Introduction: After initial treatment, differentiated thyroid cancer (DTC) patients are stratified as low and high risk based on clinical/pathological features. Recently, a risk stratification based on additional clinical data accumulated during follow-up has been proposed.Objective: To evaluate the predictive value of delayed risk stratification (DRS) obtained at the time of the first diagnostic control (8–12 months after initial treatment).Methods: We reviewed 512 patients with DTC whose risk assessment was initially defined according to the American (ATA) and European Thyroid Association (ETA) guidelines. At the time of the first control, 8–12 months after initial treatment, patients were re-stratified according to their clinical status: DRS.Results: Using DRS, about 50% of ATA/ETA intermediate/high-risk patients moved to DRS low-risk category, while about 10% of ATA/ETA low-risk patients moved to DRS high-risk category. The ability of the DRS to predict the final outcome was superior to that of ATA and ETA. Positive and negative predictive values for both ATA (39.2 and 90.6% respectively) and ETA (38.4 and 91.3% respectively) were significantly lower than that observed with the DRS (72.8 and 96.3% respectively,P<0.05). The observed variance in predicting final outcome was 25.4% for ATA, 19.1% for ETA, and 62.1% for DRS.Conclusions: Delaying the risk stratification of DTC patients at a time when the response to surgery and radioiodine ablation is evident allows to better define individual risk and to better modulate the subsequent follow-up.

Context: A substantial proportion of athyreotic levothyroxine (LT4)-treated patients experience hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type 2-deiodinase (D2)-mediated activation of LT4. The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clinical conditions. Objectives: To investigate the effects of DIO2 polymorphisms in thyroid hormone homeostasis. Design: We compared the presurgical hormonal status of thyroidectomized LT4-treated patients who had a similar thyroid-stimulating hormone (TSH) level with their postsurgery status and analyzed their DIO2 genotype in a subgroup of 102/140 (72.8%) of patients. We measured the enzymatic properties of Thr92Ala in living cells and in relevant generated mouse models. Subjects and methods: A total of 140 thyroidectomized subjects were included. Serum free T3 (FT3), free thyroxine, and TSH levels were directly measured. Immunohistochemistry and immunoblotting were performed for D2 protein. Results: The DIO2 genotyping revealed an association between low FT3 values and Thr92Ala. Specifically, the mean postsurgery FT3 levels were significantly lower in patients carrying the mutated allele(s) than in wild-type patients, in whom FT3 postsurgical levels were similar to presurgery levels. The −258 G/A variation was not associated with hormonal alteration. We found that endogenous wild-type D2 and Thr92Ala share the same subcellular localization but differ in protein stability. Importantly, Thr92Ala reduced D2-mediated thyroxine to T3 conversion. Conclusions: Thyroidectomized patients carrying Thr92Ala are at increased risk of reduced intracellular and serum T3 concentrations that are not adequately compensated for by LT4, thus providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients.

Background: In differentiated thyroid cancer (DTC) patients at intermediate risk of recurrences, no evidences are provided regarding the optimal radioactive iodine (RAI) activity to be administered for post-surgical thyroid ablation.Methods: This study aimed to evaluate the impact of RAI activities on the outcome of 225 DTC patients classified as intermediate risk, treated with low (1110–1850 MBq) or high RAI activities (≥3700 MBq).Results: Six to 18 months after ablation, remission was observed in 60.0% of patients treated with low and in 60.0% of those treated with high RAI activities, biochemical disease was found in 18.8% of patients treated with low and in 14.3% of patients treated with high RAI activities, metastatic disease was found in 21.2% of patients treated with low and in 25.7% of patients treated with high RAI activities (P=0.56). At the last follow-up (low activities, median 4.2 years; high activities, median 6.9 years), remission was observed in 76.5% of patients treated with low and in 72.1% of patients treated with high RAI activities, persistent disease was observed in 18.8% of patients treated with low and in 23.5% of patients treated with high RAI activities, recurrent disease was 2.4% in patients treated with low and 2.1% in patients treated with high RAI activities, deaths occurred in 2.4% of patients treated with low and in 2.1% of patients treated with high RAI activities (P=0.87).Conclusion: Our study provides the first evidence that in DTC patients at intermediate risk, high RAI activities at ablation have no major advantage over low activities.

Children belonging to the multiple endocrine neoplasia type 2 (MEN 2) pedigree and carrying germline RET mutations are candidates for prophylactic thyroidectomy, the timing of which is based on the mutation-associated risk and the calcitonin (CT) levels. The aim of this study was to establish the reference range for serum CT in a pediatric population. The study included 2740 subjects (1339 females and 1401 males) ranging in age from 1 day to 16 years and undergoing blood testing for any medical condition not affecting serum CT. Overall, serum CT was undetectable in 61.5% of the samples and detectable in 38.5%. Detectable samples were more frequent in the first 2 years of life. Thereafter, undetectable samples became more frequent, particularly in females. Mean serum CT concentrations were higher in the first year of life (9.81 ± 8.8 pg/mL; range, 2.0-48.9 pg/mL) and the second year of life (4.56 ± 2.64 pg/mL; range, 2.0-14.7 pg/mL). A significant decrease of serum CT levels was observed thereafter (P < .001), and starting from the third year of life serum CT levels were similar to those found in adults. No gender difference was found in any age group. Based on these results, age-specific CT reference ranges are needed in the pediatric population, and especially in the first 2 years of life. This is the first study defining the reference range for serum CT in the pediatric population and large enough to be statistically meaningful. Our proposal may facilitate the process of decision making when dealing with gene carriers of MEN 2.

Management of thyroid nodules in the era of precision medicine is continuously changing. Neck ultrasound plays a pivotal role in the diagnosis and several ultrasound stratification systems have been proposed in order to predict malignancy and help clinicians in therapeutic and follow-up decision. Ultrasound elastosonography is another powerful diagnostic technique and can be an added value to stratify the risk of malignancy of thyroid nodules. Moreover, the development of new techniques in the era of “Deep Learning,” has led to a creation of machine-learning algorithms based on ultrasound examinations that showed similar accuracy to that obtained by expert radiologists. Despite new technologies in thyroid imaging, diagnostic surgery in 50–70% of patients with indeterminate cytology is still performed. Molecular tests can increase accuracy in diagnosis when performed on “indeterminate” nodules. However, the more updated tools that can be used to this purpose in order to “rule out” (Afirma GSC) or “rule in” (Thyroseq v3) malignancy, have a main limitation: the high costs. In the last years various image-guided procedures have been proposed as alternative and less invasive approaches to surgery for symptomatic thyroid nodules. These minimally invasive techniques (laser and radio-frequency ablation, high intensity focused ultrasound and percutaneous microwave ablation) results in nodule shrinkage and improvement of local symptoms, with a lower risk of complications and minor costs compared to surgery. Finally, ultrasound-guided ablation therapy was introduced with promising results as a feasible treatment for low-risk papillary thyroid microcarcinoma or cervical lymph node metastases.