Despite the universal calibration of commercial IGF1 immunoassays to WHO IS 02/254, substantial inter-assay variability persists, leading to inconsistent patient classification. Harmonization towards a higher-order analytical anchor may reduce such variability. Four matrix-matched, multi-level serum reference materials (RMs) were prepared from donor serum and value-assigned using an LC-MS/MS method calibrated to WHO IS 02/254. Commutability was assessed according to IFCC recommendations across four immunoassays (Cobas, iSYS, Immulite, Liaison). Deming regression-based recalibration equations derived from commutable RMs were applied to patient samples and healthy donor samples. The primary quantitative endpoint was reduction in standard error of estimate (SEE) relative to the LC-MS/MS method. Age- and sex-specific LC-MS/MS-anchored reference intervals were constructed as a downstream application. Prior to recalibration, immunoassays showed positive bias relative to LC-MS/MS of up to 60%. All four RMs were commutable for Liaison and iSYS, whereas the lowest concentration RM was classified as non-commutable for Cobas and Immulite. Recalibration towards the LC-MS/MS anchor resulted in marked alignment towards the identity line and reduced pooled SEE from 7.82 to 4.89 nmol/L (-37.4%) in patient samples and from 7.34 to 2.09 nmol/L (-71.5%) in healthy samples. Although harmonization effects were assay-dependent at the individual platform level, overall cross-platform dispersion was substantially attenuated. Matrix-matched, commutable serum RMs value-assigned by a higher-order LC-MS/MS procedure enable substantial reduction of inter-assay bias and variability among IGF1 immunoassays. Harmonization towards a higher-order analytical anchor is achievable in routine practice and provides a robust foundation for consistent cross-platform interpretation.

To evaluate the profile of patients and tumor features of differentiated thyroid carcinoma (DTC) with biochemical evidence without structurally demonstrable metastatic disease in the postoperative follow-up, regarding the response to empirical radioiodine therapy (RIT). A retrospective study of 196 patients with DTC followed up at a tertiary service from 1990 to 2018 was performed. All of them presented negative diagnostic whole-body scan (WBS) and high TG levels. Based on criteria indicating greater severity, as higher TG levels, 72 of them received empirical RIT. All remained in follow-up with their outcomes assessed. Carcinoma histopathological characteristics were similar between the groups of patients. In all the assessed moments, TG levels were higher in patients who received RIT than in patients who did not receive it. Regarding WBS after RIT, 57.74% of cases showed uptake, with one-third showing evidence of distant metastasis and 23.94% with cervical uptake in remnant/recurrence of thyroid or lymph node tissue. Patients who received RIT showed a partial reduction in suppressed serum TG, while patients who did not receive RIT exhibited stability of TG during follow-up. After radioiodine therapy administered with biochemical evidence of metastases but without identification of iodine-avid structural disease, metastatic foci avid for iodine were identified in 57% of cases, with a subsequent reduction in serum TG, indicating a potential therapeutic benefit. Despite similar tumor histopathological characteristics, the outcomes differed between patients who received RIT and those who did not, highlighting the importance of individualizing this indication.

X-linked hypophosphatemia (XLH) is the most common congenital phosphate disorder affecting individuals throughout the lifespan. We investigated the skeletal burden, the cardiovascular involvement, the diagnostic performance and the therapeutic management in a cohort of Italian adults with XLH. Cross-sectional study involving 15 Italian tertiary centers. Retrospective study. In total, 170 adults (110 females and 60 males), aged 44.6 ± 14.6 (19-83) years, were identified. i) Skeletal deformities were detected in 87.1% of individuals, fractures/pseudofractures in 44.7%, osteophytosis in 65.4% and enthesopathies in 57.6%. Dental disease affected 72.4% of individuals. The skeletal burden was heavier in males than in females. ii) Hypertension occurred in 14.7% of individuals and was associated with elevated plasma intact FGF23 levels; dyslipidemia, diabetes and cerebrovascular events occurred in very few individuals. iii) FGF23 levels were measured in 30.0% of individuals; they were >30 pg/mL (nv 23-95) in nearly all individuals but overtly elevated in 58.8%. Genetic analysis has been performed in 86.5% of the cohort, and PHEX mutations were identified in 95.2% of the individuals without evidence of genotype/phenotype correlation. iv) 44.2% of individuals were on conventional therapy, 32.5% were on burosumab, and 23.3% were untreated. Individuals having received diagnosis in the adulthood (n = 14) were neither medically nor surgically treated during their childhood. The burden of XLH disease in adulthood is determined by skeletal manifestations and dental disease and may be more severe in males. Additionally, cardiometabolic impairment may not be common. The disease burden impacts most of the individuals, beyond those presenting the criteria for burosumab reimbursement. Data from a consistent cohort of adults with XLH highlighted that skeletal and dental disease-related complications significantly affect XLH individuals during adulthood and aging. Skeletal features associated with aging occur earlier in adults with XLH, being more evident when untreated or poorly treated with conventional therapy. The disease burden impacts most of individuals, beyond those presenting the criteria for burosumab reimbursement. The study contributes in increasing awareness toward adult XLH individuals and provides data for implementing the disease management and the health policy planning.

ObjectiveThis study investigates the utilisation of modern glucocorticoid medications (Acecort®, Alkindi®, Efmody®, and Plenadren®) for congenital adrenal hyperplasia due to 21-hydroxylase deficiency, examining prescribing patterns, barriers to adoption, and geographical and temporal trends.MethodsA two-part study was conducted: a retrospective analysis of treatment regimens from the International Congenital Adrenal Hyperplasia Registry across 46 centres in 20 countries (2017–2023) and a qualitative survey of 39 centres regarding barriers to prescribing modern medications. Patients included both paediatric and adult populations. Data analysed included regional prescription trends, timing of modern glucocorticoid adoption, and identified barriers.ResultsFrom 2017 to 2023, 44 of 790 (5%) patients transitioned from traditional to modern glucocorticoid therapy, with the highest adoption in high-income Western European countries. Alkindi® was exclusively prescribed to patients under 8 years, while 97% of Efmody® users were 7 years or older. By 2023, modern glucocorticoid availability varied among centres: Alkindi® (54%), Efmody® (46%), Plenadren® (33%), and Acecort® (15%).ConclusionAdoption of modern glucocorticoid medications for congenital adrenal hyperplasia remains limited, with only approximately 5% of patients transitioning from traditional therapies. Significant barriers include legislative approval, supply chain challenges, and elevated costs.Plain language summaryThis international study looked at how new medications for congenital adrenal hyperplasia are used globally. We found that despite increasing availability of new medications during the study time period, only a small number of patients (5%) switched to these newer treatments. This limited use is mainly due to high costs, problems with getting legal approval, and supply issues, highlighting unequal access to care worldwide.

BackgroundCurrently, there is very limited information on referral patterns, diagnostic workup, and management of adrenal tumours (ATs) across secondary and tertiary endocrine centres in the UK.ObjectiveTo evaluate current practices in assessing and managing ATs across the UK, including diagnostic pathways and adherence to international guidelines on screening of patients with newly diagnosed ATs.MethodsA 12-item web-based survey was distributed to members of the Society for Endocrinology, UK (approximately 1,600 contacts), capturing centre characteristics, number of patients with ATs, and diagnostic strategies.ResultsIn total, 85 responses representing 80 centres were analysed. Over 45% of respondents, mainly from tertiary centres, reported more than 100 annual referrals. Malignancy rates were <5% in 89.5% of centres. Nearly all centres (99.8%) reported full or partial adherence to 2023 ESE–ENSAT guidelines. However, only 55% held regular adrenal-specific multidisciplinary meetings and 24% reported referral-to-diagnosis times exceeding 6 months. Steroid profiling (urinary or serum) was incorporated into diagnostic workup by 71.8% of centres.ConclusionsThis survey provides the first national overview of AT management pathways in the UK. Findings highlight strong guideline adherence but variability in multidisciplinary practice and diagnostic timelines. These data offer a foundation for policy development and future research, particularly as increasing incidental detections from cross-sectional imaging place growing demands on NHS resources.

AimsChemotherapy regimens can induce severe hyperglycemia, which may be underestimated using conventional point-of-care blood glucose (POC-G) measurement techniques. Real-time continuous glucose monitoring (rtCGM) systems may offer a more accurate assessment of glucose metabolism. In this study, we compared blood glucose monitoring using POC-G and rtCGM in patients with rare endocrine cancers caused by chemotherapy and steroid medication.MethodsIn this single-center observational study, we analyzed data from 76 hospitalized patients with pancreatic neuroendocrine tumors (n = 48) or adrenocortical carcinoma (n = 28) undergoing chemotherapy. Patients were monitored using either POC-G (n = 38) or rtCGM (n = 38). Glycemic metrics included time in range (TIR), prevalence of steroid-induced hyperglycemia (SIH), and HbA1c.ResultsUsing POC-G, TIR was 23.6 ± 0.9 h/day in patients without diabetes (NoD) and 20.0 ± 4.2 h/day in patients with diabetes undergoing chemotherapy (mean: five cycles). However, when rtCGM was used, drastic changes in TIR were documented under the same regimen. The mean TIR decreased from 21.7 h/day in patients with NoD to 14.6 h/day in patients with diabetes (P < 0.01). Similarly, the overall incidence of SIH was 30% using conventional POC monitoring, but this figure rose to 79% using rtCGM. During rtCGM use, HbA1c decreased by 0.3% over the course of the chemotherapy cycles, whereas during POC-G use, HbA1c increased by 0.2% (P < 0.01).ConclusionWe demonstrated a previously underestimated frequency of hyperglycemia and SIH in patients undergoing chemotherapy by using rtCGM. The use of rtCGM enabled more detailed recognition of dysglycemia and may improve glucose metabolism during and after chemotherapy regimens.

BackgroundThis study aimed to investigate the effects of miR-451 on proliferation, invasion, and migration of the papillary thyroid carcinoma (PTC) cell line TPC-1, focusing on its regulatory role in the PI3K/AKT/mTOR signaling pathway.MethodsTPC-1 cells were transfected with siRNA-NC, miR-451 mimic, or miR-451 inhibitor and treated with the PI3K activator 740Y-P (miR-451 mimic + 740Y-P) where indicated. Cell proliferation, migration, and invasion were assessed using MTT, wound healing, and transwell assays, respectively. Protein expression and pathway activation were analyzed by western blot.ResultsCompared to the blank and siRNA-NC groups, the miR-451 mimic group showed significantly lower expression of Bcl-2, p-PI3K, p-AKT, and p-mTOR proteins, along with significantly higher expression of Bax (P < 0.05). Conversely, the miR-451 inhibitor group exhibited significantly elevated levels of Bcl-2, p-PI3K, p-AKT, and p-mTOR and significantly reduced Bax expression (P < 0.05). Furthermore, compared with the miR-451 mimic group, the miR-451 mimic + 740Y-P group displayed significantly increased expression of Bcl-2, p-PI3K, p-AKT, and p-mTOR, along with significantly decreased Bax levels (P < 0.05).ConclusionsmiR-451 expression is significantly reduced in PTC tissues and TPC-1 cells. Overexpression of miR-451 inhibits proliferation, invasion, and migration in TPC-1 cells, likely via the PI3K/AKT/mTOR signaling pathway, suggesting its potential as a molecular target for further investigation in PTC.

ObjectiveTo determine the prevalence and clinical impact of rhabdomyolysis (RML) among adults hospitalized with diabetic ketosis.DesignTen-year retrospective single-center cohort study.MethodsWe reviewed adults admitted with diabetic ketosis, including isolated ketosis and diabetic ketoacidosis (2015–2024). RML was defined as peak creatine kinase >1,000 U/L; patients with confirmed acute myocardial infarction were excluded. The primary endpoint was a composite poor outcome, defined as in-hospital death or discharge against medical advice (DAMA) due to critical illness with a grave prognosis. Predictors of poor outcome were assessed using Firth-corrected multivariable logistic regression.ResultsOf 920 eligible patients, 18 (1.96%) developed RML. Compared with controls, patients with RML were older and more likely to have neurological comorbidities, recent falls, impaired consciousness, infection, effective serum osmolality >320 mOsm/kg, leukocytosis, higher C-reactive protein, elevated creatinine, acute kidney injury, markedly raised myoglobin, and elevated troponin I. RML was associated with a longer hospital stay, higher costs, a higher in-hospital mortality (11.1 vs 0.67%), and a higher rate of the composite poor outcome (16.7 vs 1.11%). Leukocytosis (>9.5 × 109/L; adjusted OR: 4.29, 95% CI: 1.35–14.37, P = 0.014) and troponin I > 0.03 ng/mL (adjusted OR: 5.79, 95% CI: 1.56–21.86, P = 0.009) independently predicted poor outcome.ConclusionsRML is an uncommon but important complication of diabetic ketosis, conferring a higher short-term mortality, healthcare use, and composite poor outcome. Routine screening for RML and concurrent inflammatory or cardiac injury provides a crucial window for early risk stratification, enabling clinicians to optimize therapeutic strategies and resource use for high-risk individuals.

PurposeSteroidogenic factor 1 (SF-1), encoded by NR5A1, is essential for spleen development and function. NR5A1 variants have been linked to abnormal spleen development. Hyposplenism exposes individuals to severe complications with potentially serious sequelae. This study aimed to determine the prevalence and principal features of hyposplenism in a cohort of French patients with NR5A1 variants.MethodsWe conducted a cross-sectional multicentre ancillary study among 34 patients carrying heterozygous NR5A1 variants within the GR-EX cohort, which includes individuals from families affected by red blood cell diseases. All participants underwent splenic imaging (ultrasound, CT, or MRI) and pocked red blood cell (pRBC) quantification. pRBC thresholds of <7%, 7–20%, and >20% corresponded to normal splenic function, moderate hyposplenism, and severe hyposplenism, respectively. The primary endpoints were the prevalence of hyposplenism and its severity.ResultsFunctional hyposplenism was observed in 21/34 patients (61.7%), including 16/34 (47%) with severe forms. Morphological spleen abnormalities were identified in 15/34 patients (44.1%), with asplenia in 4/34 (11.7%). All patients with morphological spleen abnormalities on imaging also presented functional hyposplenism. Conversely, 6/21 patients (28%) with functional hyposplenism showed no morphological abnormalities on imaging. No association was found between NR5A1 genotypes, gonadal phenotypes, and splenic anomalies.ConclusionsFunctional hyposplenism was frequent in this cohort of patients carrying NR5A1 variants, regardless of genotype and gonadal phenotype. Assessing splenic function is mandatory to help manage these patients. Preventive measures are also critical when hyposplenism is present.

BackgroundAdolescents and young adults (AYA) with rare forms of diabetes – including Wolfram syndrome (WS), Alström syndrome (AS), Bardet-Biedl syndrome (BBS), and maturity-onset diabetes of the young (MODY) – face unique challenges during the transition to adult care. These challenges are intensified by multisystem endocrine involvement, neurocognitive and sensory impairments, and limited adult provider expertise.ObjectiveThis narrative review describes transition-specific barriers in rare diabetes syndromes, explores current initiatives, and proposes recommendations for care models and health system reform.Key issuesSyndromic forms of diabetes often involve complex endocrine dysfunctions beyond glycemic control, including diabetes insipidus, hypogonadism, and thyroid or pituitary anomalies. Transitions are further hindered by diagnostic uncertainty, fragmented care structures, and insufficient interdisciplinary coordination. Pediatric care is often proactive and family-centered, while adult services are fragmented and reactive. Dedicated multidisciplinary transition services remain scarce.RecommendationsBest practices include early transition planning, syndrome-specific education, the use of patient-reported outcome measures (PROMs), and integration of digital tools. Structured collaboration between pediatric and adult providers – including virtual models – should be supported. Patient-centered approaches must address both medical and psychosocial readiness, with tailored communication for those with sensory or cognitive impairments.Health system and policy needsSustainable transition programs require dedicated funding, institutional prioritization, and policy inclusion in national and European rare disease frameworks. Without adequate financial support, disparities in care continuity and outcomes are likely to persist.ConclusionA coordinated, multidisciplinary, and resourced transition model is essential to safeguard health, autonomy, and long-term outcomes in AYA with rare diabetes syndromes.Plain language summaryYoung people with rare forms of diabetes – such as Wolfram syndrome (WS), Alström syndrome (AS), Bardet-Biedl syndrome (BBS), or maturity-onset diabetes of the young (MODY) – face special challenges when moving from pediatric to adult healthcare. These rare conditions often affect more than just blood sugar and can involve vision, hearing, and other parts of the body. As they grow older, these adolescents must not only manage their complex health needs but also learn to take more responsibility for their care. This article explains why the transition to adult care is especially difficult for this group. It shares experiences from families and healthcare providers and describes what can help: early preparation, teamwork between child and adult doctors, digital tools, and emotional support. The authors call for stronger guidelines and better cooperation across healthcare systems so that young people with rare diabetes can stay healthy and feel supported during this important time in life.Graphical abstract