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.

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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.

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Background: Diabetic hypoglycaemia affects medication adherence, patients' productivity and quality of life. It is also associated with an increased risk of cardiovascular complications. Aims: To examine the impact of hypoglycaemia in insulin-treated patients in the Lebanese cohort of the Hypoglycaemia Assessment Tool (HAT) study. Methods: The HAT study was an observational study covering a 6-month retrospective and a 4-week prospective period in 24 countries including Lebanon. Data were collected using self-assessment questionnaires and patient diaries from 1158 invited lebanese patients, aged ≥ 18 years, with type 1 or type 2 diabetes mellitus (T1DM/T2DM) treated with insulin for > 12 months. The primary endpoint was the proportion of patients experiencing ≥ 1 hypoglycaemic event during the 4-week follow-up period. Results: After 4 weeks of follow-up, 177/225 [78.7%; 95% confidence interval (CI): 72.7-83.8] of patients with T1DM and 291/630 (46.2%; 95% CI: 42.2-50.2) patients with T2D experienced at least 1 hypoglycaemic event. Rates of nocturnal and severe hypoglycaemia were 10.7 (95% CI: 9.1-12.3) and 13.2 (95% CI: 11.5-14.9) events/patient-year for T1DM, and 3.3 (95% CI: 2.8-3.8) and 4.2 events/patient-year (95% CI: 3.6-4.8) for T2DM, respectively. Fear of hypoglycaemia was significantly associated with nocturnal and severe hypoglycaemia in both diabetes types (P < 0.001). Conclusion: The results suggest that the less-advanced healthcare systems in Lebanon are implicated in lower levels of patient knowledge about hypoglycaemia and related preventive measures. Treatment strategies and glycaemia goals should be individualized according to patient preference, medical benefits, and risk of hypoglycaemia.