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ContextThe risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features.ObjectiveTo develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors.MethodsIn a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction.ResultsBy ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis.ConclusionCurrent risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

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PURPOSE OF REVIEW The prevalence of thyroid nodules in the general population is high but only about 5% are malignant lesions. Cytology is usually appropriate to rule out malignancy in sonographically suspicious nodules but in many cases, reports are indeterminate. Molecular testing is a more recent approach to rule out malignancy and guide subsequent management. RECENT FINDINGS Although several different molecular testing approaches have proven useful in reducing unnecessary surgery, there are still several remaining issues, such as the possible occurrence of RAS mutations (which are difficult to interpret in clinical management) and the role of molecular analysis in specific histotypes, such as Hurthle cell carcinomas. Furthermore, conclusive evidence is lacking regarding the cost-effectiveness and appropriateness of surgical options following molecular tests. SUMMARY To be useful in clinical practice, molecular tests should be applied to appropriate candidates. In truly uncertain thyroid nodules in which diagnostic surgery may be considered, molecular testing may change the clinical approach and 'save' a number of thyroids.

The new discipline of Network Medicine stems from the growing realization that conventional scientific reductionism is inadequate for dissecting complex diseases, increasing efficacy of prevention strategies, or tailoring precise therapies. In addition, Network Medicine acknowledges that health and disease must be viewed in the context of the interplay among multiple molecular and environmental determinants that must be fully considered in precision diagnostics and therapeutics. Network Medicine, therefore, aims to use innovative technology, information, and big data to create an integrated set of principles and discoveries that can fully capture these inherent dependencies, are relevant and translatable to the clinic, and, consequently, are truly innovative in their implementation. The principles and discoveries aim to influence prevention, diagnosis, and treatment beneficially.

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aim of this study was 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 (ITCO) 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% CI, 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 non-treated 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.

Network Medicine is now an established scientific discipline, having generated key insights on integrated mechanisms underlying complex human diseases. The next discovery phase will emphasize innovating analytics that optimize networks for advancing precision medicine. Accomplishing this goal will require organizing a scientifically diverse team studying big datasets shared globally.

Introduction: A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio >1. An intraobserver variability of up to 18% in AP diameter evaluations has been described, which may lead to overreporting of this feature. To potentially improve the reliability of the TTW definition, we propose an arbitrary ratio of ≥1.2. Objective: The aim of this study was to estimate the impact of this definition on diagnostic performance. Methods: We prospectively analyzed 553 thyroid nodules referred for cytology evaluation at an academic center. Before fine-needle aspiration, two examiners jointly defined all sonographic features considered in risk stratification systems developed by the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), the American College of Radiology (ACR TIRADS), the European Thyroid Association (EU-TIRADS), and the Korean Society of Thyroid Radiology (K-TIRADS). TTW was defined according to the current definition (AP/T diameter ratio >1) and an arbitrary alternative definition (AP/T ratio >1.2). Results: The alternative definition classified fewer nodules as TTW (28, 5.1% vs. 94, 17%). The current and proposed definitions have a sensitivity of 26.2 and 11.9% (p = 0.03) and a specificity of 83.8 and 95.5% (p < 0.001). Thus, as a single feature, the arbitrary definition has a lower sensitivity and a higher specificity. When applied to sonographic risk stratification systems, however, the proposed definition would increase the number of avoided biopsies (up to 58.2% for ACR TIRADS) and the specificity of all systems, without negative impact on sensitivity or diagnostic odds ratio. Conclusions: Re-defining TTW nodules as those with an AP/T ratio ≥1.2 improves this marker’s specificity for malignancy. Using this definition in risk stratification systems will increase their specificity, reducing the number of suggested biopsies without significantly diminishing their overall diagnostic performance.

Context Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck. Objective To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy. Design Retrospective analysis of prospectively recorded data. Setting Academic center. Patients Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable ( Interventions Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes. Main Outcome Measures Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits. Results In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment. Conclusions Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels

The aim of the study was to describe the spontaneous TSH level variations and levothyroxine dose adjustments in athyreotic patients with differentiated thyroid cancer (DTC) in real-life practice. Patients with DTC were retrospectively evaluated at a tertiary referral center between October 2006 and November 2013. Hormone measurements (TSH and FT4 serum levels), L-T4 prescription information (dose per kg per day) and other medications were recorded at 1 month and 3, 12, 24, 36 and 48 months after primary treatment (surgery ± radioiodine therapy). The cohort was composed of 452 patients; about 20% of patients with stable levothyroxine dose have clinically meaningful spontaneous TSH variations (defined as ΔTSH > 2 mcUI/mL) at yearly follow-up visit. Furthermore, about 25% of athyreotic DTC patients with stable dose have a ΔTSH > 1.5 mcUI/mL and about 40% a ΔTSH > 1 mcUI/mL during each follow-up visit. We further investigated whether this TSH variation would lead to subsequent dose changes. About 19.9–37.7% of DTC patients on stable LT4 dose on the previous visit had their levothyroxine dose reduced, while 7.8–14.9% increased due to TSH variations. We further evaluated the decision to change the dose in relation with the age-specific TSH range. Up to 77.2% of patients had their dose adjusted due to TSH falling below the age-specific range. Spontaneous serum TSH variations determine levothyroxine replacement therapy in athyreotic patients with DTC, requiring multiple dose changes.

Hu antigen R (HuR) is indeed one of the most studied RNA-binding protein (RBP) since its fundamental role both in tumorigenesis and cancer progression. For this reason, downregulation in HuR protein levels or inhibition of HuR biological function are, nowadays, attractive goals in cancer research. Here, we examined the antitumor effects of CMLD-2 in four thyroid cancer cell lines (SW1736, 8505 C, BCPAP and K1). Indeed, CMLD-2 competitively binds HuR protein disrupting its interaction with RNA-targets. 35 μM CLMD-2 produced a significant downregulation in thyroid cancer cell viability, coupled to an increase in apoptosis. Moreover, CMLD-2 treatment hindered both migration and colony formation ability. MAD2 is a microtubules-associated protein known to be greatly overexpressed in cancer and correlating with tumor aggressiveness. Furthermore, MAD2 is known to be a HuR target. CMLD-2 treatment induced a strong MAD2 downregulation and rescue experiments depicted it as a key effector in HuR-mediated in cancer. Altogether, these data contributed to foster HuR inhibition as valid antineoplastic treatment in thyroid cancer, highlighting MAD2 as a novel therapeutic target.

Purpose: Several studies have shown that different tumour types sharing a driver gene mutation do not respond uniformly to the same targeted agent. Our aim was to use an unbiased network-based approach to investigate this fundamental issue using BRAF mutant tumours and the BRAF inhibitor vemurafenib. Methods: We applied SWIM, a software able to identify putative regulatory (switch) genes involved in drastic changes to the cell phenotype, to gene expression profiles of different BRAF mutant cancers and their normal counterparts in order to identify the switch genes that could potentially explain the heterogeneity of these tumours' responses to vemurafenib. Results: We identified lung adenocarcinoma as the tumour with the highest number of switch genes (298) compared to its normal counterpart. By looking for switch genes encoding for kinases with homology sequences similar to known vemurafenib targets, we found that thyroid cancer and lung adenocarcinoma have a similar number of putative targetable switch gene kinases (5 and 6, respectively) whereas colorectal cancer has just one. Conclusions: We are persuaded that our network analysis may aid in the comprehension of molecular mechanisms underlying the different responses to vemurafenib in BRAF mutant tumours.

Follicular thyroid cancer (FTC) is the second most common histologic subtype of differentiated thyroid cancer behind papillary thyroid cancer (PTC). The rate of FTC diagnosis is declining over time due to changes in the diagnostic criteria and to environmental factors such as iodine sufficiency. The diagnosis is challenging because FTCs are distinguished from follicular thyroid adenomas (FTAs) solely by the presence of capsular and/or vascular invasion, neither of which can be assessed in cytology specimens. FTC spreads through blood vessels, and lymph node metastases are rarer (

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.

Despite impressive efforts invested in epigenetic research in the last 50 years, clinical applications are still lacking. Only a few university hospital centers currently use epigenetic biomarkers at the bedside. Moreover, the overall concept of precision medicine is not widely recognized in routine medical practice and the reductionist approach remains predominant in treating patients affected by major diseases such as cancer and cardiovascular diseases. By its’ very nature, epigenetics is integrative of genetic networks. The study of epigenetic biomarkers has led to the identification of numerous drugs with an increasingly significant role in clinical therapy especially of cancer patients. Here, we provide an overview of clinical epigenetics within the context of network analysis. We illustrate achievements to date and discuss how we can move from traditional medicine into the era of network medicine (NM), where pathway-informed molecular diagnostics will allow treatment selection following the paradigm of precision medicine.

Ultrasonography (US) is the most accurate tool for exploring cervical lymph nodes for persistent/recurrent lesions in patients with papillary thyroid cancers (PTCs). Certain features are highly informative (the sole presence of punctuate hyperechogenicity or a cystic appearance, which predicts PTC involvement with an accuracy of 100 %; visualization of the lymph node “fatty” hilum, which virtually excludes malignancy). Other findings, such as nonvisualization of the hilum or a round rather than oval shape, are considered diagnostically indeterminate because of their limited specificity. The suspicious node’s location, the patient’s estimated risk of recurrence, and serum Tg levels are important considerations as well. Confirmation of metastatic involvement is usually based on cytological assessment of a fine-needle aspirate, but even in experienced hands, cytology can yield false-negative results (6–8 % of cases), and up to 10 % of aspirates are inadequate for diagnosis. The diagnostic yield can be enhanced by immunometric assay of Tg levels and/or PCR-based assay of transcript levels for thyroid-specific genes (Tg, TSHR) in washout fluid from the needle used to collect the cytology aspirate. The former can accurately identify PTC lymph node metastases (sensitivity, 88–100 %; specificity, 69–100 %), even in the presence of circulating Tg antibodies. Thanks to the use of PCR amplification, the genetic approach can correctly identify metastases from PTCs, even when the washout fluid contains only a few cells, and its accuracy vs. histology is 100 %.

Radioactive iodine (RAI) remnant ablation (RRA) is not routinely performed after thyroidectomy for patients with low-to-intermediate American Thyroid Association (ATA) risk for recurrent papillary thyroid cancer (PTC). The specificity of serum thyroglobulin (Tg) assay positivity as a marker of persistent/recurrent disease may be lost in these cases since there is no way to distinguish Tg production by neoplastic tissue from that synthesized by the normal thyroid remnant. However, temporal trends in serum Tg levels can still be informative in these cases. In most cases, remnant Tg production drops below 0.2 ng/mL during the first year of follow-up after total thyroidectomy. In a small subset of patients, however, the decline plateaus above this cutoff level. If Tg levels remain stable and neck ultrasound (US) findings are negative during the follow-up, watchful waiting by performing periodic neck US examinations and Tg assays may be an appropriate approach.

Context Current guidelines recommend a selective use of radioiodine treatment (RAI) for papillary thyroid cancer (PTC). Objective This work aimed to determine how policy changes affect the use of RAI and the short-term outcomes of patients. Methods A retrospective analysis of longitudinal data was conducted in an academic referral center of patients with nonaggressive PTC variants; no extrathyroidal invasion or limited to soft tissues, no distant metastases, and 5 or fewer central-compartment cervical lymph node metastases. In cohort 1, standard treatments were total thyroidectomy and RAI (May 2005-June 2011); in cohort 2 decisions on RAI were deferred for approximately 12 months after surgery (July 2011-December 2018). Propensity score matching was used to adjust for sex, age, tumor size, lymph node status, and extrathyroidal extension. Intervention included immediate RAI or deferred choice. Main outcome measures were responses to initial treatment during 3 or more years of follow-up. Results In cohort 1, RAI was performed in 50 of 116 patients (51.7%), whereas in cohort 2, it was far less frequent: immediately in 10 of 156 (6.4%), and in 3 more patients after the first follow-up data. The frequencies of structural incomplete response were low (1%-3%), and there were no differences between the 2 cohorts at any follow-up visit. Cohort 2 patients had higher rates of “gray-zone responses” (biochemical incomplete or indeterminate response). Conclusion Selective use of RAI increases the rate of patients with “uncertain” status during early follow-up. The rate of structural incomplete responses remains low regardless of whether RAI is used immediately. Patients should be made aware of the advantages and drawbacks of omitting RAI.

Ultrasonographic risk-stratification systems (RSS), including various Thyroid Imaging Reporting and Data Systems (TIRADS), were proposed to improve reporting and reduce the number of fine-needle aspiration biopsies. However, age might be a confounder since some suspicious ultrasonographic features lack specificity in elderly patients. We aimed to investigate whether the diagnostic performance of the RSS varied between age groups. All patients consecutively referred for thyroid biopsy between November 1, 2015, and March 10, 2020, were included. The malignancy risk of each nodule was estimated according to five RSS: the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi guidelines, the American College of Radiology (ACR) TIRADS, the American Thyroid Association guidelines, the European TIRADS, and the Korean TIRADS. Overall, 818 nodules (57 malignant) were evaluated. The malignancy rate was higher in patients &le, 65 years (8.1%) than in patients &gt, 65 years (3.8%, p = 0.02). All RSS confirmed a significant discriminative performance in both age groups, with a negative predictive value of 100% in patients &gt, 65 years, although specificity was lower in older patients. The ACR TIRADS was the best performing in both age groups. RSS could avoid a sizable number of biopsies when applied as rule-out tests in elderly patients.

Computer-aided diagnosis (CAD) is becoming a prominent approach to assist clinicians spanning across multiple fields. These automated systems take advantage of various computer vision (CV) procedures, as well as artificial intelligence (AI) techniques, to formulate a diagnosis of a given image, e.g., computed tomography and ultrasound. Advances in both areas (CV and AI) are enabling ever increasing performances of CAD systems, which can ultimately avoid performing invasive procedures such as fine-needle aspiration. In this study, a novel end-to-end knowledge-driven classification framework is presented. The system focuses on multimodal data generated by thyroid ultrasonography, and acts as a CAD system by providing a thyroid nodule classification into the benign and malignant categories. Specifically, the proposed system leverages cues provided by an ensemble of experts to guide the learning phase of a densely connected convolutional network (DenseNet). The ensemble is composed by various networks pretrained on ImageNet, including AlexNet, ResNet, VGG, and others. The previously computed multimodal feature parameters are used to create ultrasonography domain experts via transfer learning, decreasing, moreover, the number of samples required for training. To validate the proposed method, extensive experiments were performed, providing detailed performances for both the experts ensemble and the knowledge-driven DenseNet. As demonstrated by the results, the proposed system achieves relevant performances in terms of qualitative metrics for the thyroid nodule classification task, thus resulting in a great asset when formulating a diagnosis.

Background. Spontaneous serum TSH variations during levothyroxine replacement therapy and multiple dose changes in athyreotic patients seem to be frequent in clinical practice. Aim. To describe the rate and extent of spontaneous serum TSH variations in patients after total thyroidectomy for differentiated thyroid cancer (DTC) in real-life practice, and the number of resulting levothyroxine (LT4) dose adjustments. Methods. Data of DTC patients were prospectively collected at a single referral center between January 2005 and May 2019. TSH and fT4 serum levels, LT4 dose and formulation, and concomitant medications were recorded at 1, 3, and 12 months after primary treatment (surgery ± radioiodine therapy), and then yearly; the data were retrospectively evaluated for this study. Visit at one month was used to tailor LT4 dose and was not considered into the data analysis. Patients with structural evidence of disease or during pregnancy were excluded. Results. Data of 2883 evaluations (472 patients) were collected; at baseline, the median age was 49.7 years, 73.5% were females. The LT4 formulation administered at baseline were tablets (84.9%), liquid solution (11.4%), or soft-gel capsule (3.7%). Overall, in 27.5% of clinical evaluation with unchanged levothyroxine dose (341/1243), there were meaningful spontaneous TSH variations (defined as delta TSH > 1.5 mcUI/ml) at yearly follow-up visit. It is clinically significant: in 6.6% of visits, overt thyrotoxicosis was recorded. Furthermore, the treating clinicians decided to change the LT4 dose in 37.1% of cases. These figures were not significantly higher in the first years, and a rate above 25% persist even after ten years of follow-up. The median maintenance dose needed was 1.61 (interquartile range [IQR] 1.41-1.92) mcg/Kg/day for tablets, 1.54 (IQR 1.39-1.79) mcg/Kg/day for liquid solution, and 1.46 (IQR 1.23-1.71) mcg/Kg/day for soft-gel capsules. After correction for daily dose, there was no difference in the rate of TSH variations > 1.5 mcUI/ml, or in the absolute value of median delta of TSH between the three formulations. In 20.1% of patients, the LT4 formulation was changed during the follow-up: it was more common in patients with a known gastroenteric disease (OR 1.76, p=0.03). Conclusions. TSH spontaneous variations and dose adjustments are very common in patients after total thyroidectomy, even during long-term follow-up: wide variations happen in more than 1/4 of all visits, and dose changes are needed in more than 1/3 of all evaluations. We were more inclined to change LT4 formulation in patients with known interference in LT4 absorption: however, no difference in TSH variations was recorded between users of three different formulations, even if soft-gel capsules seem to have a lower maintenance dose.

Background. Management and follow-up of differentiated thyroid cancer (DTC) are guided by the likelihood of disease persistence or recurrence. The American Thyroid Association (ATA) practice guidelines provide a risk-estimation system based on data mainly derived by retrospective, single-center, and small cohorts. Aim. To validate the ATA risk-stratification system in predicting persistent structural disease. Methods. We analyzed data from the Italian Thyroid Cancer Observatory’s observational, web-based database, which prospectively enrolls newly diagnosed DTC patients in 40 Italian centers. For the present study we selected consecutive cases satisfying the inclusion criteria: 1) histological diagnosis of DTC, including papillary, follicular, and poorly differentiated tumors; 2) registration in the ITCO database between January 1, 2013 and April 23, 2019; 3) clinical evaluation between 6 and 18 month after primary treatment, including enough data to estimate the response to the initial treatment. Exclusion criteria were: histological diagnosis of NIFTP, medullary, or anaplastic thyroid cancer. The response to the initial treatment was categorized as excellent, biochemical incomplete, structural incomplete, or indeterminate based on imaging findings (neck ultrasound and other imaging studies, if performed), basal or stimulated serum thyroglobulin levels, and anti-Tg antibody levels. To model the response to treatment, we used a cumulative link model; given the hierarchical structure of the data, with patients nested within centers, we used a mixed-effect model, with a center-specific intercept summarizing unobserved center-specific characteristics. Results. Complete data about initial treatment and response to treatment after 6-18 months since initial treatment was available for 2071 patients. According to the ATA system, 1109 patients (53.6%) were classified as low-risk, 796 (38.4%) as intermediate, and 166 (8.0%) as high-risk. Excellent response was recorded in 1576 (76.1%) patients, indeterminate in 376 (18.2%), biochemical incomplete in 33 (1.6%), and structural incomplete in 86 (4.2%).The ATA risk stratification system is a significant predictor of response to treatment after 6-18 months: classification as intermediate- and high-risk increased the likelihood of a response worse than excellent (OR 1.68 [95% confidence intervals, CI 1.34-2.10] and 3.23 [95% CI 2.23-4.67], respectively), and a persistent structural disease (OR 4.67 [95% CI 2.59-8.43] and 16.48 [95% CI 7.87-34.5], respectively. In both analyses, the effect of the center (taking into account center-specific features) was negligible and not statistically significant. Conclusion. The 2015 ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC, also if applied in a real-world setting consisting of several different clinical sites.

Deciding whether patients with a cytologically indeterminate thyroid nodule should be referred for surgery or for active surveillance is an important challenge for clinicians. The aim of this study was to evaluate the performance of a novel dual-component molecular assay as an ancillary molecular method for resolving indeterminate thyroid nodule cytology. We selected 156 thyroid nodules from those that had undergone fine-needle aspiration processed by liquid-based cytology and surgical resection between June 2016 and December 2017. The sample set included 63 nodules cytologically classified as indeterminate, and 93 other nodules randomly selected from those with non-diagnostic, benign, suspicious, or malignant cytology. Nucleic acids from each nodule were subjected to next-generation sequencing analysis for mutation detection in 23 genes and to digital polymerase chain reaction (PCR) evaluation for miR-146b-5p expression levels. Used alone, mutation analysis in the indeterminate subset (cancer prevalence: 22.5%) displayed high sensitivity (89%) and NPV (96%). In contrast, the miR-146b-5p assay offered high specificity (93%) and PPV (93%). Combined use of both analyses improved panel performance by eliminating false-negative results. These preliminary data suggest that a dual-component molecular test can increase the diagnostic accuracy of thyroid cytology alone by reducing the number of nodules that will be classified as indeterminate and increasing those that can be reliably classified as benign. If these findings are confirmed, this test can be considered for use in clinical practice and is expected to reduce diagnostic surgery and health care costs, and to improve patient quality of life.

A preoperative neck ultrasound (US) is recommended for all patients with suspected thyroid cancer, to identify features potentially changing surgical extent. The extrathyroidal extension (ETE) is considered an indication for total thyroidectomy, but there is limited consensus on its US definition, and the interobserver reliability is low. This study aimed to evaluate the predictive value of neck US for ETE before surgery and to estimate the diagnostic performance of different US findings, evaluated during real-time examinations. Patients referred to surgery between November 1, 2015, and May 31, 2019, for a suspicious thyroid cancer underwent a preoperative neck US, with systematic assessment for ETE. Three definitions were tested: very restrictive (capsular disruption with suspicious images of surrounding tissues invasion), restrictive (including also capsular abutment with evidence of capsular disruption), and nonrestrictive (capsular abutment is sufficient). Histopathology report of ETE involving at least soft tissues was considered positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The study cohort included 128 patients, with 102 (79.7%) confirmed malignancies, and 44 (43.1%) histological ETE. The nonrestrictive definition had good sensitivity (86.4%) but low specificity (29.8%), with an NPV of 80.6%; the restrictive definition had higher specificity (81%), while the very restrictive had specificity and PPV of 100%. A more extensive surgical approach should not be based on US suspicion of ETE alone, with the possible exception of gross invasion appearance. The absence of any sign of ETE, on the other hand, has a substantial negative predictive value.

Over 50% of newly diagnosed thyroid nodules are either cytologically benign or presumed to be benign on the basis of low-suspicion sonographic findings. The strategies used for their long-term surveillance are based mainly on the estimated residual risk of malignancy calculated with various ultrasonographic classification systems (e.g., Thyroid Image Reporting and Data Systems [TIRADS]). We conducted a longitudinal study to evaluate the temporal stability of the initial risk estimates computed with five widely used systems and to determine whether risk class increases during follow-up are indeed predictive of malignancy.We re-analyzed data prospectively collected at a single academic referral center on 232 patients (age: 54.1 ± 13.7 years) with 432 asymptomatic, sonographically or cytologically benign thyroid nodules at baseline (T0) and 122 new nodules that were present five years later (T5). At both time points, the sonographically estimated risk of malignancy was calculated as recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi, the American College of Radiologists' TIRADS, the American Thyroid Association's 2015 practice guidelines, the European Thyroid Association's TIRADS (EU-TIRADS), and the TIRADS of the Korean Society of Thyroid Radiology (K-TIRADS).For 57 to 127 (13.2-29.4%) of the original nodules, depending on the system used, the estimated malignancy risk increased over the 5-year interval. Of the nodules whose baseline risk had not warranted cytological assessment, very few (6.3-8.3%) met the criteria for cytology at the 5-year evaluation. Biopsy was indicated for only 4 to 8 (3.3-6.6%) of the new nodules based on T5 risk estimates. Despite these changes, none of the 232 patients was ever diagnosed with a cancer.Ultrasound-based risk classes of presumably benign thyroid nodules remain fairly stable over time, and changes warranting biopsy are rare indeed. The appearance of new nodules is a frequent event, but very few (5%) are classified as high risk, and only the 3-7% meet the criteria for cytological assessment. Collectively, these findings support the view that patients with presumably benign thyroid nodules can be safely followed with less intensive protocols.

Whole exome sequencing (WES) was used to investigate two Italian siblings with wild-type RET genotype, who developed medullary thyroid cancers (MTCs) and, later, primary prostate and breast cancers, respectively. The proband's MTC harbored a p.Met918Thr RET mutation; his sister's MTC was RET/RAS wild-type. Both siblings had a germline mutation (p.Arg417Gln) in the extracellular Sema domain of the proto-oncogene MET. Experiments involving ectopic expression of MET p.Arg417Gln in MET-negative T47D breast cancer cells documented the mutant receptor's functionality and its ability to enhance cell migration and invasion. Our findings highlight a possible link between MET germline mutations and MTCs and suggest that MET p. Arg417Gln may promote an invasive malignant phenotype. The possibility that MTC can be driven/co-driven by a MET mutation has potential management implications, since the tyrosine-kinase inhibitor cabozantinib-approved for treating advanced MTCs-is a specific MET inhibitor.