OBJECTIVE:The cardiometabolic risk associated with nonfunctioning adrenal incidentalomas (NFAIs) remains controversial. This study aimed to compare cardiovascular risk and related complications in patients with bilateral versus unilateral NFAIs. METHODS:This is a retrospective cross-sectional study including outpatients from a tertiary referral center. The cardiovascular risk was assessed using validated scores, and data about the presence of cardiometabolic complications and organ damage were collected. RESULTS:We included 906 patients with NFAIs in primary cardiovascular prevention (820 unilateral, 86 bilateral), diagnosed and treated in our center between 2000 and 2024. Multivariable linear regressions showed that bilateral NFAIs are associated with higher cardiovascular risk, compared to unilateral NFAI, when calculated using the Framingham score (P = .006), the CUORE Project (P < .001), the SCORE (P < .001), and the SCORE-2 (P = .035). While multivariable logistic regressions revealed that patients with bilateral NFAIs are associated with the presence of type 2 diabetes mellitus (OR 2.36, 95% CI 1.18-4.72; P = .015) and with the presence of organ damage (OR 2.09, 95% CI 1.00-4.37; P = .050), after adjusting for age, male sex, body mass index, smoking habit, arterial hypertension and number of antihypertensive drugs; estimated glomerular filtration rate was additionally included as a covariate in the model predicting type 2 diabetes mellitus. CONCLUSIONS:Bilateral NFAIs are independently associated with greater cardiometabolic risk and complications compared to unilateral lesions. These findings support the concept of bilaterality as a distinct clinical phenotype and suggest that patients with bilateral NFAIs may benefit from closer cardiometabolic monitoring.

Paragangliomas (PGLs), encompassing pheochromocytomas and extra-adrenal paragangliomas, are genetically heterogeneous non-epithelial neuroendocrine neoplasms that segregate into molecular clusters with distinct biological and clinical behavior. Architectural correlates of genotype have not been systematically investigated. This study aimed to assess the reticulin framework as a potential morphologic structural surrogate of molecular background and to introduce a novel deep learning model for its spatially resolved quantitative analysis and genotype prediction. A total of 104 adrenal and extra-adrenal PGLs with complete clinical, pathological, and genetic data were retrospectively analyzed. Reticulin stain was evaluated qualitatively and quantitatively using a supervised convolutional neural network trained on expert-annotated reticulin-stained whole-slide images (WSIs) to map and quantify areas of intact framework and very small nest patterns. Two bias-reduced logistic regression models (Firth’s method) were developed to predict germline cluster 1 genotype, each combining clinical variables (age, tumor size, extra-adrenal presentation) with one artificial intelligence (AI)-derived morphometric feature-percentage of intact framework (Model-INTACT) or very small nests (Model-VSN). PGLs harboring germline cluster 1 variants occurred at a younger age, were larger, more frequently extra-adrenal, and showed significant enrichment of intact reticulin and very small nest patterns compared with cases harboring germline cluster 2 variants and sporadic cases. The supervised AI model accurately mapped and quantified these architectural features across the WSIs. Predictive models integrating AI-derived morphometrics with clinical variables achieved excellent discrimination for germline cluster 1 genotype (AUC 0.981 for Model-INTACT; AUC 0.990 for Model-VSN). Preservation of the reticulin framework, particularly with very small nests, represents a histoarchitectural correlate of pseudohypoxic PGLs. Integration of AI-based morphometric descriptors with clinical parameters enables reliable pre-test prediction of germline cluster 1 genotype, bridging conventional histopathology and molecular classification.

CONTEXT:Osilodrostat has demonstrated efficacy in clinical trials for Cushing's syndrome (CS). Real-world data remain limited. OBJECTIVE:To assess real-world effectiveness and safety of osilodrostat in a large cohort of CS patients. DESIGN&SETTING:Multicenter, retrospective, phase IV-study across 11 Italian endocrine referral centers. PATIENTS:100 CS patients [74% pituitary, 16% adrenal, 10% ectopic]. MAIN OUTCOME MEASURES:Primary endpoint was the percentage of patients with UFC≤ULN at their last observation. Secondary endpoints included biochemical and hormonal control, clinical outcomes, QoL, AEs. RESULTS:81% of patients had normal UFC levels at last observation, 92% at least once within study period. Excluding 12 patients with normal baseline UFC levels, 78.4% of patients had normal UFC levels at their last observation, whereas 90.9% at least once within the study period.The mean±SD (median,range) time to the first normalization of UFC levels, in the 80 patients who achieved normalization, was 92.1±86.3 (67.5,8-455) days, at a mean± SD (median,range) osilodrostat dose of 7.2±6.8 (5,1-40) mg/day.Significant reductions in late-night salivary cortisol and morning serum cortisol levels were observed. Improvements were noted in anthropometric parameters, blood pressure, glucose metabolism, clinical signs, and QoL. AEs occurred in 29% of patients, mostly mild-to-moderate; adrenal insufficiency was the most common AE reported in 20% of patients. Hormonal control and safety profiles were consistent across CS etiologies. CONCLUSIONS:Osilodrostat is effective, generally well tolerated in routine clinical practice, representing a valuable therapy for CS management, able to achieve rapid and sustained hormonal control, significant metabolic, cardiovascular, clinical and QoL improvements with a well-tolerated safety profile.

Thyroid cancer, the most frequent endocrine tumor, has a good prognosis. However, the survival rate of patients with recurrent or metastatic forms that become resistant to conventional treatments, drops to less than 20% at 10 years, with a mean life expectancy of 3-5 years. The molecular mechanisms that drive the advancement of these forms are still largely unknown, and, therefore, the identification of disease progression biomarkers is of great clinical relevance. Dickkopf-1 (DKK1) is a regulator of the Wnt signaling cascade that controls several biological processes including cell proliferation, differentiation and migration. DKK1 has been associated with progression and poor prognosis in different types of tumors; however, its role in thyroid cancer is still not well defined, and a better characterization is needed. The present study investigated the role of DKK1 in the growth of papillary and follicular thyroid cancers, in in vitro and in vivo models. In vitro, DKK1 silencing, through siRNA, and deletion, via CRISPR/Cas9 editing, were performed in different papillary and follicular thyroid cancer cell lines. Both silencing and deletion reduced cell growth and migration, with the involvement of β-catenin-dependent Wnt and PI3K/mTOR pathways. In vivo xenograft tumor models, DKK1 deletion reduced tumor growth. In conclusion, our findings support the key role of DKK1 in the growth of differentiated thyroid cancers both in vitro and in vivo.

Objective: Our objectives were to describe molecular profiling in a real-life cohort of patients with radioiodine-resistant (RAI-R) differentiated or poorly differentiated thyroid cancer (DTC or PDTC) treated with lenvatinib and to focus on factors potentially influencing the quality of tissue samples for molecular analysis, including the impact of storage time, defined as the interval between tissue collection and molecular testing. Design: We retrospectively included all lenvatinib-treated RAI-R DTC or PDTC patients tested with DNA- and/or RNA-based next-generation sequencing (NGS) in our center, also analyzing the results of fluorescence in situ hybridization (FISH) for RET fusions if the sample did not satisfy quality criteria for RNA-based NGS analysis. We investigated differences in terms of histotype, biopsy site, or storage time between adequate and inadequate samples for RNA-based NGS. Results: At least one gene alteration was detected in 50% of the cohort (18 out of 36 patients); RAS and BRAF were the most frequent mutations, while gene fusions accounted for 5.6% of cases. Tissue samples were more frequently adequate for DNA-based NGS compared to RNA-NGS analysis (93.9% vs. 58.3%, p < 0.001). The median storage time was significantly longer in the case of inadequate samples for RNA-based NGS compared with adequate specimens (41.5 vs. 9.5 months, p = 0.016); samples archived for ≥3 years led more frequently to an inadequate result. Conclusions: Advanced RAI-R TC candidates for systemic therapy often harbor gene alterations. An adequate result was less frequently achieved in cases of RNA-based NGS than in DNA-based NGS, especially if the interval between tissue collection and molecular analysis was longer; nevertheless, the limited cohort size precludes definitive conclusions.

OBJECTIVE:The 1-mg dexamethasone suppression test (DST) may be affected by dexamethasone (DEX) exposure and assay-related variability. We aimed to define pragmatic post-DST DEX benchmarks and to compare the diagnostic performance of cortisol measured by chemiluminescent immunoassay (CLIA) vs liquid chromatography-tandem mass spectrometry (LC-MS/MS). DESIGN:Consecutive real-world observational study. METHODS:Post-test cortisol was measured by CLIA, while cortisol, cortisone, and DEX were quantified by LC-MS/MS on stored samples. Diagnoses were clinically adjudicated. ROC analyses and DeLong tests compared AUCs. RESULTS:The study involved 636 participants: 351 controls (55.2%), 135 non-functioning adrenal incidentaloma (21.2%), 14 aldosterone-cortisol cosecretion (2.2%), 116 mild autonomous cortisol secretion (18.2%), and 20 overt Cushing's syndrome (3.2%). Lower-tail DEX values were uncommon and even below lower-tail thresholds, DST results often remained clinically interpretable. DEX was higher in obesity than BMI <30 kg/m2 (4.87 ± 2.26 vs 4.40 ± 2.44 ng/mL; P = .030). For predicting overt hypercortisolism, AUCs were 0.976 (CLIA cortisol), 0.974 (LC-MS/MS cortisol), and 0.959 (LC-MS/MS cortisone), without significant pairwise differences. For the diagnosis of all forms of hypercortisolism, AUCs were 0.961 (CLIA cortisol), 0.951 (LC-MS/MS cortisol), and 0.931 (cortisone). LC-MS/MS cortisol optimal cut-offs were close to CLIA practice. CONCLUSIONS:Very low post-DST DEX concentrations are rare, and DST interpretation often remains informative even when DEX is below conventional thresholds, supporting a selective rather than routine use of DEX measurement. LC-MS/MS cortisol provides excellent discrimination with thresholds close to CLIA practice; cortisone appears best suited as an adjunct marker.

Hypertension is associated with increased fracture risk. However, evidence on its association with BMD is conflicting. Here, we demonstrate that hypertensive patients have lower trabecular bone scores compared to normotensive subjects, despite similar BMD. This degradation of bone microarchitecture may help explain the increased skeletal fragility observed in hypertensive patients. Hypertension is associated with an increased fracture risk. However, evidence on its association with bone mineral density (BMD) is conflicting, and data on bone microarchitectural quality are scarce. The in vivo effects of anti-hypertensive medications on bone quality are poorly explored. The primary aim of this study was to evaluate whether bone microarchitecture, non-invasively assessed by trabecular bone score (TBS), is altered in hypertensive patients. The association between anti-hypertensive medications and TBS was also evaluated as a secondary endpoint. We extracted individual data of 7053 subjects included in the 2005–2008 cycles of the National Health and Nutrition Examination Survey (NHANES), in which lumbar spine dual-energy X-ray absorptiometry (DXA) scans were acquired. TBS values were calculated from DXA images using dedicated software. The association between hypertension, anti-hypertensive medications, and bone outcomes was assessed by regression analyses, adjusted for relevant confounders. Hypertension was independently associated with lower TBS values (β = −0.010; 95

OBJECTIVES:Differentiated and poorly differentiated thyroid cancer (DTC/PDTC) generally carries a favorable prognosis in the absence of persistent or recurrent disease. However, evidence indicates that long-term health-related quality of life (HRQOL) may remain impaired even in patients with good oncological outcomes. Real-world data on HRQOL among DTC/PDTC patients with a structural incomplete response (SIR), including those receiving tyrosine kinase inhibitors, are still limited. This study aimed to investigate the determinants of HRQOL in DTC/PDTC patients with SIR. METHODS:This prospective, multicenter, cross-sectional study enrolled a total of 148 adult participants with a cytologically or histologically confirmed diagnosis of DTC/PDTC and evidence of SIR. All participants completed the self-administered European Organization for Research and Treatment of Cancer questionnaires (EORTC QLQ-C30 and thyroid cancer-specific module QLQ-THY34), as well as the Hospital Anxiety and Depression Scale. RESULTS:Patients with SIR reported significantly reduced HRQOL compared with disease-free survivors, particularly in domains related to fatigue, sleep disturbance, concern for others, exhaustion, and joint pain. Neither disease management strategy (active surveillance vs tyrosine kinase inhibitor or other treatments) nor disease status (stable vs progressive) significantly predicted overall HRQOL. Lower physical functioning, female gender, and higher emotional distress were independently associated with poorer HRQOL, with gender-related differences emerging only among patients with preserved physical functioning. CONCLUSIONS:Despite the absence of a longitudinal design and internal control group, this study emphasizes the importance of systematically assessing HRQOL in DTC/PDTC patients with SIR and highlights the interplay between psychosocial factors and functional status in shaping patient-reported outcomes.

CONTEXT:The role of copeptin in assessing hyponatremic patients at emergency department (ED) admission remains debated. OBJECTIVE:This work aimed to assess copeptin's effectiveness in evaluating extracellular fluid (ECF) volume and its predictive value in hyponatremic adults admitted to the medical ED. METHODS:This work comprises a report from the IPSO-URG, a prospective cohort study with recruitment from June 2018 to August 2019 and 6-month follow-up. The setting is a medical ED of a single tertiary center. Patients included a consecutive sample of 123 adults with hyponatremia confirmed by direct and indirect ion-selective electrode assay after glucose correction. Excluding 33 individuals with missing consent or criteria and 6 without hypotonic hyponatremia, 84 patients were analyzed. Data included symptoms, vital signs, ultrasound, medical history, Charlson Comorbidity Index, and pretreatment blood and urine samples. ECF status was reassessed post discharge by 3 endocrinologists, blinded to copeptin results, who classified cases etiologically and resolved disagreements through discussion. In-hospital and 6-month mortality were recorded. RESULTS:A copeptin-to-urinary sodium (u-Na) ratio less than or equal to 29.5 pmol/mmol increased the likelihood of preserved ECF more than 4-fold (odds ratio 4.28; P = .026), outperforming standard u-Na (area under the curve difference 0.177; P = .013). Copeptin predicted in-hospital mortality (hazard ratio [HR] 1.005), with greater than 60.1 pmol/L as the optimal cutoff (P = .0005). Copeptin (HR 1.005; P = .02), N-terminal prohormone of brain natriuretic peptide (HR 1.004; P = .031), and comorbidity burden (HR 1.207; P = .009) predicted 6-month mortality, with copeptin greater than 13.6 pmol/L indicating a more than 4-fold risk (HR 4.507; P = .0001). CONCLUSION:Measuring copeptin on ED admission in hypotonic hyponatremia aids diagnosis and mortality prediction. The copeptin/u-Na index more accurately identifies preserved ECF than the standard u-Na cutoff.

Endogenous Cushing’s syndrome (CS) is rare, with an incidence of 0.7–2.4 per million population per year according to population-based studies. However, evaluation of patients presenting disorders potentially related to cortisol excess, and therefore with a ‘high risk of clinical suspicion’ profile, could bring out several unrecognized cases. CS represents one of the most challenging endocrine diseases, with clinical features overlapping with those of common conditions affecting general population, invariably resulting in potential mis- or delayed diagnosis with negative consequences in terms of morbidity and mortality. CS is remarkably prevalent among young females, variably presenting with menstrual irregularities and/or signs and symptoms of hyperandrogenism. Herein we briefly reviewed literature on prevalence and clinical impact of menses abnormalities, acne and hirsutism -also coexisting in the context of a polycystic ovary syndrome- in CS, aiming at clarifying if, when and how to screen for hypercortisolism young women with these disorders.

BACKGROUND:Cyclic Cushing's syndrome (cCS) features fluctuating cortisol secretion, often causing diagnostic errors or delays, and possibly poorer outcomes. We aimed to identify unpublished cCS cases to characterise clinical challenges and guide strategies for improving outcomes by characterising cycle patterns, peak frequency, and evaluating complications. METHODS:This was a retrospective observational study at 43 endocrine centres in 21 countries, including patients with confirmed Cushing's syndrome showing two or more hypercortisolaemic peaks and one or more spontaneous eucortisolaemic or hypocortisolaemic trough. Data included both clinical (eg, comorbidities and physical signs of cortisol excess) and biochemical (eg, screening and confirmatory tests) parameters, imaging, treatment, complications, and outcomes. FINDINGS:Between Dec 1, 2023 and Feb 2, 2025, 116 potentially eligible patients were identified and 110 were included. Most patients were female (84 [76%] of 110 patients), with a median age at diagnosis of 44·0 years (IQR 31·8-58·3). cCS origin was pituitary in 70 (64%), ectopic in 25 (23%), adrenal in three (3%), and occult in 12 (11%). Cyclicity was primarily determined by 24 h urinary free cortisol, with median peaks of 7·40 × ULN (range 0·44-299) and troughs of 0·31 × ULN (0·02-0·98). The median peak count was 3·0 (IQR 2·0-4·0), mostly (55 [86%] of 64 patients) occurring at irregular intervals, and was most frequent and pronounced in ectopic cCS. Symptoms worsened in 87 (81%) of 108 patients during peaks and improved in 79 (74%) of 107 patients during troughs; 31 (28%) of 110 patients had spontaneous adrenal insufficiency. Bilateral inferior petrosal sinus sampling (BIPSS) was performed during troughs in 14 patients (18% of the 78 procedures done). Imaging missed tumours in 35 (32%) of the 110 patients, and nine (8%) underwent unwarranted surgeries at the wrong anatomical site due to misclassification. After 5·8 years (IQR 2·6-10·5) median follow-up, 55 (50%) of 110 patients had complete biochemical surgical remission, seven (6%) had spontaneous remission, 22 (20%) were medically controlled, six (5%) had partial remission, 11 (10%) remained uncontrolled, nine (8%) were lost to follow-up. During the entire observation period, 3% (3/110) died. Delayed diagnosis (45 [41%] of 110 patients) and therapy (47 [43%]) were also observed. INTERPRETATION:Even in specialised centres, cCS diagnosis and management remain challenging with high rates of spontaneous adrenal insufficiency, inappropriate surgeries, and poor outcomes. Ectopic cCS showed the most frequent and severe peaks. These findings might help to guide imaging localisations or the timing of BIPSS in patients with active occult ACTH-dependent cCS. Hypercortisolism needs to be biochemically confirmed before BIPSS to enable correct tumour localisation. Patients with suspected or proven cCS should be equipped with salivary cortisol collection kits to capture dynamic changes as well as being prescribed glucocorticoids to be used as a precaution. FUNDING:None.

Background: Tyrosine kinase inhibitors (TKIs) are crucial to treating endocrine-related malignancies, including advanced thyroid cancers and neuroendocrine tumors, but their benefit is tempered by cutaneous adverse events (CAEs) that impair adherence and quality of life. Objective: To summarize the dermatologic toxicities of TKIs used in endocrine oncology and provide practical, multidisciplinary guidance for prevention and management. Methods: Narrative synthesis of clinical trial reports, post-marketing studies, and specialty guidelines pertinent to lenvatinib, vandetanib, cabozantinib, and other commonly used TKIs, integrating dermatologic and endocrine perspectives on mechanisms and care pathways. Results: VEGFR-targeted TKIs frequently cause hand-foot skin reaction, xerosis, fissuring, paronychia, and impaired wound healing; multikinase inhibition also produces alopecia, pigmentary changes, and mucositis. Epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) inhibition with vandetanib is associated with acneiform eruption, photosensitivity, and nail fragility. Pathogenesis reflects on-target inhibition of VEGF/EGFR signaling leading to keratinocyte dysfunction, vascular fragility, and altered eccrine mechanics. Early risk stratification, patient education, and bundle-based prophylaxis (emollients, keratolytics, urea-based creams, sun protection) reduce incidence and severity. Grade-based algorithms combining topical corticosteroids/antibiotics, dose interruptions or reductions, and short systemic courses (e.g., doxycycline, antihistamines) enable symptom control while maintaining anticancer intensity. Close coordination around procedures minimizes wound-healing complications. Conclusions: Dermatologic toxicities are predictable, mechanism-linked, and manageable with proactive, multidisciplinary care. Standardized prevention and treatment pathways tailored to specific TKIs-particularly lenvatinib, vandetanib, and cabozantinib-can preserve dose intensity, optimize quality of life, and sustain antineoplastic efficacy.

Background: Differentiated thyroid carcinoma (DTC) in pediatric patients has specific clinical, pathological, and molecular characteristics, making its management different from that of adults. Our study aimed to evaluate the outcome and factors associated with persistent disease in a large cohort of pediatric patients. Methods: We performed a multicenter retrospective cohort study, including patients aged ≤18 years, diagnosed with a DTC, since January 2000. Both biochemical (BIR) and structural (SIR) incomplete responses were evaluated. Results: We included 538 patients, 401/538 (74.5%) females, with a median age of 15 years (interquartile range [IQR] 13-17 years). Papillary thyroid cancer was the most prevalent histotype and 277/530 (52.3%) had lymph node metastases at diagnosis. Vascular invasion and gross extrathyroidal extension (ETE) were reported in 133/326 (40.8%) and 91/533 (17.1%) of patients, respectively. T4 tumors represented 5% of the entire cohort. Radioactive iodine treatment (RAIT) was administered to 493/533 (92.5%) patients, and among them 138/493 (28%) received more than one RAIT cycle. After a median follow-up of 85 months (IQR 42-126 months), 414/538 patients (77%) had no evidence of disease and 124/538 patients (23.0%) a disease persistence: BIR in 68/538 patients (12.6%) and SIR in 56/538 patients (10.4%). In a multivariable analysis, the features significantly associated with persistent disease (BIR or SIR) were gross ETE (odds ratio [OR] 2.81, confidence interval [CI] 1.49-5.32, p = 0.0015) and lymph node uptake at whole-body scan (WBS) after the first RAIT (OR 3.31, CI 1.77-6.19, p = 0.0002). Multivariable analysis showed that the features significantly associated with SIR were T4 tumor (OR 4.3, CI 1.38-13.44, p = 0.01) and lymph node uptake at WBS after the first RAIT (OR 3.39, CI 1.5-7.67, p = 0.003). Conclusions: Our study of a very large series of pediatric DTC with long follow-up provides valuable insights into the clinical and pathological features associated with disease persistence. We identified T4 tumor, lymph node uptake on WBS, and gross ETE as independent factors associated with persistent disease. These findings emphasize the importance of careful risk stratification in pediatric DTC, allowing for more individualized treatment approaches.

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.