Larson, Joseph J.

Abstract Disclosure: B. Salama: None. M. Bassiony: None. J. Saini: None. P. Dogra: None. E. Atkinson: None. J. Larson: None. I. Vodanovic: None. D. Kastelan: None. D.A. Delivanis: None. J. Hubska: None. U. Ambroziak: None. I. Bancos: None. Background: Frailty is a clinical syndrome characterized by diminished physiological reserve and increased vulnerability to stressors. Patients with Mild Autonomous Cortisol Secretion (MACS) demonstrate a high prevalence of frailty, however, no data are available on the impact of management on frailty progression. Objectives: To determine the impact of conservative vs surgical management on and the progression of frailty in patients with MACS. Methods: We conducted a multicenter prospective cohort study of patients with (MACS), primary aldosteronism (PA), or non-functioning adrenal adenomas (NFA) between June 2020 and April 2025. Participants completed standardized frailty assessment (frailty index) at baseline and annually. Results: A total of 691 patients were included: 253 with MACS (median age 62 years, 73% women, 230 with NFA (median age 62 years, 67% women), and 208 with PA (median age 54 years, 50% women). At baseline, prevalence of frailty was highest patients with MACS (39%), followed by patients with PA (31%) and NFA (24%). Frailty was reassessed at 1 year post baseline in 189 patients with NFA (22% frail, median frailty index of 0.17) and 116 patients with MACS (27% frail, median frailty index of 0.16) managed conservatively, as well as in 108 patients with MACS treated with adrenalectomy (49% frail, median frailty score of 0.24). Conservatively treated patients with MACS and those treated with adrenalectomy had similar post-dexamethasone cortisol (median 2.9 mcg/dL vs 3.1 mcg/dL, p=0.396), but were older (median age 65 years vs 58 years, p=0.001) At one year follow up, patients with MACS treated with adrenalectomy demonstrated an improvement in frailty when compared to conservative management (delta frailty index: Est of −0.044, p = 0.004), after adjusting for age and sex. In contrast, when compared to conservatively managed patients with NFA, conservatively managed patients with MACS demonstrated worse frailty at 1 year follow up (delta frailty index: Est of 0.028, p = 0.013). Conclusion: In comparison to patients with NFA, conservatively managed patients with MACS demonstrated worse frailty at 1 year follow up. In contrast, adrenalectomy in patients with MACS led to improvement of frailty. Frailty index could be valuable to identify patients most likely to benefit from adrenalectomy. Patients with higher baseline frailty scores were more likely to undergo adrenalectomy, 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 Objective Data on bone health in patients with mild autonomous cortisol secretion (MACS) are limited and heterogenous. We sought to assess the prevalence of osteoporosis and symptomatic fragility fractures in patients with adrenal adenomas and hypercortisolism, and explore associations with the degree of cortisol excess and frailty. Design This multicenter cross ‐sectional study involved prospective enrollment of adults with nonfunctioning adrenal adenomas (NFA), MACS, Cushing syndrome (CS) and referent subjects without adrenal disorders during the study period (January 2019–September 2022). All participants completed a bone health questionnaire at enrollment and had dual‐energy X ‐ray absorptiometry bone mineral density assessment within 12‐months. Final analyses were adjusted for age, sex, body mass index, smoking status, alcohol use. Results Participants included 117 with NFA (median age 62 years, 80% women), 191 with MACS (median age 63 years, 74% women), 62 with CS (median age 50 years, 92% women), and 101 referent subjects (median age 59 years, 47% women). Both patients with CS (OR: 3.0, 95% CI: 1.1–8.3) and MACS (OR: 2.2, 95% CI: 1.9–4.9) had a higher prevalence of osteoporosis when compared to referents. Among patients with MACS, only those with post 1‐mg dexamethasone suppression test (post‐1mg‐DST) cortisol > 83 nmol/L had a higher prevalence of osteoporosis when compared to referents (OR: 3.2, 95% CI: 1.4–7.5) and NFA (OR: 2.2, 95% CI: 1.1–4.4). For clinical fragility fractures, only patients with CS showed an increased prevalence when compared to referents (OR: 6.1, 95% CI: 1.7–26.4) and NFA (OR: 3.8, 95% CI: 1.3–11.2). Prevalence of clinical fragility fractures was similar to referents in patients with MACS (OR: 1.8, 95% CI: 0.6–6.9) and NFA (OR: 1.5, 95% CI: 0.4–6.1), and was not associated with post‐1mg‐DST cortisol or frailty in the MACS and NFA groups. Conclusion Patients with CS, and those with MACS and post‐1mg‐DST cortisol > 83 nmol/L, exhibited a higher burden of osteoporosis. However, only CS was associated with an elevated risk of symptomatic fragility fractures.

Abstract Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Patients and Methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL −1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4–69.0 months). Patients with PD-L1–positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1–negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

Abstract Disclosure: J. Saini: None. R. Nathani: None. J. Larson: None. V. Fell: None. I. Bancos: None. Background: Surgical menopause due to bilateral salpingo-oophorectomy (BSO) at a younger age is associated with an increased risk of cardiovascular disease, cognitive decline, and increased mortality. Aging is associated with abnormalities in steroid metabolome, most notably an increased glucocorticoid to androgen ratio (“adrenal aging”). We hypothesized that in postmenopausal women of the same age, the duration of menopause is associated with adrenal aging. Objective: To determine the differences in the adrenal steroid metabolome of women with a history of BSO as compared to age-matched women following natural menopause. Methods: We conducted a single-center cross-sectional study in postmenopausal women with or without a history of BSO, between December 2020 to December 2022 Each participant collected 24-hour urine, which was analyzed for steroid profiling by liquid chromatography-tandem mass spectrometry (25 steroids). Exclusion criteria were inability to collect a 24h urine sample, exogenous glucocorticoid use, advanced malignancy, and chronic opioid use. Primary endpoints were glucocorticoid/androgen ratio, 11β-hydroxysteroid dehydrogenase type 2 activity (cortisol/cortisone, Tetrahydrocortisol (THF) + 5 α-tetrahydrocortisol (5 α-THF)/ Tetrahydrocortisone, THE) and 5 α-reductase type activity (Tetrahydrocortisol (THF)/5 α-tetrahydrocortisol (5 α-THF) and Etiocholanolone/Androsterone, Et/An). Results: A total of 245 women were enrolled: 124 women (median age of 66 years, IQR 63-72) with a history of BSO and 121 women (median age of 68 years, IQR 64-71) who underwent natural menopause (P=0.214). Median age at menopause was 44 years (IQR 41-46) in the BSO group, and 50 years (IQR 48-53) in the natural menopause group. History of hormone replacement therapy with estrogen was reported in 161 (66%) women, more frequently (92% vs 39%, P<0.001) and for a longer duration (median 12 years (IQR 6-16) vs 6 years (IQR 3-9), P<0.001) in in the BSO group, as compared to the natural menopause group. Although both groups had similar levels of urinary androgens (median 1387 vs 1686 mcg/24h, P=0.063) and total glucocorticoids (median 10877 vs 10277 mcg/24h, P=0.354), women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio (median 7.9 (IQR 5.0-11.1) vs 6.7 (4.3-9.9), P=0.014), and a lower Et/An ratio (median 1.4 vs 1.6, P=0.045), but not THF/5aTHF ratio (median 1.7 vs 1.8, P=0.380) in comparison to women with natural menopause. No differences were found in other ratios. Conclusion: Women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio in comparison to women undergoing natural menopause, suggestive of BSO-induced accelerated “adrenal aging”. Future studies need to examine associations between the abnormal steroid metabolome and increased cardiovascular morbidity, frailty, and mortality reported following BSO. Presentation: 6/3/2024

Abstract Disclosure: E.Y. Ferreira: None. J. Saini: None. J. Larson: None. E. Atkinson: None. C. Powell: None. S. Nevin: None. V. Fell: None. I. Bancos: Grant Recipient; Self; HRA Pharmaceuticals. Research Investigator; Self; HRA Pharmaceuticals. Context: Mild autonomous cortisol secretion (MACS) is the most prevalent hormonal abnormality demonstrated in 20-45% of patients with adrenal adenomas. MACS is associated with increased prevalence and incidence of cardiovascular morbidity, frailty, fragility fractures, psychiatric and sleep disorders, as well as increased mortality. Bilateral MACS due to bilateral adrenal adenomas or macronodular adrenal hyperplasia is seen in around 20% of patients with MACS. Management of patients with unilateral MACS who are not surgical candidates or do not desire adrenalectomy, and management of patients with bilateral MACS is challenging. Safe and effective medical therapy is urgently needed in these patients. Objective: 1) assess safety and tolerability of overnight metyrapone therapy in patients with MACS, 2) evaluate the impact of overnight metyrapone on steroid profiling and circadian cortisol secretion and 3) determine the efficacy of overnight metyrapone on metabolic and bone parameters, mood, sleep, cognition, quality of life, frailty and senescence biomarkers. Methods: This open-label, phase 2 interventional single-center study using overnight metyrapone opened for enrollment in December 2023 (NTC06106295) and plans to enroll 30 patients with MACS. Eligible participants include adults with adrenal adenoma or macronodular adrenal hyperplasia and MACS, and at least one comorbidity attributed to hypercortisolism. Metyrapone is administered overnight at 250 mg to 1000 mg. Duration of the study is 6 months (main study) and up to 42 months for extension study. Primary endpoint is incidence of treatment related adverse events. Key secondary endpoints include: glucocorticoid/androgen ratio, morning/evening cortisol curve, metabolic parameters (change in blood pressure, hyperglycemia, weight), frailty index and senescence biomarkers. Results: Between December 15th 2023 and April 6th, 7 patients with MACS (4, 57% women) enrolled at a median age of 62 years (IQR 56-68). Median BMI was 29 kg/m2(IQR 25-34). Post-dexamethasone cortisol was 3.1 mcg/dL (IQR 2.4-6.2), corticotropin (ACTH) was 7.3 pg/mL (IQR 5-20), and dehydroepiandrosterone-sulfate (DHEAS) was 73 mcg/dL (IQR 59-86). Median hypercortisolism clinical severity score was 9 (IQR 2-11) and biochemical severity score was 3.5 (IQR 2-5). Prevalence of hypertension (57%), dysglycemia (67%), dyslipidemia (86%), depression (57%), anxiety (43%), and bone disease (70%) was high. In 7 participants, median frailty index was 0.2 (IQR 0.2-0.4), and 3 (43%) were considered frail (frailty index >0.25). As of April 6th, 2024, no major treatment-related adverse events were reported, and no patient discontinued therapy. Conclusion: Results of this study will characterize safety and tolerability of overnight metyrapone in patients with MACS and evaluate the impact of overnight metyrapone on MACS-associated comorbidities. Presentation: 6/1/2024

Abstract Disclosure: J. Saini: None. R. Nathani: None. J. Larson: None. V. Fell: None. I. Bancos: None. Background: Surgical menopause due to bilateral salpingo-oophorectomy (BSO) at a younger age is associated with an increased risk of cardiovascular disease, cognitive decline, and increased mortality. Aging is associated with abnormalities in steroid metabolome, most notably an increased glucocorticoid to androgen ratio (“adrenal aging”). We hypothesized that in postmenopausal women of the same age, the duration of menopause is associated with adrenal aging. Objective: To determine the differences in the adrenal steroid metabolome of women with a history of BSO as compared to age-matched women following natural menopause. Methods: We conducted a single-center cross-sectional study in postmenopausal women with or without a history of BSO, between December 2020 to December 2022 Each participant collected 24-hour urine, which was analyzed for steroid profiling by liquid chromatography-tandem mass spectrometry (25 steroids). Exclusion criteria were inability to collect a 24h urine sample, exogenous glucocorticoid use, advanced malignancy, and chronic opioid use. Primary endpoints were glucocorticoid/androgen ratio, 11β-hydroxysteroid dehydrogenase type 2 activity (cortisol/cortisone, Tetrahydrocortisol (THF) + 5 α-tetrahydrocortisol (5 α-THF)/ Tetrahydrocortisone, THE) and 5 α-reductase type activity (Tetrahydrocortisol (THF)/5 α-tetrahydrocortisol (5 α-THF) and Etiocholanolone/Androsterone, Et/An). Results: A total of 245 women were enrolled: 124 women (median age of 66 years, IQR 63-72) with a history of BSO and 121 women (median age of 68 years, IQR 64-71) who underwent natural menopause (P=0.214). Median age at menopause was 44 years (IQR 41-46) in the BSO group, and 50 years (IQR 48-53) in the natural menopause group. History of hormone replacement therapy with estrogen was reported in 161 (66%) women, more frequently (92% vs 39%, P<0.001) and for a longer duration (median 12 years (IQR 6-16) vs 6 years (IQR 3-9), P<0.001) in in the BSO group, as compared to the natural menopause group. Although both groups had similar levels of urinary androgens (median 1387 vs 1686 mcg/24h, P=0.063) and total glucocorticoids (median 10877 vs 10277 mcg/24h, P=0.354), women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio (median 7.9 (IQR 5.0-11.1) vs 6.7 (4.3-9.9), P=0.014), and a lower Et/An ratio (median 1.4 vs 1.6, P=0.045), but not THF/5aTHF ratio (median 1.7 vs 1.8, P=0.380) in comparison to women with natural menopause. No differences were found in other ratios. Conclusion: Women with a history of BSO demonstrated a higher glucocorticoid/androgen ratio in comparison to women undergoing natural menopause, suggestive of BSO-induced accelerated “adrenal aging”. Future studies need to examine associations between the abnormal steroid metabolome and increased cardiovascular morbidity, frailty, and mortality reported following BSO. Presentation: 6/3/2024

Biliary tract cancers, including cholangiocarcinoma, gallbladder, and ampulla of Vater cancers, rank second among hepatobiliary cancers, known for their poor prognoses. The United States has witnessed a notable increase in intrahepatic cholangiocarcinoma incidence. This study examines the incidence and survival outcomes of biliary tract cancers in Olmsted County, Minnesota from 1976 to 2018. Using data from the Rochester Epidemiology Project (REP), residents aged 20 and above were analyzed across four eras. Incidence rates were calculated and adjusted for age and sex, and temporal trends were assessed using Poisson regression. Intrahepatic cholangiocarcinoma exhibited a significant escalation in incidence rates over time, while gallbladder cancers showed a decline among women. Median survival times for biliary tract cancers notably improved. These findings confirm the rising incidence of intrahepatic cholangiocarcinoma and suggest improving survival rates. Nevertheless, the overall prognosis for biliary tract cancers remains very poor, emphasizing the continual need for enhanced management strategies and further research.