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M Schlumberger and S I Sherman

Patients with advanced thyroid cancer may benefit from l-thyroxine treatment at doses that suppress serum TSH level, local treatment interventions, and radioiodine therapy. In those patients who are refractory to radioiodine therapy and in whom progressive disease has been documented, the efficacy of cytotoxic chemotherapy is poor. Encouraging results have been obtained with the use of kinase inhibitors that should be offered as first-line treatment, preferably in the context of a prospective trial.

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M Schlumberger, M Ricard and F Pacini

Recombinant human TSH (rhTSH) is an effective and safe alternative to thyroid hormone withdrawal during the post-surgical follow-up of papillary and follicular thyroid cancer. Its clinical efficiency for the detection of persistent and recurrent disease is similar to that of thyroid hormone withdrawal. The main purpose for its use is to avoid hypothyroidism.

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M. Schlumberger, P. Fragu, C. Parmentier and M. Tubiana

Abstract.

The usefulness of serum thyroglobulin (Tg) assay in the follow-up of differentiated thyroid carcinomas has been evaluated in 109 subjects divided into two groups.

Group 1 included 64 patients who had undergone total thyroid ablation. In 40 of the 41 patients in complete remission serum Tg was undetectable during replacement therapy (TSH below 5 μU/ml). In 18 out of the 40 patients serum TG was detectable following endogenous TSH stimulation. As 83% of these patients had ectopic uptake prior to the last radioiodine treatment, this release of Tg under TSH stimulation suggests the persistence of occult neoplastic tissue. Of the other 23 patients, 20 had bone or lung metastases and 3 patients had lymph node recurrences: in all these patients, serum Tg was detectable during replacement therapy and increased after TSH stimulation.

Group 2 included 45 patients in whom normal residual thyroid tissue was present at the time of the investigation. Of these, 35 patients were in apparent remission and 19 of them had detectable Tg level within the normal range. The other 10 patients had detectable metastases and in 4 of these the Tg level was also within the normal range. Thus, no conclusion can be drawn from a normal Tg level in the presence of residual thyroid tissue. Bovine TSH stimulation did not improve significantly the diagnostic value of Tg assay in this group of patients.

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F Arturi, D Russo, D Giuffrida, M Schlumberger and S Filetti

OBJECTIVE: To investigate the molecular mechanisms underlying the influence of alteration of iodine trapping on the prognosis of metastatic papillary thyroid carcinomas, focusing on the expression of the Na+/I(-) symporter (NIS). DESIGN: We evaluated the expression of the NIS gene in a series of 11 enlarged neck lymph-node metastases of papillary thyroid carcinomas, including four patients in whom an enlarged lymph node represented the first sign of the tumoral disease. Nine lymph nodes, either reactive or metastatic for non-thyroid tumors, were also investigated. METHODS: Expression of the NIS gene was evaluated by RT-PCR in material obtained by fine-needle aspiration biopsy. RESULTS: The NIS gene was expressed in eight (73%) of 11 differentiated thyroid cancer metastatic lymph nodes examined. Five of these metastatic lymph nodes were positive at the post-treatment total-body iodine-131 scan; in the other three, the total-body scan showed no uptake in the metastatic tissues, indicating an alteration downstream to the NIS mRNA synthesis causing the loss of iodide uptake. As expected, when the NIS mRNA expression was absent, total-body (131)I scan showed no uptake in the metastatic lymph nodes. CONCLUSIONS: Our study demonstrates that NIS gene expression may be absent in metastatic differentiated thyroid carcinomas and that different mechanisms, other than loss of NIS transcription, may also be involved in the loss of iodide uptake in metastatic thyroid cells. Study of NIS gene expression in the metastatic lymph nodes, therefore, may provide useful information in the management of patients with thyroid carcinoma.

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I Borget, C Corone, M Nocaudie, M Allyn, S Iacobelli, M Schlumberger and G De Pouvourville

Introduction: The clinical benefits of recombinant human thyroid-stimulating hormone (rhTSH; Thyrogen) are well established as an alternative stimulation procedure to thyroid hormone withdrawal in the diagnostic follow-up of thyroid cancer patients. By avoiding periods of hypothyroidism, patients do not suffer from a decreased quality of life and keep their ability to work. This study compared the frequency, the duration and the cost of sick leave for follow-up control between rhTSH and withdrawal.

Methods: The study population consisted of patients with thyroid carcinoma first treated by thyroidectomy and radioiodine ablation. Patients were recruited at their control visit between October 2004 and May 2006 in three hospitals, both prospectively and retrospectively. Collection data consisted of patient information, job characteristics and duration of sick leave during the month before and the month after control. The valuation of sick leave used the friction cost method.

Results: Among the 306 patients included, 292 (95%) completed the entire questionnaire. The mean age was 46.7 years. Among the 194 active patients, patients treated with rhTSH, when compared with patients treated by withdrawal, were less likely to require sick leave (11 vs 33%; P=0.001). The mean duration of sick leave was shorter (3.1 vs 11.2 days; P=0.002) and indirect costs due to absenteeism accounted for €454 ± 1673 vs €1537 ± 2899 for withdrawal stimulation.

Conclusion: For active patients, rhTSH treatment reduced the length and the cost of sick leave by 8.1 days and €1083 per control respectively, when compared with withdrawal treatment.

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L Lacroix, C Mian, T Barrier, M Talbot, B Caillou, M Schlumberger and JM Bidart

OBJECTIVE: Genetic alterations involving the thyroid transcription factor PAX8 and the peroxisome proliferator-activated receptor gamma 1 (PPARgamma1) genes have been described in thyroid neoplasms. We investigated in a series of thyroid samples, including 14 normal, 13 hyperfunctioning tissues, 26 follicular adenomas, 21 follicular and 41 papillary carcinomas, both the frequency of the PAX8-PPARgamma1 rearrangement and the expression of the PAX8 and PPARgamma transcripts. METHODS: Using RT-PCR followed by sequencing PCR products, PAX8-PPARgamma1 translocation was not detected in benign tissues nor in papillary carcinomas and was detected in 4 (19%) of 21 follicular carcinomas and in one (4%) of 26 follicular adenomas. RESULTS: Specific real-time quantitative RT-PCR (Q RT-PCR) methods detected high levels of PPARgamma transcripts in follicular carcinomas presenting the rearrangement. Interestingly, the level of PPARgamma transcripts was significantly decreased in papillary carcinomas in comparison with those found in benign adenomas and follicular carcinomas. Finally, PAX8 gene expression was decreased in both papillary and follicular thyroid carcinomas, and in these tumors to the same extent in the presence or absence of the rearrangement. These alterations in both PPARgamma and PAX8 gene expression may explain the poorly differentiated histotype of follicular carcinomas harboring the translocation.Immunohistochemistry showed that nuclear PPARgamma staining was weak in normal tissues, adenomas, papillary carcinomas and in some follicular carcinomas, and strong in the follicular carcinomas positive for the PAX8-PPARgamma1 translocation, but also in some follicular tumors in which no translocation could be evidenced. CONCLUSION: These observations confirm that the PAX8-PPARgamma1 translocation characterizes a subset of thyroid follicular carcinomas but is not a specific marker of carcinoma and that its frequency is lower than that initially reported. Finally, immunohistochemistry is not a reliable method for the specific detection of the translocation, that can be specifically evidenced by Q RT-PCR.

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L Lacroix, C Mian, B Caillou, M Talbot, S Filetti, M Schlumberger and JM Bidart

OBJECTIVE: The expression of two recently identified iodide transporters, namely the sodium/iodide symporter (NIS) and pendrin, the product of the gene responsible for the Pendred syndrome (PDS), was studied in a series of various extra-thyroidal human tissues, and especially in those known to concentrate iodide. METHODS: To this end, we used real-time kinetic quantitative PCR to detect NIS and PDS transcripts and immunohistochemistry for the analysis of their protein products. RESULTS: NIS gene and protein expression was detected in most tissues known to concentrate iodine, and particularly in salivary glands and stomach. In contrast, PDS gene expression was restricted to a few tissues, such as kidney and Sertoli cells. Interestingly, in kidney, pendrin immunostaining was detected at the apical pole of epithelial cells of the thick ascending limb of the Henle's loop and of the distal convoluted tubule. CONCLUSION: This study provides new insights on the localization and expression of two genes involved in iodide transport and emphasizes the interest of combining real-time quantitative PCR and immunohistochemistry for the comparison of gene and protein expression in tissues.

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L Vayre, JC Sabourin, B Caillou, M Ducreux, M Schlumberger and JM Bidart

131Iodine concentration has been described in several extra-thyroidal tissues. Recent evidence has shown that iodine uptake is achieved by the recently cloned human Na(+)/I(-) symporter (hNIS) gene. However, conflicting results were observed in the expression of hNIS transcripts in extra-thyroidal tissues. In order to document further the distribution of hNIS, we investigated its expression using an immunohistochemical method, based on a polyclonal antibody raised against a synthetic peptide. Various extra-thyroidal tissues were examined, particularly from the digestive tract. Our results confirm that the salivary glands and the stomach express hNIS protein significantly. In contrast, hNIS was undetectable in the colon but the rectal mucosa, which has never been examined, exhibited positive immunohistochemical staining. Other digestive tissues, including the oesophagus, small intestine and appendix, were negative. Weak staining was observed in the mammary gland, indicating that hNIS is expressed in this tissue. The pancreas, skin, ovaries, spleen and kidney showed no positive immunostaining.

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F Arturi, I Presta, D Scarpelli, JM Bidart, M Schlumberger, S Filetti and D Russo

BACKGROUND: Various clinical and experimental findings support the concept that human chorionic gonadotropin (hCG) can stimulate iodide uptake in thyroid cells. DESIGN: We investigated the molecular mechanisms underlying the effects of hCG on iodide uptake, and particularly its action on the expression of Na+/I- symporter (NIS) mRNA and protein. METHODS: Iodide uptake was analyzed in FTRL-5 cells by measuring (125)I concentrations in cells after a 30-min exposure to 0.1 microCi carrier-free Na (125)I in the presence or absence of hCG or, for control purposes, TSH. Expression of NIS mRNA and NIS protein synthesis were evaluated, respectively, with a semiquantitative 'multiplex' RT-PCR method and Western blot analysis. RESULTS: Iodide uptake was increased by hCG in a dose- and time-dependent manner: maximal effects were observed after 72 h of stimulation. The effect was cAMP dependent and paralleled that of TSH, although it lacked the early cycloheximide-independent component seen with TSH, and its peak effect was lower. Semiquantitative multiplex RT-PCR revealed that hCG produced a significant increase in NIS mRNA levels that was detectable after 4 h and peaked after 48 h. In contrast, in TSH-stimulated FRTL-5 cells, maximum NIS mRNA expression was observed after 24 h of stimulation. Western blot analysis demonstrated that hCG also caused a 2.5-fold increase over basal values in NIS protein levels, which was similar to that observed after TSH stimulation although the peak effects of the latter hormone were less marked and occurred earlier. CONCLUSION: Our data demonstrated that hCG stimulates iodide uptake in FRTL-5 cells by increasing NIS mRNA and protein levels. Thus, the functional status of the thyroid may be influenced by hCG-dependent changes in NIS expression occurring during pregnancy.