CONTEXT:Precision medicine has transformed many areas in oncology. However, it remains largely unexplored in metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), where there is a need for further innovative therapies. OBJECTIVE:To evaluate individual tumor responses to different agents, we have established a standardized personalized drug screening and risk assessment platform using patient-derived GEP-NEN primary cultures (n = 23, 16/23 from metastatic tumors, n = 12 small intestinal neuroendocrine tumors [siNETs], n = 10 pancreatic NETs [pNETs], n = 1 neuroendocrine carcinoma [NEC]). METHODS:We assessed GEP-NEN primary culture cell viability, performed signaling pathway analysis by automated Western blotting and immunohistochemically evaluated tumor composition. RESULTS:Systematic drug testing of 27 agents including signaling inhibitors (i) (mechanistic target of rapamycin inhibitor [mTORi] everolimus, tyrosine kinase inhibitors cabozantinib/sunitinib, AKTi capivasertib, PI3Ki alpelisib, CDK4/6i ribociclib), DNA damage response inhibitors (PARPi niraparib, WEE1i adavosertib, ATRi berzosertib), chemotherapeutics (temozolomide, 5-fluorouracil, lurbinectedin), drug repurposed agents (zoledronic acid), and a personalized risk assessment (glucagon-like peptide [GLP]-2 analogue teduglutide, GLP-1 analogue semaglutide, sex hormones) was performed. We demonstrated statistically significant group effects and individualized responsiveness/resistance data. We identified differences in drug response between pNETs/siNETs and between GEP-NETs/GEP-NEC, respectively. CONCLUSION:We provide novel data on the efficacy of putative and established therapies in patient-derived GEP-NEN primary cultures. Our standardized platform for personalized drug screening and risk assessment in GEP-NEN primary cultures enables prediction of individual tumor treatment response in this orphan disease.

CONTEXT:Pheochromocytomas and paragangliomas (PPGL) are rare endocrine tumors with high heritability. Carriers of pathogenic variants (PVs) in susceptibility genes face a lifelong risk of recurrence or metastatic disease. Quality of life (QoL) in patients with PPGL, a history of PPGL and PV carriers, remains insufficiently studied. METHODS:We assessed patient-reported QoL in patients with PPGL before and after surgery and in carriers of susceptibility PVs for the development of PPGLs within the prospective ProsPheo study. QoL was evaluated using standardized questionnaires (SF-12, PHQ-D, and GAD-7). RESULTS:A total of 202 participants were analyzed. SF-12 physical component summary scores (PCS) differed significantly across subgroups (P = .006), with the lowest PCS scores in patients with metastatic PPGL (40.3) and unresected head and neck paragangliomas (HNPGL) (40.0), compared with PV carriers after curative PPGL resection (50.2). Within metastatic disease, hormonally active tumors showed lower PCS scores than inactive tumors (36.9 vs 46.2; P = .03). Perceived physical health in carriers of a PV without history of a PPGL was significantly lower compared to the age-matched general population. Mental health was not significantly impaired across all subgroups. Clinically relevant anxiety was reported in 15.2% of PV carriers and 21.7% of patients with unresected HNPGLs, compared with about 5.9% in the general population. CONCLUSIONS:Patient-reported physical health was reduced in patients with metastatic PPGLs, unresected HNPGLs, and PV carriers without prior PPGL, whereas patients after curative PPGL resection reported QoL comparable to the general population, regardless of PV status, suggesting that annual follow-up has minimal impact on QoL.

Glucocorticoid-producing cells of the adrenal cortex (i.e. zona fasciculata, zF) constitute the critical effectors of the hypothalamic-pituitary-adrenal axis, mediating the mammalian stress response. With glucocorticoids being essential for life, zF dysfunction perturbs multiple organs that participate in optimizing cardiometabolic fitness. The zF forms a dynamic and heterogenous cell population endowed with the capacity to remodel through the engagement of both proliferative and differentiation programs that enable the adrenal to adapt and respond to diverse stressors. However, the mechanisms that sustain such differential responsiveness remain poorly understood. In this study, we resolve the transcriptome of the steroidogenic lineage by scRNA-seq using Sf1-Crehigh; RosamT/mG reporter mice. We identify HHEX, a homeodomain protein, as the most enriched transcription factor in glucocorticoid-producing cells. We utilize genetic mouse models to demonstrate that Hhex deletion causes glucocorticoid deficiency in male animals. Molecularly, we demonstrate that HHEX is an androgen receptor (AR) target gene, shaping the sexual dimorphism of the adrenal gland by repressing the female transcriptional program at puberty, while also maintaining zF cholesterol ester content by protecting lipid droplets from androgen-induced-lipophagy. Moreover, our study reveals that, in both sexes, HHEX is crucial for maintaining the identity of the innermost adrenocortical cell subpopulation. Specifically, loss of HHEX impairs the expression of Abcb1b (P-glycoprotein/MDR1), an efflux pump regulating steroid export and cellular levels of xenobiotics. Together, these data demonstrate that HHEX serves as a multi-functional regulator of post-natal adrenal maturation that is potentiated by androgens. In the adrenal cortex, cholesterol used for steroid production is stored in lipid droplets. The authors demonstrate here the importance of the transcription factor HHEX in maintaining glucocorticoid levels and protecting lipid droplets from androgen-induced lipid depletion.

OBJECTIVES:Screening for primary aldosteronism (PA) using the aldosterone:renin ratio (ARR) has suboptimal diagnostic accuracy, particularly in females. We assessed whether accuracy could be improved using sex-specific relationships of aldosterone with renin. METHODS:Plasma aldosterone and renin were measured in 442 females and 491 males prospectively screened for PA. Patients were divided into test (n=717) and validation (n=216) cohorts. Sex-specific cut-offs for renin-dependent aldosterone concentrations and the ARR were developed using logistic regression models in the test cohort. Diagnostic performance of models in both cohorts was compared to that of the ARR. RESULTS:Females without PA had higher (p<0.001) ARRs than males due to higher plasma aldosterone and lower renin concentrations. Consequently, rates of false-positives were higher (p<0.001) in females than males. At diagnostic sensitivities close to 95 % suitable for screening, and with sex-specific cut-offs for the ARR, specificities for the test cohort were 44 % in females compared to 73 % in males. Compared to the ARR, use of formulas (termed ARRplus) for sex-specific and renin-dependent cut-offs for aldosterone resulted in increased (p≤0.005) areas under receiver operating characteristic (ROC) curves for both sexes and enhanced specificity to 71 % in females and 82 % in males. Superiority of the ARRplus compared to the ARR was confirmed in the validation cohort according to ROC curve comparisons and 47-82 % reductions in false-positive results. CONCLUSIONS:Renin-dependent and sex-specific aldosterone cut-offs using the ARRplus offer higher diagnostic accuracy than the ARR and considerably reduced rates of false-positives to minimize follow-up of screened patients, particularly women.

Pancreatic neuroendocrine tumors (pNETs) are rare tumors, often detected at advanced stages for which current therapies are mostly unsuccessful. Despite significant progress in the understanding of pathogenic molecular pathways, most single targeted treatments only slow disease progression while patients develop resistance due to compensatory mechanisms. To identify novel combination therapies, we assessed the effects of TNFα, insulin and GSK3 inhibition (GSK3i) in spheroids of the metastatic pNET model BON-1 on subcellular localization and activation of cell cycle components and apoptosis. While cyclin D1 and CDK4 and 6 (cyclin-dependent kinase) stainings, related protein levels and apoptosis were not affected or only weakly affected by single treatments, the combinatorial treatments acted synergistically to induce cell death, as assessed by cleaved caspase-3 immunopositivity. Protein levels of CDK4 and CDK6 were furthermore validated in primary pNET cultures. Compensatory mechanisms under the single treatments might include activation of CDK1/2 and the DNA damage response, as assessed by the activation of phospho-Chk2, since this was perturbed under the combinatorial treatments. Taken together, our work identifies combinatorial treatments that substantially reduce the viability of spheroidal BON-1 cultures and patient-derived primary cultures as potential novel therapies for the treatment of pNETs.

BACKGROUND:Benign adrenal tumours, found in 1-7% of adults, can be non-functioning (NFAT) or show mild autonomous cortisol secretion (MACS), i.e., biochemical cortisol excess without manifestations of Cushing's syndrome (CS). MACS occurs in 20-50% of cases and is linked to increased cardiometabolic burden. METHODS:In a cross-sectional study, we analysed the 24-h urinary steroid metabolome of 1305 prospectively recruited patients (649 NFAT, 591 MACS, 65 adrenal CS) by tandem mass spectrometry. A sub-group (104 NFAT, 140 MACS, 47 adrenal CS) underwent untargeted serum metabolome analysis by mass spectrometry. Data were analysed using linear regression and supervised machine learning. FINDINGS:Alongside the expected increase in glucocorticoid excretion from NFAT over MACS to adrenal CS, steroid analysis revealed decreased classic androgen metabolite excretion. By contrast, adrenal-derived 11-oxygenated androgen metabolites remained unchanged. Both glucocorticoid metabolites and the major 11-oxygenated androgen metabolite 11β-hydroxyandrosterone correlated with a higher risk of hypertension and type 2 diabetes. Untargeted metabolome analysis revealed gradual changes towards a lipotoxic phenotype from NFAT over MACS to adrenal CS, with perturbations in glycerophospholipids, lysoglycerophospholipids, triacylglycerides, ceramides, sphingolipids, and acylcarnitines. INTERPRETATION:MACS represents a metabolic continuum between NFAT and adrenal CS. Increased activity of the adrenal enzyme 11β-hydroxylase (CYP11B1), which catalyses key steps in cortisol and 11-oxygenated androgen biosynthesis, may contribute to steroid excess and cardiometabolic morbidity in MACS. These findings suggest that CYP11B1 may be a potential therapeutic target to ameliorate metabolic dysfunction in MACS. FUNDING:NIHR Birmingham Biomedical Research Centre; Diabetes UK; Wellcome Trust; European Commission; Medical Research Council.

Context:Cushing syndrome (CS) is a rare disease with severe physical and psychological effects, especially depression, which often persists despite biochemical remission. Objective:The aim of this study was to identify possible prognostic markers for depression in patients with CS. Methods:Biochemical and clinical data from the German Cushing registry were retrospectively analyzed, along with the Beck Depression Inventory II and Patient Health Questionnaire-9 depression scores. Pain and body image were collected using the Fragebogen zum eigenen Körpers (Questionnaire on one's own body) (FBeK), Fragebogen Körperbild (Questionnaire on body image) (FKB-20), and a numerical analogue scale for pain. The study included 90 patients with CS and 200 controls with clinically suspected but biochemically excluded CS. For detailed analysis, 15 CS patients with and 10 CS patients without depression were examined. Results:Manifest depression was diagnosed in 44% of CS patients. There were no significant differences in anthropometric or biochemical parameters between patients with and without depression. Patients with persistent depression exhibited significantly more negative body image results (FBeK: scales 1 and 2, P < .001; FKB-20: vital body dynamics, P < .001; and negative body perception, P = .02). They also reported significantly higher pain levels (P < .001). A significant correlation between pain and body image disturbances was found in most questionnaires. In comparison to depressive and obese groups from the literature, CS patients present with a complex body image disturbance. Conclusion:Pain and body image are relevant factors influencing depressive mood. CS treatment should address the physical changes and the body's lack of energy, strength, and ability to cope with everyday life.

Transcription factors orchestrate and shape cellular identity during development. Krüppel-like factors (KLFs) are involved in stemness, proliferation and apoptosis, while the master regulator steroidogenic factor 1 (SF-1) regulates the differentiation and steroidogenic profile of the developing adrenal gland. The transcriptional regulatory networks governing the heterogeneity of adrenocortical carcinomas (ACC) are incompletely understood. Here, we report the existence of model-dependent differences in the expression of SF-1, KLF9 and KLF13 and their cross-regulation in three ACC in vitro models (TVBF-7, NCI-H295R and MUC-1). We demonstrate that KLF9 and KLF13 are responsive to dexamethasone and angiotensin II, but undergo dosage-dependent repression by SF-1. Combinatorial silencing of these three transcription factors revealed that KLF9/KLF13 counteract SF-1 activity on nuclear receptors (glucocorticoid receptor and androgen receptor) and metabolic genes (IRF1, RARA, and FOXO3) forming a cross-regulatory loop that might modulate steroidogenesis. Transitioning to 3D spheroid cultures uncovered a KLF4-dependent regulation of the DNA damage response, shifting the balance between cell survival and apoptosis. Together, our findings identify a novel transcriptional axis composed of KLF9/KLF13 and SF-1, alongside KLF4-mediated cell cycle regulation, offering potential pathways for target-based therapeutic interventions in ACC.

How β-catenin (βCat) mediates tissue hyperplasia is poorly understood. To explore this, we employed the adrenal cortex as a model system given its stereotypical spatial organization and the important role βCat plays in homeostasis and disease. For example, excessive production of aldosterone by the adrenal cortex (primary aldosteronism [PA]) is a major cause of cardiovascular morbidity and is associated with βCat gain of function (βCat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona glomerulosa (zG) cells via a cadherin-βCat-α-catenin complex and mediate aldosterone production. Whether βCat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we showed that aldosterone secretagogues (K+ and AngII) and βCat-GOF mediated AJ formation via Rho/ROCK/actomyosin signaling. In addition, Rho/ROCK inhibition led to altered zG rosette morphology and decreased aldosterone production. Mice with zG-specific βCat-GOF demonstrated increased AJ formation and zG hyperplasia, which was blunted by Rho/ROCK inhibition and deletion of α-catenin (αCat). βCat also impacted AJ formation independently of its role as a transcription factor. Furthermore, analysis of human aldosterone-producing adenomas revealed high levels of βCat expression were associated with increased membranous expression of K-cadherin. Together, our findings identified Rho/ROCK signaling and αCat as key mediators of AJ formation and βCat-driven hyperplasia.

Aims Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality, both of which may persist after long-term remission. Our aim was to evaluate the prevalence of type 2 diabetes mellitus, fat distribution and other metabolic characteristics in patients with prior CS compared with matched population-based controls to assess metabolic risk factors. Methods Comorbidities were retrospectively analyzed in a cohort of 99 patients with CS from a single tertiary care center. Patients were longitudinally evaluated at baseline during active disease and at 7 years after biochemical remission. Data were compared to a control group matched for age and sex (n = 396) from the KORA study in a 1:4 fashion. Results Despite long-term improvements, patients with CS in sustained remission still exhibit adverse metabolic outcomes 7 years after remission, including higher relative fat mass (39% vs. 35%, p = 0.0013), a higher waist-to-hip ratio (0.89 vs. 0.82, p < 0.0001), elevated HbA1c (5.5% vs. 5.4%, p = 0.0087), and increased diabetes prevalence (19% vs. 4%, p < 0.0001) compared with controls. These persistent metabolic alterations were strongly associated with inflammatory markers, suggesting inflammation as a potential contributor to the sustained diabetes risk. Conclusion Patients with prior CS remain burdened by adverse metabolic profiles that may contribute to their increased long-term cardiovascular risk.

Commonly used screening tests for primary aldosteronism (PA) provide suboptimal diagnostic accuracy, particularly with antihypertensive medication use. This study utilized three datasets totaling 1380 patients with and without PA to develop machine learning models for screening based on plasma steroids, potassium, and renin. A feedforward neural network (FNN) model with steroids and potassium improved diagnostic accuracy compared to models without potassium. Inclusion of renin negligibly improved accuracy. The FNN and other renin-independent models showed similar accuracy before and after antihypertensive medication washout, whereas renin-dependent models exhibited poorer accuracy without medication washout. Three further optimized renin-independent models outperformed the aldosterone-to-renin ratio (ARR) for screening according to areas under receiver-operating-characteristic curves of 0.948-0.954 versus 0.839 for the ARR. Those models minimize need for medication washout and, at cut-offs for optimal 90-95% diagnostic sensitivity, reduce false positives by 53-72% to more effectively screen for PA than with the ARR.

BACKGROUND:Primary aldosteronism (PA) has been linked with reduced health-related quality of life (QoL) and increased prevalence of anxiety and depression. While most studies compared patients with PA to healthy subjects, this study focused on comparison with hypertensive patients without PA to identify PA-specific effects. Furthermore, the impact of targeted therapy on QoL and mental health was evaluated. METHODS:Mental and physical health-related QoL, anxiety and presence of depressive and panic symptoms were assessed using the SF-12, GAD-7 and PHQ questionnaires in 925 patients with arterial hypertension tested for PA in a prospective, multi-center international prospective cohort study. Questionnaires were assessed at baseline as well as 3-6 months after initiation of targeted therapy. RESULTS:Amongst 833 of 925 patients who completed the necessary diagnostic procedures, 211 were diagnosed with PA. 98 of 116 patients with unilateral PA received unilateral adrenalectomy. At baseline, QoL, anxiety and mental health scores did not differ in patients with PA vs patients with hypertension without PA. At outcome assessment, SF-12 mental and physical component summaries as well as GAD-7 specifically improved in patients with unilateral PA after adrenalectomy (mean Δ = 4.2, p = 0.018, Δ = 3.6, p = 0.038 and Δ = -1.9, p = 0.006, respectively) in contrast to no improvement in patients with PA on MRA treatment. CONCLUSIONS:There was no difference in health-related QoL, anxiety and mental health in patients with hypertension with versus without PA. Unilateral adrenalectomy but not medical therapy improved health-related QoL and decreased anxiety in patients with PA.

Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with poor survival rates and few treatment options. Preclinical models are indispensable to further strengthen our understanding of disease progression and development of novel therapeutic treatments. Here, we report the establishment of a new cell line named ZUC-1 originating from the resection of an advanced primary ACC and its characterization at the genomic, cellular and molecular level. ZUC-1 cells were successfully propagated as monolayer cultures and three-dimensional spheroids. LC-MS/MS analysis revealed for ZUC-1 cells co-secretion of cortisol, aldosterone and testosterone, and the model represented in direct comparison with other current ACC pre-clinical models furthermore significantly elevated expression of SF-1, CYP11B1 and CYP11B2 genes. Whole genome sequencing identified various mutations in genes linked to DNA repair/stress response, stemness, and also steroidogenesis. Interestingly, ZUC-1 represents genotypic and phenotypic variations that might be of interest beyond ACC, including congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS). Moreover, 18-oxocortisol and 18-hydroxycortisol release was detected in ZUC-1, conditions which are often linked to hyperaldosteronism, but forskolin, potassium and, at higher concentration, angiotensin II modulability of CYP11B2 for this model is retained. ZUC-1 spheroids exhibited furthermore an intra-spheroidal heterogeneous mix of canonical and non-canonical Wnt pathway activation. We conclude that due to its origin and unique geno- and phenotypes, ZUC-1 represents an intriguing model to further gain a basic understanding of adrenal function, the pathogenesis of ACC, but it might be also of interest in the context of CAH and PCOS.

CONTEXT:Cushing´s syndrome (CS) is associated with an unfavorable lipid profile. However, data on lipid alterations during early postoperative remission, a particularly cardiovascular vulnerable period, are lacking. OBJECTIVE:Evaluation of lipid profiles during active CS and the early postoperative period. PATIENTS AND METHODS:In this single-center cohort study at LMU Hospital Munich, we analyzed lipid profiles (Total cholesterol, LDL, HDL, ApoA1, ApoB, Lipoprotein (a), Triglycerides and Non-esterified fatty acids) and metabolic markers in 26 patients with endogenous CS before surgery and 1, 3, 6, 12 and 24 months (n=23) after curative surgery, and compared them with 26 age-, BMI-, and sex-matched controls without hypercortisolism at baseline. RESULTS:Paradoxically most lipid parameters postoperatively worsened. One month postoperatively, HDL (1mo postoperative 38 mg/dL [35-46] vs. active CS 49.5 mg/dL [45-61.3], p<0.0001) and ApoA1 concentrations (1mo postoperative 160 mg/dL [147-168] vs. active CS 193 mg/dL [169-211], p<0.0001) were significantly lower compared to preoperative levels. Similarly one month following surgery triglycerides concentrations (1mo postoperative 185 mg/dL [154-218] vs. active CS 129 mg/dL [89.3-186] preoperatively, p<0.0001) were higher. These changes remained evident until 6 months post-surgery. The triglyceride-glucose index increased during early remission and showed a positive correlation with inflammatory markers CRP and IL-6. Non-esterified fatty acids displayed three distinct postoperative trajectories depending on BMI at baseline. CONCLUSION:During the early remission phase following curative surgery, we observed a further deterioration in lipid parameters. This can affect cardiovascular health and provides the basis for targeted therapy.

Pheochromocytomas and paragangliomas (PPGLs) are endocrine tumors that may express somatostatin receptors (SSTRs). Importantly, SSTR2 expression is associated with metastatic behavior and succinate dehydrogenase B (SDHB) pathogenic variants. Somatostatin receptor analogue (SSA) positron emission tomography-computed tomography (PET/CT) is therefore widely used for diagnosis and localization of PPGLs, particularly in extra-adrenal, metastatic, or SDHB-related disease. This study aimed to evaluate whether cellular SSTR expression by immunohistochemistry (IHC) correlates with radionuclide uptake on SSA PET/CT and could serve as a biomarker for detectability on SSA imaging. In 35 patients with PPGLs treated at the University Hospital Zurich, IHC for SSTR2 and SSTR5 was performed on tumor tissue samples and evaluated both manually and with digital image analysis (DIA). SSTR2 mRNA expression was determined by qRT-PCR. The association of SSTR expression at the cellular level and standardized uptake value (SUV) on [68Ga]Ga-DOTATATE PET/CT was analyzed. IHC expression was assessed in 38 lesions. Manual and DIA quantification of IHC SSTR2 expression correlated strongly (rs 0.86; p < 0.001). Manual SSTR2 expression correlated with both liver-corrected PET maximum SUV (SUVmax) (rs 0.53, p = 0.001) and liver-corrected PET mean SUV (SUVmean) (rs 0.48, p = 0.002) of the corresponding lesion. SSTR2 expression by IHC was highest in head and neck paragangliomas (HNPGLs), with significantly higher SUVmax and SUVmean compared to pheochromocytomas and abdominal paragangliomas. SSTR2 mRNA expression did not correlate with SSTR2 expression by IHC or PET metrics. SSTR2 expression by IHC correlates with [68Ga]Ga-DOTATATE uptake, with highest expression found in HNPGLs.

OBJECTIVE:Subtyping of primary aldosteronism usually requires adrenal vein sampling (AVS). Interpretation can be compromised by apparent bilateral aldosterone suppression (ABAS), which we hypothesised reflects an artefact of the Liaison immunoassay of aldosterone. We therefore compared measurements of aldosterone by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with those by Liaison and iSYS immunoassays. DESIGN:Observational multicentre study. PATIENTS:The study involved 216 patients who underwent bilaterally selective non-stimulated AVS. MEASUREMENTS:Adrenal and peripheral venous plasma aldosterone concentrations were measured by Liaison and iSYS immunoassays in 110 and 106 respective samplings compared to LC-MS/MS in all. Ratios of aldosterone-to-cortisol below 1.0 in adrenal versus peripheral vein samples defined relative aldosterone suppression. RESULTS:Among all AVS procedures, 9.7% (21/216) of samplings with immunoassay measurements showed ABAS, threefold more (p = 0.0004) than the 3.2% (7/216) with LC-MS/MS. Rates of ABAS were particularly high with the Liaison immunoassay compared to LC-MS/MS (14.5% vs. 0.9%, p < 0.0001) and remained higher after substitution of immunoassay-measured with LC-MS/MS-measured cortisol (10.9% vs. 0.9%, p = 0.0007). Among 106 procedures involving iSYS immunoassay measurements, rates of ABAS at 4.7% were a third (p = 0.0202) those of the Liaison immunoassay and did not differ from LC-MS/MS measurements (5.7%). ABAS confined to LC-MS/MS measurements in one patient was resolved by a second sampling that revealed pronounced aldosterone secretion versus earlier suppression. CONCLUSION:ABAS is a relatively common artefact of the Liaison immunoassay of aldosterone. More rarely, ABAS may reflect sampling blood from an adrenal venous tributary that does not drain from the site of excess aldosterone secretion.

BACKGROUND:Biopsy of phaeochromocytomas and paragangliomas (PPGLs) is discouraged due to the perceived risk of catecholamine-related complications. However, a systematic review showed that this recommendation is primarily supported by case reports. We aimed to assess the safety of percutaneous biopsy in patients with PPGLs. METHODS:This international, multicentre, retrospective study included patients of any age with PPGLs referred to participating centres who had had percutaneous core-needle biopsy or fine-needle aspiration. Biopsies of head and neck paragangliomas were excluded. Participating centres completed standardised data-collection forms. The primary outcome was biopsy-related mortality rate for all patients who had biopsies performed at participating centres, given that biopsies done elsewhere that had fatal outcomes would be unlikely to be referred. Secondary outcomes included the incidence of serious catecholamine-related and non-catecholamine-related complications among all included patients. FINDINGS:Between Sep 1, 1993, and May 31, 2025, 222 patients (110 [50%] female, 112 [50%] male) underwent 234 biopsies in 19 hospitals across 11 countries. 139 (67%) of 207 patients had elevated epinephrine or norepinephrine (or metabolites) and 27 (12%) of 232 biopsies were preceded by the administration of α-adrenoceptor blockade. One (mortality rate 0·9% [95% CI 0·0-5·1]) of 106 biopsies led to death due to biopsy-related infection. Serious catecholamine-related complications occurred after four (1·7% [0·5-4·3]) of 233 biopsies and included tachyarrhythmia, hypertensive crisis, and cardiogenic shock. No serious catecholamine-related complications occurred in patients without catecholamine excess (n=59), receiving fine-needle aspiration (n=46), or after biopsy of metastatic lesions (n=114). Serious non-catecholamine-related complications occurred after ten (4·3% [2·1-7·8]) of 233 biopsies, mainly bleeding and infection. INTERPRETATION:Percutaneous biopsy of PPGLs was associated with a low mortality rate. Serious complication rates were also low, most of which were not catecholamine-related. These findings challenge current recommendations that biopsy should be avoided in suspected or confirmed PPGLs, and instead support a personalised, risk-benefit-based approach to the procedure. FUNDING:Cancerfonden. TRANSLATIONS:For the Chinese and French translations of the abstract see Supplementary Materials section.

Objective:Somatostatin receptor analogues are well-established in the treatment of metastatic gastro-enteropancreatic neuroendocrine tumours (GEP-NETs), especially for symptom control in patients with the carcinoid syndrome, and to control tumour growth. However, they need to be discontinued before peptide receptor radionuclide therapy (PRRT) as they may saturate the somatostatin receptor 2 (SSTR2) and prevent binding of the radioactive ligand. Design:We evaluated the effects of the novel somatostatin analogue paltusotine on 18F-SiTATE radioligand uptake and on GEP-NET cell viability in comparison to octreotide. Methods:Paltusotine and octreotide were evaluated in varying concentrations in an 18F-SiTATE uptake assay using stable hSSTR2 over-expressing BON-1 cells, and in a cell viability assay utilising different NET cell lines and human patient-derived GEP-NET primary cultures (n = 13). Results:Low, clinically-relevant concentrations of paltusotine (7.3-25.4 nM) demonstrated no influence on cellular radioligand uptake compared to the control. In contrast, octreotide reduced radioligand uptake at low, clinically-relevant concentrations (7.3-25.4 nM) and led to a further significant reduction of radioligand uptake at higher concentrations (73-508 nM). Both paltusotine and octreotide showed overall little or no significant anti-tumour effects in vitro in NET cell lines. However, in contrast to octreotide, paltusotine led to a slight decrease in cell viability of patient-derived GEP-NET primary cultures. Conclusions:Treatment with paltusotine did not significantly reduce radioligand binding of 18F-SiTATE in vitro, indicating no influence on SSTR2 targeting. This might enable a continuation of somatostatin receptor analogue therapy with paltusotine during PRRT, potentially improving symptom control in GEP-NET patients with the carcinoid syndrome.

OBJECTIVE:Individual patients' data sharing requires interoperability, security, ethical, and legal compliance. The aim was to assess the landscape and sharing capacities between endocrine researchers. DESIGN:A standardized survey (SurveyMonkey®) with 67 questions was sent to European Network for the Study of Adrenal Tumors centers. METHODS:Answers were counted as absolute numbers and percentages. Comparisons between inclusiveness target countries (ITC) and non-ITC (defined by Cooperation in Science & Technology Action) were performed using Fisher's exact test. RESULTS:Seventy-three centers from 34 countries answered the survey. Electronic health record (EHR) systems are now the main source of data (90%). However, significant variability was reported, entailing >35 EHR providers, and variable data collected. Variable stakeholders' implication for enabling data sharing was reported, with more lawyers (P = .023), patient representatives (P < .001), ethicists (P = .002), methodologists (P = .023), and information technology experts (P < .001) in non-ITC centers. Implication of information technologies experts for data collection and sharing was underwhelming (33%). Funding for clinical research was higher in non-ITC than in ITC for clinical trials (P = .01) and for registry-based and cohort studies (P = .05). However, for retrospective studies addressing a specific clinical question, the funding was either very low (<10%) or nonexistent for both ITC and non-ITC (37% and 46%, respectively), with no dedicated funding for information technology (86%) and ethical and regulatory aspects (88%). CONCLUSIONS:In the absence of dedicated funding for retrospective research, current requirements for data sharing are obstacles.