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Context: 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., Methods: 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., Results: 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., Conclusions: 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.

During the last two decades, the understanding of molecular biology of thyroid cancers has greatly improved, and this has permitted the development of novel therapeutic tools in patients with refractory disease. Kinase inhibitors inhibit kinases of the vascular endothelial growth factor (VEGF) receptors, and by doing this inhibit angiogenesis, and some of these agents also inhibit other kinases of the MAPkinase pathway. These inhibitors are effective in differentiated and medullary thyroid cancers, and induce a partial response or a long term stabilisation in more than half of patients.

Purpose: The aim of this prospective study was to analyze the safety of methylene blue dye (MBD) and compare its efficacy with that of isotopic mapping for sentinel lymph node (SLN) identification in breast cancer., Patients and Methods: The SLN procedure, involving isotopic mapping and MBD (subareolar intraparenchymal injections of 2 mL, 10 mg/mL), was performed on 100 patients with early breast cancer., Results: The procedure was safe with a success rate of 99%; SLNs were, respectively, found in 65% by MBD, in 73% by lymphoscintigraphy and in 94% by gamma-probe. Out of 40 metastatic SLNs, 37 were "hot" and 32 stained. Digital examination allowed the detection of 2 additional metastatic LNs., Conclusion: MBD is safe and combination mapping associated with digital examination is the superior method. Modification of the procedure, favouring injections of dilute MBD (4 mL, 1.25 mg/mL) increases MBD efficiency (90%) and maintains low rates of complications.

An elevated serum calcitonin level is a highly sensitive marker for medullary thyroid carcinoma (MTC) that can be used for screening, differential diagnosis, prognostic assessment, follow-up monitoring, and assessment of treatment response. Nevertheless, additional data are required to definitively support routine measurement of calcitonin levels in the initial work-up of patients with thyroid nodules, mainly because there is no convincing evidence that such testing actually reduces MTC-related mortality. By contrast, the prognostic value of measuring calcitonin levels preoperatively, postoperatively, and during follow-up of patients with MTC is widely acknowledged. Furthermore, determination of calcitonin levels is also used to evaluate the response of MTC to novel forms of systemic treatment, such as tyrosine kinase inhibitors. In this Review, we discuss the key issues surrounding the use of this laboratory test in the clinical management of patients with MTC.

Serum thyroglobulin determination plays a central role, in combination with neck ultrasonography, in the follow-up of thyroid cancer patients. Its specificity is improved by thyroid remnant ablation, and its sensitivity is optimal following prolonged withdrawal or stimulation with recombinant human thyroid-stimulating hormone (TSH). Modern methods with an improved functional sensitivity may facilitate its use during follow-up.