CONTEXT:Partial lipodystrophies (PLD) can closely mimic the clinical presentation of Cushing's syndrome (CS). Simplified risk scores have been developed to estimate the clinical probability of CS. However, their ability to discriminate CS from overlapping conditions such as PLD remains unclear. Moreover, reduced leptin action in lipodystrophy may influence the hypothalamic-pituitary-adrenal (HPA) axis, although human data are limited. OBJECTIVES:To compare clinical and metabolic features of PLD and CS, evaluate the discriminatory ability of clinical risk scores for CS, and explore leptin-HPA axis interactions in PLD. METHODS:Retrospective multicenter study including 61 patients with PLD and 56 patients with CS. Clinical and laboratory data were retrieved from medical records. Two clinical risk score for CS were calculated, and PLD and CS features were compared. RESULTS:Most PLD patients showed at least one feature suggestive of hypercortisolism. Facial fullness, facial plethora, dorsocervical fat pad, and hirsutism (p < 0.001, p = 0.049, p < 0.001, and p < 0.001 respectively) were more frequent in PLD, while proximal muscle atrophy and osteoporosis (p < 0.001 and p = 0.010) were more common in CS. Higher rates of diabetes and hypertriglyceridemia were also observed in PLD (p < 0.001). PLD patients achieved similar or even higher clinical CS score values than CS patients. In multivariable regression analysis, proximal muscle atrophy and osteoporosis were associated with CS (p < 0.04), whereas diabetes and hypertriglyceridemia were associated with PLD (both p < 0.001). No correlation was found between leptin levels and glucocorticoid-related hormonal parameters. CONCLUSIONS:PLD patients often exhibit cushingoid features, limiting the specificity of simplified clinical risk scores for CS. Increased awareness of lipodystrophy phenotypes and their distinguishing features is essential to reduce misdiagnosis.

L’apoplessia ipofisaria è un’emergenza endocrinologica che richiede una valutazione e gestione tempestive a causa del potenziale rischio di mortalità associato al coinvolgimento dell’asse corticotropo. L’approccio terapeutico deve essere personalizzato in base alla presentazione clinica, con indicazione alla decompressione chirurgica urgente in caso di alterazione del livello di coscienza o deficit visivi. È generalmente necessario un follow-up a lungo termine per monitorare la funzione ipofisaria, poiché la maggior parte dei pazienti presenta un ipopituitarismo parziale o completo.

Background:Autoimmune gastritis (AIG) is characterized by chronic inflammation and represents a key step in the multistage precancerous process of the stomach. Patients with AIG are at increased risk of developing type I gastric neuroendocrine tumors (T1gNETs), but clinical and histological associated factors still remain incompletely defined. Aim:To evaluate the occurrence of T1gNETs in our AIG patients cohort and to identify clinical, biochemical, and histological factors associated with tumor development. Methods:Retrospective analysis of histologically confirmed AIG followed at Humanitas Research Hospital (from January 2020 to February 2025). Clinical, biochemical, and histological variables were extracted from a dedicated database. Associations between T1gNETs incidence and risk factors (smoking, BMI, gastrin,chromogranin- CgA levels, histology, clinical presentation) were tested using chi-square, Spearman and Mann-Whitney tests, with bootstrap-derived confidence intervals for effect sizes. Results:Among 175 AIG patients, 28 (16%) were diagnosed with T1gNETs. ECL cell hyperplasia emerged as the strongest histological factor associated with T1gNETs (82.1 vs 55.8; p= 0.0109, OR = 3.65). Conversely, dyspeptic symptoms showed a significant inverse correlation with tumor occurrence (21.4% vs 43.5%; p=0.035, OR = 0.35), suggesting that T1gNETs often develop in asymptomatic patients. No significant predictive value was found for smoking, alcohol, BMI, severe hypergastrinemia/CgA (>3x ULN) levels or degree of corpus atrophy, although a trend was observed for corpus metaplasia. Conclusions:Patients with AIG face significantly elevated occurrence of T1gNETs compared with the general population, with percentage being in line with recent studies. ECL hyperplasia was found as a factor associated with NET development, according to literature, confirming that the chronic stimulation of a cell with the ability to proliferate, results in tumors formation. Most patients with T1gNETs were asymptomatic and no correlation was found with smoking, alcohol and BMI. As a future perspective, these findings, even though preliminary, may help in the risk stratification of patients for more personalized endoscopic surveillance protocols, but further data are warranted to better standardize their use.

ContextThe potent inhibitory action on bone resorption and concomitant stimulatory effect on bone modeling make denosumab (DEN) as a possible alternative to anabolic drugs for treatment of severe osteoporosis.ObjectiveTo compare the real-world effectiveness of DEN and teriparatide (TPTD) in patients with severe osteoporosis.MethodsThis retrospective study included 357 patients (300 females, 57 males; mean age 70.2 ± 10.7 years) attending a referral center for osteoporosis in the period between July 2021 and June 2025. All the patients had indications for treatment with TPTD according to the national drug reimbursement criteria. However, 198 patients were treated with TPTD for 24 months, whereas 159 patients received DEN for contraindications to TPTD (110 cases), patient preference (39 cases) or side effects after few doses of the drug (10 cases). Patients were evaluated for clinical/morphometric VFs and non-vertebral fractures (NVFs) at baseline and after 24 months of treatment.ResultsDuring the study period, 34 patients (9.5%) developed new VFs (clinical in 13 cases) and 7 patients (2.0%) experienced NVFs. The risk of new VFs was significantly associated with vertebroplasty procedure (odds ratio 2.409; p=0.037). Moreover, new VFs occurred less frequently in patients treated with TPTD as compared to DEN (12/198 vs. 22/159; p=0.013). In the multivariable analysis, the favorable effect of TPTD on risk of VFs was still significant after correction for vertebroplasty (odds ratio 0.39; confidence interval 95% 0.19-0.83; p=0.014). No significant difference in NVFs was found between DEN and TPTD (2/159 vs. 5/198; p=0.468).ConclusionsThis real-world study shows that DEN might be less effective than TPTD in preventing VFs in patients with severe osteoporosis.

INTRODUCTION:Lung (LCs) and thymic carcinoids (ThCs) belong to thoracic well-differentiated neuroendocrine tumors (NETs), whose therapeutic options for advanced stages are limited. In the era of precision medicine, tyrosine kinase inhibitors (TKIs) remain a key focus of clinical investigation. This review evaluates the evolving role of TKIs in this setting. AREAS COVERED:This critical review analyzes the clinical evidence from pivotal trials regarding FDA/EMA-approved TKIs and those in advanced phases of clinical investigation for thoracic NETs, including combination strategies and tumor microenvironment modulators. EXPERT OPINION:Despite regulatory approvals (e.g. cabozantinib in 2025), TKI development faces ongoing challenges in balancing incremental efficacy with significant toxicity concerns. While some agents significantly improve progression-free survival, these gains are often overshadowed by high rates of grade 3-4 adverse events and treatment-related mortality. Consequently, alternative strategies with more manageable safety profiles are emerging. While an unfavorable benefit-to-toxicity ratio has hindered late-phase clinical trials, the persistent discrepancy in TKI performance across different malignancies suggests a developmental plateau in the NEN setting. Future research must shift toward multiomic profiling and the identification of novel actionable targets to prioritize personalized, better-tolerated therapies that balance clinical outcomes with quality of life.

The cAMP–protein kinase A (PKA) pathway is the major signal transduction pathway involved in melanocyte-stimulating hormone receptor-mediated signaling and melanin production, whereas its role in the control of melanocyte proliferation is still controversial. In this study, we evaluated the effects of selective activation of the different PKA regulatory subunits type 1A (R1A) and type 2B (R2B) on melanocyte proliferation. Immunohistochemistry demonstrated that normal melanocytes lacked R1A protein whereas this subunit was highly expressed in all human melanomas studied (N=20) and in six human melanoma cell lines. Pharmacological activation of the R2 subunits by the cAMP analogue 8-Cl-cAMP inhibited proliferation and increased caspase-3 activity by 68.77±10.5 and 72±9% respectively, in all cell lines with the exception of the only p53-mutated one. Similar effects were obtained by activating R2 subunits with other analogues and by silencing R1A expression. The antiproliferative and proapoptotic effects of 8-Cl-cAMP were comparable to those observed with commonly used antitumoral drugs. Moreover, 8-Cl-cAMP potentiated the effects of these drugs on both cell proliferation and caspase-3 activity. In conclusion, this study first reports that human melanomas are characterized by a high R1/R2 ratio and that pharmacological and genetic manipulations able to revert this unbalanced expression cause significant antiproliferative and proapoptotic effects in melanoma cells.

INTRODUCTION:Neuroendocrine neoplasms (NENs) classification and diagnosis have substantially advanced, prompting specialization of pathologists and clinicians in NEN fields and fostering close interdisciplinary collaboration. In these rare diseases, misdiagnosis may undermine therapeutic strategies, highlighting the importance of a strong clinician-pathologist partnership. While the NEN-dedicated pathologist's role is well acknowledged, in clinical practice, accurate histological review depends on the clinician's ability to pose focused diagnostic questions within a well-defined clinical context. METHODS:We retrospectively analyzed all NEN histological second opinions performed by a dedicated pathologist at our ENETS Center of Excellence in 01/2023-12/2024. Second opinions were requested by referring clinicians in cases of diagnostic uncertainty or clinical-pathological discordance. Discrepancies between initial and final diagnoses were categorized as "major" (with a substantial impact on patients' management) or "minor." RESULTS:Of 63 reviewed cases, we identified 36 not concordant cases. Among them, we reported 29/36 (81%) cases with significant discrepancies between the initial and the final diagnosis, with a following change in therapeutic strategy in 28 (e.g., shift from surveillance to surgery or modification of systemic therapy). Clinical requests for a histological review were prompted by inconsistency between clinical history and pathological diagnosis, incomplete or incoherent initial pathology report, or need for diagnostic confirmation to support specific clinical indications (e.g., surgery or chemotherapy). CONCLUSION:Our findings underscore the critical role of clinician's expertise in the multidisciplinary management of NEN patients. Underestimating clinician's role in coordinating the diagnostic process can lead to suboptimal care. Additionally, there is an urgent need to redesign the NEN care pathway, ensuring early access to specialized evaluation since the early diagnostic phase.

Bone metastases (BMs) are a rare and late event in patients with neuroendocrine tumors (NETs). The aim of our study was to investigate the clinical presentation and outcome of BMs in a large cohort of patients with NETs. A retrospective study was performed at two referral centers of Northern Italy (IRCCS Humanitas Research Hospital in Milan and Santa Maria della Misericordia University Hospital in Udine). Three hundred fifty-two consecutive patients with either gastroenteropancreatic or non-gastroenteropancreatic NETs were included: 52 patients with synchronous or metachronous BMs (BM-positive) and 300 patients with metastatic disease without BMs (BM-negative). Patients with BMs showed a higher prevalence of smoking habit (41.2 vs 21.8%, P = 0.004) and carcinoid syndrome (28.8 vs 5.7%, P <0.001) compared to patients without BMs. In addition, higher levels of chromogranin A (P = 0.001), urinary 5-hydroxyindoleacetic acid (P <0.001), parathyroid hormone (P = 0.022), and alkaline phosphatase (P = 0.018) were found compared to the BM-negative group. Patients with BMs had more frequently a primary lung NET compared to the BM-negative group (19.2 vs 0.7%, P = 0.001) and grade G2 or G3 gastroenteropancreatic tumors (P <0.001) compared to the BM-negative group. During a median follow-up of 4.2 years, a higher mortality rate was registered in the BM-positive group as compared to BM-negative group (42.3 vs 4.0%, P = 0.001). BMs were more common in patients with lung NETs, G2-G3 grade tumors, and in those with carcinoid syndrome. BMs affected patients' prognosis, highlighting the importance of investigating and managing this condition in patients with NETs.

Background:Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome (EAS) is a complex disorder caused by ACTH-producing tumors located outside the pituitary gland. EAS is most commonly associated with neuroendocrine neoplasms (NENs), rare malignancies category. Due to the nonspecific symptoms, EAS is often misdiagnosed, contributing to increased morbidity and complicating clinical management. In Italy, access to diagnostic and therapeutic resources for EAS and NENs varies significantly by region. As part of the 2024-2025 NIKE (Neuroendocrine Tumors, Innovation in Knowledge and Education) initiative, a multidisciplinary group, including endocrinologists, oncologists, pathologists, and nuclear medicine experts, designed a national survey to assess awareness, diagnostic approaches, and management of EAS in Italian centers. Methods:A 50-items structured questionnaire was developed, covering 3 sections: respondents' profile, diagnostic approaches, and treatment strategies. The survey was distributed as an anonymized form via email, with data collected from April to June 2025. Results:Sixteen Italian centers with NEN and EAS expertise participated. Most experts worked in European referral centers for rare tumors where the majority have an in-house, NEN-dedicated multidisciplinary team. Initial points of contact occurred most frequently in oncology (37.5%) and endocrinology (31.5%) clinics. A diagnostic delay was reported by 56% of respondent centers; hypokalemia was the most common presenting sign (93.8%). In 56.3% of centers, respondents reported that EAS was more commonly diagnosed before the detection of the underlying NEN, most frequently lung carcinoids or small/large cell cancers (87.5%). Regarding diagnostic practices, 56.3% of centers indicated the use of the 1 mg dexamethasone suppression test (DST), followed by the high-dose DST. The desmopressin test was considered outdated or replaceable by 43.8% of respondents. Regarding therapeutic approaches, respondents reported that upfront surgery was performed in up to 50% of centers, with preoperative bridging pharmacological therapy used to achieve eucortisolism. Osilodrostat was the most frequently preferred first-line treatment. Conclusion:This survey provides a valuable snapshot of EAS care in Italy, highlighting both strengths and areas for improvement. The findings underscore the need for a national, more structured referral network to ensure timely diagnosis and access to specialized care. These insights may guide national protocol harmonization in EAS management and better alignment with international standards.

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.

Objectives To evaluate whether adherence to oral bisphosphonate in patients with osteoporosis may be improved by teleconsultation (TC) with or without combined use of email to contact the bone specialist on-demand (enhanced TC).Methods 103 naïve patients with osteoporosis were prescribed branded alendronate (70 mg weekly) and randomised to three service modalities (presence, TC and enhanced TC), and evaluated for medication adherence after 12 months of follow-up. Patients allocated to the enhanced TC were provided with the opportunity to contact the bone specialists by email without any restriction. Patient-reported outcome(PROMs) and experience measures (PREMs) were evaluated with respect to the service modality.Results Of 89 patients who were persistent to therapy, 66% displayed optimal medication adherence, with odds being 4.5 higher in patients receiving enhanced TC versus those receiving the other services. TC service modality was considered in general to be worse in quality than in presence visits, whereas the combination with email use as in enhanced TC was sufficient to compensate for the perceived decrease in quality of care. Enhanced TC did not have any impact on the perception of quality of life as assessed by PROMs.Discussion In patients with osteoporosis, TC did not provide any advantage over traditional in presence visits in terms of improvement of adherence to therapy. However, when TC was combined with email to contact the bone specialist on demand, there was a significant improvement in adherence to the prescribed drug.Conclusions Patients with osteoporosis need to be supported after drug prescription to guarantee optimal medication therapy.

Background and aimsType I gastric neuroendocrine tumors (gNETs) are known for their favorable prognosis. We aimed to present a real-life experience at a tertiary referral center.Materials and methodsRetrospective analysis of patients diagnosed with type I gNETs at our Institution between 2014 and 2024.ResultsA total of 36 lesions were identified in 23 patients, with a median tumor size of 7 mm (range 2-20 mm). There were 29 out of 36 lesions that were G1, and 7 were G2. In 13 cases, endoscopic ultrasound (EUS) was performed prior to resection, revealing lymph node involvement in one 20-mm G1 lesion that required surgery. A 15-mm G2 lesion underwent surgery. In the remaining 34 lesions, endoscopic resection was performed: forceps in 5, cold-snare polypectomy in 4, hot-EMR in 22, EMR-cap in 1, ESD in 1, hybrid-ESD in 1. Among those, one 5-mm G2 lesion, previously removed via simple polypectomy, required surgery due to the 14.5% Ki-67 index. The median follow-up was 14 months (range 1-120), with 10 cases of local recurrence in 6 patients, median tumor size 3 mm (range 2-8 mm), all G1. In three cases, endoscopic surveillance was indicated; seven NETs underwent endoscopic resection (three forceps, two EMR-cap, two EMR), with EUS being performed in four cases with negative results. No local/distant metastases nor tumor-related deaths occurred.ConclusionsPresent data confirm an indolent behavior for type I gNETs. Preoperative EUS staging led to a change in the management in one case, which highlights the need of dedicated studies to identify predictive factors to stratify risk and plan the management of these neoplasms.

Purpose The real-world effectiveness of switching from denosumab to romosozumab remains controversial. Sequential therapy with romosozumab was shown to be associated with inadequate suppression of bone resorption and there was anecdotal evidence of major osteoporotic fractures (MOFs) after transitioning from denosumab to romosozumab. This study evaluated the effects on bone resorption of early romosozumab administration 3 months after denosumab withdrawal in fractured women with post-menopausal osteoporosis. Methods This prospective, single-center cohort study included 39 post-menopausal women with osteoporosis experiencing either MOFs or decrease in bone mineral density during long-term treatment with anti-resorptive drugs. Eighteen received romosozumab either 6 months (Group A) or 3 months (Group B) after their last denosumab dose, while 21 women switched from bisphosphonates to romosozumab and were enrolled as controls (Group C). Serum C-terminal telopeptide of type I collagen (CTX) levels were measured at baseline, 3 and 6 months. Results All women of group A and 4 out of 8 women of group B showed a clinically significant increase of CTX values (i.e., change above the least significant change) ( p = 0.023), which occurred earlier in group A as compared to group B. Moreover, 9/10 women of group A and 2/8 women of group B achieved values above the mean of reference range for pre-menopausal women ( p = 0.013). In group C, serum CTX values did not change significantly during the follow-up. Two women in Group A experienced MOFs during the follow-up. Conclusions Early romosozumab administration after denosumab withdrawal may control bone turnover rebound and possibly prevent incidence of fractures in post-menopausal osteoporosis.

PURPOSE: The incidence of inflammatory bowel diseases (IBDs) and gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) has increased, but their potential association remains unclear. Chronic inflammation in IBD may contribute to enteroendocrine cell hyperplasia and neoplasia, though evidence for a causal link is limited. This case series describes the characteristics and outcomes of patients with coexisting IBD and GEP-NETs at a tertiary referral center. METHODS: Retrospective case series including all consecutive IBD patients who were referred to the IBD Unit at the IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy, between January 2019 and December 2024 and who had been diagnosed with a GEP-NET. RESULTS: Nine Crohn’s disease patients (44.4% female, mean IBD diagnosis age: 51.1 years) also had GEP-NETs. The median interval between IBD and GEP-NET diagnoses was 39.3 months (0-180). In the totality of six cases that underwent surgical intervention, NETs diagnosis was incidental on the surgical specimen. Lesion sites included ileum (3), appendix (3), stomach (2), and rectum (1). Most NETs were G1 (88.8%); one required somatostatin analogues due to metastases. Treatments included surgery (6), endoscopy (2), and one pending. Over a median 24-month follow-up, no recurrences or disease-related deaths occurred. No cases of ulcerative colitis and concomitant GEP-NET ‘s diagnosis were observed in the patient cohort under consideration. CONCLUSIONS: Patients with Crohn’s disease may have a higher prevalence of GEP-NETs, possibly due to chronic inflammation and immune/microbiota dysregulation. This association does not appear to worsen disease outcomes. Larger studies are needed to explore underlying mechanisms.

Skeletal fragility is a complication of acromegaly closely related to hypersecretion of growth hormone (GH) and insulin-like growth factor-1. In this condition, altered-bone remodeling causes deterioration of bone microstructure and impairment of bone strength, resulting in a high risk of vertebral fractures. The management of skeletal fragility in acromegaly might be a challenge since prediction of fractures is difficult, biochemical control of GH hypersecretion does not restore normal bone structure in most of patients, and the efficacy of bone-active drugs in this clinical context is unknown. This article deals with emerging pathophysiologic, clinical, and therapeutic aspects of acromegalic osteopathy.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Somatostatin receptor ligands (SRLs) with high affinity for somatostatin receptors 2 and 5 (SSTR2 and SSTR5) are poorly efficacious in NF-PitNETs, expressing high levels of SSTR3. ITF2984 is a pan-SSTR ligand with high affinity for SSTR3, able to induce SSTR3 activation and to exert antitumoral activity in the MENX rat model. The aim of this study was to test ITF2984’s antiproliferative and proapoptotic effects in NF-PitNET primary cultured cells derived from surgically removed human tumors and to characterize their SSTR expression profile. We treated cells derived from 23 NF-PitNETs with ITF2984, and a subset of them with octreotide, pasireotide (SRLs with high affinity for SSTR2 or 5, respectively), or cabergoline (DRD2 agonist) and we measured cell proliferation and apoptosis. SSTR3, SSTR2, and SSTR5 expression in tumor tissues was analyzed by qRT-PCR and Western blot. We demonstrated that ITF2984 reduced cell proliferation (−40.8 (17.08)%, p < 0.001 vs. basal, n = 19 NF-PitNETs) and increased cell apoptosis (+41.4 (22.1)%, p < 0.001 vs. basal, n = 17 NF-PitNETs) in all tumors tested, whereas the other drugs were only effective in some tumors. In our model, SSTR3 expression levels did not correlate with ITF2984 antiproliferative nor proapoptotic effects. In conclusion, our data support a possible use of ITF2984 in the pharmacological treatment of NF-PitNET.