Sunitinib for metastatic progressive phaeochromocytomas and paragangliomas: results from FIRSTMAPPP, an academic, multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: No randomised controlled trial has ever been done in patients with metastatic phaeochromocytomas and paragangliomas. Preclinical and first clinical evidence suggested beneficial effects of sunitinib. We aimed to evaluate the safety and efficacy of sunitinib in patients with metastatic phaeochromocytomas and paragangliomas. METHODS: FIRSTMAPPP is a multicentre, international, randomised, placebo-controlled, double-blind, phase 2 trial done at 14 academic centres across four European countries. Eligible participants were adults (aged ≥18 years) with sporadic or inherited progressive metastatic phaeochromocytomas and paragangliomas. Patients were randomly assigned (1:1) to receive either oral sunitinib (37·5 mg per day) or placebo. Randomisation was stratified according to SDHB status (mutation present vs wild type) and number of previous systemic therapies (0 vs ≥1). Primary endpoint was the rate of progression-free survival at 12 months according to real-time central review (Response Evaluation Criteria in Solid Tumours version 1.1). On the basis of a two-step Simon model, we aimed for the accrual of 78 patients, assuming a 20% improvement of the 12-month progression-free survival rate from 20% to 40%, to conclude that sunitinib is effective. Crossover from the placebo group was allowed. This trial is registered with ClinicalTrials.gov, number NCT01371201, and is closed for enrolment. FINDINGS: From Dec 1, 2011, to Jan 31, 2019, a total of 78 patients with progressive metastatic phaeochromocytomas and paragangliomas were enrolled (39 patients per group). 25 (32%) of 78 patients had germline SDHx variants and 54 (69%) had used previous therapies. The primary endpoint was met, with a 12-month progression-free survival in 14 of 39 patients (36% [90% CI 23-50]) in the sunitinib group. In the placebo group, the 12-month progression-free survival in seven of 39 patients was 19% (90% CI 11-31), validating the hypotheses of our study design. The most frequent grade 3 or 4 adverse events were asthenia (seven [18%] of 39 and one [3%] of 39), hypertension (five [13%] and four [10%]), and back or bone pain (one [3%] and three [8%]) in the sunitinib and placebo groups, respectively. Three deaths occurred in the sunitinib group: these deaths were due to respiratory insufficiency, amyotrophic lateral sclerosis, and rectal bleeding. Only the latter event was considered drug related. Two deaths occurred in the placebo group due to aspiration pneumonia and septic shock. INTERPRETATION: This first randomised trial supports the use of sunitinib as the medical option with the highest level of evidence for anti-tumour efficacy in progressive metastatic phaeochromocytomas and paragangliomas. FUNDING: French Ministry of Health, through the National Institute for Cancer, German Ministry of Education and Research, and the German Research Foundation within the CRC/Transregio 205/2, EU Seventh Framework Programme, and a private donator grant.

Predictive value of C-X-C motif chemokine receptor 4-directed molecular imaging in patients with advanced adrenocortical carcinoma.

BACKGROUND: In patients affected with adrenocortical carcinoma (ACC), C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed in sites of disease in an ex-vivo setting. We aimed to determine the predictive value of CXCR4-targeting [68Ga]Ga-PentixaFor PET/CT for outcome when compared to clinical parameters. METHODS: We identified 41 metastasized ACC patients imaged with [68Ga]Ga-PentixaFor PET/CT. Scans were assessed visually and on a quantitative level by manually segmenting the tumor burden (providing tumor volume [TV], peak/mean/maximum standardized uptake values [SUV] and tumor chemokine receptor binding on the cell surface [TRB], defined as SUVmean multiplied by tumor volume). Clinical parameters included sex, previous therapies, age, Weiss-Score, and Ki67 index. Following imaging, overall survival (OS) was recorded. RESULTS: After [68Ga]Ga-PentixaFor PET/CT, median OS was 9 months (range, 1-96 months). On univariable analysis, only higher TRB (per 10 ml, HR 1.004, 95%CI: 1.0001-1.007, P = 0.005) and presence of CXCR4-positive peritoneal metastases (PM) were associated with shorter OS (HR 2.03, 95%CI: 1.03-4.02, P = 0.04). Presence of CXCR4-positive liver metastases (LM) trended towards significance (HR 1.85, 0.9-4.1, P = 0.11), while all other parameters failed to predict survival. On multivariable analysis, only TRB was an independent predictor for OS (HR 1.0, 95%CI: 1.00-1.001, P = 0.02). On Kaplan-Meier analysis, TRB above median (13.3 months vs. below median, 6.4 months) and presence of CXCR4-positive PM (6.4 months, vs. no PM, 11.4 months) were associated with shorter survival (P < 0.05, respectively). Presence of LM, however, was also linked to less favorable outcome (8.5 months vs. no LM, 18.1 months), without reaching significance (P = 0.07). CONCLUSIONS: In advanced ACC, elevated tumor chemokine receptor binding on the tumor cell surface detected through [68Ga]Ga-PentixaFor PET/CT is an independent predictor for OS, while other imaging and clinical parameters failed to provide relevant prognostic information.

Current Evidence on Local Therapies in Advanced Adrenocortical Carcinoma.

International guidelines emphasise the role of local therapies (LT) for the treatment of advanced adrenocortical carcinoma (ACC). However, large studies are lacking in this field. Therefore, we performed a review of the literature to synthesise current evidence and develop clinical guidance. PubMed database was searched for systematic literature. We identified 119 potentially relevant articles, of which 21 could be included in our final analysis. All were retrospective and reported on 374 patients treated with LT for advanced ACC (12 studies on radiotherapy, 3 on transarterial chemoembolisation and radioembolisation, 4 on image-guided thermal ablation [radiofrequency, microwave ablation, and cryoablation, and two studies reporting treatment with several different LT]). Radiotherapy was frequently performed with palliative intention. However, in most patients, disease control and with higher dosage also partial responses could be achieved. Data for other LT were more limited, but also point towards local disease control in a significant percentage of patients. Very few studies tried to identify factors that are predictive on response. Patients with a disease-free interval after primary surgery of more than 9 months and lesions<5 cm might benefit most. Underreporting of toxicities may be prevalent, but LT appear to be relatively safe overall. Available evidence on LT for ACC is limited. LT appears to be safe and effective in cases with limited disease and should be considered depending on local expertise in a multidisciplinary team discussion.

[Adrenal tumors: current standards in clinical management]. / Nebennierentumoren ­ aktuelle Standards im klinischen Management.

Adrenal tumors are among the most common tumors in humans. They are most frequently discovered incidentally during abdominal imaging for other reasons or due to clinical symptoms (e.g. Conn's or Cushing's syndrome, pheochromocytoma or androgen excess). Although over 80% of adrenal tumors are benign, in cases of hormone excess, they are associated with significantly increased morbidity. In highly malignant adrenocortical carcinoma (ACC), early diagnosis is of particular prognostic relevance. Therefore, this review presents the diagnostic procedure for what are referred to as adrenal incidentalomas and provide recommendations for the management of ACC and pheochromocytomas/paragangliomas (PPGL). In primary diagnosis, sufficient hormone diagnostics is required for all adrenal tumors, as this is the only way to identify all patients with relevant hormone excess. Imaging has increasingly improved in recent years and allows a reliable assessment of the tumor's malignancy in most cases. Imaging of first choice is unenhanced computed tomography (CT), while magnetic resonance imaging (MRI) and fluorodeoxyglucose-18 positron emission tomography (FDG-PET/CT) are reserved for special situations, as published evidence on these procedures is more limited. The treatment of ACC and PPGL is complex and is carried out on an interdisciplinary basis at specialized centers. In the case of localized disease, surgery is the only curative treatment option. There are now clear recommendations for individualized adjuvant therapy for ACC. In metastatic disease, mitotane with or without platinum-containing chemotherapy is the standard. Other lines of therapy should be discussed with a reference center. Over 35% of PPGL have a germline mutation; therefore, genetic testing should be offered. In metastatic PPGL, an individual decision is required between active surveillance, radionuclide therapy, sunitinib or chemotherapy.

Association of preclinical blood glucose with hospitalization rate and in-hospital mortality: A single-center retrospective cohort study.

Objective: Critical illness is often accompanied by elevated blood glucose, which generally correlates with increased morbidity and mortality. Prehospital blood glucose (PBG) level might be a useful and easy-to-perform tool for risk assessment in emergency medicine. This retrospective single-center cohort study was designed to analyze the association of prehospital glucose measurements with hospitalization rate and in-hospital mortality. Methods: Records of 970 patients admitted to a university hospital by an emergency physician were analyzed. Patients with a PBG ≥140 mg/dL (G1, n = 394, equal to 7.8 mmol/L) were compared with patients with a PBG <140 mg/dL (G2, n = 576). Multivariable logistic regression models were used to correct for age, prediagnosed diabetes, and sex. Results: Five hundred thirty-four patients (55%) were hospitalized. In comparison to normoglycemic patients, hyperglycemic patients were more likely to be hospitalized with an adjusted odds ratio (OR) of 1.48 (95% confidence interval [CI] 1.11-1.97), more likely to be admitted to the intensive care unit (ICU) with an adjusted OR of 1.74 (95% CI 1.31-2.31) and more likely to die in the hospital with an adjusted OR of 1.84 (95% CI 0.96-3.53). Hospitalized hyperglycemic patients had a median length of stay of 6.0 days (interquartile range [IQR] 8.0) compared to 3.0 days (IQR 6.0) in the normoglycemic group (P < 0.001). In the subgroup analysis of cases without known diabetes, patients with PBG ≥140 mg/dL were more likely to be hospitalized with an adjusted OR of 1.49 (95% CI 1.10-2.03) and more likely to be admitted to ICU/intermediate care with an adjusted OR of 1.80 (95% CI 1.32-2.45), compared to normoglycemic patients. Conclusion: Elevated PBG ≥140 mg/dL was associated with a higher hospitalization risk, a longer length of stay, and a higher mortality risk and may therefore be included in risk assessment scores.

Disruptive effects of plasticizers bisphenol A, F, and S on steroidogenesis of adrenocortical cells.

Introduction: Endocrine disrupting chemicals (EDCs) are known to interfere with endocrine homeostasis. Their impact on the adrenal cortex and steroidogenesis has not yet been sufficiently elucidated. This applies in particular to the ubiquitously available bisphenols A (BPA), F (BPF), and S (BPS). Methods: NCI-H295R adrenocortical cells were exposed to different concentrations (1nM-1mM) of BPA, BPF, BPS, and an equimolar mixture of them (BPmix). After 72 hours, 15 endogenous steroids were measured using LC-MS/MS. Ratios of substrate and product of CYP-regulated steps were calculated to identify most influenced steps of steroidogenesis. mRNA expression of steroidogenic enzymes was determined by real-time PCR. Results: Cell viability remained unaffected at bisphenol concentrations lower than 250 µM. All tested bisphenols and their combination led to extensive alterations in the quantified steroid levels. The most profound fold changes (FC) in steroid concentrations after exposure to BPA (>10µM) were seen for androstenedione, e.g. a 0.37±0.11-fold decrease at 25µM (p≤0.0001) compared to vehicle-treated controls. For BPF, levels of 17-hydroxyprogesterone were significantly increased by 25µM (FC 2.57±0.49, p≤0.001) and 50µM (FC 2.65±0.61, p≤0.0001). BPS treatment led to a dose-dependent decrease of 11-deoxycorticosterone at >1µM (e.g. FC 0.24±0.14, p≤0.0001 at 10µM). However, when combining all three bisphenols, additive effects were detected: e.g. 11-deoxycortisosterone was decreased at doses >10µM (FC 0.27±0.04, p≤0.0001, at 25µM), whereas 21-deoxycortisol was increased by 2.92±0.20 (p≤0.01) at 10µM, and by 3.21±0.45 (p≤0.001) at 50µM. While every measured androgen (DHEA, DHEAS, androstenedione, testosterone, DHT) was lowered in all experiments, estradiol levels were significantly increased by BPA, BPF, BPS, and BPmix (e.g. FC 3.60±0.54, p≤0.0001 at 100µM BPF). Calculated substrate-product ratios indicated an inhibition of CYP17A1-, and CYP21A2 mediated conversions, whereas CYP11B1 and CYP19A1 showed higher activity in the presence of bisphenols. Based on these findings, most relevant mRNA expression of CYP genes were analysed. mRNA levels of StAR, CYP11B1, and CYP17A1 were significantly increased by BPF, BPS, and BPmix. Discussion: In cell culture, bisphenols interfere with steroidogenesis at non-cytotoxic levels, leading to compound-specific patterns of significantly altered hormone levels. These results justify and call for additional in-vivo studies to evaluate effects of EDCs on adrenal gland functionality.

Effects of NPY-2 Receptor Antagonists, Semaglutide, PYY3-36, and Empagliflozin on Early MASLD in Diet-Induced Obese Rats.

(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY3-36, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY3-36) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.

GLP-1 and PYY for the treatment of obesity: a pilot study on the use of agonists and antagonists in diet-induced rats.

Objective: Combination therapies with gut hormone analogs represent promising treatment strategies for obesity. This pilot study investigates the therapeutic potential of modulators of the glucagon-like peptide 1 (GLP-1) and neuropeptide Y (NPY) system using GLP-1 receptor agonists (semaglutide) and antagonists (exendin 9-39), as well as non-selective and NPY-Y2-receptor selective peptide tyrosine tyrosine (PYY) analogs (PYY3-36/NNC0165-0020 and NNC0165-1273) and an NPY-Y2 receptor antagonist (JNJ31020028). Methods: High-fat diet (HFD)-induced obese rats were randomized into following treatment groups: group 1, nonselective PYY analog + semaglutide (n = 4); group 2, non-selective and NPY-Y2 receptor selective PYY analog + semaglutide (n = 2); group 3, GLP-1 receptor antagonist + NPY-Y2 receptor antagonist (n = 3); group 4, semaglutide (n = 5); and group 5, control (n = 5). Animals had free access to HFD and low-fat diet. Food intake, HFD preference and body weight were measured daily. Results: A combinatory treatment with a non-selective PYY analog and semaglutide led to a maximum body weight loss of 14.0 ± 4.9% vs 9.9 ± 1.5% with semaglutide alone. Group 2 showed a maximum weight loss of 20.5 ± 2.4%. While HFD preference was decreased in group 2, a strong increase in HFD preference was detected in group 3. Conclusions: PYY analogs (especially NPY-Y2 selective receptor agonists) could represent a promising therapeutic approach for obesity in combination with GLP-1 receptor agonists. Additionally, combined GLP-1 and PYY3-36 receptor agonists might have beneficial effects on food preference.

Exploring Theranostic Avenues in Adrenocortical Carcinoma Using Chemokine Receptor and Prostate-Specific Membrane Antigen-Directed PET/CT.

ABSTRACT: We report on an adrenocortical carcinoma (ACC) patient, which has exhausted previous treatment options and was scheduled for prostate-specific membrane antigen (PSMA)- and C-X-C motif chemokine receptor 4 (CXCR4)-targeted PET/CT. We identified PSMA-avid pulmonary metastases exhibiting modest radiotracer accumulation, while chemokine receptor PET/CT provided intense uptake. This dual-tracer molecular imaging approach revealed that chemokine receptor PET appears to be more suitable in patients with advanced ACC, indicating that CXCR4-directed radioligand therapy may be considered in such patients suffering from end-stage disease. Given its dismal prognosis, chemokine receptor-directed theranostics may therefore extend the therapeutic armamentarium as last-line option in advanced ACC.

Expression and Prognostic Relevance of PD-1, PD-L1, and CTLA-4 Immune Checkpoints in Adrenocortical Carcinoma.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. OBJECTIVE: Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. METHODS: The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. RESULTS: PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P = .04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. CONCLUSION: The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment.

Recovery of adrenal function after stopping mitotane in patients with adrenocortical carcinoma.

OBJECTIVE: Mitotane is the standard therapy of adrenocortical carcinoma (ACC) due to its relative selectivity of its cytotoxic effects toward adrenocortical cells. Therefore, it virtually always leads to adrenal insufficiency. Frequency and characteristics of hypothalamic-pituitary-adrenal axis recovery after discontinuation are ill-defined. METHODS: This was a retrospective study of patients with ACC adjuvantly treated with mitotane for ≥12 months who were disease-free at mitotane stop and had a minimum follow-up ≥1 year. Primary endpoint was adrenal recovery. Cox regression analyses were used to identify predictive factors. Moreover, mitotane plasma elimination rate and hormonal changes after mitotane stop were investigated. RESULTS: Fifty-six patients (36 women) treated with mitotane for a median time of 25 months and an average daily dose of 2.8 g were included. Median time after discontinuation until mitotane levels dropped below 5 and 2 mg/L, and the detection limit was 152 days (interquartile range: 114-202), 280 days (192-370), and 395 days (227-546), respectively. Full adrenal recovery was documented in 32 (57%) patients after a median time of 26 months (95% confidence interval [CI] = 19.6-32.4). In 4 patients (7.1%), adrenal insufficiency persisted >5 years after discontinuation. Mitotane peak ≥ 27 mg/L significantly correlated with longer time to adrenal recovery (hazard ratio [HR] = 0.2, 95% CI = 0.1-0.8, P = .03). Twenty-seven of 38 patients (71%) followed in reference centers achieved adrenal recovery compared with only 5/18 (28%) followed up in non-reference centers (HR = 4.51, 95% CI = 1.71-11.89, P = .002). Other investigated factors were not associated with adrenal function after discontinuation. CONCLUSIONS: Our study demonstrates that adrenal recovery occurs in most patients after stopping mitotane, particularly when followed up in specialized centers, but not in all. Elimination time of mitotane after treatment discontinuation is very long but individually quite variable.

Cellular landscape of adrenocortical carcinoma at single-nuclei resolution.

Adrenocortical carcinoma (ACC) is a rare yet devastating tumour of the adrenal gland with a molecular pathology that remains incompletely understood. To gain novel insights into the cellular landscape of ACC, we generated single-nuclei RNA sequencing (snRNA-seq) data sets from twelve ACC tumour samples and analysed these alongside snRNA-seq data sets from normal adrenal glands (NAGs). We find the ACC tumour microenvironment to be relatively devoid of immune cells compared to NAG tissues, consistent with known high tumour purity values for ACC as an immunologically "cold" tumour. Our analysis identifies three separate groups of ACC samples that are characterised by different relative compositions of adrenocortical cell types. These include cell populations that are specifically enriched in the most clinically aggressive and hormonally active tumours, displaying hallmarks of reorganised cell mechanobiology and dysregulated steroidogenesis, respectively. We also identified and validated a population of mitotically active adrenocortical cells that strongly overexpress genes POLQ, DIAPH3 and EZH2 to support tumour expansion alongside an LGR4+ progenitor-like or cell-of-origin candidate for adrenocortical carcinogenesis. Trajectory inference suggests the fate adopted by malignant adrenocortical cells upon differentiation is associated with the copy number or allelic balance state of the imprinted DLK1/MEG3 genomic locus, which we verified by assessing bulk tumour DNA methylation status. In conclusion, our results therefore provide new insights into the clinical and cellular heterogeneity of ACC, revealing how genetic perturbations to healthy adrenocortical renewal and zonation provide a molecular basis for disease pathogenesis.

Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BMs) for prognostication and monitoring of ACC. DESIGN AND METHODS: We investigated 34 patients with ACC and 23 healthy subjects (HSs) as controls. Circulating cell-free DNA was extracted by commercial kits and ccfDNA concentrations were quantified by fluorimeter (BM1). Targeted sequencing was performed using a customized panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging. RESULTS: Circulating cell-free DNA concentrations were higher in ACC than HS (mean ± SD, 1.15 ± 1.56 vs 0.05 ± 0.05 ng/µL, P < .0001), 96% of them being above the cut-off of 0.146 ng/µL (mean HS + 2 SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least 1 somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (hazard ratio [HR] = 2.63; 95% CI, 1.13-6.13; P = .010, and HR = 5.98; 95% CI, 2.29-15.6; P = .0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared with BM1. CONCLUSION: ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.

The Value of Local Therapies in Advanced Adrenocortical Carcinoma.

International guidelines recommend local therapies (LTs) such as local thermal ablation (LTA; radiofrequency, microwave, cryoablation), transarterial (chemo)embolisation (TA(C)E), and transarterial radioembolisation (TARE) as therapeutic options for advanced adrenocortical carcinoma (ACC). However, the evidence for these recommendations is scarce. We retrospectively analysed patients receiving LTs for advanced ACC. Time to progression of the treated lesion (tTTP) was the primary endpoint. The secondary endpoints were best objective response, overall progression-free survival, overall survival, adverse events, and the establishment of predictive factors by multivariate Cox analyses. A total of 132 tumoural lesions in 66 patients were treated with LTA (n = 84), TA(C)E (n = 40), and TARE (n = 8). Complete response was achieved in 27 lesions (20.5%; all of them achieved by LTA), partial response in 27 (20.5%), and stable disease in 38 (28.8%). For the LTA group, the median tTTP was not reached, whereas it was reached 8.3 months after TA(C)E and 8.2 months after TARE (p < 0.001). The median time interval from primary diagnosis to LT was >47 months. Fewer than four prior therapies and mitotane plasma levels of >14 mg/L positively influenced the tTTP. In summary, this is one of the largest studies on LTs in advanced ACC, and it demonstrates a very high local disease control rate. Thus, it clearly supports the guideline recommendations for LTs in these patients.

Single-nucleus and spatial transcriptome reveal adrenal homeostasis in normal and tumoural adrenal glands.

The human adrenal gland is a complex endocrine tissue. Studies on adrenal renewal have been limited to animal models or human foetuses. Enhancing our understanding of adult human adrenal homeostasis is crucial for gaining insights into the pathogenesis of adrenal diseases, such as adrenocortical tumours. Here, we present a comprehensive cellular genomics analysis of the adult human normal adrenal gland, combining single-nuclei RNA sequencing and spatial transcriptome data to reconstruct adrenal gland homeostasis. As expected, we identified primary cells of the various zones of the adrenal cortex and medulla, but we also uncovered additional cell types. They constitute the adrenal microenvironment, including immune cells, mostly composed of a large population of M2 macrophages, and new cell populations, including different subpopulations of vascular-endothelial cells and cortical-neuroendocrine cells. Utilizing spatial transcriptome and pseudotime trajectory analysis, we support evidence of the centripetal dynamics of adrenocortical cell maintenance and the essential role played by Wnt/ß-catenin, sonic hedgehog, and fibroblast growth factor pathways in the adult adrenocortical homeostasis. Furthermore, we compared single-nuclei transcriptional profiles obtained from six healthy adrenal glands and twelve adrenocortical adenomas. This analysis unveiled a notable heterogeneity in cell populations within the adenoma samples. In addition, we identified six distinct adenoma-specific clusters, each with varying distributions based on steroid profiles and tumour mutational status. Overall, our results provide novel insights into adrenal homeostasis and molecular mechanisms potentially underlying early adrenocortical tumorigenesis and/or autonomous steroid secretion. Our cell atlas represents a powerful resource to investigate other adrenal-related pathologies.

Adipositas Care and Health Therapy (ACHT) after Bariatric-Metabolic Surgery: A Prospective, Non-Randomized Intervention Study.

INTRODUCTION: Almost 25% of German adults have obesity and numbers are rising, making it an important health issue. Bariatric-metabolic surgery reduces body weight and complications for persons with obesity, but therapeutic success requires long-term postoperative care. Since no German standards for follow-up by family physicians exist, follow-up is provided by surgical obesity centers, but they are reaching their limits. The ACHT study, funded by the German Innovation Fund, is designed to establish and evaluate the follow-up program, with local physicians following patients supported remotely by obesity centers. METHODS: ACHT is a multicenter, prospective, non-randomized control group study. The 18-month ACHT follow-up program is a digitally supported, structured, cross-sectoral, and close-to-home program to improve success after bariatric-metabolic surgery. Four groups are compared: intervention group 1 starts the program immediately (3 weeks) after Roux-en-Y gastric bypass or sleeve gastrectomy (months 1-18 postoperatively), intervention group 2 begins the program 18 months after surgery (months 19-36 postoperatively). Intervention groups are compared to respective control groups that had surgery 18 and 36 months previously. In total, 250 patients, enrolled in the intervention groups, are compared with 360 patients in the control groups, who only receive standard care. RESULTS: The primary endpoint to compare intervention and control groups is the adapted King's score, a composite tool evaluating physical, psychological, socioeconomic, and functional health status. Secondary endpoints include changes in care structures and care processes for the intervention groups. Multivariate regression analyses adjusting for confounders (including the type of surgery) are used to compare intervention and control groups and evaluate determinants in longitudinal analyses. The effect of the intervention on healthcare costs will be evaluated based on health insurance billing data of patients who had bariatric-metabolic surgery in the 3 years prior to the start of the study and of patients who undergo bariatric-metabolic surgery during the study period. CONCLUSIONS: ACHT will be the one of the first evaluated structured, close-to-home follow-up programs for bariatric surgery in Germany. It will evaluate the effectiveness of the implemented program regarding improvements in health status, mental health, quality of life, and the feasibility of such a program outside of specialized obesity centers.

Prognostic role of quantitative [18F]FDG PET/CT parameters in adrenocortical carcinoma.

PURPOSE: We aimed to evaluate the prognostic potential of baseline [18F]FDG PET/CT for overall survival (OS) in patients with adrenocortical carcinoma (ACC). METHODS: We performed a retrospective analysis of 67 treatment-naïve ACC patients with available [18F]FDG PET/CT at time of initial diagnosis. Pretherapeutic PETs of primary tumors were manually segmented and quantitative parameters (maximum/mean/peak standardized uptake value (SUVmax/mean/peak), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG, defined as TV*SUVmean) were derived. Based on a visual read, absence (M0) or presence of metastatic disease (M1) were evaluated. Kaplan-Meier and Cox regression analyses were used to determine the prognostic value of the above mentioned markers on overall survival adjusted for established prognostic markers. RESULTS: 24/67 patients (36%) presented with M0 based on PET/CT, while the remaining 43/67 (64%) had M1-status. 32/67 patients died during follow-up and median OS was 48 months. In 12% of patients FDG-PET detected additional metastatic lesion not clearly visible by CT only. In univariable analysis, all quantitatively derived PET parameters failed to reach significance (P ≥ 0.1), and only PET/CT-based M1-status and Ki-67 were associated with increased mortality (M1: HR 13.89, 95% CI 4.15-86.32, P < 0.001; Ki-67 HR 1.29, 95% CI 1.16-1.42; P < 0.0001). Using multivariable Cox regression analyses, M1-status (HR 9.69, 95% CI 2.82-60.99) and Ki-67 index (HR 1.29, 95% CI 1.13-1.04; P < 0.05) remained significant associated with OS. CONCLUSION: In treatment-naïve ACC patients, the quantitative PET parameter failed to predict OS, but presence of metastases detected by [18F]FDG PET/CT and Ki-67 index were independently associated with shorter OS. Therefore, a simple visual PET-based read-out is of prognostic value at initial diagnosis, while time-consuming PET-based quantification can be omitted.

Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort-a work from the ENSAT-PACT working group.

OBJECTIVE: Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort. DESIGN: Analysis of pS-GRAS items of pACC from 6 countries in collaboration of ENSAT-PACT, GPOH-MET, and IC-PACT. METHODS: We received patient data of the pS-GRAS items including survival information from 9 centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0%-9% = 0; 10%-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed-/no-hormone production = 1 point) generating 8 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS). RESULTS: We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: Group 1 98%; group 2 87% [hazard ratio {HR} of death 3.6, 95% CI of HR 1.6-8.2]; group 3 43% [HR of death 2.8, 95% CI 1.9-4.4]; group 4: OS 18% [HR of death 2.1, 95% CI 1.7-2.7]). In the multivariable analysis, age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95% CI of HR 1.2-3.0), and Ki67 index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low-risk constellations with a better OS for all tumor stages. CONCLUSION: In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage, and Ki67 index are important parameters for risk stratification.

Adverse skeletal related events in patients with bone-metastatic pheochromocytoma/paraganglioma.

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.