Circulating miR-26b-5p and miR-451a as diagnostic biomarkers in medullary thyroid carcinoma patients.

PURPOSE/METHODS: The determination of tumour biomarkers is paramount to advancing personalized medicine, more so in rare tumours like medullary thyroid carcinoma (MTC), whose diagnosis is still challenging. The aim of this study was to identify non-invasive circulating biomarkers in MTC. To achieve this goal, paired MTC tissue and plasma extracellular vesicle samples were collected from multiple centres and microRNA (miRNA) expression levels were evaluated. RESULTS: The samples from a discovery cohort of 23 MTC patients were analysed using miRNA arrays. Lasso logistic regression analysis resulted in the identification of a set of circulating miRNAs as diagnostic biomarkers. Among them, miR-26b-5p and miR-451a, were highly expressed and their expression decreased during follow-up in disease-free patients in the discovery cohort. Circulating miR-26b-5p and miR-451a were validated using droplet digital PCR in a second independent cohort of 12 MTC patients. CONCLUSION: This study allowed the identification and validation of a signature of two circulating miRNAs, miR-26b-5p and miR-451a, in two independent cohorts reporting a significant diagnostic performance for MTC. The results of this study offer advancements in molecular diagnosis of MTC proposing a novel non-invasive tool to use in precision medicine.

Indication for radioiodine remnant ablation in differentiated thyroid cancer patients: does 2018 Italian consensus change anything?

PURPOSE: We speculated that radioiodine remnant ablation (RRA) could be performed less frequently in differentiated thyroid cancer (DTC) patients, if the recommendations of the 2018 Italian Consensus (ITA) were applied in clinical practice. Therefore, we compared the ITA indications for RRA with the recommendations by the 2015 American Thyroid Association guidelines (ATA). METHODS: We retrospectively evaluated 380 consecutive DTC patients treated with surgery and RRA, followed at the Section of Endocrinology, University of Siena, Italy from January 2006 to December 2019. RESULTS: Using ITA a significant increase of DTC patients classified as low or high risk and a significant decrease of patients defined at intermediate risk were observed (p < 0.0001). Consequently, the percentage of patients without routinary indication for RRA (47.4%, versus 38.2%, p < 0.0001) and those with a definite indication for RRA (8.2 versus 1.8%, p < 0.0001) was significantly higher compared to ATA. Moreover, using ITA the percentage of patients with a selective use of RRA was lower in comparison to ATA (44.7% versus 60%, p < 0.0001). Nevertheless, the prevalence of distant metastases, at post-ablative whole body scan, in patients without indication for RRA, was not different using either ATA or ITA (2.1% and 1.1% respectively, p = 0.37). CONCLUSION: The use of ITA Consensus, in clinical practice, increases significantly the number of patients for whom RRA is not routinely indicated in comparison to ATA guidelines but without differences in delaying the diagnosis of distant metastatic disease.

Variants in MCT10 protein do not affect FT3 levels in athyreotic patients.

PURPOSE: Several single-nucleotide polymorphisms in genes encoding for transporters have been associated with serum thyroid hormone concentrations with inconsistent results. The aim of this study was to assess the clinical significance of the rs17606253 in SLC16A10 gene alone and in combination with the DIO2 Thr92Ala variation in athyreotic patients. METHODS: One-hundred patients submitted to total thyroidectomy and treated with levothyroxine were included. Pre- and post surgical serum TSH levels did not differ by more than ± 0.5 mIU/l. RESULTS: Both patients carrying the wild-type allele or heterozygous for rs17606253 in SLC16A10 gene had a significant reduction in FT3 post surgical levels (p = 0.01 and p < 0.0001, respectively) while Thr92Ala in DIO2 gene was associated with reduced FT3 levels for heterozygous and rare homozygous patients (p < 0.0001 and p = 0.01, respectively). We identified two groups ("FT3 unchanged" and "FT3 reduced") using a cutoff of at least 0.5 pg/ml as a significant variation between pre- and post surgical FT3 values. In this case, the rs17606253 was not statistically associated with reduced FT3 levels at genotype and allele levels. On the contrary, the Thr92Ala in DIO2 gene was confirmed statistically associated with reduced FT3 levels after surgery with a p = 0.035 at genotype level and p = 0.014 at allele level. CONCLUSIONS: We confirmed the role of DIO2 Thr92Ala polymorphism on T3 levels. On the contrary, SLC16A1 rs17606253 polymorphism did not impair hormone levels in athyreotic patients treated with levothyroxine therapy.

Should familial disease be considered as a negative prognostic factor in micropapillary thyroid carcinoma?

PURPOSE: An increased aggressiveness of familial papillary thyroid carcinoma (FPTC) compared with sporadic form has been reported. On the contrary, the biological behavior of familial microPTC (FmPTC) is still debated. To assess if familial diseases should be considered as a negative prognostic factor in mPTC, the clinical presentation and outcome of FmPTC and sporadic mPTC (SmPTC) were compared. METHODS: We retrospectively analyzed 291 mPTC (SmPTC n = 248, FmPTC n = 43) patients followed for a median follow-up of 8.3 years. FmPTC was defined as the presence of PTC in two or more first-degree relatives, after excluding hereditary syndromes associated with PTC. RESULTS: FmPTC patients had more frequently bilateral tumor (32.6% versus 16.5%, p = 0.01) and lymph node metastases at diagnosis (30.2% versus 14.9%, p = 0.02). At the first follow-up, FmPTC patients had a higher rate of structural disease and a lower rate of remission compared to SmPTC (p = 0.01). Also in a multivariate model, using a "CHAID tree-building algorithm", familial disease correlated with a worse clinical presentation and outcome of mPTC patients. Familial disease was associated with a higher rate of intermediate risk patients in non incidental mPTC and with a higher rate of structural incomplete response in mPTC without lymph node metastases (p = 0.01). CONCLUSIONS: Like in macroPTC, the familial form of the diseases has been shown to be a negative prognostic factor also in mPTC, therefore, it should be highly regarded in the management of mPTC patients.

Autoimmune thyroid diseases are more common in patients with prolactinomas: a retrospective case-control study in an Italian cohort.

BACKGROUND: Prolactin may exert immunological effects. Over the years, a higher prevalence of autoimmune thyroid diseases (ATD) has been reported in patients with prolactinomas (PRLs) in areas with sufficient iodine intake. PURPOSE: The aim of our study was to evaluate the prevalence of ATD [Graves' disease (GD) and chronic autoimmune thyroiditis (AIT)] in a retrospective cohort of Italian patients with PRLs compared to a sex-matched control group, represented by subjects with non-functioning pituitary adenoma (NFPA) or empty sella (ES). MATERIALS AND METHODS: We enrolled 149 patients (108 F/41 M) with PRLs (110 micro/39 macro) and 143 subjects (100 F/43 M) with NFPA (n = 96, 56 micro/40 macro) or ES (n = 47), with normal serum prolactin. Neck ultrasound and thyroid function tests (anti-thyroid antibodies, TSH, FT3 and FT4) were performed in all patients. RESULTS: In PRLs, median serum prolactin was significantly higher (98.3 vs. 8.9 ng/ml, p ≤ 0.0001), while age was lower (34 vs. 46 years, p ≤ 0.001) compared to controls. The prevalence of ATD was 13.4% (20/149) in PRLs (1 GD and 19 AIT) compared to 6.3% (9/143) in the controls (p = 0.042). At the multivariate analysis, serum prolactin was the only independent factor predicting ATD. Thyroid volume (12.5 ± 5.9 ml vs. 12.8 ± 10 ml, p = 0.47) and the presence of uni- or multinodular goiter (29.5% vs. 35%, p = 0.35) did not differ between PRLs and control groups. CONCLUSIONS: Our data in an area with mild iodine deficiency confirm a higher prevalence of ATD in patients with prolactinomas.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

Small papillary thyroid carcinoma with minimal extrathyroidal extension should be managed as ATA low-risk tumor.

PURPOSE: According to American Thyroid Association (ATA) guideline, papillary thyroid cancer (PTC) with minimal extrathyroidal extension (mETE) is classified at "intermediate risk" of persistent/recurrent disease. However, the impact of mETE per se on patients' outcome is not fully understood. The aim of our study was to evaluate the prognostic significance of mETE in patients with PTC not submitted to therapeutic or prophylactic lymph node dissection, according to tumor size and other prognostic factors. PATIENTS AND METHODS: We retrospectively evaluated a total of 514 PTC patients: 127 (24.7%) had mETE (pT3Nx) and 387 (75.3%) had negative margins (pT1-2Nx). At a median follow-up of 9.1 years, patients were divided in two groups: patients with "good outcome" (no evidence of disease) and patients with "poor outcome" (persistent structural disease or recurrent disease or tumor-related death). RESULTS: The rate of patients with "poor outcome" was significantly higher in patients with mETE compared with patients with negative margins (11.8 versus 5.1%; OR 2.4576, 95% CI 1.2178-4.9594, p = 0.01). However, mETE was significantly associated with poor outcome only in patients with tumors larger than 1.5 cm. CONCLUSIONS: mETE is an unfavorable prognostic factor in tumors larger than 1.5 cm, suggesting that, in the absence of other unfavorable characteristics, smaller tumors with mETE should be classified and managed as "low risk" tumors.