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STUDY QUESTION What are the consequences of radioactive iodine (RAI) therapy for testicular function? SUMMARY ANSWER A single activity of 3.7 GBq RAI for differentiated thyroid carcinoma (DTC) treatment in young men transiently altered Sertoli cell function and induced sperm chromosomal abnormalities. WHAT IS KNOWN ALREADY Few studies, mainly retrospective, have reported the potential impacts of RAI on endocrine and exocrine testicular function. STUDY DESIGN, SIZE, DURATION A longitudinal prospective multi-center study on testicular function performed in DTC patients before a single 131I ablative activity of 3.7 GBq (V0) and at 3 months (V3) and 13 months (V13) after treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS Forty male patients, aged 18-55 years, with DTC participated. Hormonal analysis included FSH, LH, testosterone and inhibin B serum levels at V0, V3 and V13. Furthermore, sperm parameters, DNA fragmentation and sperm chromosomal abnormalities were evaluated at each time points. The differences in all parameters, between V0-V3, V0-V13 and V3-V13, were analyzed, using a Wilcoxon test. MAIN RESULTS AND THE ROLE OF CHANCE Prior to RAI administration, all patients had normal gonadal function. At V3, a statistically significant increase in FSH levels and a decrease in inhibin B levels were observed and sperm concentration, as well as the percentage of morphologically normal spermatozoa, were significantly decreased (P < 0.0001). These modifications were transient as both sperm concentration and normal morphology rate returned to baseline values at V13. However, at this later time point, FSH and inhibin B levels were still impacted by RAI administration but remained in the normal range. Although no DNA fragmentation was observed at V3 nor V13, our study revealed a statistically significant increase in the number of sperm chromosomal abnormalities both at V3 (P < 0.001) and V13 (P = 0.01). LIMITATIONS, REASONS FOR CAUTION Among the 40 patients included in the study, only 24 had all the parameters available at all visits. WIDER IMPLICATIONS OF THE FINDINGS Prospective studies with longer term follow up would be helpful to determine whether the chromosome abnormalities persist. These studies would be required before sperm banking should be suggested for all patients. However, sperm preservation for DTC patients who require cumulative radioiodine activities higher than 3.7 GBq should be proposed. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Programme Hospitalier de Recherche Clinique, AP-HP (No. P040419). The authors report no conflict of interest in this work. TRIAL REGISTRATION NUMBER NCT01150318.

International audience; A 53-year-old woman with papillary thyroid cancer treated with 800 mg sorafenib therapy rapidly experienced grade 3 toxicities. Dosing was reduced in a step-wise manner with several treatment discontinuations down to 200 mg every 2 days but severe toxicities continued. Plasma drug monitoring showed high exposure, even at low dose. Dosing was then further reduced at 200 mg every 3 days and tolerance was finally acceptable (i.e., grade 1 toxicity) with stable disease upon RECIST imaging. Pharmacogenetic investigations showed polymorphisms affecting both UGT1A9 ( UGT1A9-rs3832043) and nuclear receptor PXR ( NR1I2-rs3814055 , NR1I2-rs2472677 and NR1I2-rs10934498), possibly resulting in downregulation of liver metabolizing enzymes of sorafenib (i.e., CYP and UGT). Patient's clearance (0.48 l/h) estimated by Bayesian approach was consistently lower than usually described. This is the first time that, in addition to mutations affecting UGT1A9, genetic polymorphisms of NR1I2 have possibly been associated with both plasma overexposure and severe toxicities upon sorafenib intake.

International audience; Introduction Diagnostic I-123 scans have been shown to underestimate the disease burden in differentiated thyroid cancer (DTC) when compared to I-131 post-treatment scans, especially in children and patients who have had prior radioiodine (RAI) therapy and/or distant metastasis. I-124 PET/CT has been shown to be highly effective in imaging DTC-related metastatic disease. Methods We performed a systematic review and meta-analysis of studies investigating the sensitivity and specificity of I-124 PET/CT in identifying lesions amenable to RAI therapy as confirmed by I-131 post-treatment scanning. Results There were 141 patients and 415 lesions of DTC identified altogether. There was significant heterogeneity in the individual studies. The pooled sensitivity of the I-124 PET/CT in detecting lesions of differentiated thyroid cancer amenable to I-131 therapy was 94Á2% (91Á3–96Á4% CI, P < 0Á01), and the pooled specificity was 49Á0% (34Á8–63Á4% CI, P < 0Á01). The pooled positive likelihood ratio (LR) was 1Á43 (1Á05–1Á94 CI), and the pooled negative LR was 0Á28 (0Á15–0Á53 CI). Overall, the diagnostic odds ratio was 7Á90 (3Á39–18Á48 CI). There were a small but increased number of lesions identified by I-124 PET/CT that was not detected on post-treatment scan. Conclusion I-124 PET/CT is a sensitive tool to diagnose RAI avid DTC lesions, but also detects some new lesions that are not visualized on the post-treatment I-131 scan. Further, carefully designed dosimetric studies may be required to fully establish the role of I-124 PET CT for identifying potential lesions for I-131 therapy. I-124 PET/CT in patients with DTC may have other applications in specific clinical situations.

Medullary thyroid carcinomas (MTCs) complicated by ectopic Cushing's syndrome (CS) have a poor prognosis, partially due to the difficulty in controlling hypercortisolism by adrenal blocking drugs. Recent reports (including the initial follow-up of this patient) have suggested that tyrosine kinase inhibitors (TKIs) may be a therapeutic option due to an anti-secretory action on ACTH. However, there is a lack of long-term follow-up studies.The case is reported of a 58-year-old man with MTC-related CS resistant to a combination of several anti-cortisolic drugs. Vandetanib, an oral multi-TKI that targets RET in particular, was initiated, and a rapid reversal of the hypercortisolism was observed without any change in tumor size. Vandetanib was briefly interrupted twice, once for 45 days because of side effects and a second time for 10 days to schedule surgical debulking. Each time, plasma cortisol and calcitonin levels increased after TKI withdrawal and were rapidly lowered by vandetanib reintroduction. As described in other cases of CS caused by MTC, a marked ACTH increase after desmopressin stimulation was observed before vandetanib therapy. In contrast, a blunted ACTH response to desmopressin was documented throughout the course of vandetanib treatment. This modulation of the tumoral ACTH production is a strong argument in favor of a TKI anti-secretory action. A left thyroid lobectomy and a modified neck dissection were performed one year after the initiation of vandetanib in order to reduce the tumor mass. An activating M918T RET (c.2753TC) somatic mutation was identified in a lymph node metastasis.Three years and eight months after vandetanib initiation, there was no sign of recurrence of hypercortisolism. This case illustrates the long-term effectiveness of vandetanib in maintaining the control of hypercortisolism in MTC-related CS.

Primary hyperparathyroidism (HPP) and acromegaly (ACRO) may be associated in NEM1. However, the association of the two pathologies can be seen outside a syndrome predisposing to endocrine tumours. The objective of the study is to specify the characteristics of the non-syndromic association acromegaly-hyperparathyroidism (NSACROHPP). Materials and methods: Retrospective monocentric study of patients hospitalized in the endocrinology department of the Cochin hospital between 1999 and 2016: 156 ACRO, 468 HPP (45 of which are explained by an NEM1). Eight ACRO patients without menin mutation (5%) were identified. Results: the 8 NSACROHPP patients are women whose HPP is diagnosed before ACRO in 6 cases and whose calcemia-PTH-calciuria are elevated on average (respectively: 2,8 mmol/l [2.43-3.27], 115 ng/l [39-313] et 9 mmol/24h [5.2-13.6]). Marked decrease: renal colic (5/8), osteopenia (3/8), osteoporosis (3/8). 7/8 patients operated: 7/7 of adenoma including 2/7 with associated hyperplasia. A papillary carcinoma in 4/8 and an oxyphilic nodule in 1/8 are associated with HPP. The ACRO is diagnosed on average at 63 years (35-87) (4 macroadenomas and 5 invasive adenomas). There is no family history of endocrine tumour reported. The median age at diagnosis of PPH was significantly higher (64 years) in NSACROHPP than in acromegaly with NEM1 (31 years, [14-75], p

International audience; UNLABELLED: The hook effect, which has long been detected and documented for immunoradiometric assays (IRMA) such as those measuring prolactin or thyroglobulin, occurs when the serum antigen level is extremely high, thus inducing a bias in the methodology of measurement. RESULTS: We report the case of an 80-year-old man with confirmed medullary thyroid carcinoma (MTC). In the case reported here, the clinical status of the patient contrasts with his tumor antigen, serum calcitonin (CT), concentrations. The measured increased CT concentrations revealed the presence of a hook effect. This phenomenon occurs due to an excess of antigen during the one-step IRMA where the signal antibodies, bound to the non-captured antigens, are washed out during the measurement, inducing the loss of signal. Aiming to prevent the "hook effect", successive dilutions of the same sample of serum were done. CONCLUSIONS: Previous studies have shown when one-step IRMA reveals high concentrations of a tumor serum antigen (i.e. prolactin or thyroglobulin), a two-step IRMA or a systematic 1:10 dilution of the serum sample prevents the formation of the "hook effect". In our case report, the CT "hook effect" formation was prevented by performing serial dilutions of the serum sample.

International audience; BACKGROUND: Papillary thyroid carcinoma (PTC) in young people usually has an aggressive initial presentation, though a good general prognosis despite recurrences in 10%-20% of patients. A number of genetic alterations that activate the mitogen-activated protein kinase (MAPK) pathway have been found in PTC. Some of these alterations have been identified as prognostic factors of PTC in adults. The objective of the current study was to comprehensively characterize all known oncogenic alterations of the MAPK pathway in young people. METHODS: One hundred three PTCs removed from 9 children, 19 adolescents, and 75 young adults were submitted to molecular analyses. RESULTS: Altogether, 57 alterations were found in 56 PTCs (55%) corresponding to V600E BRAF in 20.3%, RAS mutations in 12.6%, RET/PTC 1 in 11.6%, RET/PTC 3 in 8.7%, and rearrangement of NTRK in 1.9%. The prevalence of all alterations increased with age (22.2% in children; 52.6% in adolescents, 51.4% in adults 20-25 years, and 55.1% in adults 25-35 years). Prevalence increased from 39.2% earlier to 61.3% after 20 years mainly due to BRAF mutations. Classic-type PTC was associated with a larger prevalence of alterations, predominantly BRAF and RET/PTC, whereas the follicular variant was chiefly associated with RAS. RET/PTC (1 and 3) was significantly associated with extrathyroid extension (ET) and lymph node metastasis (es) (LNM). This association was found in the adult group. There were no associations of BRAF or RAS mutations with ET or LNM. A 3-year median follow up was available for 90 patients. RET/PTC 1 and 3 was associated with short-term disease dissemination (cervical lymph node recurrences and distant metastases) in young adults (p=0.001). Persistent illness was more prevalent in patients with (15%) than in patients without (7%) genetic alterations. CONCLUSION: PTCs in young patients display a low prevalence of the already identified oncogenic alterations. The increasing prevalence with age is mainly due to V600E BRAF mutation. There is no relation between tumor aggressiveness and BRAF mutation. There is a relation between the presence of RET/PTC (1 and 3) and the histological and clinical short-term aggressiveness of PTC in the population of young adults. Such a relation is not found in children and adolescents.

International audience; The incidence of thyroid cancers, and in particular the papillary forms, has been increasing sharply for many years in Western countries. However, the factors explaining this increase have not been clearly established. Some studies mention the effects of radioactive fallout, particularly after the accident in Chernobyl. Another probable cause is related to progress in medical practice, and particularly in diagnosis. In this article, we describe time trends in the incidence of papillary and follicular cancers, taking into account the size of the tumour at the time of diagnosis. The analysis was carried out on cases from six French cancer registries for the period 1983-2000. Anatomopathological reports concerning 3381 cancer cases were systematically recoded and centralised, following ICDO-3 rules. Over the whole period, the annual percent change of the incidence of papillary cancers was +8.13% and +8.98%, respectively in men and in women. For micropapillary carcinomas (< or = 10 mm), this increase was respectively +12.05% and +12.85%. There is no significant effect of period apart from micropapillary carcinomas in women. However, a birth cohort effect exists for some groups. This effect corresponds to an acceleration in the risk for people born after the 1930s. For the most recent period (1998-2000), half the cases of papillary cancer were micropapillary carcinomas, and for one third of these, the tumour was < or = 5 mm. Our description of a time trend of incidence as a function of tumour size supports the hypothesis of the role of medical practice in a context of high prevalence. Obviously, these findings do not exclude the possible role of other factors.

AIM: The goal of this study was to estimate the cumulative activity of (131)I to be administered to patients with distant metastases from thyroid carcinoma. METHODS: A total of 444 patients were treated from 1953-1994 for distant metastases from papillary and follicular thyroid carcinoma: 223 had lung metastases only, 115 had bone metastases only, 82 had both lung and bone metastases, and 24 had metastases at other sites. Treatment consisted of the administration of 3.7 GBq (100 mCi) (131)I after withdrawal of thyroid hormone treatment, every 3-9 months during the first 2 yr and then once a year until the disappearance of any metastatic uptake. Thyroxine treatment was given at suppressive doses between (131)I treatment courses. RESULTS: Negative imaging studies (negative total body (131)I scans and conventional radiographs) were attained in 43% of the 295 patients with (131)I uptake; more frequently in those who were younger, had well-differentiated tumors, and had a limited extent of disease. Most negative studies (96%) were obtained after the administration of 3.7-22 GBq (100-600 mCi). Almost half of negative studies were obtained more than 5 yr after the initiation of the treatment of metastases. Among patients who achieved a negative study, only 7% experienced a subsequent tumor recurrence. Overall survival at 10 yr after initiation of (131)I treatment was 92% in patients who achieved a negative study and 19% in those who did not. CONCLUSION: (131)I treatment is highly effective in younger patients with (131)I uptake and with small metastases. They should be treated until the disappearance of any uptake or until a cumulative activity of 22 GBq has been administered. In the other patients, other treatment modalities should be used when tumor progression has been documented.

International audience; The increase in the thyroid cancer incidence in France observed over the last 20 years has raised public concern about its association with the 1986 nuclear power plant accident at Chernobyl. At the request of French authorities, a first study sought to quantify the possible risk of thyroid cancer associated with the Chernobyl fallout in France. This study suffered from two limitations. The first involved the lack of knowledge of spontaneous thyroid cancer incidence rates (in the absence of exposure), which was especially necessary to take their trends into account for projections over time; the second was the failure to consider the uncertainties. The aim of this article is to enhance the initial thyroid cancer risk assessment for the period 1991-2007 in the area of France most exposed to the fallout (i.e., eastern France) and thereby mitigate these limitations. We consider the changes over time in the incidence of spontaneous thyroid cancer and conduct both uncertainty and sensitivity analyses. The number of spontaneous thyroid cancers was estimated from French cancer registries on the basis of two scenarios: one with a constant incidence, the other using the trend observed. Thyroid doses were estimated from all available data about contamination in France from Chernobyl fallout. Results from a 1995 pooled analysis published by Ron et al. were used to determine the dose-response relation. Depending on the scenario, the number of spontaneous thyroid cancer cases ranges from 894 (90% CI: 869-920) to 1,716 (90% CI: 1,691-1,741). The number of excess thyroid cancer cases predicted ranges from 5 (90% UI: 1-15) to 63 (90% UI: 12-180). All of the assumptions underlying the thyroid cancer risk assessment are discussed.

International audience; The incidence of thyroid cancer, which may be induced by ionizing radiation, has been rising in most Western countries for more than 20 years. In France, public worry about this increase and its possible connection with the fallout from Chernobyl led the government to ask for an evaluation of the health impact of this accident and an assessment of the feasibility of an epidemiological study. These requests raise two methodological questions: Which risk model should be used to relate exposure to risk? What is known about the spontaneous incidence rate of thyroid cancers? This article analyzes the impact of the time trend in the spontaneous incidence of thyroid cancers over the past 20 years in France when evaluating the risk of radiation-induced cancer. Age-period-cohort models were used to model the trend of spontaneous incidence from 1978 through 1997 and then to apply two scenarios for projections up to 2007: one with a constant incidence, the other using the trend observed over the past 20 years. Then the risk was assessed for a hypothetical population of 30,000 children aged 0 to 15 y, exposed to a hypothetical 0.1 Gy thyroid dose. The analysis shows that consideration of the trend instead of a constant spontaneous incidence can yield substantial differences in the risk estimates for thyroid cancer.

International audience; 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.

International audience; Infection of erythrocytes with the human malaria parasite, Plasmodium falciparum, results in dramatic changes to the host cell structure and morphology. The predicted functional localization of the STEVOR proteins at the erythrocyte surface suggests that they may be involved in parasite-induced modifications of the erythrocyte membrane during parasite development. To address the biologic function of STEVOR proteins, we subjected a panel of stevor transgenic parasites and wild-type clonal lines exhibiting different expression levels for stevor genes to functional assays exploring parasite-induced modifications of the erythrocyte membrane. Using this approach, we show that stevor expression impacts deformability of the erythrocyte membrane. This process may facilitate parasite sequestration in deep tissue vasculature.

International audience; The molecular mechanism responsible for the antitumor activity of histone deacetylase inhibitors (HDACi) remains elusive. As HDACi have been described to alter miRNA expression, the aim of this study was to characterize HDACi-induced miRNAs and to determine their functional importance in the induction of cell death alone or in combination with other cancer drugs. Two HDACi, trichostatin A and vorinostat, induced miR-129-5p overexpression, histone acetylation and cell death in BCPAP, TPC-1, 8505C, and CAL62 cell lines and in primary cultures of papillary thyroid cancer (PTC) cells. In addition, miR-129-5p alone was sufficient to induce cell death and knockdown experiments showed that expression of this miRNA was required for HDACi-induced cell death. Moreover, miR-129-5p accentuated the anti-proliferative effects of other cancer drugs such as etoposide or human α-lactalbumin made lethal for tumor cells (HAMLET). Taken together, our data show that miR-129-5p is involved in the antitumor activity of HDACi and highlight a miRNA-driven cell death mechanism.

International audience; Prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival, based on prognostic factors, such as serum calcitonin doubling time (Ct DT). Pretargeted radioimmunotherapy (pRAIT) is a novel targeted radionuclide therapy, using a bispecific monoclonal antibody (BsMAb) and a radiolabeled bivalent hapten, designed to improve the therapeutic index and to deliver increased tumor-absorbed doses to relatively radioresistant solid tumors. Pretargeting has demonstrated a more favorable therapeutic index and clinical efficacy than directly labeled anti-carcinoembryonic antigen (CEA) MAb in preclinical MTC models. Moreover, two phase I/II clinical trials assessing anti-CEA × anti-DTPA-indium BsMAb (murine F6x734 and chimeric hMN14x734) with (131)I-di-DTPA-indium showed encouraging therapeutic results in progressive, metastatic, MTC patients, with an improved survival in intermediate- and high-risk (pre-pRAIT Ct DT

International audience; BACKGROUND: Gap junctions are membrane structures composed of connexins (Cx) that allow diffusion of small molecules between cells. They are involved in tissue homeostasis, and various organ dysfunctions have been associated with gap junction defects. To verify their possible involvement in thyroid pathologies, the expression of connexin43 (Cx43), the major Cx in the human thyroid, was evaluated in a variety of diseases including cancer. METHODS: There were 122 samples from various thyroid pathologies that were collected to analyze the presence of Cx43 by immunofluorescence. Through confocal microscopy, different patterns of Cx43 localization were identified as normal (membrane) or abnormal (cytoplasmic or lack of detection). The analysis of Cx43 expression was further performed by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry in a subset of 25 papillary carcinomas and compared with nontumoral thyroid tissues. RESULTS: The presence of Cx43 was commonly altered in thyroid cancer, as abnormal Cx43 staining was detected in 94.1% of cancer, 47.4% of adenomas, 45.7% of multinodular goiter, 16.7% of Graves' disease, and 25% of thyroiditis. In papillary carcinoma samples, the deregulation of Cx43 expression was mostly the consequence of a decrease of Cx43 mRNA (68% of cases) when compared with normal tissue. When Cx43 mRNA was not downregulated (32% of cases), both loss of membrane staining and aberrant cytoplasmic distribution of the protein were observed. CONCLUSIONS: These results show that aberrations of Cx43 expression are associated with thyroid papillary carcinoma.

International audience; PURPOSE: This prospective study evaluated the recurrence rate in 715 patients with differentiated thyroid cancer who had no evidence of persistent disease after total thyroidectomy and lymph node dissection in 94% of them followed up by radioiodine ablation (30-100 mCi) and assessed the predictive value of the initial thyroglobulin (Tg) levels for detecting recurrence, both during levothyroxine (LT4) treatment and after TSH stimulation. PATIENTS AND METHODS: Patients had Tg determinations performed at 3 months on LT4 treatment (Tg1) and at 9-12 months after stimulation by either thyroid hormone withdrawal or recombinant human TSH (Tg2); the Access kit was used (functional sensitivity of 0.11 ng/ml); they had undetectable anti-Tg antibodies. Patients were followed up annually. Predictive values were calculated by comparing Tg levels (Tg1 and Tg2) and the outcome in terms of recurrence. RESULTS: During the median follow-up of 6.2 yr, 32 patients had a recurrence. Assuming a cutoff level for Tg1 at 0.27 ng/ml, Tg1 sensitivity and specificity reached 72 and 86%, respectively, whereas predictive positive and negative values were 20 and 99%, respectively. With a cutoff level for Tg2 at 1.4 ng/ml, sensitivity and specificity reached 78 and 90%, respectively, whereas positive and negative predictive values were 26 and 99%, respectively. CONCLUSION: This large prospective cohort of patients presented a low rate of recurrence. Initial Tg measurements allow to predict long-term recurrence with an excellent specificity. Stimulated Tg determination presented a slightly higher sensitivity than Tg determination on LT4. TSH stimulation may be avoided when Tg measured 3 months after ablation is less than 0.27 ng/ml during LT4 treatment.

International audience; 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.

International audience; High throughput genetic and genomic analyses have allowed the identification of series of genes exhibiting either distinct expression profiles or a particular mutational status in the different types or subtypes of thyroid tumors. The use of molecular data to improve the preoperative diagnosis of thyroid cancer on materiel from fine-needle aspiration biopsy (FNAB) is in the course of validation by numerous teams throughout the world. We have proposed a molecular test based on the expression level of a series of 19 genes, capable of discriminating malignant from benign tumors [15]. A prospective study aiming at the clinical validation of the molecular test has been performed on a cohort of 730 patients with a thyroid nodule. In patients subjected to tumor resection (≈ 220), the preoperative molecular diagnosis (generated on FNAB material from analyses of the expression level of the 19 genes) was compared to the postoperative diagnosis given by the pathologist (used as reference). Treatment and follow-up of the serious forms of thyroid cancer should benefit by the early identification of tumors with a metastatic potential using molecular characteristics differentiating invasive and non-invasive thyroid carcinomas. We have performed genetic and genomic analyses on a series of 200 papillary thyroid carcinomas (non-invasive or NI-PTC, 50%; invasive or I-PTC, 50%). BRAF(V600E) mutation or/and RET/PTC gene rearrangement have been detected in less than 25% of NI-PTC but in more than 75% of I-PTC. Pan-genomic analyses (Agilent microarray) revealed that 1373 genes are differentially expressed (fold change greater than 2) in NI-PTC as compared to I-PTC samples. The majority of genes (≈ 1200) are overexpressed in I-PTC. Data related to the two domains: diagnosis and prognosis of thyroid cancer will be presented at 2011 International H.P. KLOTZ conference on Clinical Endocrinology.

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.

Background The Aurora kinase family members, Aurora-A, -B and -C, are involved in the regulation of mitosis, and alterations in their expression are associated with cell malignant transformation. To date no information on the expression of these proteins in medullary thyroid carcinoma (MTC) are available. We here investigated the expression of the Aurora kinases in human MTC tissues and their potential use as therapeutic targets. Methods The expression of the Aurora kinases in 26 MTC tissues at different TNM stages was analyzed at the mRNA level by quantitative RT-PCR. We then evaluated the effects of the Aurora kinase inhibitor MK-0457 on the MTC derived TT cell line proliferation, apoptosis, soft agar colony formation, cell cycle and ploidy. Results The results showed the absence of correlation between tumor tissue levels of any Aurora kinase and tumor stage indicating the lack of prognostic value for these proteins. Treatment with MK-0457 inhibited TT cell proliferation in a time- and dose-dependent manner with IC50 = 49.8 ± 6.6 nM, as well as Aurora kinases phosphorylation of substrates relevant to the mitotic progression. Time-lapse experiments demonstrated that MK-0457-treated cells entered mitosis but were unable to complete it. Cytofluorimetric analysis confirmed that MK-0457 induced accumulation of cells with ≥ 4N DNA content without inducing apoptosis. Finally, MK-0457 prevented the capability of the TT cells to form colonies in soft agar. Conclusions We demonstrate that Aurora kinases inhibition hampered growth and tumorigenicity of TT cells, suggesting its potential therapeutic value for MTC treatment.

International audience; Exceptionally high incidence rates of thyroid cancer have been reported in New Caledonia, particularly in Melanesian women. To clarify the reasons of this elevated incidence, we conducted a countrywide population-based case-control study in the multiethnic population of Caledonian women. The study included 293 cases of thyroid cancer and 354 population controls. Based on a food frequency questionnaire, we investigated the role in thyroid cancer of food items rich in iodine-such as seafood-and of vegetables containing goitrogens-such as cruciferous vegetables. A measure of total daily iodine intake based on a food composition table was also used. Our findings provided little support for an association between thyroid cancer and consumption of fish and seafood. We found that high consumption of cruciferous vegetables was associated with thyroid cancer among women with low iodine intake (OR = 1.86; 95% CI: 1.01-3.43 for iodine intake

International audience; Medullary thyroid cancer (MTC) patients with localized residual disease and/or distant metastases may survive for several years or rapidly progress and die of their disease. Thus, highly reliable prognostic factors are needed for an early distinction between high-risk patients who need to be treated and low-risk patients who warrant a watch-and-wait approach. Calcitonin doubling time is an independent predictor of survival, with a high predictive value in a population of patients who have not normalized their calcitonin, even after repeated surgery. Several imaging methods should be proposed for patients with abnormal residual calcitonin levels persisting after complete surgery: ultrasonography and computed tomography (CT) for neck exploration, and CT for chest, abdomen, and pelvis. Magnetic resonance imaging (MRI) appears to have an advantage over CT for the detection of liver metastases from endocrine tumors. Moreover, MRI appears to be a sensitive imaging technique for detecting the spread of MTC to bone/bone marrow. 2-Fluoro-2-deoxy-D-glucose positron emission tomography/CT could be used for staging patients with progressive MTC, with possible prognostication by standard uptake value quantification. For systemic treatment of patients with rapidly progressing metastatic MTC, chemotherapy is not considered a valid therapeutic option. It is too early to evaluate the potential effectiveness of multikinase inhibitors, although interesting results of phase 2 studies have shown a transient stabilization in 30% to 50% of patients. Pretargeted radioimmunotherapy has been the only innovative treatment modality convincingly showing some survival benefit when compared with a historical untreated control group.

BACKGROUND: Significant antitumor effects were previously observed with radioimmunotherapy (RIT) using an anti-carcinoembryonic antigen (CEA) monoclonal antibody (F6) labeled with iodine-131 in medullary thyroid cancer (MTC)-bearing nude mice. Nevertheless, no complete response was achieved. Because angiogenesis is critical for tumor growth, bevacizumab is used to treat solid tumor in clinical practice. The present pilot study evaluated toxicity and efficacy of RIT combined with bevacizumab in mice subcutaneously grafted with TT MTC cells. METHODS: Groups of 4-6 nude mice were treated with 5 μg/g bevacizumab twice weekly during 4 weeks and/or 100 MBq of 131I-F6. For combined therapy, bevacizumab was given at Day 0 followed by 131I-F6 at Day 30. The control group received no treatment. Animal weight, hematological toxicity, tumor volume, and serum calcitonin were monitored for 2 or 4 months. RESULTS: Bevacizumab alone induced no cytopenia and no significant weight loss. A weight loss of 12 ± 1% and 15 ± 2% was observed in mice treated by RIT alone or bevacizumab + RIT, respectively. RIT alone and combined treatment induced leukopenia and anemia. RIT alone and RIT plus bevacizumab induced tumor responses with minimum relative tumor volume of 0.38 ± 0.24 and 0.15 ± 0.07%, respectively, and time to progression of 35 ± 5 and 56 ± 11 days, respectively. CONCLUSIONS: Pretreatment with bevacizumab improved RIT efficacy, with similar toxicity as compared as RIT alone. Cancer 2010;116(4 suppl):1053–8. © 2010 American Cancer Society.

International audience; The increasing incidence rate of thyroid cancer warrants investigation of potentially modifiable factors, especially overweightness. Few prospective studies have investigated anthropometry from childhood to adulthood in relation to thyroid cancer. We analyzed data from 91,909 women of the E3N study, a cohort of French women insured by a national health scheme mostly covering teachers with the age of 40-65 years at inclusion in 1990. Risk estimates of first primary differentiated thyroid cancer (n = 317) were computed using Cox proportional hazards models. There was a significant dose-effect relationship between thyroid cancer risk and weight or body mass index (BMI) but not height. Compared with women whose BMI was 18.5-22 kg/m(2), women with BMI 22-25 and those with BMI over 30 had a 39% [95% confidence interval (CI) 7-81] and 76% (12-176) higher risk of thyroid cancer, respectively, with a 21% (5-39) increased risk per 5 kg/m(2) increase in BMI. A large body shape from age 35-40 was significantly associated with an increased risk of differentiated thyroid cancer when compared with a lean one, while earlier body shapes were not. The highest risk was observed in women whose body shape increased from lean to large between menarche and adulthood, with a HR of 2.17 (95% CI 1.04-4.53) when compared with women who were lean at both periods. Our study adds to the existing evidence in relation to excess weight to the risk of thyroid cancer, particularly in women whose body shape increased from menarche to adult age.

French Polynesia has one of the world's highest incidence rates of thyroid cancer. A case-control study among native residents of French Polynesia included 201 women diagnosed with differentiated thyroid cancer before the age of 56 years, between 1981 and 2004, matched to 324 population controls on date of birth. Face-to-face interviews were conducted from 2002 to 2004. Odds ratios were calculated by using conditional logistic regression and were reported in the total group and by ethnic group ("Polynesian" vs. "mixed"). The risk of thyroid cancer increased with natural (odds ratio = 1.9) or artificial (odds ratio = 4.5) menopause compared with that associated with a premenopausal status and with number of births (p for trend = 0.03): odds ratios for one, two, three, four or five, six or seven, and eight or more births were, respectively, 0.90, 1.6, 2.3, 2.2, 2.7, and 1.7 compared with a nulliparous status. Similar results were observed for Polynesian women. No association was observed with irregular menstrual cycles, age at menopause, history of miscarriage or induced abortion, time since last birth, age at and outcome of first pregnancy, or breastfeeding. This study confirms the role of menstrual and reproductive factors in the risk of differentiated thyroid cancer in Pacific island populations.

International audience; Exceptionally high incidence rates of thyroid cancer are observed in New Caledonia, particularly in Melanesian women. To investigate further the etiology of thyroid cancer and to clarify the reasons of this elevated incidence, the authors conducted a countrywide population-based case-control study in this multiethnic population. The study included 332 cases with histologically verified papillary or follicular carcinoma (293 women and 39 men) diagnosed in 1993-1999 and 412 population controls (354 women and 58 men) frequency matched by gender and 5-year age group. Thyroid cancer was negatively associated with tobacco smoking and alcohol drinking, but no inverse dose-response relation was observed. Height was positively associated with thyroid cancer, particularly in men. Strong positive associations with weight and body mass index were observed in Melanesian women aged 50 years or more, with an odds ratio of 5.5 (95% confidence interval: 1.5, 20.3) for a body mass index of 35 kg/m(2) or greater compared with normal-weight women, and there was a clear dose-response trend. This study clarifies the role of overweight for thyroid cancer in postmenopausal women. Because of the high prevalence of obesity among Melanesian women of New Caledonia, this finding may explain in part the exceptionally elevated incidence of thyroid cancer in this group.

International audience; Exceptionally high incidence rates of thyroid cancer are observed in New Caledonia, particularly in Melanesian women. To investigate further the etiology of thyroid cancer and to clarify the reasons of this elevated incidence, the authors conducted a countrywide population-based case-control study in this multiethnic population. The study included 332 cases with histologically verified papillary or follicular carcinoma (293 women and 39 men) diagnosed in 1993-1999 and 412 population controls (354 women and 58 men) frequency matched by gender and 5-year age group. Thyroid cancer was negatively associated with tobacco smoking and alcohol drinking, but no inverse dose-response relation was observed. Height was positively associated with thyroid cancer, particularly in men. Strong positive associations with weight and body mass index were observed in Melanesian women aged 50 years or more, with an odds ratio of 5.5 (95% confidence interval: 1.5, 20.3) for a body mass index of 35 kg/m(2) or greater compared with normal-weight women, and there was a clear dose-response trend. This study clarifies the role of overweight for thyroid cancer in postmenopausal women. Because of the high prevalence of obesity among Melanesian women of New Caledonia, this finding may explain in part the exceptionally elevated incidence of thyroid cancer in this group.

International audience; Exceptionally high incidence rates of thyroid cancer are observed in New Caledonia, particularly in Melanesian women. To investigate further the etiology of thyroid cancer and to clarify the reasons of this elevated incidence, the authors conducted a countrywide population-based case-control study in this multiethnic population. The study included 332 cases with histologically verified papillary or follicular carcinoma (293 women and 39 men) diagnosed in 1993-1999 and 412 population controls (354 women and 58 men) frequency matched by gender and 5-year age group. Thyroid cancer was negatively associated with tobacco smoking and alcohol drinking, but no inverse dose-response relation was observed. Height was positively associated with thyroid cancer, particularly in men. Strong positive associations with weight and body mass index were observed in Melanesian women aged 50 years or more, with an odds ratio of 5.5 (95% confidence interval: 1.5, 20.3) for a body mass index of 35 kg/m(2) or greater compared with normal-weight women, and there was a clear dose-response trend. This study clarifies the role of overweight for thyroid cancer in postmenopausal women. Because of the high prevalence of obesity among Melanesian women of New Caledonia, this finding may explain in part the exceptionally elevated incidence of thyroid cancer in this group.

International audience; Germline RET mutations are responsible for different inherited disorders: Hirschsprung disease (congenital aganglionic megacolon), caused by loss of function mutations, familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2, caused by gain of function mutations. Intriguingly, some RET mutations, including C620R, are associated with both types of diseases. To investigate the dual role of such RET mutations, a mouse model with a targeted mutation ret(C620R) was generated. ret(C620R/C620R) offspring die during the first postnatal day, and show kidney agenesis and intestinal aganglionosis. Decreased outgrowth of the Ret-positive cells was observed in ret(C620R/C620R) neuronal cell cultures, which is suggestive of an impaired migration, proliferation or survival of the Ret-expressing cells. Electronmicroscopy revealed the absence of membrane-bound Ret in ret(C620R/C620R) cells as compared to ret(+/+) and ret(+/C620R) cells. On the other hand, aged ret(+/C620R) mice develop precancerous lesions in the adrenal gland or in the thyroid. Our results suggest that the ret(C620R) mutation has a loss of function effect in homozygotes and exhibits a dominant gain of function effect with low penetrance causing hyperplasia in heterozygotes.

International audience; OBJECTIVE: As in many countries, cancer registries cover only part of the population in France. Incidence/mortality ratio observed in registries is usually extrapolated to produce national estimates of cancer incidence. District-level estimates are not currently available. For cancer sites such as thyroid, the incidence/mortality ratio widely varies between districts, and alternative indicators must be explored. This study aims to produce national and district-level estimations of thyroid cancer incidence in France, using the ratio between incidence and hospital-based incidence. METHODS: Analyses concerned population living in France and aged over 20, for the period 1998-2000. For each sex, number of incident cases were analysed according to number of surgery admissions for thyroid cancer (Poisson model) in the districts covered by a registry. Age was included in the model as fixed effect and district as random effect. The model's ability to predict incidence was tested through cross-validation. The model was then extrapolated to produce national incidence estimations, and for women, district-level estimations. RESULTS: The national estimations of incidence rate age-standardised on the world population were 3.1 [95% prediction interval: 2.8-3.4] for men and 10.6 [9.8-11.4] for women, corresponding respectively to 1,148 [1,042-1,264] and 4,104 [3,817-4,413] annual new cases. For women, district-level incidence rates presented wide geographical variations, ranging broadly from 5 to 20 per 100,000. These estimations were quite imprecise, but their imprecision was smaller than the extent of geographical disparities. CONCLUSION: National incidence estimations obtained are relatively precise. District-level estimations in women are imprecise and should be treated carefully. They are informative though regarding the extent of geographical disparities. The approach can be useful to improve national incidence estimates and to produce district-level estimates for cancer sites presenting a high variability of the incidence/mortality ratio.

International audience; INTRODUCTION: Dermal mucinosis can be associated with numerous pathologies, in particular involving the thyroid, but has never been described in the case of a medullar cancer of the thyroid (MCT). CASE-REPORT: A 69-year-old man consulted for a facial erythrosis, which had been developing for a few weeks without any identified triggering factor. The skin biopsy showed dermal mucinosis and tests revealed a sporadic medullar cancer of the thyroid with secondary bone, ganglion and medullar localizations. DISCUSSION: The association between medullar cancer of the thyroid and dermal mucinosis has never been described. Several hypotheses may explain this: the thyroid pathology itself, whatever its nature, the capacity of the MCT to synthesize mucin and the medullar metastatic overgrowth.

International audience; We described the relative survival of thyroid cancer cases diagnosed in Europe during the period 1990-1994 and analysed time trends in relative survival during the period 1983-1994 using the EUROCARE-3 database. Relative survival of thyroid cancers is one of the highest amongst cancer sites, with age-standardised relative survival rates of 74% in men and 82% in women over the period 1990-1994, with marked differences between countries. The higher relative survival rates are observed in Scandinavian countries and the lower rates are observed in the UK and the countries of Eastern Europe. Relative survival is higher in women than in men, and decreases with age whatever the histological group. There are significant differences in relative survival according to histological type. Relative survival has slightly increased over the period 1983-1994 only when all histological types have been considered together. Time trend was, however, non-existent when the different histological groups were taken into account except during the most recent period of observation. One possible explanation for the differences in relative survival between countries and sex may probably be found in the changes in thyroid classification and diagnosis techniques. When these changes are not homogeneous, the distribution of thyroid cancers by histology and by stage at diagnosis may be very different. The only way to understand these differences is to conduct specific studies including a description of stage at diagnosis, diagnosis procedures used for staging and details of treatment.

Objective: Platelet-activating factor (PAF) is a pro-inflammatory and angiogenic lipid mediator involved in several types of cancer in humans. The levels of PAF, lyso-PAF (the PAF precursor), phospholipase A2activity (PLA2, the enzymatic activity implicated in lyso-PAF formation) and acetylhydrolase activity (AHA, the PAF-degrading enzyme) were investigated in various diseased thyroid tissues.Subjects: Control and diseased tissue of patients with a hyperplastic goitre (n= 14), a benign adenoma (n= 12) and a papillary thyroid carcinoma (n= 15) were investigated.Results: PAF receptor transcripts were found in the human thyroid tissue. PAF, lyso-PAF, PLA2and AHA were present in control thyroid tissues, their levels being significantly correlated with each other, suggesting tiny regulations of the PAF metabolic pathways inside the thyroid gland. PAF, lyso-PAF, PLA2and AHA levels remained unchanged in diseased tissues of patients with a hyperplastic goitre, a benign adenoma and a papillary thyroid carcinoma. No difference was found between PAF, lyso-PAF, PLA2and AHA levels with respect to the TNM tumour status and the histological sub-type of papillary thyroid carcinoma. No correlation was found between tissue PAF levels and those of vascular endothelial growth factor and basic fibroblast growth factor, two angiogenic growth factors involved in thyroid cancer and that mediate their effect through PAF release in breast and colorectal cancer.Conclusion: PAF, PAF receptor transcripts and the enzymatic activities implicated in PAF production and degradation are present in the thyroid gland. While the physiological role of PAF is presently unknown in thyroid physiology, this study highlights no evidence for a potentially important role of PAF during human thyroid cancer, a result that markedly differs from breast and colorectal ones.

International audience; Exceptionally high incidence rates of thyroid cancer have been reported for Melanesian women in New Caledonia (South Pacific). To investigate the occurrence of thyroid cancer in that country and to clarify the role of goiter and hormonal factors in that disease in women, a countrywide population-based case-control study was conducted in 1993-1999. The study included 293 cases, identified through pathology registers and whose thyroid cancer was verified histologically, and 354 population controls. Thyroid cancer was associated with goiter, age at menarche, irregular menstruation, and hysterectomy. There was a dose-response trend with number of full-term pregnancies (p = 0.01), with an odds ratio of 2.2 (95% confidence interval: 1.1, 4.3) for women with eight or more pregnancies. Miscarriage, particularly as an outcome of the first pregnancy, was also indicated as a risk factor. The association between voluntary abortion and thyroid microcarcinoma could be explained by enhanced medical surveillance and improved cancer detection in women undergoing abortion. Oral contraceptives and hormone replacement therapy were unrelated to thyroid cancer. The very high birth rate among Melanesian women in New Caledonia, as well as late age at menarche, may explain, in part, their elevated incidence of thyroid cancer.

International audience; Exceptionally high incidence rates of thyroid cancer have been reported for Melanesian women in New Caledonia (South Pacific). To investigate the occurrence of thyroid cancer in that country and to clarify the role of goiter and hormonal factors in that disease in women, a countrywide population-based case-control study was conducted in 1993-1999. The study included 293 cases, identified through pathology registers and whose thyroid cancer was verified histologically, and 354 population controls. Thyroid cancer was associated with goiter, age at menarche, irregular menstruation, and hysterectomy. There was a dose-response trend with number of full-term pregnancies (p = 0.01), with an odds ratio of 2.2 (95% confidence interval: 1.1, 4.3) for women with eight or more pregnancies. Miscarriage, particularly as an outcome of the first pregnancy, was also indicated as a risk factor. The association between voluntary abortion and thyroid microcarcinoma could be explained by enhanced medical surveillance and improved cancer detection in women undergoing abortion. Oral contraceptives and hormone replacement therapy were unrelated to thyroid cancer. The very high birth rate among Melanesian women in New Caledonia, as well as late age at menarche, may explain, in part, their elevated incidence of thyroid cancer.