ObjectiveAnaplastic thyroid carcinoma (ATC) is an extremely aggressive cancer, traditionally refractory to conventional treatments. The combined therapy with lenvatinib and pembrolizumab (L + P) is supported by a preclinical rationale based on the distinctive immunological profile of ATC. We propose a real-life study to evaluate relevant clinical outcomes and identify survival predictors in a cohort of ATC patients treated with the combined therapy in two Italian referral centers. MethodsSixteen ATC patients treated with the combination of L + P were retrospectively included. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were assessed according to RECIST 1.1 criteria. Baseline patient characteristics, including immuno-nutritional status (calculated using the CONUT score), were analyzed to identify potential predictors of response. ResultsA median OS of 10 months (95% CI: 4.2–15.9 months) and a median PFS of 6.0 months (95% CI: 0–12.7 months) were observed after L + P therapy. Complete response was observed in 6.2% and partial response in 31.3% of patients, resulting in an ORR of 37.5%; the DCR was 68.8%. Progressive disease occurred in 25% of patients. Furthermore, a baseline CONUT score ≤ 2 resulted in a significantly longer OS (log-rank, P = 0.001) and PFS (P = 0.05) compared to CONUT score ≥ 3, while a non-significantly longer OS was observed between patients with a baseline ECOG PS of 0–2 and those with a baseline ECOG PS ≥ 3. ConclusionOur study confirms the efficacy and safety of L + P therapy, identifying the CONUT score as a prognostic factor.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor originating from calcitonin producing C-cells and accounts for 1-5% of thyroid cancers. Total thyroidectomy is curative in localized disease (N0), whereas lymph node metastases (N1) are associated with poorer prognosis. However, the molecular mechanisms driving the metastatic shift remain poorly understood. This study aimed to identify miRNA features linked to metastatic spread in MTC, focusing on the transition from N0 to N1. Co-expression networks were constructed for N0 and N1 tumors, and differential connectivity analysis was used to identify key miRNAs acting as regulatory hubs. Functional annotation of their target genes was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Reactome pathway analyses. Validation experiments were carried out in MTC cells to evaluate the effects of selected miRNAs on cell proliferation, survival, and MAPK pathway activation. Network analysis revealed distinct miRNA co-expression patterns between N0 and N1 tumors. Differential network analysis highlighted miR-145-3p as a central regulatory hub, exhibiting 29 altered co-expression changes and a marked loss of connectivity in N1. Target enrichment identified 59 validated genes, including key oncogenic drivers such as MYC, PTEN, BCL2, PIK3CA, AKT1, and MAPK7. In MTC cells, simultaneous inhibition of miR-145-3p together with its top co-expressed miRNAs increased proliferation and survival, and enhanced ERK phosphorylation, indicating MAPK pathway activation and a shift toward a more aggressive phenotype. In conclusion, this study identifies a miRNA regulatory hub centered on miR-145-3p that is associated with metastatic progression and highlights the value of network-based approaches in uncovering mechanisms of cancer dissemination. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Ultrasound (US) is the most accurate tool for the assessment of thyroid nodules (TNs). Despite the subcapsular position of TNs may represent a game changer for clinical practice in selecting cases for biopsy or surgery, this parameter is not included in US-based risk stratification systems. The present study evaluated the agreement of endocrinologists using US in clinical practice with the experts’ results employed as reference standard. A sub-series of TNs for which the agreement between US expert endocrinologists and radiologists was perfect was assumed as reference. Participants of the 2025 Thyroid Update of Associazione Medici Endocrinologi (AME) were asked to assess TNs in a 3-choice answer: subcapsular, non-subcapsular, or uncertain. The agreement was determined according to majority consensus (i.e., ratings > 50

BACKGROUND AND AIM:Recent preclinical studies have confirmed that inhibiting the MAP kinase pathway can induce the re-differentiation of radioiodine (RAI)-refractory (RAIR) follicular cell thyroid cancers (TCs). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myo-inositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells. Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into two groups: (1) a control group in which patients are treated with KIs (subgroup a: trametinib plus dabrafenib; subgroup b: lenvatinib); (2) a group in which patients (divided into the two subgroups) are treated with the same KIs in addition to MI. After 30 days of MI treatment, all patients, treated with levothyroxine (L-T4) at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). On day 35, the patients will be subjected to whole-body scintigraphy, with hybrid imaging where possible (SPECT/CT), after the administration of diagnostic activity (185-222 MBq of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0); after 30 days of MI therapy; and then on days 31, 32, 33, 34, and 35 after MI therapy. Quality of life (QoL) will be assessed at the beginning of the MI treatment and at the end of its administration. The primary endpoint is the restoration of 123-I uptake in RAIR-TC patients already on KI therapy alone and on KI therapy plus MI. The restoration of 123-I uptake in target lesions will be evaluated. CONCLUSIONS:MI may have a synergistic effect at the cellular level, and the possible increase in the re-differentiation of RAIR-TC in patients treated with KIs plus MI may have great clinical relevance. The re-uptake of RAI will be evaluated as the primary endpoint, and Tg values and QoL will be evaluated as the secondary endpoints. The main limitation of this study is that we do not investigate any clinical effects. We will have to postpone the clinical analysis to a later date after the administration of RAI for therapeutic purposes.

The BRAF p.V600E mutation activates the RAS/BRAF/MEK/ERK pathway, leading to cancer cell dedifferentiation and uncontrolled growth. In radioiodine-refractory thyroid cancers, MEK and/or BRAF inhibitors can induce redifferentiation, resensitizing tumors to radioiodine. However, compensatory mechanisms limit this efficacy. We used the SWitchMiner software to identify a small pool of regulatory genes, called switch genes, critically associated with drastic changes in cell phenotypes, using TCGA transcriptomic data from BRAF-mutant papillary thyroid carcinoma and normal thyroid tissues, which highlighted miR-335-5p. Restoring miR-335-5p in thyroid cancer cell lines harboring the BRAF mutation increased expression of thyroid-specific genes and proteins, especially in well-differentiated cell lines, with enhanced sodium-iodide symporter localization and iodine uptake confirmed in organoids. Due to the connection between thyroid-specific and EMT-related genes in the protein-protein interaction network, we examined how miR-335-5p overexpression affects EMT pathway genes that modulate thyroid-specific genes and Kinase Inhibitor (KI) resistance. miR-335-5p inhibited the expression of nearly all analyzed genes in less-differentiated thyroid cell lines. Thus, miR-335-5p may be a viable therapeutic target to restore radioiodine avidity in BRAF-mutant metastatic thyroid cancer and enhance KI treatment redifferentiation.

Indeterminate thyroid cytology presents a significant diagnostic challenge, often leading to difficult treatment decisions for both physicians and patients. Effective communication of these uncertainties is crucial, especially in a surgical setting, where decisions can have long-lasting impacts. This is particularly important for younger surgeons who may lack extensive clinical experience. This study aimed to plan, develop, implement, and pilot a communication protocol designed for surgeons, particularly those in training, to navigate uncertainty and build trust with their patients. Additionally, it documented the reactions of patients managed using this approach. Fifty-two patients diagnosed with indeterminate thyroid cytology were enrolled between March 2023 and January 2024 at the Endocrine Surgery Unit of "Azienda Ospedialiera Universitaria Policlinico Umberto I" in Rome, Italy. A communication protocol based on the SPIKES model (Setting, Perception, Invitation, Knowledge, Emotion, Strategy), a six-step protocol for guiding difficult conversations, was designed to structure discussions around uncertain diagnoses. Patient consultations were conducted in three phases: the initial outpatient visit, pre-surgery admission, and a follow-up one week after surgery. During each encounter, patients' emotional responses were recorded using open-ended questions. To ensure clarity, a Decision Aid (DA) tool was introduced during the K-Knowledge phase of SPIKES, to better explain the risks and treatment options. A mixed-methods approach was used to analyze both qualitative and quantitative data from patient feedback. The adapted protocol was found to be effective in enhancing patient comprehension and emotional response. Approximately 80% of patients reported emotional relief after the first consultation, and by the third encounter, 91% expressed a sense of well-being or trust. The most frequently reported emotional states across all three encounters were serenity, reassurance, and trust. A small subset of patients continued to experience concern or fatigue. Additionally, 96% of participants rated the communication as clear, and 88.5% considered the final therapeutic decision as the correct one. This pilot study suggests that a structured SPIKES-based communication protocol can help address gaps in patient understanding, trust, and satisfaction when managing indeterminate thyroid cytology. Implementing such protocols may streamline communication in surgical settings, improve patient-centered care, and support physicians, particularly trainees, in managing complex patient interactions.

L’intelligenza artificiale ha rivoluzionato l’analisi delle immagini ecografiche di noduli tiroidei, automatizzando la segmentazione, passaggio chiave per l’estrazione delle caratteristiche radiomiche e la stratificazione del rischio di malignità. La rassegna descrive i principali modelli di segmentazione automatica, analizzandone limiti e prospettive di integrazione clinica.

In patients with follicular cell-derived thyroid cancer that have distant metastases and no iodine uptake, redifferentiation—ie, the restoration of tumoural 131I uptake with systemic therapy—is now possible. The use of mitogen-activated protein kinase (MAPK) inhibitors for a short period of time before the administration of high activity 131I shows promising results with iodine uptake restoration and tumour response. Redifferentiation has been used in patients with BRAF-mutated and RAS-mutated tumours in prospective trials and in the case of patients with RET or NTRK fusions. The iodine uptake restoration ranges from 33% to 95%, and tumour response rates from 11% to 80%. There is substantial variability between trials with regards to inclusion criteria, duration of redifferentiation drug therapy, activity of radioactive iodine, and use of dosimetry. Randomised studies are missing to clearly establish the effectiveness and applicability of redifferentiation. Thus, long-term studies are needed to establish the most effective redifferentiation protocols. The objectives of this Review are to: (1) provide a comprehensive review of the available results from prospective trials and case reports, including results regarding the restoration of radioiodine uptake and treatment efficacy (morphological and biological); (2) describe the differences in redifferentiation trial design between studies and discuss their potential impact on treatment efficacy; (3) describe the implications and limitations of dosimetry; and (4) outline the key questions to be addressed in future redifferentiation trials.

Thyroidal organogenesis is controlled by specific transcription factors; alterations in their ex-pression can cause developmental abnormalities like ectopia of the gland. Ectopic thyroid tissue can be found anywhere along the line of the obliterated thyroglossal duct, from the tongue to the diaphragm. The thoracic cavity is the most common non-cervical location. We describe the case report of a "forgotten goiter", a retrosternal ectopic thyroid tissue, detected after a cervical total thyroidectomy. Due to the size of the lesion, anatomical localization, and presence of calcifications, the patient underwent a complete surgical resection of the mass via sternotomy. The histological examination showed benign mediastinal ectopic thyroid tissue. The postoperative course was uneventful and without complications. Any surgical initiative in patients with retrosternal ectopic thyroid tissue must be individualized and based upon the size of the goiter, the characteristics of the mediastinal goiter and its anatomical relationships, the risk of complications and reoperations, the experience of the surgeon, the comorbidities of the patient, and the trajectory of growth in active surveillance. To date, there is no universal consensus on the best surgical approach.

Background: Ultrasound (US) examination is the pivotal test to assess the risk of cancer and the indication for fine needle aspiration cytology (FNAC) in thyroid nodules (TNs). The subcapsular location of a TN may strengthen the indication for FNAC as, in TN resulting malignant at cytology may favor surgery rather than active surveillance. However, the definition of a subcapsular TN remains unclear. This study aimed to evaluate the interobserver agreement (IOA) among thyroid US experts in classifying TNs as subcapsular or not. Methods: Twelve raters received an electronic link to a file containing static US images and were asked to assess 60 TNs for subcapsular location, blinded to all other TN characteristics. The overall IOA was calculated, and the TN US features were subsequently analyzed to evaluate their potential influence on interobserver variability. The raters had high or very high thyroid US experience. Two experienced operators preliminarily selected the case series and analyzed the findings. All cases were derived from patients undergoing surgery and histological diagnosis. The IOA was calculated according to Fleiss' kappa, ranging from 0.0 (no agreement) to 1.0 (perfect agreement). Results: The overall IOA was fair (κ = 0.34), with a slightly better result in the subgroup of raters with higher experience (κ = 0.39). A higher IOA value (κ = 0.38) was observed in TNs of medium size. Following multiple sub-analyses, the highest κ value (0.46) was observed in the subgroup of TNs that were categorized as EU-TIRADS 5 and were smaller than 2 cm. Conclusions: The overall IOA among US experts when assessing TNs as subcapsular was unsatisfactory. A clear and standardized definition of subcapsular position is needed to improve clinical decision-making. Future guidelines should address this issue to ensure consistent assessment and management of subcapsular TNs.

CONTEXT:The risk of recurrence of papillary thyroid carcinoma (PTC) smaller than 1 cm (microPTC) is low. Predictors of disease persistence in microPTC are still unclear. OBJECTIVE:To compare the clinical and pathological characteristics of microPTCs with macrocarcinomas (PTC > 1 cm), identifying the predictors of biochemical and structural incomplete response 1 year after initial treatment in microPTC. METHODS:We included patients consecutively enrolled in the Italian Thyroid Cancer Observatory (NCT04031339), and selected patients with a histological diagnosis of PTC for whom complete pathological, clinical, treatment information, and results at the 1-year follow-up visits were available. RESULTS:Among 5038 patients in the cohort, 2345 (46.5%) had a microPTC. Patients with microPTCs had tumors with more indolent pathological features: only 3% of patients were classified as high risk according to the American Thyroid Association (ATA) risk stratification system for persistent or recurrent disease and 1% had distant metastases at diagnosis. MicroPTCs had a significantly better outcome: only 5% had a biochemical response and 2.3% a structural incomplete (SIR) response. Distant metastases at diagnosis were the best predictor of SIR in microPTCs (OR 5.13, 95% CI 1.11-23.73, P = .04). In a subgroup of 925 patients treated by total thyroidectomy and radioiodine treatment, the best predictor of SIR was the ATA high risk (OR 5.47, 95% CI 1.42-21.04, P = .01). CONCLUSION:Our study confirms the favorable initial outcome of microPTC in a large series. We demonstrate that the ATA risk classification is reliable in predicting biochemical and structural persistence in patients with microPTC. Distant metastases, although rare, remain the best predictor of structural persistence at 1-year follow-up. These findings underscore the importance of tailored management strategies based on comprehensive risk stratification, rather than solely on tumor size.

Introduction: Little is known about sex differences in lenvatinib treatment safety and efficacy. Methods: Real-word retrospective Italian multicenter study enrolling patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib. Results: A total of 138 patients (64 females) were included, with a median follow-up of 26 months (2–72). More men performed physical activities (34% vs 17%, P = 0.024). The frequency of smoking and alcohol consumption was higher in men (58% vs 33%, P = 0.003; 45% vs 17%, P = 0.001). We did not find sex differences in lenvatinib dose reduction due to adverse events (AEs) (78% females vs 85% males). Ninety-nine percent of patients developed at least one adverse event (AE), with no sex difference in their number and the time to first AE. Severe AEs occurred in 74% of males and 66% of females (P = 0.398), with a mean dose of 18.2 mg (±5.7), and a median time to the first serious AE of 9 weeks (1–154). Stomatitis/mucositis and hematological disorders were more frequent in females (48% vs 30%, P = 0.016; 17% vs 4%, P = 0.011). Gastrointestinal disorders were higher in males (15% vs 2%, P = 0.010). Eighty-seven patients interrupted lenvatinib due to AEs (median time: 3 months (0–48), mean dose: 17 mg ±5.5). Discontinuation occurred in 21 patients, five for severe AEs. No sex differences were found in progression-free survival, overall survival or disease control rate. Liver metastases were associated with disease progression (HR: 3.73, 95% CI: 1.06–13.12, P = 0.040) or death (HR: 4.82, 95% CI: 1.75–13.25, P = 0.002) only in females. Conclusion: Lenvatinib is effective in both sexes and exhibits a good safety profile, with a sex difference in the frequencies of some adverse events.

BACKGROUND:Endocrine science remains underrepresented in European Union research programs despite the fundamental role of hormone health in human well-being. Analysis of the CORDIS database reveals a persistent gap between the societal impact of endocrine disorders and their research prioritization. At national funding level, endocrine societies report limited or little attention of national research funding toward endocrinology. The EndoCompass project-a joint initiative between the European Society of Endocrinology and the European Society of Paediatric Endocrinology, aimed to identify and promote strategic research priorities in endocrine science to address critical hormone-related health challenges. METHODS:Research priorities were established through comprehensive analysis of the EU CORDIS database covering the Horizon 2020 framework period (2014-2020). Expert consultation in thyroid endocrinology was conducted to identify key research priorities, followed by broader stakeholder engagement including society members and patient advocacy groups. RESULTS:For thyroid disorders, research priorities encompass neoplastic and nonneoplastic conditions, focusing on disease mechanisms, improved diagnostics and treatments, and the impact of environmental and metabolic factors. Key areas include personalized medicine approaches, artificial intelligence applications, and the establishment of pan-European registries to advance understanding of rare thyroid conditions. CONCLUSIONS:The thyroid component of the EndoCompass project provides an evidence-based roadmap for strategic research investment. This framework identifies crucial investigation areas into thyroid disease pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of thyroid disorders on individuals and society. The findings support the broader EndoCompass objective of aligning research funding with areas of highest potential impact in endocrine health.

Although thyroid nodules are less common in the pediatric population, the risk of malignancy is higher than in adult patients. The aim of this study was to evaluate the ultrasonographic predictive factors of malignancy in thyroid nodules and to validate American College of Radiologists (ACR) TI-RADS performance in transition age patients. One hundred forty-two patients aged between 14 and 21 years referred to the participating centers for FNA biopsy of a thyroid nodule between 2007 and 2022 were included and ultrasound reports and sonographic images were retrospectively analyzed. Nodule features were defined according to the ACR-TIRADS lexicon. Two reference standards were applied: FNA cytology and surgical histology. The diagnostic performance of single sonographic features was estimated. Significant predictors were then included in a multivariate regression model. Nodules included in ACR-TIRADS categories TR4 or TR5 had 10-fold increased risk of indeterminate or suspicious/malignant cytology [p < 0.001]. In univariate analysis, solid composition [p = 0.016] and presence of hyperechoic foci [p = 0.040] significantly increased the likelihood of malignant histology. In multivariate regression analysis, irregular margins [p = 0.011] and hyperechoic foci [p = 0.019] were independent predictors of indeterminate or suspicious/malignant cytology. Nodules included in ACR-TIRADS categories TR4 or TR5 had 10-fold increased risk of indeterminate or suspicious/malignant cytology in transition age. ACR-TIRADS was not able to rule-out malignancy compared to FNAB alone, suggesting the need to reconsider recommendations in the transition age group.

Context The utility of thyroglobulin (Tg) in the follow-up of patients with differentiated thyroid cancer has been well-documented. Although third-generation immunoassays have improved accuracy, limitations persist (interfering anti-Tg antibodies and measurement variability). Evolving treatment strategies require a reevaluation of Tg thresholds for optimal patient management.Objective To assess the performance of serum Tg testing in 2 populations: patients receiving total thyroidectomy and radioiodine remnant ablation (RRA) or treated with thyroidectomy alone.Design Prospective observational study.Setting Centers contributing to the Italian Thyroid Cancer Observatory database.Patients We included 540 patients with 5 years of follow-up and negative anti-Tg antibodies.Interventions Serum Tg levels assessed at 1-year follow-up visit.Main Outcome Measure Detection of structural disease within 5 years of follow-up.Results After excluding 26 patients with structural disease detected at any time point, the median Tg did not differ between patients treated with or without radioiodine. Data-driven Tg thresholds were established based on the 97th percentile of Tg levels in disease-free individuals: 1.97 ng/mL for patients undergoing thyroidectomy alone (lower than proposed by the Memorial Sloan Kettering Cancer Center protocol and ESMO Guidelines, yet demonstrating good predictive ability, with a negative predictive value of 98% and 0.84 ng/mL for patients receiving postsurgical RRA. High sensitivity and negative predictive value supported the potential of these thresholds in excluding structural disease.Conclusion This real-world study provides evidence for the continued reliability of 1-year serum Tg levels. The data-driven Tg thresholds proposed offer valuable insights for clinical decision-making in patients undergoing total thyroidectomy with or without RRA.