Citations

OBJECTIVE In this study, the authors aimed to establish a supervised machine learning (ML) model based on multiple tree-based algorithms to predict long-term biochemical outcomes and intervention-free survival (IFS) after endonasal transsphenoidal surgery (ETS) in patients with Cushing’s disease (CD). METHODS The medical records of patients who underwent ETS for CD between 2013 and 2023 were reviewed. Data were collected on the patient’s baseline characteristics, intervention details, histopathology, surgical outcomes, and postoperative endocrine functions. The study’s primary outcome was IFS, and the therapeutic outcomes were labeled as "under control" or "treatment failure," depending on whether additional therapeutic interventions after primary ETS were required. The decision tree and random forest classifiers were trained and tested to predict long-term IFS based on unseen data, using an 80/20 cohort split. RESULTS Data from 150 patients, with a median follow-up period of 56 months, were extracted. In the cohort, 42 (28%) patients required additional intervention for persistent or recurrent CD. Consequently, the IFS rates following ETS alone were 83% at 3 years and 78% at 5 years. Multivariable Cox proportional hazards analysis demonstrated that a smaller tumor diameter that could be detected by MRI (hazard ratio 0.95, 95% CI 0.90–0.99; p = 0.047) was significantly associated with greater IFS. However, the lack of tumor detection on MRI was a poor predictor. The ML-based model using a decision tree model displayed 91% accuracy (95% CI 0.70–0.94, sensitivity 87.0%, specificity 89.0%) in predicting IFS in the unseen test dataset. Random forest analysis revealed that tumor size (mean minimal depth 1.67), Knosp grade (1.75), patient age (1.80), and BMI (1.99) were the four most significant predictors of long-term IFS. CONCLUSIONS The ML algorithm could predict long-term postoperative endocrinological remission in CD with high accuracy, indicating that prognosis may vary not only with previously reported factors such as tumor size, Knosp grade, gross-total resection, and patient age but also with BMI. The decision tree flowchart could potentially stratify patients with CD before ETS, allowing for the selection of personalized treatment options and thereby assisting in determining treatment plans for these patients. This ML model may lead to a deeper understanding of the complex mechanisms of CD by uncovering patterns embedded within the data.

OBJECTIVE Stereotactic radiosurgery (SRS) offers excellent tumor control for pituitary adenoma (PA); however, treatment failure occasionally necessitates salvage surgery. Comprehensive studies on salvage surgical outcomes for recurrent PA after SRS remain scarce. This study aimed to elucidate the outcomes of salvage endonasal transsphenoidal surgery (sETS) for progressive PA failing SRS. METHODS This retrospective, two institution–based cohort study analyzed data from patients who underwent sETS for progressive PA failing SRS. Progression-free survival (PFS), disease-specific survival (DSS), and neurological and endocrinological outcomes in the sETS group were analyzed and compared with those in the primary ETS (pETS) group after propensity score matching using the following variables: age at surgery, maximum tumor diameter, highest Knosp–Steiner classification, and tumor type. RESULTS Thirteen sETS patients (8 males [62%], median age at surgery of 56 years) with 5 nonfunctioning (39%), 6 corticotropic (46%), and 2 other functioning (15%) PAs who received median (range) follow-up of 125 ( 23–169) months were included. None of the patients experienced new neurological deficits or death after sETS. The median (range) tumor resection rate was 90% (80%–100%). The 5-year PFS and DSS rates were 55% and 77%, respectively. All 4 patients (31%) who experienced recurrence after sETS had corticotropic tumors. In the matched cohort analysis between the sETS group with 12 patients and the pETS group with 12 patients, no significant differences were observed in surgical outcomes. PFS rates were marginally higher in the sETS group than in the pETS group (80% vs 49% at 3 years, p = 0.216, log-rank test), and DSS was similar between the two groups (p = 0.543, log-rank test). CONCLUSIONS The authors’ results indicate that ETS can be safely performed as a salvage treatment after failed SRS with low complication rates and satisfactory tumor control in treatment-resistant PA.

Background: Spinal cord (SC) atrophy is a key imaging biomarker of progressive multiple sclerosis (MS). Progressive MS is more common in men and postmenopausal women. Objective: Investigate the impact of sex and menopause on SC measurements in persons with MS (pwMS). Methods: In pwMS and age- and sex-matched controls, upper cervical SC area from brain MRI (UCC brain ) was obtained. Impact of sex and menopause on UCC brain (adjusted for total intracranial volume) and its association with progression and disability, including MS functional composite (MSFC), were investigated. Results: UCC brain was smaller in pwMS ( n = 118, 51.4 ± 5.3 mm 2 ) than controls ( n = 118, 54.2 ± 4.4 mm 2 , p < 0.001) and inversely correlated with older age in pwMS ( r = −0.24, p = 0.010) but not in controls ( r = −0.025, p = 0.786). In 173 pwMS (413 brain MRIs), UCC brain was smaller in men (49.5 ± 5.9 mm 2 ) than women (51.6 ± 5.5 mm 2 , p = 0.001), postmenopausal women (49.4 ± 5.6 mm 2 ) than premenopausal women (52.9 ± 4.1 mm 2 , p < 0.001), and progressive (47.5 ± 5.6 mm 2 ) than relapsing MS (52.1 ± 5.2 mm 2 , p < 0.001). UCC brain also correlated with disease duration ( r = −0.39, p < 0.001), 9-hole peg test ( r = −0.26, p = 0.005), and severe ambulatory disability (Expanded Disability Status Scale ⩾6) ( r = −0.27, p < 0.001). Conclusion: UCC brain , a biomarker of progressive MS, is inversely associated with age, disease duration, male sex, and menopause, highlighting the potential impact of sex and hormones on neurodegeneration in MS.

ABSTRACT There is an increasing need for biomarkers of senescent cell burden to facilitate the selection of participants for clinical trials. p16 Ink4a is encoded by the CDKN2A locus, which produces five variant transcripts in humans, two of which encode homologous p16 proteins: p16 Inka4a , encoded by p16_variant 1 , and p16ɣ, encoded by p16_variant 5. While distinct quantitative polymerase chain reaction primers can be designed for p16_variant 5, primers for p16_variant 1 also measure p16_variant 5 ( p16_variant 1 + 5 ). In a recent clinical trial evaluating the effects of the senolytic combination, dasatinib + quercetin (D + Q), on bone metabolism in postmenopausal women, we found that women in the highest tertile for T‐cell expression of p16_variant 5 had the most robust skeletal responses to D + Q. Importantly, the assessment of p16_variant 5 was more predictive of these responses than p16_variant 1 + 5 . Here, we demonstrate that in vitro, p16_variant 1 + 5 increased rapidly (Week 1) following the induction of DNA damage, whereas p16_variant 5 increased later (Week 4), suggesting that p16_variant 5 becomes detectable only when the abundance of senescent cells reaches some threshold. Further analysis identified a SASP panel in plasma that performed as well in identifying postmenopausal women with a positive skeletal response to D + Q. Collectively, our findings provide further support for the T‐cell p16_variant 5 assay as a biomarker for selecting participants in clinical trials of senolytic interventions. In addition, our data indicate that correlated plasma SASP markers could be used in lieu of the more technically challenging T‐cell p16 assay. Trial Registration: ClinicalTrials.gov identifier: NCT04313634.

Abstract Objectives The impact of mild autonomous cortisol secretion (MACS) on cognition is incompletely characterized. We aimed to assess cognition in patients with MACS, identify factors associated with lower cognition, and determine the impact of adrenalectomy on cognition. Methods We conducted a cross-sectional study (4/2019 to 10/2022) and a longitudinal cohort study (10/2021 to 9/2023) of adults with MACS and referent subjects. Cognition was assessed with National Institute of Health Toolbox Cognition Battery and reported as standardized T scores (adjusted for age, sex, race/ethnicity, and education) for fluid, crystallized, and total composite cognition. Participants were assessed with urine steroid profiling (liquid chromatography-tandem mass spectrometry), frailty index, Beck’s Depression Inventory (BDI), and Short Form-36 (SF-36). Results A total of 84 patients (median age 57 years, 67% women) and 201 referent subjects (median age 63 years, 58% women) were included. Patients with MACS demonstrated lower mean (SD) total composite (50.9 [9.3] vs 55.4 [8.9], P &lt; .001) and fluid composite T score (49.3 [10.6] vs 55.2 [10.2], P &lt; .001), but not crystallized composite T score (52.3 [8.4] vs 54.0 [8.4], P = .130) when compared with referent subjects. Multivariable analysis adjusted for age, sex, BDI, SF-36, frailty index, total glucocorticoids, and androgens demonstrated that MACS status was associated with lower cognition. When cognition was reassessed in 37 patients post-adrenalectomy and 31 referent subjects, adjusted group differences of cognition change were similar except for a higher comparative increase in attention and executive functioning in patients with MACS. Conclusion Patients with MACS demonstrate lower cognition than referent subjects. Adrenalectomy for MACS had a minor positive impact on cognition.

Abstract Motivated by studies showing an association between beta blocker (BB) use and positive bone outcomes, a pilot randomized control trial was performed at the Mayo Clinic which randomized postmenopausal women to placebo, propranolol (40 or 80 mg twice daily), atenolol (50 mg/d), or nebivolol (5 mg/d) to determine changes in bone turnover markers (BTMs) and in BMD over 20 wk. Pharmacogenetic effects and microRNA-mediated mechanisms involving beta adrenergic receptor and related genes have previously been found. We sought to validate these effects and discover new candidates in an ancillary study to the pilot clinical trial. We genotyped all participants and performed microRNA (miRNA) sequencing at baseline and at 20 wk for 24 participants from the atenolol or placebo groups. We discovered several variants in ADRB1, ADRB2, and HDAC4 which showed significant pharmacogenetic effects with BMD at multiple sites and with BTMs. Our miRNA results showed a significant treatment effect for miR-19a-3p over time with atenolol use in the low-responder group compared to placebo. Overall, the longitudinal miRNA analysis showed a large number of miRNAs which were up-regulated over the trial in the low responders but not the high responders compared to placebo, of which miR-19a-3p was one example. Finally, we compared the response to atenolol treatment for cardiovascular traits (pulse and blood pressure) with the response for the bone resorption marker, C-terminal telopeptide, and found a largely independent effect. Our results have implications for personalized therapy and for understanding mechanisms of BB treatment effect on bone.