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Objective Primary aldosteronism (PA) is one of the most frequent causes of secondary hypertension. Although clinical practice guidelines recommend a diagnostic process, details of the steps remain incompletely standardized. Design In the present SCOT-PA survey, we have investigated the diversity of approaches utilized for each diagnostic step in different expert centers through a survey using Google questionnaires. A total of 33 centers from 3 continents participated. Results We demonstrated a prominent diversity in the conditions of blood sampling, assay methods for aldosterone and renin, and the methods and diagnostic cutoff for screening and confirmatory tests. The most standard measures were modification of antihypertensive medication and sitting posture for blood sampling, measurement of plasma aldosterone concentration (PAC) and active renin concentration by chemiluminescence enzyme immunoassay, a combination of aldosterone-to-renin ratio with PAC as an index for screening, and saline infusion test in a seated position for confirmatory testing. The cutoff values for screening and confirmatory testing showed significant variation among centers. Conclusions Diversity of the diagnostic steps may lead to an inconsistent diagnosis of PA among centers and limit comparison of evidence for PA between different centers. We expect the impact of this diversity to be most prominent in patients with mild PA. The survey raises 2 issues: the need for standardization of the diagnostic process and revisiting the concept of mild PA. Further standardization of the diagnostic process/criteria will improve the quality of evidence and management of patients with PA.

After successful treatment for Cushing's syndrome (CS), secondary adrenal insufficiency develops as a result of the prior suppression of the hypothalamic-pituitary-adrenal (HPA) axis by excess cortisol in the body. Until the recovery of the HPA axis, glucocorticoid replacement therapy is required to enable normal functioning of the body and prevent adrenal crisis. Significant variation in the median time of recovery of the HPA axis is found in various cohorts of CS patients ranging from several weeks to years. Despite the use of physiological glucocorticoid replacement, after cure for CS, patients often experience symptoms of glucocorticoid withdrawal syndrome (GWS). The optimal glucocorticoid regimen to reduce GWS needs to be established and requires an individualized approach aiming to avoid overtreatment at one side and minimize the risk of undertreatment and possible adrenal crisis and GWS on the other side.

Objective: Indices based on aldosterone/cortisol (A/C) concentration in the successfully cannulated adrenal vein (AV) and in the inferior vena cava (IVC) (AV/IVC) appear to be possible markers to verify the subtype of primary aldosteronism (PA) in the case of inconclusive results of adrenal vein sampling (AVS). The variability of results in previous studies encouraged us to calculate AV/IVC and adrenal A/C cutoff values that could predict the aetiology of PA. Methods: This retrospective study included 96 patients who underwent AVS due to PA between 2015 and 2020. The derivation cohort ultimately consisted of 60 patients with bilaterally successful AVS and a clear diagnosis of unilateral or bilateral disease. Receiver operating characteristic analysis was used to find the optimal A/C and AV/IVC cutoff values predicting the subtype of PA. The validation cohort consisted of 11 patients with either unsuccessful cannulation or a borderline lateralization index (LI), those patients underwent adrenalectomy because their indices were suggestive of unilateral disease based on the derivation cohort data. Results: The cutoff values of A/C ≤ 0.63 or AV/IVC ≤ 0.37 identified unaffected glands with a sensitivity of 91.2% and 97.1%, respectively, and a specificity of 90.7% and 88.4%, respectively. Unilateral ipsilateral gland involvement was characterized by A/C ≥ 3.5 or AV/IVC ≥ 3.4 with a corresponding specificity of 100%. All patients in the validation cohort achieved biochemical remission postoperatively. Conclusions: A/C and AV/IVC cutoff values could be a useful tool to determine the subtype of PA in patients with unilateral successful AVS as well as in patients with a borderline LI.

Background\ud \ud The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing).\ud \ud \ud \ud Methods\ud \ud We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800–0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50–138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants.\ud \ud \ud \ud Findings\ud \ud Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53–68]; median follow-up 7·0 years [IQR 4·7–10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19–1·94) and autonomous cortisol secretion (1·77, 1·20–2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93–9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values

The purpose of the present study was to analyze the impact of the neutrophil-lymphocyte ratio (NLR) on the long-term outcomes of patients with adrenocortical carcinoma (ACC).This retrospective, single-institution study included 48 patients with the diagnosis of ACC. The primary outcomes of the study were differences in overall survival (OS) and disease-specific survival (DSS) with respect to the NLR level.Patients with ENSAT stage IV had higher levels of NLR compared to those with ENSAT stage I-III (5.7 (1.6-12.5) vs 3.3 (1.3-11);The study demonstrated that a higher NLR level in ACC patients was associated with unfavorable outcomes in terms of DSS and OS. These results indicate that NLR might be used as an additional marker in ACC risk stratification and identification of patients with the most adverse prognosis.

Context Adrenal venous sampling (AVS) is the current criterion standard lateralization technique in primary aldosteronism (PA). Japanese registry data found that 30% of patients with unilateral PA did not undergo adrenalectomy, but the reasons for this and whether the same pattern is seen internationally are unknown. Objective To assess the rate of AVS-guided adrenalectomy across an international cohort and identify factors that resulted in adrenalectomy not being performed in otherwise eligible patients. Design, Setting, and Participants Retrospective, multinational, multicenter questionnaire-based survey of management of PA patients from 16 centers between 2006 and 2018. Main Outcome Measures Rates of AVS implementation, AVS success rate, diagnosis of unilateral PA, adrenalectomy rate, and reasons why adrenalectomy was not undertaken in patients with unilateral PA. Results Rates of AVS implementation, successful AVS, and unilateral disease were 66.3%, 89.3% and 36.9% respectively in 4818 patients with PA. Unilateral PA and adrenalectomy rate in unilateral PA were lower in Japanese than in European centers (24.0% vs 47.6% and 78.2% vs 91.4% respectively). The clinical reasoning for not performing adrenalectomy in unilateral PA were more likely to be physician-derived in Japan and patient-derived in Europe. Physician-derived factors included non-AVS factors, such as good blood pressure control, normokalemia, and the absence of adrenal lesions on imaging, which were present before AVS. Conclusion Considering the various unfavorable aspects of AVS, stricter implementation and consideration of surgical candidacy prior to AVS will increase its diagnostic efficiency and utility.

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: 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.

Corticotroph tumor progression after bilateral adrenalectomy/Nelson’s syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing’s disease (CD) included in the European Registry on Cushing’s Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2–9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5–6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

Context Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. Objective To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms. Design Cross-sectional study. Setting University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT). Patients We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs). Intervention Ribonucleic acid (RNA) sequencing. Main Outcome Measures Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing. Results Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation. Conclusions MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

Acromegaly is a rare condition typically caused by benign pituitary adenomas, resulting in excessive production of growth hormone. Clinical manifestations of acromegaly are diverse, varying from the overgrowth of body tissue to cardiovascular, metabolic, and osteoarticular disorders. Symptoms may emerge slowly, overlapping with other diseases and often involve many different healthcare specialists. In the last decade, efforts to provide an accurate and timely diagnosis of acromegaly have improved disease management and clinical experience. Despite this progress, marked differences in the diagnosis, treatment, and management of acromegaly exist from country-to-country. To address these inconsistencies in the region comprising Central and Eastern Europe, Israel, and Kazakhstan, a panel of acromegaly experts from 13 of these countries was convened. Acromegaly experts from each country provided available information on the approaches from their country, including regional treatment centers and multidisciplinary teams, treatment access, reimbursement and availability, and physician education, disease awareness, and patient advocacy. Across several areas of acromegaly management, divergent approaches were identified and discussed, including the provision of multidisciplinary care, approved and available treatments, and disease awareness programs. These were recognized as areas of potential improvement in the management of acromegaly, in addition to participation in national and regional acromegaly registries. Further experience exchange will facilitate the identification of specific strategies that can be adapted in each country, and widespread participation in acromegaly registries will enable their evaluation. It is anticipated that this approach will support the optimization of acromegaly patient care across this region.

Introduction Frailty is characterized by multisystem function decline related to aging and can be measured using frailty Index (FI). FI is constructed based on the proportion of deficits present in an individual out of the total number of health variables considered. FI in various populations has been shown to predict adverse health outcomes. We aimed to determine the impact of hormone excess on frailty in a prospective cohort of patients with adrenal adenomas. Methods We conducted a multicenter prospective observational study of adult patients with adrenal adenomas and referent subjects without adrenal disorders (Jan 2019-Dec 2021). Adrenal adenomas comprised non-functioning adrenal adenomas (NFA), adenomas with mild autonomous cortisol secretion (MACS), defined as dexamethasone suppression test (DST)>1.8 mcg/dL, Cushing syndrome (CS), and primary aldosteronism (PA). FI was calculated as a sum of 47 variables (20 comorbidities, 13 symptoms, 14 activities of daily living) divided by 47.1 Frailty was defined as FI>0.25. In a subset of patients (n=176), functional measurements (handgrip strength, timed up and go test, gait speed) were performed and compared to FI. Results Of 233 patients (72.1% women), 71 were diagnosed with NFA (median age 64.5 years), 108 with MACS (median age 60.7 years), 11 with CS (median age 58.0 years), 46 with PA (median age 52.4 years), and 33 were referent subjects (median age 51.3 years). When compared to referent subjects, age- and sex-adjusted frailty prevalence was highest in CS (OR 29, 95%CI 4.3-202), followed by MACS (OR 16, 95%CI 3.5-73.7), and PA (OR 11.7, 95%CI 2.4-56), but not in patients with NFA (OR 5.1, 95%CI 0.99-25.8). Compared to patients with NFA, age- and sex-adjusted frailty prevalence was higher in CS (OR 5.8, 95%CI 1.4-24.4) and in MACS (OR 3.2, 95%CI 1.5-6.7), but not in PA (OR 2.3, 95%CI 0.9-6.1) group. Subgroup-analysis based on DST demonstrated a similar increase in age- and sex-adjusted frailty prevalence in patients with DST>5 mcg/dL (OR 3.1, 95%CI 1.2-8.2) and DST 1.9-5 mcg/dL (OR 3.3, 95%CI 1.5-7.4) when compared to patients with DST Conclusions Patients with functional adrenal adenomas are more likely to be frail. In patients with MACS, the prevalence of frailty was not associated with the degree of DST abnormality. FI correlated with currently validated but more cumbersome functional measurements and is a valuable tool that could be easily used in clinical practice and help individualize management decisions in patients with adrenal adenomas. 1 Singh S et al. Frailty in Patients With Mild Autonomous Cortisol Secretion is Higher Than in Patients with Nonfunctioning Adrenal Tumors. JCEM 2020 Presentation: Saturday, June 11, 2022 1:30 p.m. - 1:35 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Introduction Limited data suggest low bone density in patients with adrenal adenomas. However, most studies are retrospective, single-center, and none were conducted in the United States. We aimed to determine the impact of cortisol and aldosterone excess on bone density. Methods We conducted a preliminary analysis of data from our multicenter, prospective observational study of adult patients with adrenocortical hormone excess and referent subjects without adrenal disorders (January 2019 - March 2022). Patients were diagnosed with non-functioning adenomas (NFA), adenomas with mild autonomous cortisol secretion, MACS (defined as cortisol following an overnight 1-mg dexamethasone suppression test (DST)>1.8 mcg/dL), adrenal or pituitary Cushing syndrome (CS), primary aldosteronism (PA), and concomitant PA-MACS. Referent subjects were patients undergoing cross-sectional imaging for reasons other than adrenal disease. All participants were interviewed about their bone health, and had bone density measurements at the spine, hips, and/or radius. Bone disease was defined as osteopenia (T-score -1.1 to -2.4), or osteoporosis (T-score < -2.5). Results A total of 417 participants included 156 referent subjects (88, 56% women, median age 65, range 2-95 years) and 261 patients (190, 73% women, median age 59, range 21-88 years). Patients were diagnosed with NFA (51, 19%), PA (46, 17%), MACS (122, 47%), PA-MACS (12, 5%), and CS (30,12%). When compared to referent subjects, sex- and age-adjusted analysis demonstrated an increased prevalence of bone disease only in patients with CS (OR 4.8, 95%CI 1.7-13), but not in other adrenal disorders. After excluding patients with CS, those with post-DST cortisol >5 mcg/dL demonstrated a higher prevalence of bone disease when compared to patients with post-DST cortisol between 1.8-5 mcg/dL (OR 2.8, 95%CI 1.2-6.5) and those with post-DST cortisol Conclusions The prevalence of osteopenia and osteoporosis increases proportional to the increase in post-DST cortisol concentrations. Patients with CS, and those with MACS and post-DST cortisol > 5mcg/dL have the highest prevalence of bone disease. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

The aim of our study was to evaluate the efficacy and safety of Leksell gamma-knife radiosurgery in the treatment of residual growth hormone-secreting pituitary adenomas after the surgery.We conducted a retrospective analysis of 23 acromegaly patients treated with gamma-knife radiosurgery between 1996 and 2019. The therapeutic success of radiosurgery was defined as IGF-1 normalization without suppressive medication (complete response) or as IGF-1 normalization with medication (partial response).The median follow-up was 57 (10-198) months. Complete response was achieved in 11 patients (47.8%) with actuarial remission rates of 17.4%, 26.1%, 39.1% and 47.8% at 1, 2, 4, and 7 years, respectively. The median time to complete the response was 21 (6-85) months. Partial response was achieved in another nine patients (39.1%) after a median time of 48 (6-144) months from radiosurgery. Patients who achieved complete remission had significantly lower IGF-1 levels before radiosurgery (Gamma-knife radiosurgery offers endocrine remission and tumour growth control in a substantial proportion of patients with GH-secreting adenomas. Given the high cost of life-long medical treatment and a moderate risk of radiation-induced side effects, radiosurgery for growth hormone-secreting pituitary adenomas should be considered in all patients with residual tumours.

Purpose of review: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis depending mostly on the disease stage and tumor grade. The staging system proposed by the European Network for the Study of Adrenal Tumors has a reliable prognostic potential and defines ACC stages I-IV. Due to the absence of extraadrenal tissue invasion, patients with stage I-II have a lower recurrence rate and better prognosis. This article elaborates on the current understanding of the clinical approach to this group of patients. ----- Recent findings: Concerning the treatment, complete surgical resection of the tumor provides the only chance for cure. However, even after tumor removal, the risk of recurrence remains high and the main predictors of recurrence include tumor stage, grade (measured by Ki-67 proliferative index), and the tumor resection status. Adjuvant mitotane and/or adjuvant radiotherapy should be considered in patients with high risk of recurrence taking into account potential harmful effects of such treatment. Accordingly, careful selection of patients who may benefit from adjuvant treatment is of the utmost importance both for improving disease outcome and for avoiding potential overtreatment in patients who are at low risk of disease recurrence. ----- Summary: Many aspects of the management of patients with ACC stages I and II are not entirely evidence-based, and treatment decisions rely mostly on expert opinions and data from retrospective studies. Therefore, the treatment of these patients should be restricted to specialized centers with high expertise in ACC.

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.

Purpose The purpose of this study was to evaluate the clinical relevance of the early postoperative basal cortisol level in assessing the postoperative hypothalamic-pituitary-adrenal (HPA) axis function after pituitary tumor surgery. Methods We performed a prospective observational study that enrolled 83 patients operated for pituitary adenoma or other sellar lesions at the University Hospital Center Zagreb between December 2013 and April 2017 (44 nonfunctioning pituitary adenomas, 28 somatotropinomas, 5 craniopharyngiomas, 2 prolactinomas resistant to medical therapy and 4 other lesions - Rathke's cleft cyst, arachnoid cyst, chondroma and gangliocytoma). Exclusion criteria were Cushing's disease, chronic therapy with glucocorticoids prior to surgery and preoperative adrenal insufficiency. Early postoperative basal cortisol levels (measured on the second postoperative day) and the Synacthen stimulation test (performed 3 months after the surgery with the peak cortisol level of>500 nmol/L considered as a normal response) were analyzed to assess HPA axis function during follow-up. Results ROC analysis showed a cut-off of the basal cortisol level of ≥300 nmol/L measured on the second postoperative day to predict normal postoperative HPA axis function with the sensitivity of 92.31%, specificity of 87.14% and positive predictive value of 57.14%. Conclusion The basal cortisol level on the second postoperative day is a valuable tool to predict integrity of the HPA axis after pituitary tumor surgery. Our data suggest that the cortisol level of ≥300 nmol/L accurately predicts adrenal sufficiency and that in these patients glucocorticoid therapy can be withdrawn.

Objective Patients with Cushing’s syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. Methods In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2–5.5) years. Results Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. Conclusion Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.

1 Background: The ESE-ENSAT guidelines on ACC management suggest adjuvant mitotane for patients at high risk of recurrence. This indication has limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation. The primary endpoint of the study was RFS. Patients who refused randomization were eligible for the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in ADIUVO except for randomization. A total of 91 patients were enrolled in ADIUVO, 45 in the mitotane and 46 in the observation arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with mitotane and observation groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohort was analyzed in parallel to deal with the lower than expected recruitment in ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55-3.32, p = 0.54) and HR for death 2.171 (95%CI, 0.52-12.12, p = 0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed that of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-yr RFS is 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care. Clinical trial information: NCT00777244.

Background: The ESE-ENSAT guidelines on the management of adrenocortical carcinoma (ACC) suggest adjuvant mitotane for patients at high risk of recurrence following radical surgery. This indication has a limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in ACC patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane (MIT) or observation (OBS). The primary endpoint of the study was RFS. Patients who refused randomization were offered inclusion in the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in the ADIUVO study. A total of 91 patients were enrolled in ADIUVO, 45 in the MIT and 46 in the OBS arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with MIT and OBS groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohorts could be analyzed in parallel to those of ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. Tumor size was a predictor of RFS in multivariable analysis. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55–3.32, p=0.54) and HR for death 2.171 (95%CI, 0.52–12.12, p=0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed the findings of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-year RFS is about 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care.

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs

Background: The adrenocortical carcinoma (ACC) is a rare malignancy with poor outcomes and overall survival of less than 40%. Different prognostic factors were evaluated in patients with ACC. We analyzed overall survival (OS) and recurrence-free survival (RFS) in patients with ACC depending on Ki-67 and ENSAT staging. Methods: We performed a retrospective study on 62 ACC patients treated at the Croatian Referral Center for adrenal gland disorders from 2005 to 2019. Six patients (10%) had ENSAT stage I disease, 30 patients (48%) stage II, 14 patients (23%) stage III and 12 patients (19%) stage IV. RFS was analyzed in 47 patients with the ACC ENSAT stage I-III and R0 resection. Based on Ki-67 patients were stratified in two groups: Ki-67 ≤ 10% and Ki-67 > 10%. Results: The mean age of patients was 49.1 ± 15.5 years and 70.9% were females. During the study, 15 patients died of whom 10 deaths were related to ACC. The mean OS was 83.3 ± 14.3 months, 153.7 ± 11.3 months, 77.1 ± 14.5 months and 19.7 ± 4.9 months for ENSAT stage I, II, III, and IV, respectively (P < 0.001). Disease recurrence was observed in 9 patients (19%) of whom two patients had Ki-67 ≤ 10%.The mean RFS was 68.3 ± 9.5 months, 109.9 ± 9.4 months and 82.4 ± 16.4 months for ENSAT stage I, II and III, respectively (P = 0.916). Ki-67>10% was associated with poorer survival (P = 0.04). Conclusion: Our data confirmed that the ENSAT stage and Ki-67 are major predictors of ACC patient’s survival. However, in our cohort of patients, Ki-67 has not been associated with the ACC recurrence.

Introduction: Adrenocortical carcinoma (ACC)is a rare disease with an unfavourable prognosis. Complete surgical resection of the tumour provides the only chance for long-term cure. The aim of this study was to compare long term outcomes in patients with ACC referred to surgery in an expert adrenal centre (EC) versus nonspecialised centres (NSC). Materials and methods: This retrospective study included 48 patients with ACC, ENSAT stage I-III. All of study participants underwent complete tumour resection of whom 35 (73%) were operated in a high-volume centre by a dedicated surgeon, whereas 13 (27%) patients were operated in nonspecialised centres. The study analysed the differences between the two groups in terms of recurrence free survival (RFS) and overall survival (OS). Results: Median duration of follow- up was 51 months (5–174) in EC group and 46 months (3–165) in NSC group. Disease recurrence was observed in 5 (14.3%) patients in the EC group and in 5 (38.5%) patients in the NSC group (P = 0.067). Patients in the EC group had longer PFS but the difference did not reached the level of statistical significance (28 (11–45) month vs 19 (3–43) months ; P = 0.083). Overall, seven patients died during follow-up (5 EC, 2 NSC). ACC was the cause of death in two EC patients (5.7%) and in two NSC patients (15.4% ; P = 0.16). Conclusion: The above-mentioned results show thatACC recurrence is less likely to occur in patients operated by a dedicated surgeon in an expert adrenal centre.

© 2021 European Society of Endocrinology, Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Objective. Several smaller studies on adrenal incidentalomas (AI) suggested an association between autonomous cortisol secretion (ACS) and mortality (Di Dalmazi Lancet Diabetes Endocrinol 2014, Debono J Clin Endocrinol Metab 2014, Patrova Endocrine 2017). However, a recent meta-analysis (9 studies, 1356 patients) could not confirm these findings (Elhassan Ann Intern Med 2019). Aim. To investigate the effects of ACS on mortality, prevalence of cardiovascular (CV) risk factors, and (CV) morbidity, in a representative cohort of AI. Design. Retrospective observational study conducted at 27 ENS@T centers from 15 countries. Methods. Inclusion criteria: AI diagnosed 1996-2015, 1 mg dexamethasone suppression test, follow-up (FU) of ≥36 months, known survival status. Exclusion criteria: clinically relevant adrenal hormone excess (i.e. Cushing’s syndrome, pheochromocytoma, primary hyperaldosteronism), known malignancy. Patient stratification: serum cortisol after dexamethasone (>5 µg/dl, ACS; 1.9-5 µg/dl, possible ACS (PACS); ≤1.8 µg/dl, non-functioning adenoma (NFA)). Definition of CV events (CVE): hospitalization due to myocardial infarction and related interventions (PTCA, surgical bypass), stroke, deep vein thrombosis, pulmonary embolism. Results. 3640 patients (57% NFA, 36% PACS, 7% ACS) were considered eligible: 64% females; median age 61 years (range 18-91); median FU 84 months (36-277) (distribution between subgroups n.s.). 352 patients died during FU. Age- and sex adjusted overall survival was significantly reduced in patients with PACS (HR 1.55; 95%CI 1.24-1.94) and ACS (1.84; 1.29-2.61). Prevalence of CV risk factors were significantly higher in PACS and ACS than in NFA (hypertension: 72, 73, 57%, p

BACKGROUND: Adrenal venous sampling (AVS) is strongly recommended for a subtype diagnosis of primary aldosteronism (PA) if adrenalectomy (ADX) is desired by the patient. Given various issues related to AVS such as technical demand, invasive nature, expensive cost and radiation exposure, AVS is expected to lead efficiently to the subtype diagnosis and ADX. Aim: Primary objective was to assess the performance of AVS to determine treatment of PA by investigating the ratio of unilateral disease and rate of ADX following AVS in patients with unilateral disease. Methods: Sixteen major referral centers in ENS@T (n=10) and Japan (n=6) participated in the study. Study period was from 2006 to 2018. Data on total number of PA patients, AVS (total number and number of successful procedures), number of patients with unilateral diseases, and number of patients that underwent ADX were collected by a questionnaire-based survey. In addition, reasons for not proceeding to ADX in patients with a unilateral diagnosis were investigated. The diagnosis of PA was based on the positive case detection and at least one positive result in confirmatory testing. Results: Total number of confirmed PA patients and conducted AVS showed a dramatic increase during the past decade (PA: 1061 pts/ 2006–2011 to 3718 pts/ 2012–2018; AVS: 720/ 2006–2011 to 2448/ 2012–2018). Success rate of AVS was improved from 79.0% (2006–2011) to 92.5% (2012–2018). Both rate of unilateral PA and ADX of successful procedures decreased from 42.7% (2006–2011) to 37.3% (2012–2018) and from 40.8% (2006–2011) to 34.9% (2012–2018), respectively. Of the patients with successful AVS, bilateral disease was diagnosed in 63.5% (1812/2854 pts). Of the unilateral PA patients, 11.9% (125/ 1054 pts) were not subjected to ADX. The rate of the patients not subjected to ADX was significantly higher in Japan than in ENS@T centers both in patients with successful AVS (75.8% vs. 53.4%) and with unilateral disease (19.9% vs. 8.6%). Clinical decision against ADX in unilateral disease was made by the physicians in 33.3%, the patients in 33.3%, and both in 33.3%. Medical factors for Dr.’s decision against ADX in unilateral disease included good blood pressure control, normokalemia, comorbidities (e.g. DM, CKD), non-lateralized CT findings (e.g. no tumor, contralateral tumor), and discordant results among different criteria of AVS. Conclusions: High prevalence of bilateral disease and change of treatment policy after implementation affected the efficiency of AVS as an essential diagnostic procedure prior to ADX. Development of non-invasive procedures to exclude bilateral PA and more strict indication of AVS are warranted.