A Prospective Multicenter Study Examining the Relationship Between Thyroid Cancer Treatment Outcomes and the Presence of Autoimmune Thyroiditis.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

Adult Multipotent Cardiac Progenitor-Derived Spheroids: A Reproducible Model of In Vitro Cardiomyocyte Commitment and Specification.

BACKGROUND: Three-dimensional cell culture systems hold great promise for bridging the gap between in vitro cell-based model systems and small animal models to study tissue biology and disease. Among 3D cell culture systems, stem-cell-derived spheroids have attracted significant interest as a strategy to better mimic in vivo conditions. Cardiac stem cell/progenitor (CSC)-derived spheroids (CSs) provide a relevant platform for cardiac regeneration. METHODS: We compared three different cell culture scaffold-free systems, (i) ultra-low attachment plates, (ii) hanging drops (both requiring a 2D/3D switch), and (iii) agarose micro-molds (entirely 3D), for CSC-derived CS formation and their cardiomyocyte commitment in vitro. RESULTS: The switch from a 2D to a 3D culture microenvironment per se guides cell plasticity and myogenic differentiation within CS and is necessary for robust cardiomyocyte differentiation. On the contrary, 2D monolayer CSC cultures show a significant reduced cardiomyocyte differentiation potential compared to 3D CS culture. Forced aggregation into spheroids using hanging drop improves CS myogenic differentiation when compared to ultra-low attachment plates. Performing CS formation and myogenic differentiation exclusively in 3D culture using agarose micro-molds maximizes the cardiomyocyte yield. CONCLUSIONS: A 3D culture system instructs CS myogenic differentiation, thus representing a valid model that can be used to study adult cardiac regenerative biology.

Post-Surgical Indications to Radioiodine Treatment and Potential Risk Factors for Post-Treatment Recurrence in Patients with Intermediate-Risk Differentiated Thyroid Carcinoma.

In this multicentric retrospective observational study, we investigated the potential risk factors for radioiodine (RAI) indication and the post-treatment recurrence of intermediate-risk differentiated thyroid cancer (DTC) 1 and 3 years from diagnosis. We included 121 patients who underwent thyroidectomy for intermediate-risk DTC. The 92 patients (76.0%) who underwent RAI treatment had a higher prevalence of extra-thyroid micro-extension (mETE) (p = 0.03), pT3 staging (p = 0.03) and recourse to therapeutic central (p = 0.04) and lateral (p = 0.01) neck dissection, as well as higher numbers (p = 0.02) and greater dimensions (p = 0.01) of lymph node metastases, compared with untreated patients. Relapse was observed in 18.1% and 20.7% of cases 1 and 3 years from diagnosis, respectively, with no significant differences between groups. A lower age at diagnosis (p = 0.03) and higher levels of stimulated thyroglobulin (Tg) (p = 0.04) emerged as the only independent risk factors for tumour relapse at 1 year. Tumour relapse at 3 years was only independently predicted by the presence of tumour relapse at 1 year (p = 0.04). In conclusion, mETE, pT3 and the presence of large, multiple or clinically evident lymph node metastases represent the main indicators for referring patients to RAI treatment. Early recurrence may be considered the most relevant factor when planning further surveillance.

The pattern of TSH and fT4 levels across different BMI ranges in a large cohort of euthyroid patients with obesity.

Purpose: A multifold association relates the hypothalamo-pituitary-thyroid axis to body weight. The potential underlying mechanisms are incompletely understood. Further, the mild severity of obesity and the small proportion of individuals with obesity in so far published cohort studies provide little insights on metabolic correlates of thyroid function in obesity. Methods: We retrospectively enrolled 5009 adults with obesity (F/M, 3448/1561; age range, 18-87 years; BMI range, 30.0-82.7 kg/m2), without known thyroid disease in a study on TSH and fT4 levels, lipid profile, glucose homeostasis and insulin resistance, anthropometric parameters including BIA-derived fat mass (%FM) and fat-free mass (FFM). Results: The overall reference interval for TSH in our obese cohort was 0.58-5.07 mIU/L. As subgroups, females and non-smokers showed higher TSH levels as compared to their counterparts (p<0.0001 for both), while fT4 values were comparable between groups. There was a significant upward trend for TSH levels across incremental BMI classes in females, while the opposite trend was seen for fT4 levels in males (p<0.0001 for both). Expectedly, TSH was associated with %FM and FFM (p<0,0001 for both). TSH and fT4 showed correlations with several metabolic variables, and both declined with aging (TSH, p<0.0001; fT4, p<0.01). In a subgroup undergoing leptin measurement, leptin levels were positively associated with TSH levels (p<0.01). At the multivariable regression analysis, in the group as a whole, smoking habit emerged as the main independent predictor of TSH (ß=-0.24, p<0.0001) and fT4 (ß=-0.25, p<0.0001) levels. In non-smokers, %FM (ß=0.08, p<0.0001) and age (ß=-0.05, p<0.001) were the main significant predictors of TSH levels. In the subset of nonsmokers having leptin measured, leptin emerged as the strongest predictor of TSH levels (ß=0.17, p<0.01). Conclusions: Our study provides evidence of a gender- and smoking-dependent regulation of TSH levels in obesity.

Prophylactic central neck dissection in differentiated thyroid cancer: risks and benefits in a population with a high rate of tumour recurrence.

BACKGROUND: The role of prophylactic central neck dissection (pCND) in differentiated thyroid cancer (DTC) is still controversial. METHODS: In a cohort of 274 DTC cN0 patients with a high rate of tumour recurrence, who underwent total thyroidectomy with or without pCND, clinical and histopathological features were retrospectively analysed. RESULTS: In our cohort, no clinical or histopathological features are able to predict the presence of central lymph node metastases (CLNM) at diagnosis, which instead represents the only variable significantly associated with a higher risk of long-term tumour relapse, independently from age, sex, BMI and radioiodine treatment (OR=1.03, CI95% 1.002-1.074, p<0.05). Moreover, our study demonstrates that pCND does not significantly increase the risk of post-surgical complications. CONCLUSIONS: In our setting, pCND could have a key role in the management of DTC. The risks and benefits of pCND should be evaluated for each population to make the most appropriate therapeutic choice.

Endocrine disrupting chemicals: effects on pituitary, thyroid and adrenal glands.

BACKGROUND: In recent years, scientific research has increasingly focused on Endocrine Disrupting Chemicals (EDCs) and demonstrated their relevant role in the functional impairment of endocrine glands. This induced regulatory authorities to ban some of these compounds and to carefully investigate others in order to prevent EDCs-related conditions. As a result, we witnessed a growing awareness and interest on this topic. AIMS: This paper aims to summarize current evidence regarding the detrimental effects of EDCs on pivotal endocrine glands like pituitary, thyroid and adrenal ones. Particularly, we directed our attention on the known and the hypothesized mechanisms of endocrine dysfunction brought by EDCs. We also gave a glimpse on recent findings from pioneering studies that could in the future shed a light on the pathophysiology of well-known, but poorly understood, endocrine diseases like hormone-producing adenomas. CONCLUSIONS: Although intriguing, studies on endocrine dysfunctions brought by EDCs are challenging, in particular when investigating long-term effects of EDCs on humans. However, undoubtedly, it represents a new intriguing field of science research.

Unraveling and Targeting Myocardial Regeneration Deficit in Diabetes.

Cardiomyopathy is a common complication in diabetic patients. Ventricular dysfunction without coronary atherosclerosis and hypertension is driven by hyperglycemia, hyperinsulinemia and impaired insulin signaling. Cardiomyocyte death, hypertrophy, fibrosis, and cell signaling defects underlie cardiomyopathy. Notably, detrimental effects of the diabetic milieu are not limited to cardiomyocytes and vascular cells. The diabetic heart acquires a senescent phenotype and also suffers from altered cellular homeostasis and the insufficient replacement of dying cells. Chronic inflammation, oxidative stress, and metabolic dysregulation damage the population of endogenous cardiac stem cells, which contribute to myocardial cell turnover and repair after injury. Therefore, deficient myocardial repair and the progressive senescence and dysfunction of stem cells in the diabetic heart can represent potential therapeutic targets. While our knowledge of the effects of diabetes on stem cells is growing, several strategies to preserve, activate or restore cardiac stem cell compartments await to be tested in diabetic cardiomyopathy.

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4).

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p = 0.65), tumor size >2 cm (OR 1.45, p = 0.34), aggressive PTC histology (OR 0.55, p = 0.15), and age at diagnosis (OR 0.90, p = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients (p = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Predictor Analysis in Radiofrequency Ablation of Benign Thyroid Nodules: A Single Center Experience.

Purpose: To confirm the efficacy of ultrasound (US) guided radiofrequency ablation (RFA) in the treatment of benign thyroid nodules, we evaluated as primary outcome the technical efficacy and clinical success in a single center dataset. The secondary outcome was to find a correlation between nodules' pre-treatment features and volume reduction rate (VRR) ≥75% at 12 months after RFA and during follow-up period. Methods: This retrospective study included 119 consecutive patients (99 females, 20 males, 51.5 ± 14.4 years) with benign thyroid nodules treated in our hospital between October 2014 and December 2018 with a mean follow-up of 26.8 months (range 3-48). Clinical and US features before and after RFA were evaluated by a US examination at 1, 3, 6, 12 months and annually thereafter up to 48 months. Results: The median pre-treatment volume was 22.4 ml; after RFA we observed a statistically significant volume reduction from the first month (11.7 ml) to the last follow-up (p < 0.001 for all follow-up times). The median VRR was 47.1, 55.3, 61.2, 67.6, 72.8, 71.3, and 62.9% at 1, 3, 6, 12, 24, 36, and 48 months of follow-up respectively, showing a progressive significant improvement up to 24 months (VRRs 1 vs 3 months, 3 vs 6 months and 6 vs 12 months p < 0.001, 12 vs 24 months p = 0.05) while no differences at 24 vs 36 and 36 vs 48 months were observed. Symptoms improved significantly (complete resolution 64.35%, partial resolution 35.65%), and neck circumference was reduced as compared to pre-treatment (p < 0.001). Lower pre-treatment neck circumference (37.5 vs 36.0 cm, p = 0.01) was a positive predictor of VRR ≥75% at 12 months. Macrocystic echostructure (HR 2.48, p 0.046) and pre-treatment volume >22.4 ml (HR 0.54, p 0.036) were found to be independent positive and negative predictors of VRR ≥75% respectively. One-month post RFA VRR ≥50% represented the best positive predictor of technical success. Conclusions: This study confirmed the efficacy of RFA in the treatment of benign thyroid nodules. In particular we show that by selecting macrocystic nodules smaller than 22.4 ml better long-term response can be achieved, which is predicted by an early shrinkage of the nodule.

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.

Predictive factors of a worse response to radioactive Iodine-I131 treatment in hyperthyroidism: outcome analysis in 424 patients. A single centre experience.

PURPOSE: Aim of our study was to search for variables associated with worse outcomes in patients treated with radioactive iodine (RAI) for hyperthyroidism by a dosimetric-based approach. METHODS: Four hundred twenty-four patients with hyperthyroidism related to Toxic Multinodular Goiter (TMG; n = 213), Grave's disease (GD; n = 150) and toxic adenoma (TA; n = 61) treated with RAI between 2000 and 2018 and with at least 12 months follow-up were retrospectively evaluated. Association between outcomes (response vs. no response) at 6 and 12 months and baseline TSH values, anti-thyroid drugs (ATD) duration and posology, RAI absorbed dose and dimensional reduction of target mass at ultrasound was evaluated by Mann-Whitney test. Risk factors for response vs. no-response were analysed by binary logistic regression model. RESULTS: Overall response rate was 78.7 and 83% at 6 and 12 months, respectively. Both at 6 and 12 months higher TSH baseline values (p < 0.001), lower ATD duration (p = 0.004 and p = 0.043), lower ATD posology (p = 0.014 and p = 0.005), and lower dose to target (DT) (327 vs. 373 Gy, p = 0.003) were associated to response. Longer ATD duration and higher ATD posology were independent risk factors for no response at 6 and 12 months in GD and TMG, with no response at 6 months in TA subgroups. CONCLUSIONS: Low TSH levels, longer duration and higher posology of ATD were associated with worse response to RAI. These data confirm that RAI therapy should be considered earlier in patients' management to allow better outcome and avoid ATD toxicity.

A Simplified Ultrasonographic Score for the Prediction of Cytologically Suspicious Thyroid Nodules.

PURPOSE: The major aim of ultrasound (US)-based risk stratification systems is to reduce unnecessary thyroid biopsies without losing the ability to recognize nodules with clinically significant malignancy. Each of the classic suspicious features of a thyroid nodule detected on US scan (hypoechoic pattern, microcalcifications, irregular margin, taller than wide shape, irregular vascularization) is significantly independently associated with the probability of malignancy, but none of them has good diagnostic accuracy. Thus, we evaluated the predictive value of a binary score simply based on the combination of these US features, regardless of the specific predictive value of each US feature, against the outcome of suspected malignancy at cytological diagnosis (TIR3 to TIR5 categories by SIAPEC-IAP [TIR+]). MATERIALS AND METHODS: 1009 thyroid nodules from 1081 patients were considered. The US features of suspicion of all nodules were categorized in 5 binary scores (U1 to U5), each including from 1 to 5 of those features. RESULTS: U2 (at least 2 US suspicious features) was the most balanced predictor of TIR+ (PPV 0.48, NPV 0.93, LR+ 3.05 and LR- 0.24). Weighting the predictivity of the single features did not improve the estimate. Using U2 as the criterion to send nodules to FNAC would have reduced the number of biopsies by 60 % (604 patients) and the false negatives would have only accounted for 41 cases out of 237 TIR+ (17 %) with 39 cases of TIR3 and 2 cases of TIR4, including only 6 malignant nodules on histological examination. U2 performed much better than the ATA recommendations for detecting those nodules, resulting in TIR+ at cytology. CONCLUSION: This simple and reproducible sonographic score based on 2 US features of suspicion of malignancy has quite a good performance with respect to identifying thyroid lesions categorized by cytology as medium-high risk of malignancy and could allow us to reduce cytology costs for low-risk nodules.

Retrospective analysis of the ultrasound features of resected thyroid nodules.

PURPOSE: Several ultrasound (US) risk stratification systems (US-RSSs) have been proposed to stratify the risk of malignancy (ROM) of thyroid nodules. This risk might be overestimated due to selection bias and comparison with the cytological report alone. Our study aimed to compare ROM and diagnostic performance of three guidelines (ATA, AACE/ACE/AME, EUTIRADS) and evaluate the changes in unnecessary biopsy according to the nodule size cutoff for biopsy, using histology as gold standard. METHODS: This retrospective observational study included 146 consecutive patients who underwent surgery after US and cytological characterization. We analyzed the effectiveness and accuracy of three US-RSSs. RESULTS: 46.6% of nodules were diagnosed as malignant. Applying US-RSS, the percentage of nodules that should have been analyzed by biopsy was 84.25% with ATA, 69.86% with EUTIRADS and 64.38% with AACE/ACE/AME systems. The ROM was 94.9%, 86.0%, 87.0% for high-risk category, 36.4%, 32.0%, 35.4% for intermediate-risk category and 22.9%, 0.0%, 22.9% for low-risk category by ATA, AACE/ACE/AME and EUTIRADS systems, respectively. EUTIRADS and AACE/ACE/AME systems were more accurate in differentiating malignant from benign cases. ATA score was the more sensitive US-RSS to identify malignant tumors within the high-risk category. About the unnecessary biopsies, in the intermediate-risk category, the application of the size criterion helps to increase specificity in all systems. CONCLUSIONS: The US categorization of low and high-risk thyroid nodules using current US-RSSs helps alone to determine the optimal treatment option. Nodule size remains relevant to recommend biopsy for the intermediate-risk category.

Molecular characterisation and clinical correlation of papillary thyroid microcarcinoma.

PURPOSE: Papillary thyroid microcarcinoma (mPTC) is defined as a papillary thyroid cancer sized 10 mm or less. Despite their generally indolent clinical course and good prognosis, a subset of mPTCs shows potentially aggressive behaviour. METHODS: To search for predictors of clinical outcome of mPTCs, we retrospectively evaluated the genetic tumour profile of 100 patients (23 M/77 F, mean age ± SD 53.8 ± 13.4 years) with histologically confirmed mPTCs through analysis of BRAF, NRAS and TERT promoter mutations as well as RET/PTC translocations. RESULTS: Mean follow-up period was 8.4 ± 3.6 years. In 55 cases, mPTC were detected incidentally after surgery. Capsular invasion, bilateralism and multifocality were found in 11/100, 17/100 and 24/100 cases, respectively, while lymph-nodes metastases were present at diagnosis in 9/100 cases. After 3.5 ± 2.0 years, tumour relapse occurred in 6/100 cases and was locoregional in five (two in the thyroid bed, three in laterocervical lymph-nodes), while lung metastasis occurred in one case. Biochemical persistence of disease was seen in 1/100 case. Mutations occurred in 55/100 cases; BRAFV600E was the most frequently detected (49/100) and was associated with higher tumour size, bilateralism and follicular variant but not with capsular invasion. RET/PTC rearrangements were found in 2/100 cases, NRASQ61R in 4/100, while no mutations of TERT promoter gene were detected. Despite the observed association between BRAFV600E mutation and unfavourable histopathological features, we found no direct association with tumour recurrence, distant metastases and mortality. CONCLUSION: In our study, the search for the most frequent genetic alterations as prognostic markers in mPTCs would not have changed the therapeutic strategy.

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the MEN1 tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on MEN1 gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at c.836C>A in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.

The role of metabolic setting in predicting the risk of early tumour relapse of differentiated thyroid cancer (DTC).

BACKGROUND: The role of insulin resistance and adipocytokines in determining the phenotype and recurrence of differentiated thyroid cancer (DTC) is still unknown. In a previous study, we observed an association between metabolic setting, circulating adipocytokines and thyroid cancer phenotype. The aim of this study was to evaluate the clinical follow-up of patients with DTC and the predictive role of metabolic setting on the risk of tumour relapse. METHODS: Between September 2016 and January 2017, 57 patients were admitted to our institution to undergo total thyroidectomy because of suspected DTC. Thirty patients with post-surgical histological diagnosis of DTC were included in the study. Each subject underwent pre-surgical analysis of anthropometric parameters, thyroid function and autoimmunity, glucose metabolism, insulin resistance (HOMA-IR) and levels of unacylated and acylated ghrelin, obestatin, leptin and adiponectin. Tumour recurrence at 1 and 3 years from diagnosis was assessed. RESULTS: Most patients were females (21F, 9M) with a median age at diagnosis of 50.0 (41.0-58.8). At baseline, overweight was found in 7 patients and obesity in 6 cases. Insulin resistance was detected in 14 patients. Overall, 17 patients (56.7%) underwent radioiodine treatment after surgery. During the follow-up, we observed a persistent biochemical disease in one patient whereas tumour relapse was found in six patients at 1 year from diagnosis (lymph node metastases) and in one patient at 3 years from diagnosis (lung metastases). Independently from age, sex, stage of disease and the presence of lymph node metastasis at diagnosis, higher BMI, leptin and insulin levels as well as HOMA-IR were associated with a higher risk of tumour relapse (p < 0.05 for all). CONCLUSIONS: Our results highlight a possible role for BMI, leptin and insulin resistance as predictors of early DTC relapse.

Immunomodulatory Effects of Vitamin D in Thyroid Diseases.

Vitamin D is a secosteroid with a pleiotropic role in multiple physiological processes. Besides the well-known activity on bone homeostasis, recent studies suggested a peculiar role of vitamin D in different non-skeletal pathways, including a key role in the modulation of immune responses. Recent evidences demonstrated that vitamin D acts on innate and adaptative immunity and seems to exert an immunomodulating action on autoimmune diseases and cancers. Several studies demonstrated a relationship between vitamin D deficiency, autoimmune thyroid disorders, and thyroid cancer. This review aims to summarize the evidences on the immunomodulatory effect of vitamin D on thyroid diseases.