Martin Fassnacht

BACKGROUND: The cardiac hormone ANP (atrial natriuretic peptide) maintains intravascular volume homeostasis through coordinated endothelial and renal effects. Since in vitro studies suggested that this circuit involves the inhibition of adrenal aldosterone release, here we investigated whether ANP indeed mediates endocrine heart-to-adrenal communication in vivo. METHODS: Mouse models with zona glomerulosa (ZG)-restricted deletion of the ANP receptor, GC-A (guanylyl cyclase-A), or the downstream cyclic GMP-stimulated PDE (phosphodiesterase) 2A were established through Cre/LoxP technology. RESULTS: Immunoblots and immunohistochemistry demonstrated high expression of GC-A and PDE2A in ZG cells. Cell-specific deletion of GC-A led to mildly expanded ZG, with more aldosterone synthase-expressing cells and elevated plasma aldosterone. While in control mice a high-salt diet reduced ZG thickness and aldosterone production, in their ZG GC-A knockout littermates these responses were blunted, provoking hypervolemic hypertension. Notably, ZG PDE2A knockout mice did not exhibit such alterations. In cultured human adrenal cells, ANP counteracted the stimulatory effects of Angiotensin II on aldosterone synthase expression and cell proliferation pathways through activation of cGMP-dependent protein kinase I. Notably, in human aldosterone-producing adrenal adenomas, the expression of GC-A was markedly lower than in healthy adrenal cortical tissue, suggesting reduced ANP/GC-A signaling in the tumor cells. CONCLUSIONS: ANP-mediated heart-adrenal communication moderates ZG cell growth and aldosterone release and participates in the inhibitory effects of dietary salt/volume load. Conversely, impaired ANP/cGMP signaling leads to excessive ZG cell growth and aldosterone production. Reinforcing this pathway with novel antibody- or peptide-based therapies may benefit patients with hyperaldosteronism and resistant hypertension.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease and is strongly associated with obesity. A novel approach of categorizing subtypes of MASLD has been proposed recently. Intent of this study was to investigate the influence of these clusters on weight loss and diabetes outcomes of metabolic-bariatric surgery (MBS). Material and Methods: We retrospectively analysed all patients undergone primary Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) between 2015 and 2025 in a german tertiary obsesty center. We performed the cluster differentiation proposed by Raverdy et al. along with a correlation of histolophathologic findings from liver biopsies collected during surgery and evaluated weight loss and diabetes remission at 12, 24 and 60 months after surgery. Results: Overall, 588 out of 850 patients met the inclusion criteria for sufficient clustering of whom 49 were assigned to the cardiometabolic, 52 to the liver specific and 487 to the control cluster. Baseline characteristics differed regarding age, HbA1c, and type 2 diabetes (T2DM) (HbA1c: 8.4 in the cardiometabolic vs 6.2 liver specific; p < .001) between clusters. Liver fibrosis was found in 65% of the cardiometabolic, 41,4% in the liver specific cluster and 16.4% in the control cluster (p < .001). Postoperative complications did not differ between clusters. Total body weight loss (%TBWL) at 12, 24, 36 and 48 months was 22.1%, 19.7%, 17.9% and 18.7% in the cardiometabolic cluster vs. 29.5%, 29.9%, 29.3% and 25.2% in the liver specific cluster (p < .001). Secondary worsening of T2DM occurred in 36% at 24 months 37.5% at 60 months in the cardiometabolic cluster but in 0% in the liver specific (both p < .001). Conclusion: Preoperative data-driven clustering for MASLD identifies distinct types of MASLD in MBS candidates, correlating with histological results. Cluster subtypes are associated with weight loss and diabetes outcomes with inferior outcomes for the cariometabolic cluster. These findings may have an impact on the risk–benefit ratio and on expectation management of MBS. Key points: Data-driven MASLD Clustering is reproducible in MBS candidates and correlates with histological findings. Cluster subtypes are associated with weight loss and diabetes outcomes after MBS. Patients assigned to cardiometabolic cluster show inferior weigth loss and diabetes outcomes. Clustering may impact individual treatment planning, expectation management, and targeted follow-up strategies.

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare tumor. Diagnosis relies on combined histopathological criteria that, in a multifactorial scoring system, may suggest malignancy. The recent ADIUVO trial, a multicenter trial randomizing ACC patients between mitotane treatment or surveillance only, demonstrated that patients with localized, low-grade ACC (Ki67 labeling index (LI) ≤ 10%) have a better prognosis than historically anticipated, questioning the routine use of adjuvant mitotane. This post hoc analysis aimed to investigate whether automated, centralized Ki67 LI assessment improves prognostic stratification beyond expert manual assessment in low-risk ACC patients enrolled in the original ADIUVO trial. Methods: Ki67 LI was centrally reassessed in 70 ADIUVO patients by digitizing slides and applying an automated algorithm to manually selected hotspots. Primary endpoints were correlation between methods and the impact of automated scoring on recurrence-free survival (RFS) and overall survival (OS). Results: Automated Ki67 LI assessment was feasible in 47 patients. Manual and automated Ki67 LI values showed good agreement (mean 5.6 ± 3.1% vs. 5.4 ± 5.3%). Automated scoring identified eight patients with KI67 LI > 10%. In this subgroup, RFS and OS did not differ significantly between patients treated with mitotane and those under surveillance. Patients with an automated Ki67 LI > 10% had larger tumors (median 16.0 cm vs. 7.0 cm, p = 0.003). Conclusions: Our findings support the original ADIUVO results and support continued use of manual expert Ki67 LI scoring. This traditional approach remains robust and pragmatic for most clinical settings, especially where automated systems are not readily accessible.

Objective: The CHIRACIC trail supported the beneficial effect of adrenalectomy on hypertension in patients with unilateral adrenal incidentalomas associated with mild autonomous cortisol secretion (MACS). Additional assessments evaluated the impact of adrenalectomy on body weight excess, metabolic abnormalities and quality of life. Design: Multicenter superiority open-label randomized trial comparing adrenalectomy to conservative management. Methods: Following a run-in phase to control hypertension, receive lifestyle advice and treatment for comorbidities, patients underwent a workup including measurement of body mass index, visceral and total fat, fat mass, fasting blood glucose, HbA1c, oral glucose tolerance test, plasma lipids, and quality of life (QoL). Following randomization, assessment of comorbidities and adaptation of their treatment were performed every 3 months for 13 months. Workup was repeated at the end of the study. Results: Forty-eight patients were randomly assigned to adrenalectomy (n = 23) and conservative management (n = 25). 93%, 71% and 90% of patients were overweight/obese, prediabetics/diabetics and dyslipidemic, respectively. There was no statistically significant improvement in anthropometric and metabolic parameters after adrenalectomy as compared to conservative management: 21% and 4% of adrenalectomized and conservatively treated obese/overweight patients lost > 5% of body weight, respectively (difference 22%, 95% CI: −2% to 39%). Glycemic status improved in 44% and 33% of adrenalectomized and conservatively treated dysglycemic patients, respectively (difference 10%, 95% CI: −22% to 43%). Dyslipidemia improved in 20% of adrenalectomized and none of conservatively treated dyslipidemic patients. Changes in QoL were not different between groups. Conclusion: The beneficial effects of adrenalectomy on excess weight, metabolic disorders and QoL demonstrated in the CHIRACIC trial are more limited than those observed for hypertension. Additional randomized interventional studies involving a larger number of patients are needed to support the use of adrenalectomy in the treatment of these comorbidities.

Background: Limited availability of corticotropin-releasing hormone (CRH) currently complicates the differentiation of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS). The diagnostic value of common screening tests in distinguishing Cushing's disease (CD) from ectopic CS (ECS) remains unclear. Objective: To assess the diagnostic performance of screening tests, alone and in combination, in differentiating CD from ECS. Methods: Retrospective multicenter study enrolling patients with confirmed ACTH-dependent CS and available screening tests at diagnosis. Data are expressed as multiples of upper limit of normal (×ULN). Optimal cut-offs were determined using Youden's Index. Combination with composite score models and machine learning algorithm were performed. Results: A total of 566 patients were included (509 [90%] with CD). The optimal morning ACTH cut-off was 1.8×ULN (sensitivity 74%, specificity 77%, AUC=0.776 [CI-95% .688–.853]). 24h-urinary free cortisol (24h-UFC) showed the best performance (cut-off 5.9×ULN, sensitivity 72%, specificity 83%, AUC=0.854 [.816–.923]), followed by the 1 mg dexamethasone suppression test (12.8×ULN, sensitivity 70%, specificity 86%, AUC=.828 [.740–.906]). Using a composite score, a cut-off of 1.5 yielded 78% sensitivity and 92% specificity (AUC=0.865 [.798–.933]). Combining this score with findings derived from pituitary magnetic resonance imaging (MRI), sensitivity and specificity were 88% and 85% (AUC=0.931 [.887–.974]). Machine learning algorithm (balanced random forest) including screening tests-results yielded a sensitivity of 71% and specificity of 84% (AUC=0.853 [.741-.966]), while including the MRI-findings variant achieved a sensitivity and specificity of 76% and 91% (AUC=0.902 [.805-.999]). Conclusion: Combining screening tests in composite scoring and machine learning differentiates subtypes of ACTH-dependent CS and offers a potential diagnostic alternative to the CRH stimulation test.

Paediatric adrenocortical tumours (pACTs) are rare but potentially life-threatening neoplasms, most of which are hormonally active and frequently present with androgen excess. Although a comprehensive evaluation is recommended, no consensus exists on the optimal diagnostic work-up. The goal of this document is to provide evidence-based recommendations to standardize the diagnostic evaluation of children with suspected pACTs. We applied a modified three-step Delphi process with an international panel of pACT experts to develop consensus on the initial diagnostic work-up. Following a literature review, the steering committee formulated statements, which were distributed electronically to 28 experts from Europe, the Americas, and Asia. Agreement was rated on a six-point Likert scale; ≥70% agreement was defined as consensus. Between rounds, results and feedback were reviewed within the ENS@T-KIDS group. In round one, 33 statements achieved consensus; 12 were revised and re-voted in round 2, with 7 reaching consensus. Five statements were further modified and one reached consensus in round three. Response rates were 86% (n = 24) in round 1, 82% (n = 23) in round 2, and 86% (n = 24) in round 3. Forty-one statements received consensus covering 4 domains: (I) General Aspects and Clinical Assessment (17), (II) Endocrine Work-up (15), (III) Imaging (4), and (IV) Genetics (6). The diagnostic evaluation of pACTs varies widely between centres and countries, influenced by resources and local expertise. This work delivers the first expert-derived, international consensus statements outlining a practical and standardized diagnostic pathway to support timely and consistent evaluation of children with suspected pACTs.

Adrenocortical carcinoma (ACC) in children is a rare and aggressive malignancy. Despite representing a small fraction of pediatric adrenal tumors, ACC poses distinct challenges due to its heterogeneous biological behavior, frequent hormone secretion, and the limited availability of standardized, pediatric-specific treatment protocols. Complete surgical resection remains the cornerstone of curative intent therapy, and complete adrenalectomy offers the best chance for long-term survival. Given the aggressiveness of ACC, particularly in advanced disease, adjuvant therapies are often considered to improve outcomes. The aim of this consensus meeting was to bring together international experts to develop international guidance based on the best available evidence and collective clinical experience to harmonize long-term management. A modified 3-step Delphi consensus method was used to finalize the statements from an international panel of pediatric ACC experts from 4 continents (Europe, the Americas, and Asia, and Oceania). An electronic survey was developed by the steering committee (ENSAT Kids) and distributed to the panel. Agreement and disagreement were rated using a 6-point Likert scale with the opportunity to provide structured feedback. Consensus was defined a priori as ≥75% agreement. This Delphi process yielded consensus statements for therapy guidance, comprising 12 surgical statements and 68 medical treatment statements, organized by strategy and disease stage. These statements are intended to support clinicians in delivering more consistent and standardized therapeutic strategies for pediatric ACC. Future efforts should prioritize the design and conduct of high-quality, collaborative research studies in order to provide more evidence and therapy improvements.

Context: Prognosis of anaplastic thyroid cancer (ATC) remains poor. In the absence of immediately actionable molecular alterations, guidelines recommend multimodal therapy including radiotherapy and cytotoxic chemotherapy, but optimal regimens are not established. Many centers in Germany have adopted carboplatin/paclitaxel (CP), with or without radiotherapy, as a preferred first-line approach. Objective: This study aims to compare the outcome of patients treated first-line with CP ± radiotherapy vs other cytotoxic chemotherapy regimens in ATC. Design: Retrospective multicenter registry study in Germany. Setting and patients: 158 adults with histologically confirmed ATC treated with first-line cytotoxic chemotherapy at 7 German tertiary centers (2000-2024). Main Outcome Measures: Progression-free survival (PFS) and overall survival (OS) were compared with Kaplan–Meier and log-rank tests; a Cox proportional hazard model was used to identify risk factors. Results: 97 patients received first-line CP, and 61 received other chemotherapy. PFS (102 vs 89 days; log-rank P = .23) and OS (278 vs 295 days; P = .50) did not differ between CP and other regimens. Complete response occurred in 13% with CP and 8% with other chemotherapy (P = .46). In multivariable analyses, age ≥65 years, lymph node metastasis, and distant metastasis were associated with higher mortality risk. Surgery was associated with a lower mortality risk. CP was not associated with improved OS. The outcome of second-line treatment was not different for chemotherapy vs kinase inhibition ± immunotherapy. Conclusion: In this registry study, CP showed no survival benefit in ATC; outcomes depended on disease burden and resectability, underscoring the need for rapid molecular diagnostics. Chemotherapy may serve as a bridging strategy.