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.

Cell-free DNA (cfDNA) quantity and quality in plasma has been investigated as a non-invasive biomarker in cancer. Previous studies have demonstrated increased cfDNA amount and length in different types of cancer with respect to healthy controls. The present study aims to test the hypothesis that the presence of longer DNA strands circulating in plasma can be considered a biomarker for tumor presence in thyroid cancer. We adopted a quantitative real-time PCR (qPCR) approach based on the quantification of two amplicons of different length (67 and 180 bp respectively) to evaluate the integrity index 180/67. Cell-free DNA quantity and integrity were higher in patients affected by nodular thyroid diseases than in healthy controls. Importantly, cfDNA integrity index was higher in patients with cytological diagnosis of thyroid carcinoma (Thy4/Thy5) than in subjects with benign nodules (Thy2). Therefore, cfDNA integrity index 180/67 is a suitable parameter for monitoring cfDNA fragmentation in thyroid cancer patients and a promising circulating biomarker in the diagnosis of thyroid nodules.

Objective: Decreased survival and higher cardiovascular morbidity have been recently reported in a UK cohort of 61 RTHβ patients, but there is no evidence from other countries. Design: Retrospective cohort study from an historical group of 284 Italian RTHβ patients, diagnosed between 1984 and 2023. Methods: We collected data on diagnosis of 284 cases and longitudinal data of 249 RTHβ who carried heterozygous pathogenic variants in the THRB gene. We studied how thyroid function and recognized risk factors for cardiovascular disease, such as hypertension and diabetes, affected overall mortality and major cardiovascular events. Results: The cumulative prevalence of sinus/supraventricular tachycardia and atrial fibrillation was 40% and 18%, respectively. FT4 values 57% higher than the upper limit of normal were associated with premature cardiovascular manifestations. Major cardiovascular events (MACEs) occurred in RTHβ patients at a median age (IQR) of 59.4 years (50.4-66.4) and early mortality resulted in a mean of 11 years of life lost. While at univariable analysis hypertension, dyslipidemia, high fasting glucose/diabetes were also associated with MACEs, at multivariable analysis only age at diagnosis, increased fT4 levels, and male gender remained significantly associated with MACEs and age at diagnosis and higher fT4 levels with mortality. Previous thyroidectomy or radioiodine therapy had no statistically significant effect in the prevention of major cardiovascular events or all-cause mortality. Conclusions: These data should raise the general awareness on the cardiovascular risk and prompt a proactive cardiovascular monitoring in RTHβ, especially in men and those with fT4 levels above 30 pmol/L.

To compare ATA risk staging of histologically proven Papillary Thyroid Cancer (PTCs) in patients who received a pre-surgery cytologic result of either Indeterminate-Thyroid-Nodules (ITN, Bethesda III/IV) or suspicious for malignancy/malignant (TIR4/5, Bethesda V/VI). Clinical, ultrasonographic, cytological data from patients with histologically diagnosed PTC were retrospectively collected. Patients were stratified according to the pre-operative FNAC into two groups, 51 ITNs (TIR3A/3B) and 118 suspicious/malignant (TIR4/5). Male/female ratio, age, pre-surgery TSH level were similar between the two groups. At ultrasound, TIR 4/5 nodules were significantly more frequently hypoechoic (p=0.037), with irregular margins (p=0.041) and with microcalcifications (p=0.020) and were more frequently classified as high-risk according to EU-TIRADS (p=0.021). At histology, the follicular PTC subtype was significantly more prevalent among ITNs while classical PTC subtype was more frequent in TIR4/5 group (p=0.002). In TIR4/5 group a higher rate of focal vascular invasion (p<0.001) and neck lymph-node metastasis (p=0.028) was observed. Intermediate-risk category according to ATA was significantly more frequent in TIR4/5 group while low-risk category was more frequently found among ITNs (p=0.021), with a higher number of patients receiving radioiodine in TIR4/5 group (p=0.002). At multivariate logistic regression, having a TIR4/5 cytology was associated with a significant risk of having a higher ATA risk classification as compared to ITN [OR 4.6 (95% C.I. 1.523-14.007), p=0.007], independently from pre-surgery findings (nodule size at ultrasound, sex, age and EU-TIRADS score). PTCs recorded among ITNs are likely less aggressive and are generally assessed as at lower risk according to ATA classification.