Citations

Abstract Disclosure: J. Saini: None. S. Singh: None. A.L. Ebbehøj: None. C.D. Zhang: None. R. Nathani: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. A. Rivard: None. R.J. Singh: None. S.K. Grebe: None. I. Bancos: None. Abstract Context: Mild autonomous cortisol secretion (MACS) is diagnosed based on post-dexamethasone cortisol>1.8 mcg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS. Objective: To characterize 24-hour urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS versus referent subjects. Design: Cross-sectional study, 2018-2023. Setting: Referral center Participants: 72 patients with MACS and 72 age-, sex-, BMI-, and menopausal status-matched referent subjects. Measurements: Urine was collected over a 24-hour (h) period in separate day- and night-time collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects were admitted for every 2-hour serum measurement of free and total cortisol. Outcomes: Steroids, sums, and ratios Results: Patients with MACS had lower mcg/24h median androgens (2084 vs 3283, P<0.001), higher glucocorticoids (15754 vs 12936, P<0.001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P<0.001). Steroid day/night ratios were lower in patients when compared to referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour area under the curves for total and free cortisol were similar. However, nocturnal mean total (5.3 vs 4.0 mcg/dL, P=0.056) and free (0.2 vs 0.1 mcg/dL, P=0.035) cortisol were higher in patients vs referent subjects. Conclusion: Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production. Presentation: 6/3/2024

Abstract Disclosure: J. Saini: None. V. Fell: None. B. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have a higher prevalence of frailty and reduced muscle strength as compared to patients with nonfunctioning adrenal adenomas or subjects without adrenal disorders. Objective: To determine the impact of adrenalectomy on frailty and parameters of functional strength in patients with MACS. Methods: We conducted a single-center prospective longitudinal study of adults with MACS scheduled for adrenalectomy and referent subjects evaluated between 2018 and 2023. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Patients and referent subjects had a baseline and a follow-up evaluation at least 10 months later. Differences were assessed using paired t-tests for (1) Frailty Index (FI)--calculated using a questionnaire containing 47 variables on comorbidities, symptoms, and daily living activities (frailty defined as FI>0.25) (2) physical function assessed using handgrip strength (Jamar Plus digital hand dynamometer), timed up-and-go test (time taken to rise from a chair, walk to and from 3 m, and sit down), gait speed, 6-minute walk test, and (3) Advanced Glycation End (AGE) Product (using AGE reader). Results: We evaluated 41 patients before and after adrenalectomy, and 31 referent subjects at baseline and follow-up visit, at a similar interval (median 1.6, IQR 1.2-2.0 vs 1.5 years, IQR 1.0-2.2, P=0.759). While sex distributions were no different between the 2 groups (women, 66% vs 84%, P=0.086), patients with MACS were older than the referent group (median age 57.3, IQR 48.8-66.9 vs 49.0, IQR 41.7-57.9 years, P=0.005). Post-adrenalectomy, FI decreased by a mean of 0.057 (SD 0.08), P<0.001 in patients, and remained unchanged in the referent group. AGE decreased in patients by 0.148 (SD 0.45), P=0.04 but not in referent subjects (-0.047, SD 0.242, P=0.5). Patients demonstrated no improvement in parameters of muscle strength: gait speed (mean change 0.305 m/s, P=0.453), 6-minute walk test (mean change 16.4 meters, P=0.201), dominant (mean Z score change -0.055, P=0.72) and nondominant (mean Z score change -0.199, P=0.192) hand grip muscle strength. At follow-up, both patients (mean change 1.897 seconds, P<0.001) and referent subjects (mean change=1.475 seconds, P<0.001) demonstrated a deterioration on the timed up-and-go test. Conclusions: While no improvement was seen in the parameters of muscle strength, adrenalectomy improved the frailty index in patients with MACS. In addition, AGE, a biomarker associated with cardiovascular morbidity, decreased after adrenalectomy, suggesting a beneficial cardiovascular impact of MACS reversal. Presentation: 6/1/2024

Abstract Disclosure: L. Rahimi: None. J. Saini: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Introduction: Patients with mild autonomous cortisol secretion (MACS) have higher prevalence of cardiovascular comorbidities including chronic kidney disease. However, considering that patients with MACS may have relative skeletal muscle atrophy, it is unclear whether the creatine-based assessment of kidney function is accurate in this population. Objective: To characterize the differences in assessing estimated glomerular filtration rate using cystatin (eGFRcys) versus creatinine (eGFRcre) in patients with MACS versus referent subjects. Methods: Cross-sectional single-center study, 2019-2022. MACS was defined as serum cortisol concentration >1.8 mcg/dL after the 1 mg overnight dexamethasone suppression test (DST). For each patient, eGFRcre, eGFRcys and eGFRcre/eGFRcys ratio were measured and compared between the two groups. Body composition was measured by DXA scan. The Kruskal-Wallis test was used to compare measurements between groups. Result: A total of 37 patients with MACS (median age 59 years (interquartile range, IQR 47-67), 25 (68%) women) and 45 referent subjects (median age 57 years (IQR 51-66), 30 (67%) women) were included. The distribution of BMI, total body fat mass and total body lean mass were similar between the two groups. In the MACS cohort, the median cortisol following 1-mg DST was 3.0 ug/dL (IQR, 2.2-4.0). While assessment of kidney function with eGFRcre showed no differences between patients with MACS and referent subjects (median 85.1 vs 87.0 ml/min/1.73m2, P=0.431), kidney function using eGFRcys was lower in MACS (median 78.0 vs 89.3 ml/min/1.73m2 in referents, P<0.014), resulting also in a higher eGFRcre/eGFRcys ratio (median 1.07 vs 0.97 in MACS vs referents, P=0.053). After adjusting for age, sex, and BMI, a higher 1 mg DST cortisol level in the MACS cohort was associated with a higher eGFRcre/eGFRcys ratio (Spearman correlation coefficient of 0.35, P = 0.042). Lower eGFRcys was associated with higher fat mass (Spearman correlation of -0.26, P = 0.023), and a higher eGFRcre/eGFRcys ratio showed a trend towards lower lean mass (Spearman correlation of -0.20, P = 0.081). Conclusion: Creatinine-based eGFR assessment in patients with MACS underestimates the degree of kidney dysfunction, likely due to underlying skeletal muscle atrophy. eGFRcys is a more accurate indicator of kidney function in patients with hypercortisolism. Presentation: 6/1/2024

Abstract Disclosure: J. Saini: None. V. Fell: None. B. Atkinson: None. S. Achenbach: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) have an impaired quality of life and a higher prevalence of sleep and mood disturbances as compared to patients with nonfunctioning adrenal adenomas. The impact of adrenalectomy on quality of life, mood, and sleep is unclear. Objective: To determine the impact of adrenalectomy on quality of life, sleep, and mood in patients with MACS Methods: We conducted a single-center prospective longitudinal study of adults with MACS scheduled for adrenalectomy and referent subjects evaluated between 2018 and 2023. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test in patients with adrenal adenomas and no features of overt hypercortisolism. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Patients and referent subjects had a baseline and a follow-up evaluation at least 10 months later. Differences were assessed using paired t-tests for (1) Quality of life using Short Form-36 (SF 36) survey (Physical and Mental component summary score), sex and age-adjusted (2) Mood using Beck’s Depression Inventory (BDI) (3) Sleep using Pittsburgh Sleep Quality Index (PSQI). Results: We evaluated 41 patients before and after adrenalectomy, and 31 referent subjects at baseline and follow-up visit, at a similar interval (median 1.6, IQR 1.2-2.0 vs 1.5 years, IQR 1.0-2.2, P=0.759). While sex distribution was similar between the groups (66% vs 84% women, P=0.086), patients with MACS were older than the referent group (median age 57.3, IQR 48.8-66.9 vs 49.0, IQR 41.7-57.9 years, P=0.005). After adrenalectomy, patients improved their mood with a mean decrease of -4.71 (SD: 9.11), P=0.002 on the BDI questionnaire. Patients also demonstrated improvement in the SF-36 mental component score by a mean of 6.48 (SD: 10.97), P<0.001. While the overall SF36 physical component score did not improve after adrenalectomy (1.953 (SD: 11.02), P=0.269), one of the PCS components, role-physical limitation, increased by a mean of 6.25 (SD: 13.03). Patients reported better sleep with PSQI score decreasing by a mean of -2.59 (SD: 3.64), P<0.001. No differences in BDI, SF36, and PSQI were observed between baseline and follow-up in referent subjects. Conclusions: After adrenalectomy, patients with MACS showed an improvement in sleep, mood, and mental component of quality of life. Presentation: 6/3/2024

BACKGROUND AND OBJECTIVES: Venous air embolism (VAE) can cause significant morbidity and mortality. Prevention and management of VAE include cessation of air entrainment, positioning changes, and hemodynamic support. The degree to which position change and cardiac output (CO) moderate resolution of intracardiac air has not been rigorously studied using contemporary transesophageal echocardiography (TEE). METHODS: This observational cohort-type study aimed to identify the effect of supine vs sitting positioning on the movement and resolution of intracardiac air. In 20 patients undergoing seated neurosurgery, central venous air aspiration catheters were placed through the median basilic vein. TEE was used to estimate the time required for clearance of agitated microbubbles from the right atrium and ventricle in both the supine and sitting position. Estimates of CO were also obtained echocardiographically in each position. RESULTS: Average clearance time was faster in the sitting vs the supine position with no significant difference in CO. A negative correlation between CO and right atrial clearance time across all patients was demonstrated with a Pearson coefficient of −0.4 (95% CI −0.07, −0.65) with P = .02. CONCLUSION: During VAE, both patient position and CO can significantly affect how bubbles move through intracardiac chambers. However, augmenting CO during VAE may be clinically more feasible, efficient, and productive than changing positioning—especially during crises unless the changing in position is intended to halt the entrainment of air. Further TEE studies of intravascular air movement affected by other position changes (lateral, reverse Trendelenburg) and vasopressors should be considered.

Mixed invasive ductal and lobular carcinoma (MDLC) is a rare histologic subtype of breast cancer displaying both E-cadherin positive ductal and E-cadherin negative lobular morphologies within the same tumor, posing challenges with regard to anticipated clinical management. It remains unclear whether these distinct morphologies also have distinct biology and risk of recurrence. Our spatially resolved transcriptomic, genomic, and single-cell profiling revealed clinically significant differences between ductal and lobular tumor regions including distinct intrinsic subtype heterogeneity – e.g., MDLC with triple-negative breast cancer (TNBC) or basal ductal and estrogen receptor positive (ER+) luminal lobular regions, distinct enrichment of cell cycle arrest/senescence and oncogenic (ER and MYC ) signatures, genetic and epigenetic CDH1 inactivation in lobular but not ductal regions, and single-cell ductal and lobular subpopulations with unique oncogenic signatures further highlighting intraregional heterogeneity. Altogether, we demonstrated that the intratumoral morphological/histological heterogeneity within MDLC is underpinned by intrinsic subtype and oncogenic heterogeneity which may result in prognostic uncertainty and therapeutic dilemma.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

Background: The epigenome, the set of modifications to DNA and associated molecules that control gene expression, cellular identity, and function, plays a major role in mediating cellular responses to outside factors. Thus, evaluation of the epigenetic state can provide insights into cellular adaptions occurring over the course of disease. Methods: We performed epigenome-wide association studies of primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) using the Illumina MethylationEPIC Bead Chip. Results: We found evidence of increased epigenetic age acceleration and differences in predicted immune cell composition in patients with PSC and PBC. Epigenetic profiles demonstrated differences in predicted protein levels including increased levels of tumor necrosis factor receptor superfamily member 1B in patients with cirrhotic compared to noncirrhotic PSC and PBC. Epigenome-wide association studies of PSC discovered strongly associated 5′-C-phosphate-G-3′ sites in genes including vacuole membrane protein 1 and SOCS3, and epigenome-wide association studies of PBC found strong 5′-C-phosphate-G-3′ associations in genes including NOD-like receptor family CARD domain containing 5, human leukocyte antigen-E, and PSMB8. Analyses identified disease-associated canonical pathways and upstream regulators involved with immune signaling and activation of macrophages and T-cells. A comparison of PSC and PBC data found relatively little overlap at the 5′-C-phosphate-G-3′ and gene levels with slightly more overlap at the level of pathways and upstream regulators. Conclusions: This study provides insights into methylation profiles of patients that support current concepts of disease mechanisms and provide novel data to inspire future research. Studies to corroborate our findings and expand into other -omics layers will be invaluable to further our understanding of these rare diseases with the goal to improve and individualize prognosis and treatment.

Abstract Context Mild autonomous cortisol secretion (MACS) is diagnosed based on postdexamethasone cortisol >1.8 µg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS. Objective To characterize 24-hour (h) urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS vs referent subjects. Methods Cross-sectional study, 2018-2023, at a referral center. Patients with MACS and age-, sex-, body mass index–, and menopausal status–matched referent subjects were included. Urine was collected over a 24 hour period as separate daytime and nighttime collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects was admitted for serum measurements of free and total cortisol every 2 hours. Outcomes were steroids, steroid sums, and ratios. Results Patients with MACS (n = 72) had lower µg/24 hour median androgens (2084 vs 3283, P < .001), higher glucocorticoids (15 754 vs 12936, P < .001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P < .001) than referent subjects. Patients also had lower steroid day/night ratios than referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour areas under the curve for total and free serum cortisol were similar. However, evening mean total (5.3 vs 4.0 µg/dL, P = .056) and free (0.2 vs 0.1 µg/dL, P = .035) cortisol was higher in patients vs referent subjects. Conclusion Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production.

Abstract Context Patients with nonfunctioning adenomas (NFAs), adenomas with mild autonomous cortisol secretion (MACS) and Cushing syndrome (CS) demonstrate an increased cardiovascular risk. Objective This work aimed to determine the extent of lipoprotein abnormalities in NFA, MACS, and CS. Methods We conducted a single-center, cross-sectional study of patients with NFA (n = 167), MACS (n = 213), CS (n = 142), and referent individuals (n = 202) between January 2015 and July 2022. Triglyceride-rich lipoprotein particles (TRLP), low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), their subclasses and sizes were measured using nuclear magnetic resonance spectroscopy. Multivariable logistic analyses were adjusted for age, sex, body mass index, smoking, hypertension, diabetes and lipid-lowering drug therapy. Results In age- and sex-adjusted analysis, all patients categories demonstrated increased very large TRLP, large TRLP, and greater TRLP size (odds ratio [OR], 1.22-2.08) and total LDLP (OR, 1.22-1.75) and decreased LDL and HDL size compared to referent individuals. In fully adjusted analysis, LDLP concentrations remained elevated in all patient categories (OR, 1.31-1.84). Total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B (ApoB) were also higher in all patient categories in age- and sex-adjusted analysis, with ApoB remaining elevated in all patient categories in fully adjusted analysis. Similar LDLP and ApoB elevations were observed in all patient categories after excluding individuals on lipid-lowering therapy. Conclusion Patients with overt, mild, and even absent cortisol excess demonstrate lipoprotein profile abnormalities, in particular, high LDLP and ApoB concentrations, which conceivably contribute to high cardiometabolic risk.