Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

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.

Endocrine Disruptors: Focus on the Adrenal Cortex.

Endocrine-disrupting chemicals (EDCs) are exogenous substances known to interfere with endocrine homeostasis and promote adverse health outcomes. Their impact on the adrenal cortex, corticosteroids and their physiological role in the organism has not yet been sufficiently elucidated. In this review, we collect experimental and epidemiological evidence on adrenal disruption by relevant endocrine disruptors. In vitro data suggest significant alterations of gene expression, cell signalling, steroid production, steroid distribution, and action. Additionally, morphological studies revealed disturbances in tissue organization and development, local inflammation, and zone-specific hyperplasia. Finally, endocrine circuits, such as the hypothalamic-pituitary-adrenal axis, might be affected by EDCs. Many questions regarding the detection of steroidogenesis disruption and the effects of combined toxicity remain unanswered. Not only due to the diverse mode of action of adrenal steroids and their implication in many common diseases, there is no doubt that further research on endocrine disruption of the adrenocortical system is needed.

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.

A novel LC-MS/MS-based assay for the simultaneous quantification of aldosterone-related steroids in human urine.

OBJECTIVES: Primary aldosteronism is the most common cause of endocrine hypertension and is associated with significant cardiovascular morbidities. The diagnostic workup depends on determinations of plasma aldosterone and renin which are highly variable and associated with false-positive and false-negative results. Quantification of aldosterone in 24 h urine may provide more reliable results, but the methodology is not well established. We aimed to establish an assay for urinary aldosterone and related steroids with suitability for clinical routine implementation. METHODS: Here, we report on the development and validation of a quantitative LC-MS/MS method for six urinary steroids: aldosterone, cortisol, 18-hydroxycorticosterone, 18-hydroxycortisol, 18-oxocortisol, tetrahydroaldosterone. After enzymatic deconjugation, total steroids were extracted using SepPak tC18 plates and quantified in positive electrospray ionization mode on a QTRAP 6500+ mass spectrometer. RESULTS: Excellent linearity was demonstrated with R2>0.998 for all analytes. Extraction recoveries were 89.8-98.4 % and intra- and inter-day coefficients of variations were <6.4 and <9.0 %, establishing superb precision. Patients with primary aldosteronism (n=10) had higher mean 24 h excretions of aldosterone-related metabolites than normotensive volunteers (n=20): 3.91 (95 % CI 2.27-5.55) vs. 1.92 (1.16-2.68) µmol/mol for aldosterone/creatinine, 2.57 (1.49-3.66) vs. 0.79 (0.48-1.10) µmol/mol for 18-hydroxycorticosterone/creatinine, 37.4 (13.59-61.2) vs. 11.61 (10.24-12.98) µmol/mol for 18-hydroxycortisol/creatinine, 1.56 (0.34-2.78) vs. 0.13 (0.09-0.17) µmol/mol for 18-oxocortisol/creatinine, and 21.5 (13.4-29.6) vs. 7.21 (4.88-9.54) µmol/mol for tetrahydroaldosterone/creatinine. CONCLUSIONS: The reported assay is robust and suitable for routine clinical use. First results in patient samples, though promising, require clinical validation in a larger sample set.

Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma.

BACKGROUND: International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. METHODS: We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. PRIMARY ENDPOINT: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. RESULTS: In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. CONCLUSIONS: This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

In Situ Metabolomics of Cortisol-Producing Adenomas.

BACKGROUND: Recent advances in omics techniques have allowed detailed genetic characterization of cortisol-producing adrenal adenoma (CPA). In contrast, the pathophysiology of CPAs has not been elucidated in detail on the level of tumor metabolic alterations. METHODS: The current study conducted a comprehensive mass spectrometry imaging (MSI) map of CPAs in relation to clinical phenotypes and immunohistochemical profiles of steroidogenic enzymes. The study cohort comprised 46 patients with adrenal tumors including CPAs (n 35) and nonfunctional adenomas (n 11). RESULTS: Severity of cortisol hypersecretion was significantly correlated with 29 metabolites (adjusted P 0.05). Adrenal androgens derived from the classic androgen pathway were inversely correlated with both cortisol secretion (rs 0.41, adjusted P 0.035) and CYP11B1 expression (rs 0.77, adjusted P 2.00E-08). The extent of cortisol excess and tumor CYP11B1 expression further correlated with serotonin (rs 0.48 and 0.62, adjusted P 0.008 and 2.41E-05). Tumor size was found to be correlated with abundance of 13 fatty acids (adjusted P 0.05) and negatively associated with 9 polyunsaturated fatty acids including phosphatidic acid 38:8 (rs 0.56, adjusted P 0.009). CONCLUSIONS: MSI reveals novel metabolic links between endocrine function and tumorigenesis, which will further support the understanding of CPA pathophysiology.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Changes in Plasma Metabolomic Profile Following Bariatric Surgery, Lifestyle Intervention or Diet Restriction-Insights from Human and Rat Studies.

Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI -34.3% (OP) vs. -1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.

The role of molecular profiling in adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care.

CXCR4-targeted theranostics in oncology.

A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [68 Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [68 Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [177Lu]/[90Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.

Impact of preoperative weight loss achieved by gastric balloon on peri- and postoperative outcomes of bariatric surgery in super-obese patients: a retrospective matched-pair analysis.

BACKGROUND: An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m2) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied. METHODS: In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls. RESULTS: Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m2) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0% vs. 32.2%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53% vs 23.78 ± 9.89% after 1 year, p < 0.05 and 32.13 ± 10.5% vs 22.21 ± 10.9% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up. CONCLUSION: A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients' expectations.

Questionable value of [99mTc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound.

PURPOSE: A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [99mTc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. METHODS: A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. RESULTS: From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13-93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [99mTc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [11C]-methionine or [11C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24-33.56). CONCLUSION: [11C]-Methionine or [11C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.

Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing's syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing's syndrome.

PURPOSE: In selected cases of severe Cushing's syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing's syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing's syndrome regarding postoperative outcomes. METHODS: We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008-2021. Patients with adrenal Cushing's syndrome due to adenoma were compared with patients with ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival. RESULTS: Of 83 patients with adrenalectomy for hypercortisolism (65.1% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing's syndrome in 60 patients (72.2%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing's disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0% vs. 33%; p < 0.001) and delayed recovery (median: 10.2% vs. 79.2%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2% vs. 25.0% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0% vs. 8.3%; p = 0.081). CONCLUSION: While unilateral adrenalectomy for adrenal Cushing's syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing's syndrome or Cushing's disease is a more complicated intervention with a mortality of nearly 10%.

Exquisite sensitivity of adrenocortical carcinomas to induction of ferroptosis.

Adrenocortical carcinomas (ACCs) are rare and highly malignant cancers associated with poor survival of patients. Currently, mitotane, a nonspecific derivative of the pesticide DDT (1,1-(dichlorobiphenyl)-2,2-dichloroethane), is used as the standard treatment, but its mechanism of action in ACCs remains elusive. Here we demonstrate that the human ACC NCI-H295R cell line is remarkably sensitive to induction of ferroptosis, while mitotane does not induce this iron-dependent mode of regulated necrosis. Supplementation with insulin, transferrin, and selenium (ITS) is commonly used to keep NCI-H295R cells in cell culture. We show that this supplementation prevents spontaneous ferroptosis, especially when it contains polyunsaturated fatty acids (PUFAs), such as linoleic acid. Inhibitors of apoptosis (zVAD, emricasan) do not prevent the mitotane-induced cell death but morphologically prevent membrane blebbing. The expression of glutathione peroxidase 4 (GPX4) in H295R cells, however, is significantly higher when compared to HT1080 fibrosarcoma cells, suggesting a role for ferroptosis. Direct inhibition of GPX4 in H295R cells led to high necrotic populations compared to control, while cotreatment with ferrostatin-1 (Fer-1) completely reverted ferroptosis. Interestingly, the analysis of public databases revealed that several key players of the ferroptosis pathway are hypermethylated and/or mutated in human ACCs. Finally, we also detected that growth hormone-releasing hormone (GHRH) antagonists, such as MIA602, kill H295R cells in a nonapoptotic manner. In summary, we found elevated expression of GPX4 and higher sensitivity to ferroptosis in ACCs. We hypothesize that instead of treatment with mitotane, human adrenocortical carcinomas may be much more sensitive to induction of ferroptosis.

Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study.

BACKGROUND: After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. METHODS: In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. RESULTS: Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). CONCLUSIONS: Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

A Copeptin-Based Approach in the Diagnosis of Diabetes Insipidus.

BACKGROUND: The indirect water-deprivation test is the current reference standard for the diagnosis of diabetes insipidus. However, it is technically cumbersome to administer, and the results are often inaccurate. The current study compared the indirect water-deprivation test with direct detection of plasma copeptin, a precursor-derived surrogate of arginine vasopressin. METHODS: From 2013 to 2017, we recruited 156 patients with hypotonic polyuria at 11 medical centers to undergo both water-deprivation and hypertonic saline infusion tests. In the latter test, plasma copeptin was measured when the plasma sodium level had increased to at least 150 mmol per liter after infusion of hypertonic saline. The primary outcome was the overall diagnostic accuracy of each test as compared with the final reference diagnosis, which was determined on the basis of medical history, test results, and treatment response, with copeptin levels masked. RESULTS: A total of 144 patients underwent both tests. The final diagnosis was primary polydipsia in 82 patients (57%), central diabetes insipidus in 59 (41%), and nephrogenic diabetes insipidus in 3 (2%). Overall, among the 141 patients included in the analysis, the indirect water-deprivation test determined the correct diagnosis in 108 patients (diagnostic accuracy, 76.6%; 95% confidence interval [CI], 68.9 to 83.2), and the hypertonic saline infusion test (with a copeptin cutoff level of >4.9 pmol per liter) determined the correct diagnosis in 136 patients (96.5%; 95% CI, 92.1 to 98.6; P<0.001). The indirect water-deprivation test correctly distinguished primary polydipsia from partial central diabetes insipidus in 77 of 105 patients (73.3%; 95% CI, 63.9 to 81.2), and the hypertonic saline infusion test distinguished between the two conditions in 99 of 104 patients (95.2%; 95% CI, 89.4 to 98.1; adjusted P<0.001). One serious adverse event (desmopressin-induced hyponatremia that resulted in hospitalization) occurred during the water-deprivation test. CONCLUSIONS: The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).

Method-Specific Cortisol and Dexamethasone Thresholds Increase Clinical Specificity of the Dexamethasone Suppression Test for Cushing Syndrome.

BACKGROUND: The dexamethasone suppression test (DST) is the recommended first-tier test for suspected Cushing syndrome (CS). Missed dexamethasone intake or insufficient dexamethasone serum exposure may yield false positive results. Quantification of serum dexamethasone in DST samples may therefore improve test performance. METHODS: Simultaneous quantification of dexamethasone and cortisol by liquid chromatography-tandem mass spectrometry in 400 DST serum samples (100 overt CS, 200 excluded CS, 100 adrenal incidentalomas with (possible) autonomous cortisol secretion, AI-ACS) randomly selected within the indication groups. The 2.5th percentile of dexamethasone in patients with excluded CS was considered the lower limit of normal (LLN). RESULTS: Serum dexamethasone varied from undetectable to 20.2 ng/mL with a median of 4.8 ng/mL (95% CI 4.5-5.1 ng/mL). Dexamethasone was undetectable in only 16 patients (4%), suggesting non-compliance. The dexamethasone LLN was 1.8 ng/mL (4.6 nmol/L). Decreased glomerular filtration rate and diabetes mellitus were associated with higher serum dexamethasone concentration, while body mass index, sex, age, nicotine, and oral contraceptives had no significant effect. By excluding the 27 samples with dexamethasone

Harmonization of LC-MS/MS Measurements of Plasma Free Normetanephrine, Metanephrine, and 3-Methoxytyramine.

BACKGROUND: Plasma-free normetanephrine and metanephrine (metanephrines) are the recommended biomarkers for testing of pheochromocytoma and paraganglioma (PPGL). This study evaluated the status of harmonization of liquid chromatography-tandem mass spectrometry-based measurements of plasma metanephrines and methoxytyramine and clinical interpretation of test results. METHODS: 125 plasma samples from patients tested for PPGLs were analyzed in 12 laboratories. Analytical performance was also assessed from results of a proficiency-testing program. Agreement of test results from different laboratories was assessed by Passing-Bablok regression and Bland-Altman analysis. Agreement in clinical test interpretation based on laboratory specific reference intervals was also examined. RESULTS: Comparisons of analytical test results by regression analysis revealed strong correlations for normetanephrine and metanephrine (R ≥ 0.95) with mean slopes of 1.013 (range 0.975-1.078), and 1.019 (range 0.963-1.081), and intercepts of -0.584 (-53.736 to 54.790) and -3.194 (-17.152 to 5.933), respectively. The mean bias between methods was 1.2% (-11.6% to 16.0%) for metanephrine and 0.1% (-18.0% to 9.5%) for normetanephrine. Measurements of 3-methoxytyramine revealed suboptimal agreement between laboratories with biases ranging from -32.2% to 64.0%. Interrater agreement in test interpretation was >94% for metanephrine and >84% for normetanephrine; improvements in interrater agreement were observed with use of harmonized reference intervals, including age-specific cut-offs for normetanephrine. CONCLUSIONS: Analytical methods for metanephrines are well harmonized between laboratories. However, the 16% disagreement in test interpretation for normetanephrine suggests use of suboptimal method-dependent reference intervals for clinical decision-making for this metabolite. Improved analytical methods and reference interval harmonization are particularly required for 3-methoxytyramine.