 5-year disease-free survival (DFS) was 74.7% (SE: 7.3%). One patient died after progression of a poorly differentiated cancer. Persistent disease was observed in six high-risk patients. One of them underwent a second transplantation and disease remained stable after 5 years of follow-up. Thyroid cancer had been diagnosed before transplantation in 32 patients. One patient with cystic fibrosis and thyroid lung metastases at the time of lung transplantation underwent a 4-year remission. For the 31 patients in remission at the time of transplantation, the 5-year DFS was 93.1% (SE: 4.8%). Two patients with local recurrence presented subsequent remission. For the entire study population, the 5-year and 9-year DFS were 81.9% (SE: 5.5%) and 75.6% (SE: 7.9%), respectively. Recurrence or persistent disease occurred in patients with high-risk tumors.

Conclusions: The prognosis of thyroid cancer does not seem to be altered by transplantation. This suggests that a history of thyroid cancer should not be considered a contraindication.
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October 2013

Thyroid cancers in children, adolescents, and young adults with and without a history of childhood exposure to therapeutic radiation for other cancers.

Thyroid 2013 Jul 21;23(7):805-10. Epub 2013 Jun 21.

Rhône-Alpes Thyroid Cancer Registry, Cancerology Research Center of Lyon (UMR INSERM 1052, CNRS 5286), RTH Laennec Faculty of Medicine, University of Lyon, Lyon, France.

Background: The thyroid is highly sensitive to the carcinogenic effect of radiation in children. We compared, in patients with and without earlier childhood radiation, the features of papillary thyroid cancer (PTC) diagnosed in later childhood through young adulthood.

Methods: Patients were from the Rhône-Alpes Thyroid Cancer Registry. Twenty-four patients (RAD group) had been treated by radiation therapy for nonthyroid neoplasms at the age of 8.0±6.0 years (mean±SD) and by surgery for PTC at the age of 17±6.4 years. They were compared with 413 patients with PTC but no radiation exposure (sPTC group, age 23±4.8 years). The two groups were subdivided into three subgroups, ages 8-14 (children), 15-20 (adolescents), and 21-29 years (adults) at time of PTC diagnosis, and compared to matched subgroups from 80 patients in the sPTC group (M-sPTC). Age in years at PTC diagnosis (RAD vs. M-sPTC) was 12±2 compared with 12±2 for children, 17±1 compared with 19±1 for adolescents, and 25±3.2 compared with 25±2.5 for adults. The matched subgroups had comparable pTNM, treatments, and follow-up. We compared the histopathological characteristics of the initial specimens and the outcome events.

Results: The RAD group and the sPTC group were similar in terms of age when PTC was diagnosed. RAD tumors had significantly more lymph node metastases (p=0.007) and a higher proportion of invasive pTN3 stage tumors (p=0.01). The adult RAD subgroup (n=8) was more likely to have lymph node metastases (p=0.004) and a higher proportion of invasive pT3N+ stage tumors (p=0.01) than the adult sPTC subgroup (n=316). During the 6.5 years of follow-up, there was no difference in the risk of cervical recurrence between the RAD group and the M-sPTC groups. Risk of cervical recurrence was also similar for tumors that were high risk (pT3N+).

Conclusion: Young adults with PTC associated with radiation therapy for nonthyroid neoplasms in childhood have a more aggressive initial presentation than young adults with sporadic PTC. The risk of recurrent disease in patients who received radiation in early childhood through adolescence and who developed PTC in late childhood through early adulthood is similar to those who did not receive radiation.
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July 2013

Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.

J Nucl Med 2012 Aug 28;53(8):1185-92. Epub 2012 Jun 28.

Nuclear Medicine Department, University Hospital and ICO Gauducheau Cancer Institute, IRCNA, Cancer Research Center, Université de Nantes, Inserm, UMR 892, Nantes, France.

Unlabelled: The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome.

Methods: From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later.

Results: The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004).

Conclusion: pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.
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August 2012

Strategies of radioiodine ablation in patients with low-risk thyroid cancer.

N Engl J Med 2012 May;366(18):1663-73

Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy and University Paris-Sud, Villejuif, France.

Background: It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care.

Methods: In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework.

Results: There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods.

Conclusions: The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; number, NCT00435851; INCa number, RECF0447.).
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May 2012

Pregnant French women living in the Lyon area are iodine deficient and have elevated serum thyroglobulin concentrations.

Thyroid 2012 May 2;22(5):522-8. Epub 2012 Apr 2.

Laboratory of Hormonology, East Center for Biology and Pathology, East Hospital Group, Civil Hospices of Lyon, 59 boulevard Pinel, Bron, France.

Background: Iodine deficiency (ID) remains common in Europe, and may be especially detrimental during pregnancy. The aim of our study was to assess iodine status and thyroid function in healthy pregnant women in the Lyon metropolitan area.

Methods: In a cross-sectional study, healthy pregnant women (n=228) with no history of thyroid disease were consecutively recruited from an obstetric clinic during all trimesters. Thyrotropin (TSH), free thyroxine (FT4), anti-thyroid peroxidase (anti-TPO) antibodies, thyroglobulin (Tg), and urinary iodine concentration (UIC) (n=100) were measured. Thyroid functions were compared with those in a control group of nonpregnant adults.

Results: The median (range) UIC was 81 (8-832) μg/L, and 77% of pregnant women had a UIC <150 μg/L, indicating inadequate iodine intake. Overall, 11% of women had abnormal TSH or anti-TPO. The median FT4 (pmol/L) was 14.9, 12.6, and 11.5 in the first, second, and third trimesters, respectively. The median Tg in pregnant women was 16.2 μg/L, did not differ across trimesters, and was significantly higher than in the control group of nonpregnant adults (11.7 μg/L) (p=0.02). Controlling for maternal age and week of gestation, UIC was not a significant predictor of any of the thyroid function tests.

Conclusions: Pregnant women in the Lyon area are iodine deficient and have increased serum Tg concentrations compared with nonpregnant controls, likely due to physiological thyroid hyperstimulation during gestation exacerbated by ID.
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May 2012

[Thyroid cancer screening: is it useful?].

Presse Med 2011 Dec 21;40(12 Pt 1):1182-8. Epub 2011 Nov 21.

Fédération d'endocrinologie et centre de médecine nucléaire, groupement hospitalier Lyon-Est, 69677 Bron cedex, France.

Differentiated thyroid cancer has a good overall prognosis, however, unfavourable evolution may be observed in cases discovered at an advanced stage. Thyroid cancer incidence has increased in occidental countries over the last 20 years without any significant change in mortality. This has been partially related to changes in diagnostic procedures with an increased detection of small cancers. Indeed, microcarcinomas (less than 10mm diameter), frequently incidentally discovered are now, the most frequent form of thyroid cancer, representing around 40 % of cases. Their prognosis is excellent and the benefit of their surgical management remains to be demonstrated. Unexpectedly, the proportion of large thyroid cancer at diagnosis has remained stable representing around 20 % of cases. These forms are responsible of most of the thyroid cancer specific mortality and an intensification of their clinical screening is necessary. By contrast, a systematic ultrasonographic screening of thyroid nodules should increase the proportion of small thyroid cancers without evidence of an earlier diagnosis of advanced forms and the ratio cost-benefit of such a strategy should be properly evaluated.
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December 2011

Results of combined treatment of anaplastic thyroid carcinoma (ATC).

BMC Cancer 2011 Nov 1;11:469. Epub 2011 Nov 1.

University of Lyon-Leon-Berard Cancer Center, Department of Medical Oncology, Lyon, France.

Background: Anaplastic thyroid carcinoma (ATC) is among the most aggressive human malignancies. It is associated with a high rate of local recurrence and with poor prognosis.

Methods: We retrospectively reviewed 44 consecutive patients treated between 1996 and 2010 at Leon Berard Cancer Centre, Lyon, France. The combined treatment strategy derived from the one developed at the Institut Gustave Roussy included total thyroidectomy and cervical lymph-node dissection, when feasible, combined with 2 cycles of doxorubicin (60 mg/m2) and cisplatin (100 mg/m2) Q3W, hyperfractionated (1.2 Gy twice daily) radiation to the neck and upper mediastinum (46-50 Gy), and then four cycles of doxorubicin-cisplatin.

Results: Thirty-five patients received the three-phase combined treatment. Complete response after treatment was achieved in 14/44 patients (31.8%). Eight patients had a partial response (18.2%). Twenty-two (50%) had progressive disease. All patients with metastases at diagnosis died shortly afterwards. Thirteen patients are still alive. The median survival of the entire population was 8 months.

Conclusion: Despite the ultimately dismal prognosis of ATC, multimodality treatment significantly improves local control and appears to afford long-term survival in some patients. There is active ongoing research, and results obtained with new targeted systemic treatment appear encouraging.
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November 2011

18F-FLT and 18F-FDG positron emission tomography for the imaging of advanced well-differentiated gastro-entero-pancreatic endocrine tumours.

Nucl Med Commun 2011 Feb;32(2):91-7

Nuclear Medicine Department, Hospices Civils de Lyon, Lyon-Sud Hospital, France.

Purpose: Gastro-entero-pancreatic (GEP) endocrine tumours are a heterogenous group of tumours of variable localization and prognosis. It has been suggested that positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) may have a prognostic value and help to identify patients at risk of progression. [18F]fluoro-3'-deoxy-3'-L-fluorothymidine (18F-FLT) has been recently developed as a PET proliferation tracer. At present, there are no studies investigating its role in GEP. The aim of this prospective study was to assess the value of 18F-FLT-PET for the evaluation of GEP.

Materials And Methods: Ten patients with biopsy-proven locally advanced or metastasized, well-differentiated GEP neuroendocrine tumours were prospectively enrolled and scheduled for 18F-FDG and 18F-FLT-PET. Images were compared with other conventional diagnostic procedures, namely computed tomography, ultrasound, somatostatin receptor scintigraphy and with clinical and diagnostic follow-up.

Results: Evaluation criteria were interpreted in terms of assumed presence of tumoral tissue. According to the patient's status, FDG was positive in five out of the seven patients with stable disease and in two out of the three patients with progressive disease. No positive case was identified by 18F-FLT in either the primary or the metastatic tumour site, whatever the status of patients, and this was probably a reflection of the slow proliferation rate of tumours.

Conclusion: These preliminary data suggest that 18F-FLT-PET is not a suitable tracer for the evaluation of advanced well-differentiated GEP tumours. FDG showed good diagnostic performance but does not help to identify patients at risk of progression.
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February 2011

Thyroglobulin measurement in fine-needle aspirates of lymph nodes in patients with differentiated thyroid cancer: a simple definition of the threshold value, with emphasis on potential pitfalls of the method.

Clin Chem Lab Med 2010 Aug;48(8):1171-7

Hospices Civils de Lyon, Service Médecine Nucléaire, Groupement Hospitalier Est, Lyon, France.

Background: Thyroglobulin measurements in fine-needle aspirate (FNA-Tg) is an accurate method for the diagnosis of lymph node metastasis in differentiated thyroid carcinoma. The goal of this study is to determine the most appropriate diagnostic threshold value for FNA-Tg.

Methods: Ultrasound-guided fine-needle aspiration-cytology (FNA-C) and FNA-Tg were performed on suspicious lymph nodes in 114 consecutive patients with thyroid cancer prior to thyroidectomy (n=13) or during follow-up (n=93), and in 16 control subjects. Functional sensitivity of the thyroglobulin assay was 0.7 ng/mL. Sensitivity and specificity of FNA-Tg and FNA-C were determined for different cut-off values within a range of 0.69-1.34 nanogram/punction (ng/p) using receiver operating characteristic curve analysis.

Results: The FNA-Tg cut-off value of 0.93 ng/p offers the best diagnostic performances: 94.2% sensitivity, 97.8% specificity. FNA-C showed 100% specificity in diagnostic samples, but low sensitivity of 71% due primarily to inadequate samples. Combining FNA-C and FNA-Tg resulted in 98% sensitivity and 100% specificity.

Conclusions: A unique threshold of 0.93 ng/p gives high sensitivity and specificity, even in non-thyroidectomized patients. However, since false negative results may be observed in poorly differentiated thyroid cancer, FNA-C should remain combined to FNA-Tg.
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August 2010

Geographical correlation between incidence of benign disease and that of cancer of the thyroid among the population of the Rhône-Alpes Région of France.

Eur J Endocrinol 2010 Jan 29;162(1):127-35. Epub 2009 Sep 29.

Hospices Civils de Lyon, Registre Rhône Alpin des Cancers thyroïdiens, Fédération d'Endocrinologie et Centre de Médecine Nucléaire Groupement Hospitalier Est, 69677 Bron Cedex, France.

Objective: To analyze, at a population level, the relation between the incidences of benign thyroid diseases in patients submitted to surgery and that of thyroid cancers based on their respective geographical distributions.

Methods: The study included 3169 cases (691 cancers and 2478 benign diseases) operated on in 2002 in the Rhône-Alpes région, which is subdivided into eight départements and 311 cantons.

Results: The total thyroid intervention rate was 54.6/100 000 (23.4 and 86.4), and the annual cancer incidence was 11.9/100 000 (4.7 and 13.8) for men and women respectively. The prevalence of cancer among thyroid surgery was 21.8% and that of cancer discovered in goiters increased with age (44% at 60 years). Intervention rates varied from départment to département. In women, the incidence of microcancers was correlated to the thyroid intervention for benign pathologies rate. In men, the incidence of supracentimetric cancers was related to the TIBR. At the canton level, the relative risk of benign diseases was correlated to that of cancers. TIBR and incidence of cancers were higher in urban cantons than in nonurban ones. The density of endocrinologists influenced the prevalence of cancers among all the cases submitted to surgery.

Conclusion: In the Rhône-Alpes population with high rates of thyroid cancer incidence and of thyroid surgery, a number of correlations were found according to gender and tumor size. However, the general incidence of cancer was not directly related to surgical activity. Geographical variability may be related to the heterogeneous medical and pathological practices.
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January 2010

Thyroid gene expression in familial nonautoimmune hyperthyroidism shows common characteristics with hyperfunctioning autonomous adenomas.

J Clin Endocrinol Metab 2009 Jul 21;94(7):2602-9. Epub 2009 Apr 21.

Institute of Interdisciplinary Research, School of Medicine, Free University of Brussels, campus Erasme, 808 Route de Lennik, 1070 Brussels, Belgium.

Context: Dominant activating mutations of the TSH receptor are the cause of familial nonautoimmune hyperthyroidism (FNAH) (inherited mutations affecting the whole gland since embryogenesis) and the majority of hyperfunctioning autonomous adenomas (AAs) (somatic mutations affecting only one cell later in the adulthood).

Objective: The objective of the study was defining the functional and molecular phenotypes of FNAH and comparing them with the ones of AA.

Design: Functional phenotypes were determined in vitro and molecular phenotypes by hybridization on microarray slides.

Patients: Nine patients with FNAH were investigated, six for functional in vitro study of the tissue and five for gene expression.

Results: Iodide metabolism, H(2)O(2), cAMP, and inositol phosphate generation in FNAH slices stimulated or not with TSH were normal. The mitogenic response of cultured FNAH thyrocytes to TSH was normal but more sensitive to the hormone. Gene expression profiles of FNAH and AAs showed that among 474 genes significantly regulated in FNAH, 93% were similarly regulated in AAs. Besides, 783 genes were regulated only in AAs. Bioinformatic analysis pointed out common down-regulations of genes involved in immune response, cell/cell and cell/matrix adhesions, and apoptosis. Pathways up-regulated only in AAs mainly involve diverse biosyntheses. These results are consonant with the larger growth of AAs than FNAH tissues.

Conclusions: Whether hereditary or somatic after birth, activating mutations of the TSH receptor have the same qualitative consequences on the thyroid cell phenotype, but somatic mutations in AAs have a much stronger effect than FNAH mutations. Both are variants of one disease: genetic hyperthyroidism.
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July 2009

Thyroid cancer: is the incidence rise abating?

Eur J Endocrinol 2009 Jan 24;160(1):71-9. Epub 2008 Oct 24.

Hospices Civils de Lyon, Registre Rhône Alpin des Cancers Thyroïdiens, Fédération d'Endocrinologie et Centre de Médecine Nucléaire Groupement Hospitalier Est, Bron, France.

Objective: The aim of the present study was to determine recent trends in thyroid cancer incidence rates and to analyze histopathological characteristics and geographical distribution.

Methods: Histologically proven 5367 cases were collected over the period 1998-2006 in France from the Rhône-Alpes thyroid cancer registry. Geographical variations of incidence were analyzed using a mixed Poisson model.

Results: The average incidence rates, age standardized to the world population, were 3.9/100,000 in men and 12.3/100,000 in women, higher than those previously reported in France. After an initial increase during the first 3 years, a steady level of incidence was observed for the period 2001-2006. The annual incidence rate of microcarcinomas was correlated with that of all cancers in men and women (r=0.78 and 0.89; P<0.01) respectively. Papillary microcarcinomas represented 38% of tumors and two-thirds of them measured less than 5 mm in diameter. They were fortuitously discovered after thyroidectomy for benign diseases in 64% of cases. Histological marks of aggressiveness differed according to the size of the tumor. Despite recent advances in diagnosis, 13% of tumors were diagnosed at advanced stage especially in men. Geographical distribution of incidence based on subregional administrative entities showed lower incidence rates in rural than in urban zones in men (relative rate: 0.72; 95% CI: 0.62-0.84) and women (relative rate: 0.85; 95% CI: 0.73-0.93).

Conclusion: The present study suggests that the rise in thyroid cancer incidence is now abating. It could reflect standardization in diagnostic procedures. Further studies, performed on a more prolonged period, are necessary to confirm these data.
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January 2009

Management of Graves' hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy.

Eur J Endocrinol 2009 Jan 10;160(1):1-8. Epub 2008 Oct 10.

Department of Endocrinology and Medicine, Aalborg Hospital, Aalborg, Denmark.

Graves' disease is a common autoimmune disorder in women in fertile ages. The hyperthyroidism is caused by generation of TSH-receptor activating antibodies. In pregnancy both the antibodies and the antithyroid medication given to the mother pass the placenta and affect the foetal thyroid gland. Thyroid function should be controlled not only in the mother with Graves' hyperthyroidism but also in her foetus.The review includes two cases illustrating some of the problems in managing Graves' disease in pregnancy. Major threats to optimal foetal thyroid function are inadequate or over aggressive antithyroid drug therapy of the mother. It should be taken into account that antithyroid drugs tend to block the foetal thyroid function more effectively than the maternal thyroid function, and that levothyroxin (L-T(4)) given to the mother will have only a limited effect in the foetus. Surgical thyroidectomy of patients with Graves' hyperthyroidism does not lead to immediate remission of the autoimmune abnormality, and the combination thyroidectomy+withdrawal of antithyroid medication+L-T(4) replacement of the mother involves a high risk of foetal hyperthyroidism. Conclusion Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function. Surgical thyroidectomy of a pregnant woman with active disease may lead to isolated foetal hyperthyroidism.
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January 2009

131I effective half-life and dosimetry in thyroid cancer patients.

J Nucl Med 2008 Sep 14;49(9):1445-50. Epub 2008 Aug 14.

Department of Nuclear Medicine, Institut Gustave Roussy, Villejuif, France.

Unlabelled: (131)I treatment in thyroid cancer patients may induce side effects, including extrathyroidal cancer and leukemia. There are still some uncertainties concerning parameters that may influence the effective half-life of (131)I and the absorbed doses by extrathyroidal organs.

Methods: Whole-body retention of radioiodine was measured in 254 patients, and repeated quantitative whole-body scans and measurements of the urinary excretion of (131)I were performed on 30 of these patients.

Results: The mean effective half-life (10.5 h) was shorter by 31%, with little difference between patients, in the 36 patients who received recombinant human thyroid-stimulating hormone than in the 218 patients who underwent thyroid hormone withdrawal (15.7 h). The residence times in the stomach and in the rest of the body were significantly shorter in patients who received recombinant human thyroid-stimulating hormone than in patients who underwent withdrawal, but the residence times were similar in the colon and bladder.

Conclusion: In patients who undergo thyroid hormone withdrawal, the longer mean effective half-life is mainly due to delayed renal excretion of (131)I and results in dose estimates higher than the data in report 53 of the International Commission on Radiological Protection, which were obtained from healthy, euthyroid subjects.
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September 2008