Subclinical hyperthyroidism appears to be a common disorder. It may be caused by exogenous or endogenous factors: excessive TSH suppressive therapy with l-thyroxine (l-T4) for benign thyroid nodular disease, differentiated thyroid cancer, or hormone over-replacement in patients with hypothyroidism are the most frequent causes. Consistent evidence indicates that ‘subclinical’ hyperthyroidism reduces the quality of life, affecting both the psycho and somatic components of well-being, and produces relevant signs and symptoms of excessive thyroid hormone action, often mimicking adrenergic overactivity. Subclinical hyperthyroidism exerts many significant effects on the cardiovascular system; it is usually associated with a higher heart rate and a higher risk of supra-ventricular arrhythmias, and with an increased left ventricular mass, often accompanied by an impaired diastolic function and sometimes by a reduced systolic performance on effort and decreased exercise tolerance. It is well known that these abnormalities usually precede the onset of a more severe cardiovascular disease, thus potentially contributing to the increased cardiovascular morbidity and mortality observed in these patients. In addition, it is becoming increasingly apparent that subclinical hyperthyroidism may accelerate the development of osteoporosis and hence increased bone vulnerability to trauma, particularly in postmenopausal women with a pre-existing predisposition. Subclinical hyperthyroidism and its related clinical manifestations are reversible and may be prevented by timely treatment.
Bernadette Biondi, Emiliano Antonio Palmieri, Michele Klain, Martin Schlumberger, Sebastiano Filetti and Gaetano Lombardi
Colette Thomas-Morvan, Pierre Carayon, Martin Schlumberger, Anne Vignal and Maurice Tubiana
TSH stimulation of adenylate cyclase (AC) and iodine uptake was compared in 39 surgical specimens of primary tumours and/or lymph node metastases from 29 human differentiated thyroid carcinomas.
TSH stimulation of AC was significantly lower (2.1 ± 0.3 fold the basal level) in patients without in vivo 131I uptake than in patients with 131I uptake (4.7 ± 0.8). A significant correlation between TSH responsiveness of AC and TSH stimulation of in vitro 125I uptake was found. There was also a relationship between 127I tissue content and AC responsiveness. Nevertheless analysis of individual data showed discrepancies in about one quarter of the cases. Thus the response of neoplastic cell membrane to TSH appears to be necessary for iodine metabolism, but it is not sufficient. Additional defects may in some cases explain the lack of either iodine uptake or organification. There is a general correlation between TSH stimulation of AC and histological type. However, data from papillary carcinomas with various degrees of uptake capacity show that TSH stimulation of AC correlates better with functional activity than with cell morphology or tissue architecture.
Stimulation by GMP P(N)P was decreased in carcinomas, while NaF stimulation was not significantly different from normal. This suggests that alterations in thyroid cancer are more related to defects in the regulatory than in the catalytic subunit of AC.
Furio Pacini, Martin Schlumberger, Henning Dralle, Rossella Elisei, Johannes W A Smit and Wilmar Wiersinga
Group-author : the European Thyroid Cancer Taskforce
Sophie Mauclère-Denost, Sophie Leboulleux, Isabelle Borget, Angelo Paci, Jacques Young, Abir Al Ghuzlan, Desiree Deandreis, Laurence Drouard, Antoine Tabarin, Philippe Chanson, Martin Schlumberger and Eric Baudin
The benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown.
To evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC.
Twenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of >14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3–4 neurological or hematological toxicities were observed in three patients (13.6%).
Employing a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.
Marina Muzza, Daniela Cordella, Johny Bombled, Brigitte Bressac-de Paillerets, Fabiana Guizzardi, Zelia Francis, Paolo Beck-Peccoz, Martin Schlumberger, Luca Persani and Laura Fugazzola
Most germline-activating mutations of the RET proto-oncogene associated with inherited medullary thyroid cancer (MTC) are localized in exons 10, 11 and 13–15. Four novel RET variants, located in the extracellular domain (p.A510V, p.E511K and p.C531R) coded by exon 8 and in the intracellular juxtamembrane region (p.K666N) coded by exon 11, were identified on the leukocyte DNA from apparently sporadic cases.
Plasmids carrying Ret9-wild-type (Ret9-WT), Ret9-C634R and all Ret9 variants were transfected, and the phosphorylation levels of RET and ERK were evaluated by western blot analyses. The transforming potentials were assessed by the focus formation assay.
The p.A510V, p.E511K and p.C531R variants were found to generate RET and ERK phosphorylation levels and to have a transforming activity higher than that of Ret9-WT variant, but lower than that of Ret9-C634R variant. Differently, the p.K666N variant, located immediately downstream of the transmembrane domain, and involving a conserved residue, displayed high kinase and transforming activities. Computational analysis predicted non-conservative alterations in the mutant proteins consistent with putative modifications of the receptor conformation.
The molecular analyses revealed an oncogenic potential for all the novel germline RET variants. Therefore, the prevalence of exon 8 genomic variations with an oncogenic potential may be higher than previously thought, and the analysis of this exon should be considered after the exclusion of mutations in the classical hotspots. In addition, on the basis of these functional data, it is advisable to extend the genetic screening to all the first-degree relatives of the MTC patients, and to perform a strict follow-up of familial carriers.
Anne Laure Giraudet, Abir Al Ghulzan, Anne Aupérin, Sophie Leboulleux, Ahmed Chehboun, Frédéric Troalen, Clarisse Dromain, Jean Lumbroso, Eric Baudin and Martin Schlumberger
The progression of medullary thyroid cancer is difficult to assess with imaging modalities; we studied the interest of calcitonin and carcinoembryonic antigen (CEA) doubling times and of Ki-67 labeling and mitotic index (MI).
Patients and methods
Fifty-five consecutive medullary thyroid carcinoma (MTC) patients with elevated calcitonin levels underwent repeated imaging studies in order to assess tumor burden and progression status. We looked for relationships between tumor burden and levels of calcitonin and CEA and between progression status according to the response evaluation criteria in solid tumors (RECIST) and calcitonin and CEA doubling times, and Ki-67 labeling and MI.
The calcitonin and CEA levels were correlated with tumor burden. Ten patients with calcitonin levels below 816 pg/ml had no imaged tumor foci. Among the 45 patients with imaged tumor foci, 19 had stable disease and 26 had progressive disease, according to the RECIST. The calcitonin and CEA doubling times were strongly related to disease progression, with very few overlaps: 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease. Ki-67 labeling and MI were not significantly associated with disease progression.
For MTC patients, the doubling times of both calcitonin and CEA are efficient tools for assessing tumor progression.
Furio Pacini, Martin Schlumberger, Clive Harmer, Gertrud G Berg, Ohad Cohen, Leonidas Duntas, François Jamar, Barbara Jarzab, Eduard Limbert, Peter Lind, Cristoph Reiners, Franco Sanchez Franco, Johannes Smit and Wilmar Wiersinga
Objective: To determine, based on published literature and expert clinical experience, current indications for the post-surgical administration of a large radioiodine activity in patients with differentiated thyroid cancer.
Design and methods: A literature review was performed and was then analyzed and discussed by a panel of experts from 13 European countries.
Results: There is general agreement that patients with unifocal microcarcinomas = 1 cm in diameter and no node or distant metastases have a <2% recurrence rate after surgery alone, and that post-surgical radioiodine confers recurrence and cause-specific survival benefits in patients, strongly suspected of having persistent disease or known to have tumor in the neck or distant sites. In other patients, there is limited evidence that after complete thyroidectomy and adequate lymph node dissection performed by an expert surgeon, post-surgical radioiodine provides clear benefit. When there is any uncertainty about the completeness of surgery, evidence suggests that radioiodine can reduce recurrences and possibly mortality.
Conclusion: This survey confirms that post-surgical radioiodine should be used selectively. The modality is definitely indicated in patients with distant metastases, incomplete tumor resection, or complete tumor resection but high risk of recurrence and mortality. Probable indications include patients with tumors >1 cm and with suboptimal surgery (less than total thyroidectomy or no lymph node dissection), with age <16 years, or with unfavorable histology.
Marie-Hélène Massicotte, Maryse Brassard, Médéric Claude-Desroches, Isabelle Borget, Françoise Bonichon, Anne-Laure Giraudet, Christine Do Cao, Cécile N Chougnet, Sophie Leboulleux, Eric Baudin, Martin Schlumberger and Christelle de la Fouchardière
Tyrosine kinase inhibitors (TKIs) are used to treat patients with advanced thyroid cancers. We retrospectively investigated the efficacy of TKIs administered outside of clinical trials in metastatic sites or locally advanced thyroid cancer patients from five French oncology centers.
Design and methods
There were 62 patients (37 men, mean age: 61 years) treated with sorafenib (62%), sunitinib (22%), and vandetanib (16%) outside of clinical trials; 22 had papillary, five had follicular, five had Hürthle cell, 13 had poorly differentiated, and 17 had medullary thyroid carcinoma (MTC). Thirty-three, 25, and four patients were treated with one, two, and three lines of TKIs respectively. Primary endpoints were objective tumor response rate and progression-free survival (PFS). Sequential treatments and tumor response according to metastatic sites were secondary endpoints.
Among the 39 sorafenib and 12 sunitinib treatments in differentiated thyroid carcinoma (DTC) patients, partial response (PR) rate was 15 and 8% respectively. In the 11 MTC patients treated with vandetanib, 36% had PR. Median PFS was similar in second-line compared with first-line sorafenib or sunitinib therapy (6.7 vs 7.0 months) in DTC patients, but there was no PR with second- and third-line treatments. Bone and pleural lesions were the most refractory sites to treatment.
This is the largest retrospective study evaluating TKI therapies outside of clinical trials. DTC patients treated with second-line therapy had stable disease as best response, but had a similar median PFS compared with the first-line treatment.
Sylvie Salenave, Valérie Bernard, Christine Do Cao, Laurence Guignat, Anne Bachelot, Sophie Leboulleux, Céline Droumaguet, Hélène Bry-Gauillard, Peggy Pierre, Lise Crinière, Pietro Santulli, Philippe Touraine, Philippe Chanson, Martin Schlumberger, Dominique Maiter, Eric Baudin and Jacques Young
Mitotane is an adrenolytic and anticortisolic drug used in adrenocortical carcinoma (ACC), Cushing's disease (CD), and ectopic ACTH syndrome. Its effects on the ovaries are unknown.
To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women.
We studied 21 premenopausal women (ACC: n=13; CD: n=8; median age 33 years, range 18–45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5–6 g/day).
Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E2), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy.
In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3–36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1–4) and the median diameter of the largest cysts was 50 mm (range: 26–90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E2 levels were also increased, and SHBG levels rose markedly.
Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed.