Yu, Kai

Abstract Context The clinical relevance of etiologic concordance and temporal presentation in bilateral adrenal masses remains poorly defined, creating uncertainty in diagnostic evaluation and management. Objective To characterize the etiologic spectrum of bilateral adrenal masses, evaluate patterns by concordance and synchronicity, and identify predictors of discordance and malignant or pheochromocytoma contralateral lesions. Design Retrospective cohort study (2010-2025). Setting Tertiary referral center. Participants Adults with bilateral adrenal masses. Main Outcome Measures Etiology, concordance, synchronicity, interval to contralateral lesion, and factors associated with discordance and malignant or pheochromocytoma contralateral lesions. Results Among 1035 patients (median age 59.6 years; 51% women), 85% had concordant and 15% discordant etiologies. Concordant cases were predominantly bilateral benign cortical lesions (76%), whereas discordant cases were heterogeneous (benign 35%, malignant 31%, and indeterminate 34%). Presentation was synchronous in 84% and asynchronous in 16%, with a median interval of 45 months (interquartile range 15-87). Asynchronous disease was associated with higher discordance (23% vs 13%, P = .001) and greater prevalence of malignant lesions (bilateral malignant: 17% vs 7%; discordant malignant: 8% vs 4%; overall P < .001). Among asynchronous cases, shorter interval to contralateral lesion (<2 vs ≥5 years) was independently associated with malignant or pheochromocytoma etiology (adjusted odds ratio [OR] 2.63, 95% CI 1.01-6.85), as was larger tumor size (adjusted OR 1.06 per mm, 95% CI 1.02-1.09). Conclusion Most bilateral adrenal masses are benign and concordant; however, discordant or asynchronous disease identifies a higher-risk subgroup enriched for malignancy. Early contralateral lesion development and larger tumor size are key risk factors.

Abstract Context Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in up to 30% of patients with PA. Objectives (1) Assess cognition in patients with PA vs referent subjects with hypertension and (2) determine differences in cognition between patients with PA and those with MACS. Methods A prospective, cross-sectional study, 2019-2023. Cognition was assessed by National Institute of Health Toolbox Cognition Battery and reported as T-scores corrected for age, sex, race, and education. Only subjects with hypertension were included. Results Cognitive assessment was performed in 52 patients with PA (including 11 patients with both PA and MACS, median age of 51.0 years, 30 (57.7%) women), 47 patients with MACS (median age of 57.0 years, 31 (66.0%) women), and 52 referent subjects (median age of 66.1 years, 30 (57.7%) women). When compared to referents, and after adjusting for age, smoking, systolic blood pressure, and alcohol use, patients with PA had lower total cognition (β = −5.7, P = .023), notably fluid cognition (β = −6.8, P = .017), including attention and executive function (β = −5.6, P = .012) and cognitive flexibility and executive function (β = −8.2, P = .006). When compared to patients with MACS, patients with PA had a higher processing speed (β = 9.0, P = .003). No differences in cognition were found between patients with PA with and without MACS. Conclusion Patients with PA demonstrated lower cognition compared with referents and processing speed compared with MACS. Future studies should characterize the impact of MACS on the cognition of patients with PA.

Abstract Disclosure: K. Yu: None. J. Saini: None. E.J. Atkinson: None. S.J. Achenbach: None. V. Fell: None. I. Bancos: None. Background: Data on cognition in patients with primary aldosteronism (PA) are scarce. Mild autonomous cortisol secretion (MACS), defined based on post-dexamethasone cortisol >1.8 mcg/dL, is diagnosed in 20-30% of patients with PA. The impact of MACS on the cognition of patients with PA is unclear. Objectives: 1) to assess cognition in patients with PA versus sex-matched referent subjects with hypertension, 2) determine the differences in cognition of patients with PA (with and without MACS) and patients with MACS. Methods: A cross-sectional study, 2019-2023. Cognition was assessed by National Institute of Health Toolbox Cognition Battery and reported as T-score corrected for age, sex, race, and education. Only subjects with hypertension were included. Results: Cognitive assessment was performed in 52 patients with PA (including 11 patients with both PA and MACS, median age of 51 yrs, 30, 58% women), 47 patients with MACS (median age of 57 yrs, 31, 66% women), and 52 referent subjects (median age of 66 yrs, 30, 58% women). When compared to referents, and after age adjustment, patients with PA had lower cognition: fluid composite cognition β of -6.3 (P=0.014) and total composite of -5.6 (P=0.016). When compared to patients with MACS, and after age and sex adjustment, patients with PA had a similar total composite cognition score (β=3.6, P=0.108) but a higher fluid composite score (β=4.7, P=0.044). No differences in cognition were found between patients with PA with and without MACS, possibly due to low sample size. Conclusion: Patients with PA demonstrate lower cognition when compared to referents with hypertension. Patients with PA had a higher fluid cognition compared to patients with MACS. Future studies should delineate the impact of hyperaldosteronism vs MACS on cognition of patients with PA. Presentation: Monday, July 14, 2025

Abstract Disclosure: S.R. Chacko: None. C.A. Villavicencio Torres: None. K. Yu: None. S.G. Waguespack: None. L. Lu: None. Z. Belaya: None. T. Bandgar: None. A. Sada: None. O. Ragnarsson: None. B. Altieri: None. A. Newman: None. P. Vibhatavata: None. M. Tóth: None. E.V. Varlamov: None. C. Badiu: None. A. Paissan: None. M. St-Jean: None. H. Falhammar: None. N. Imamudeen: None. L. Haberbosch: None. M. Bobrowicz: None. A. Tabarin: None. R. Shah: None. M.R. Gadelha: None. A. Peersen: None. W.F. Young: None. J. Kaplan: None. J. Varghese: None. M.A. Habra: None. O. Golounina: None. G.A. Melnichenko: None. A.R. Lila: None. C. Yamichannaiah: None. I. Bancos: None. Context: Cushing syndrome (CS) due to ectopic ACTH secretion (EAS) is a rare condition, associated with severe hypercortisolism and consequent morbidity and mortality. Its varied and often emergent presentation make diagnosis and treatment challenging. Objectives: 1.Characterize clinical and biochemical presentation of EAS. 2.Describe the scope of hypercortisolism-related complications, overall and CS-specific mortality. 3.Identify factors associated with CS-specific mortality. Methods: We conducted a multicenter retrospective cohort study in patients with EAS at 37 centers. Outcomes were clinical/biochemical severity scores, complications, overall and CS-specific mortality. Results: In 1053 patients [median age at diagnosis 52 years (IQR 37-64), 57% women], metastatic disease was present at diagnosis in 585 (56%). The most common sources of EAS were bronchial neuroendocrine neoplasm (NEN) (304, 29%), pancreatic NEN (114, 11%) and small cell lung carcinoma (114, 11%), with the source of EAS being occult in 192 (18%). Clinical and biochemical severity scores were severe in 475 (45%) and 873 patients (92%) respectively. Hypokalemia was present in 819 patients (78%) in the year prior to diagnosis. Of 342 patients (32%) who had IPSS, 301 (88%) suggested an ectopic source, 7 (2%) a pituitary source, and 23 (7%) were non-diagnostic. Of 595 patients who had both functional and cross-sectional imaging, discordant findings were seen in 122 (21%), concordant lesion was seen on both in 326 (55%), and no lesion in 147 (25%). Of those with discordant results, cross-sectional imaging was accurate in 66 (54%) and functional imaging in 56 (46%).Management included medical therapy alone in 237 (23%), surgical excision of the source of EAS in 158 (15%), bilateral adrenalectomy in 77 (7%) and multimodal therapies in 498 patients (47%). Complications within 5 years after diagnosis included hospitalization related to CS or its therapy in 351 (33%), infection in 337 (32%), thromboembolic event in 102 (10%), cardiovascular event in 83 (8%) and cerebrovascular event in 27 (3%). During a median follow-up of 35 months (IQR 20-122) from CS diagnosis, death occurred in 462 patients (44%), with the cause of death related to CS in 149 (14%). CS-specific mortality was higher in metastatic compared with non-metastatic disease (19% vs. 7%, P<0.001). On multivariable analysis of age, sex, clinical and biochemical severity, older age (HR 1.03, 95% CI: 1.02-1.04) and lower clinical severity score (HR 0.97, 95% CI: 0.94-0.99), were associated with higher CS-specific mortality. Conclusion: Our interim analysis, the largest worldwide, found that most patients with EAS had severe hypercortisolism and hypokalemia. Metastatic disease was present in 56%, and the source of EAS was occult in 18%. CS-related death occurred in 14%, emphasizing the need for urgent management. Presentation: Monday, July 14, 2025

Abstract Disclosure: M. Salehi: None. K. Yu: None. C.A. Villavicencio Torres: None. V. Fell: None. I. Bancos: None. Context: The use of the 1 mg overnight dexamethasone suppression test (1 mg-DST) is considered the standard-of-care test for the assessment of hypercortisolism. Scarce data are available on the utility of 8 mg-DST in distinguishing adrenal from pituitary hypercortisolism. Objective: To determine the value of 8 mg-DST in diagnosing hypercortisolism subtype. Methods: We conducted a single-center retrospective cohort study (2005-2024) of consecutive adults who underwent both the 1 mg-DST and the 8 mg-DST within a 6-month period. Only patients with optimal reference standard confirming the type of hypercortisolism were included. Patients were excluded if they had an abnormal DST and dexamethasone concentration <100 ng/dL or were receiving oral estrogen therapy. Delta cortisol [(post 1 mg-DST cortisol- post 8 mg-DST cortisol) x100/post 1 mg-DST cortisol)] was calculated for each patient. Results: A total of 61 patients (50, 82% women, median age 60 years, interquartile range, IQR 47-67) underwent both 1- and 8 mg-DST at least once, with 8 (13%) patients undergoing the 1 mg-DST and 8 mg-DST twice, and 1 (1.6%) patient undergoing both tests thrice. Adrenal hypercortisolism was diagnosed in 44 (72%) patients and pituitary hypercortisolism in 17 (28%) patients. Median post 1 mg-DST cortisol was 4.6 mcg/dL (IQR 2.8-7.2) in adrenal and 13.7 mcg/dL (IQR 7.3-21.7) in pituitary hypercortisolism. Median post 8 mg-DST cortisol was 3.2 mcg/dL (IQR 2.5-6.3) in adrenal and 3.6 mcg/dL (IQR 2.2-7.5) in pituitary hypercortisolism. Median delta cortisol was higher in pituitary hypercortisolism when compared to adrenal hypercortisolism (69%, IQR 25-83 vs 5 %, IQR -20-16, P<0.001). Delta cortisol demonstrated a good discrimination in distinguishing adrenal from pituitary hypercortisolism with a median area under receiver operator of 82% (95%CI 69-92). A cut-off of 25% provided a specificity of > 85%, while a cut-off of -1% yielded a sensitivity of > 85% in diagnosing adrenal hypercortisolism. Conclusion: In this study, we show that performing 8 mg-DST in addition to 1 mg-DST in selected patients with hypercortisolism and calculating delta cortisol is a valuable in distinguishing hypercortisolism subtype. Presentation: Sunday, July 13, 2025

Abstract Disclosure: S.R. Chacko: None. C. Powell: None. B. Ndovu: None. E.Y. Ferreira: None. R. Rosenberg: None. J. Saini: None. S. Nevin: None. K. Yu: None. V. Fell: None. J.J. Larson: None. E. Atkinson: None. I. Bancos: Funding for investigator-initiated research from Esteve. Context: Mild autonomous cortisol secretion (MACS), found in about 50% of patients with adrenal incidentalomas, is associated with increased cardiovascular morbidity. While adrenalectomy improves outcomes in unilateral MACS, safe and effective medical therapy is needed for bilateral MACS. Objectives: To evaluate the tolerability and safety of overnight metyrapone in adults with MACS. Methods: Study design: Open-Label, Phase 2, Clinical Trial (NCT06106295) Participants: Patients >18-years-old with MACS and benign adrenal imaging phenotype were prospectively enrolled between December 2023 and January 2025. MACS was diagnosed based on 1 mg post-dexamethasone suppression test serum cortisol >1.8 mcg/dL. Eligibility required at least one MACS-associated comorbidity (obesity, dysglycemia, dyslipidemia, hypertension, osteopenia or osteoporosis). Intervention: Metyrapone was administered at an initial dose of 250 mg each evening with up titration in 250 mg increments every 2-4 weeks based on tolerance, to a maximum of 1000 mg. Outcomes: The primary endpoint was assessment of treatment-related adverse events (AE), categorized by CTCAE grade. Adrenal insufficiency (AI) was considered an AE, assessed on biochemistry and AddiQoL survey. Sample size: 30 patients projected Results: Twenty-six patients with MACS [median age 66 years (IQR 61-68), 69% women] were enrolled. At the time of analysis, median metyrapone dose was 1000 mg (IQR 750-1000). At median follow-up of 3 months (IQR 2-6), 22 patients (85%) developed at least one AE. None were serious, aside from one patient with an acute kidney injury (AKI), unlikely related to metyrapone. All other AEs were CTCAE Grade 1-2, including dizziness 12%, nausea 6% and fatigue 5%. Of all 90 AEs, 12 (13%) occurred at a dose of 250 mg, 10 (11%) at 500 mg, 20 (22%) at 750 mg and 48 (53%) at 1000 mg. One (1%) was definitely related to metyrapone (hypokalemia), 16 (18%) probably related, 20 (22%) possibly related, 35 (39%) unlikely to be related, and 18 (20%) unrelated to metyrapone. Dose was reduced in 5 patients (19%) due to an AE. Two discontinued metyrapone, one because of AKI, while the other withdrew from the study. Morning serum cortisol was not significantly changed between baseline [11.5 (IQR 9.2-14.8)], 3 months [12.0 (IQR 11.0-15.0)], and 6 months [9.7 (IQR 7.9-12.5)] (normal: 4.8-20 mcg/dL). No patient developed AI (morning serum cortisol <10 mcg/dL and ACTH >60 pg/ml), but plasma ACTH significantly increased from baseline to 3 months [8.0 (IQR 5.4-20.8) vs. 18.0 (IQR 14.0-28.0), P=0.021] (normal: 10-60 pg/ml). Between 3 and 6 months, no significant change occurred in ACTH. AddiQol survey scores did not change significantly between baseline, 3 and 6 months. Conclusion: Metyrapone therapy in patients with MACS demonstrated a favorable safety profile with no occurrence of AI. Further investigation into efficacy and MACS-associated outcomes is warranted. Presentation: Sunday, July 13, 2025

Abstract Context Data on diagnostic accuracy of dehydroepiandrosterone sulfate (DHEA-S) for mild autonomous cortisol secretion (MACS) and adrenal insufficiency (AI) are discrepant. Objective We conducted a systematic review and meta-analysis of published studies assessing the accuracy of DHEA-S in diagnosing MACS or AI. Methods From inception to January 8, 2024, we searched databases for original studies of at least 20 participants with MACS or AI. MACS was defined as postdexamethasone cortisol greater than 1.8 mcg/dL or postsurgical hypocortisolism. AI was defined by abnormal dynamic testing. QUADAS-2 was used to assess the risk of bias. Bivariate random effects meta-analysis was used to generate pooled diagnostic accuracy estimates. Results Seven studies on DHEA-S accuracy in diagnosing MACS (574 patients with MACS, 830 referent individuals), and 2 studies on DHEA-S accuracy in diagnosing AI (52 patients with AI, 59 referent individuals) were included. A meta-analysis of studies using DHEA-S cutoff between 60 and 70 mcg/dL to diagnose MACS demonstrated a sensitivity of 82% (95% CI, 64%-93%) and a specificity of 82% (95% CI, 74%-88%). In the 2 studies evaluating DHEA-S in diagnosing AI, the reference standard was a 1-mcg cosyntropin stimulation test. The sensitivity of DHEA-S for diagnosing AI ranged from 70.3% to 86.7%, and the specificity was 87.1%. Most studies were at a moderate risk of bias. Conclusion Based on limited heterogeneous evidence, measurement of DHEA-S provides additional value in diagnosing MACS, as well as AI.

Abstract Hereditary tumor predisposition syndromes pose a challenge for early detection and timely treatment of tumors. In von Hippel–Lindau disease, desirable personalized surveillance programs are lacking due to insufficient data on genotype-specific risk profiles of individual mutations. To describe neoplastic risk profiles for carriers of pathogenic and likely pathogenic VHL germline mutations, our observational study recruited 1,350 participants from 40 centers worldwide. 432 different VHL germline mutations were observed, with p.Asn78Ser, p.Arg161Ter, p.Arg161Gln, p.Arg167Gln, p.Arg167Trp and p.Tyr98His being the six most frequent, occurring in a total of 493 carriers (36.5%) and in ≥30 patients each. Age-related penetrance risks for retinal hemangioblastoma, central nervous system hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors and pheochromocytoma/paraganglioma in carriers of the most frequent VHL mutations were assessed. In addition, the number of organs affected, the frequency of surgery and the outcome are reported. Pairwise comparisons of the age-dependent tumor penetrance of these six mutations showed that 47 out of 90 pairs were significantly different. The most significant associations were found in p.Tyr98His (n = 19), followed by p.Arg161Ter (n = 10). All pairwise comparisons of mutations affecting different codons showed at least one significant (P < 0.05) difference, except for p.Asn78Ser vs p.Arg161Ter. Thus, tumor risk varied by VHL mutation type and location, but did not differ between the truncating mutation p.Arg161Ter and the missense mutation p.Asn78Ser. Our study demonstrates the importance of mutation-specific phenotype prediction. With appropriate validation, the data have important implications for risk assessment and decision making in tumor prevention for carriers of the respective VHL mutations.

Abstract Disclosure: J. Saini: None. B. Salama: None. S.R. Chacko: None. K. Yu: None. I. Bancos: None. Objective: Measurement of baseline dehydroepiandrosterone sulfate (DHEAS) is suggested by the guidelines in support of diagnosing mild autonomous cortisol secretion (MACS). However, evidence on the diagnostic accuracy of DHEAS in MACS is difficult to interpret due to differences in the diagnostic cutoffs, small sample size, and heterogeneous reference standards. We aimed to conduct a systematic review and meta-analysis of published literature to assess the performance of DHEAS in diagnosing MACS, as defined in the 2023 guidelines. Methods: A comprehensive search was conducted using several databases from each database’s inception to January 8th, 2024. Databases include Ovid MEDLINE (R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Databases of Systematic Reviews, and Scopus. Only original studies of at least 20 participants were included. MACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. QUADAS-2 was used to assess the risk of bias. Bivariate and random effects meta-analysis was used to generate pooled diagnostic accuracy estimates. Results: The initial search yielded 285 articles, and only 7 studies met the inclusion criteria. In 7 studies (1 from North America, 3 from Asia, and 3 from Europe), a total of 574 patients with MACS and 830 referent subjects (patients with adrenal tumors without MACS) were included. The mean age was specified only in 5 studies and was similar in patients with MACS (55.5 years) and referent group (53.3 years). Patients with MACS had a higher number of women (323/472, 68.4%) as compared to the referent group (352/658, 53.4%). DHEAS cutoffs studied included: lower cutoff of age-and sex-specific ranges (3 studies), 40 mcg/dL (3 studies), 60 mcg/dL (1 study), and 67.5 mcg/dL (1 study). With increasing DHEAS cutoff, sensitivity for MACS diagnosis increased, and specificity decreased. Most studies (4 studies) used the chemiluminescent immunoassay to measure DHEAS. A meta-analysis of studies using DHEAS cut-off between 40-70 mcg/dL was performed, with a pooled sensitivity of 68% (95% CI: 51-81) and a pooled specificity of 85% (78-89). The positive likelihood ratio was 4 (95% CI: 3-6; I2=36.94, P=0.175) and the negative likelihood ratio was 0.4 (0.3-0.6; I2=49.97, P=0.092). Most studies were at a high risk of bias for selection of patients, index, or reference standard. Conclusion: Based on limited heterogeneous evidence, measurement of DHEAS provides additional value in diagnosing MACS. Further larger diagnostic accuracy studies should explore various DHEAS cutoffs and consider assay variability. Presentation: 6/3/2024