Citations

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, OMass Therapeutics, H Lundbeck A/S, Adrenas Therapeutics. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Crinetics Pharmaceuticals, Spruce Biosciences. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Inc., Xeris, Lantheus. R. Pivonello: Advisory Board Member; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Research Investigator; Self; Corcept Therapeutics, Recordati AG, Strongbridge Biopharma, Neurocrine Biosciences, Inc. I. Bancos: Consulting Fee; Self; Corcept Therapeutics, Recordati Rare Diseases, HRA Pharmaceuticals, Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences, Sparrow Pharmaceuticals, Adrenas Therapeutics. Research Investigator; Self; Recordati Rare Diseases. G. Russo: Advisory Board Member; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. Speaker; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. S.F. Witchel: Research Investigator; Self; Neurocrine Biosciences, Inc. A.M. Isidori: Research Investigator; Self; Pfizer, Inc., Merck Serono, HRA Pharmaceuticals, Recordati AG, Corcept. P. Rodien: Consulting Fee; Self; Pfizer, Inc., Novo Nordisk, Lilly USA, LLC, Ipsen, HRA Pharmaceuticals, IBSA Pharma, Recordati Rare Diseases. U. Srirangalingam: Advisory Board Member; Self; Diurnal. Speaker; Self; Diurnal. F.W. Kiefer: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. Speaker; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. H. Falhammar: Consulting Fee; Self; Diurnal, Roche Diagnostics, Neurocrine Biosciences, Inc., H Lundbeck A/S, Adrenas Therapeutics. D.P. Merke: Research Investigator; Self; Diurnal, Adrenas Therapeutics, Neurocrine Biosciences, Inc. N. Reisch: Consulting Fee; Self; Diurnal, Crinetics Pharmaceuticals, Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. V.H. Lin: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated adrenocorticotropic hormone and adrenal androgens in patients with 21OHD in 14-day open-label Phase 2 studies. This Phase 3 study (CAHtalyst: NCT04490915) evaluated whether crinecerfont can reduce daily GC dose while maintaining androgen control in adults with 21OHD. Methods: Adults (≥18 years) with 21OHD, stable GC regimens at doses >13 mg/m2/d in hydrocortisone equivalents (HCe), and normal or elevated androstenedione (A4) were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24 weeks. GC dosing was maintained stable for 4 weeks, followed by a planned GC down-titration over 8 weeks to achieve a GC dose of 8-10 mg/m2/d. GC doses were adjusted as needed during the last 12 weeks to maintain A4 control (≤120% of baseline or ≤upper limit of normal [ULN]) by week 24. Results: In the 182 randomized participants (51% male, mean age 31 years), demographics and baseline characteristics were similar between treatment arms (122 crinecerfont, 60 placebo). Mean GC dose at baseline was 17.6 mg/m2/d HCe (32 mg/d), with 58% on HC alone, 29% taking predniso[lo]ne, and 13% taking dexamethasone; mean pre-GC A4 (620 ng/dL) was elevated >2-3-fold the ULN. Over 95% of participants completed the double-blind treatment period. At week 24, the crinecerfont arm had a significantly greater percent reduction in GC dose while maintaining A4 control vs placebo (-27% vs -10%; least squares mean difference [LSMD]: -17%; p<0.0001) (primary endpoint). At week 4 (end of GC-stable period), a greater reduction in A4 prior to the morning GC dose was observed with crinecerfont vs placebo (LSMD: -345 ng/dL; p<0.0001) (key secondary endpoint). At week 24, a higher percentage of participants reached a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control with crinecerfont (63% vs 18% for placebo; p<0.0001) (key secondary endpoint). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were fatigue (25% vs 15% for placebo), headache (16% vs 15%), and COVID-19 (14% vs 9%). There were few serious AEs (3% overall), with none assessed as related to the study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control for patients with 21OHD. In the largest interventional Phase 3 study conducted to date in adults with 21OHD, crinecerfont led to a significant reduction in A4 while GC dose was stable, enabling a significant percent reduction in GC dose while maintaining A4 control at 24 weeks. Crinecerfont was overall well tolerated. Presentation: 6/1/2024

Abstract Ciltacabtagene autoleucel (cilta-cel) was approved in 2022 for patients with relapsed/refractory multiple myeloma (RRMM). We report outcomes with cilta-cel in the standard-of-care setting. Patients with RRMM who underwent leukapheresis for cilta-cel manufacturing between 1 March 2022 and 31 December 2022 at 16 US academic medical centers were included. Overall, 255 patients underwent leukapheresis and 236 (92.5%) received cilta-cel, of which 54% would not have met CARTITUDE-1 eligibility criteria. In treated patients (N = 236), cytokine release syndrome was seen in 75% (grade ≥3, 5%), immune effector cell–associated neurotoxicity syndrome in 14% (grade ≥3, 4%), and delayed neurotoxicity in 10%. Overall and complete response rates were as follows: all patients who received cilta-cel (N = 236), 89% and 70%; patients receiving conforming cilta-cel (n = 191), 94% and 74%; and conforming cilta-cel with fludarabine/cyclophosphamide lymphodepletion (n = 152), 95% and 76%, respectively. Nonrelapse mortality was 10%, most commonly from infection. After a median follow-up of 13 months from cilta-cel, the median progression-free survival (PFS) was not reached, with 12-month estimate being 68% (95% confidence interval, 62-74). High ferritin levels, high-risk cytogenetics, and extramedullary disease were independently associated with inferior PFS, with a signal for prior B-cell maturation antigen–targeted therapy (P = .08). Second primary malignancies excluding nonmelanoma skin cancers were seen in 5.5% and myeloid malignancies/acute leukemia in 1.7%. We observed a favorable efficacy profile of standard-of-care cilta-cel in RRMM, despite more than half the patients not meeting the CARTITUDE-1 eligibility criteria.

Abstract Background Hypomagnesemia has been correlated with inferior outcomes in patients with large B cell lymphoma (LBCL) undergoing stem cell transplants. As T-cell and myeloid cell dysfunction have been associated with low magnesium conditions, we investigated whether serum magnesium (Mg) levels could predict clinical outcomes in LBCL patients who received chimeric antigen receptor T-cell therapy. Methods Patients with LBCL who received axi-cel under the ZUMA-1 trial or as FDA approved therapy at Mayo Clinic were examined. Serum samples were obtained at specified time points and cytokine analysis was performed. Single cell RNA sequencing was performed on peripheral blood mononuclear cells. The Student T-test, Kruskal Wallis, or Fisher's Exact Tests were used to compare differences in demographics across Mg levels. Survival curves were plotted using the Kaplan-Meier methodology and compared using the Wilcoxon test. Results We found that hypomagnesemia before lymphodepletion chemotherapy predicted for inferior progression-free and overall survival in the pivotal study ZUMA-1 (NCT02348216). These results were validated in an independent cohort of LBCL patients receiving axicabtagene ciloleucel (axi-cel) at Mayo Clinic. Hypomagnesemia correlated with increased inflammatory serum markers and cytokine levels including ferritin, IL-6, IL1Ra, IL-8, and MIP1a. scRNAseq analysis unveiled altered immune interactions between monocytes and T cells with a concordant immune suppressive transcriptome. Conclusions Hypomagnesemia at the time of CAR-T infusion associates with an unfavorable inflammatory profile and decreased response and survival in LBCL patients receiving axi-cel. These findings suggest a potentially actionable prognostic factor for patients with large cell lymphoma undergoing CAR-T.

Background: Ibrutinib, a potent Bruton’s tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed in vivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both in vivo and ex vivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.

160 Background: In the United States, racial/ethnic disparities in adoption of breast cancer evidence-based practices (EBPs) persist along the cancer care continuum. This scoping review applied an implementation science lens to describe the current evidence base for interventions to reduce disparities, synthesizing evidence on effective interventions while highlighting gaps in the literature. Methods: A formalized search strategy identified USA-based interventional studies aiming to improve adoption of an EBP along the breast cancer care continuum among racially/ethnically minoritized patients. Relevant articles from 1/2010 - 8/2022 (Medline, Embase, Cochrane, and Scopus) were included. For each article, two reviewers screened and extracted data, with a third resolving discrepancies. The PRISMA-ScR checklist and JBO Manual for Evidence Synthesis framework were followed. Results: Our search strategy yielded 45,215 articles. After applying inclusion/exclusion criteria, 59 articles were retained, targeting screening (85%, 50 of 59), treatment (12%, 7 of 59), and survivorship (5%, 3 of 59) (2 targeted multiple areas). No articles targeted end-of-life care. Of these, 49% (29 of 59) were randomized controlled trials (RCTs). Among 24 screening RCTs, the most common interventions—and fraction with statistically significant improved screening uptake—were patient navigation (100%, 11 of 11) and patient education (80%, 4 of 5). Among 4 treatment RCTs, 3 targeted adjuvant chemotherapy uptake. Of these, 1 had significant improvements and used patient navigation. The 2 studies without significant improvements used a patient tracking tool/alert system or patient education. Among 2 survivorship RCTs, one used email interventions, resulting in significantly improved physical activity and dietary health. A second used a nurse-facilitated internet support group, resulting in significantly improved physical/psychological symptoms. Early to mid-stage implementation outcomes (acceptability, adoption, appropriateness, feasibility, or fidelity) were commonly measured (81%, 48 of 59). No study measured later stage implementation outcomes (sustainability or costs). Conclusions: In multiple studies, patient navigation and education improved breast cancer screening among racially/ethnically minoritized populations. In one study, patient navigation improved completion of adjuvant treatment. Despite these studies, patient navigation is not reimbursed for cancer screening, and adoption has not been widespread. Future studies should focus on evaluating and improving later stage implementation outcomes (sustainability and costs). Based on these results, insurance reimbursement mechanisms for screening-related navigation may be warranted. Future breast cancer care delivery disparities research should also be expanded to include treatment, survivorship, and end-of-life care.

Abstract Aims Radiation therapy (RT) is an integral component of cancer therapy but associated with adverse events. Our goal was to establish risk prediction models for major adverse cardiovascular and cerebrovascular events (MACCE) after chest RT. Methods and results A retrospective study of lung/breast cancer patients who had chest RT with planning CT at Mayo Clinic between 01/2010 and 01/2014. Predictive models were developed based on weighted independent predictors using a derivation (406 lung and 711 breast cancer) and validation cohort (179 lung and 234 breast cancer). Patient characteristics, pre-RT CT for coronary artery calcification (CAC), and post-RT MACCE data were reviewed. Post-RT MACCE occurred in 6.1 and 5.6% in the derivation and validation cohort over a mean follow-up of 42 ± 13 months. Post-therapy model (C2AD2) included CAC (two points), MACCE history (two points), age ≥74 (three points), DM (two points), and mean heart radiation dose ≥ 850 mGy (two points), and pre-therapy model (C2AD) included post-therapy model parameters minus mean heart radiation dose. Both models stratified patients into three risk groups: low (0–2), intermediate (3–5), and high (≥6). Post-RT MACCE across these groups were 2.7, 8.9, and 19.8% in the derivation, and 3.9, 6.6, and 16.4% in the validation cohort for post-therapy model (C2AD2) and 2.8, 9.2, and 20.4% in the derivation and 3.7, 9.2, and 13.2% in the validation cohort for pre-therapy model. Both models showed statistically significant graded survival outcome. Conclusion Post-therapy (C2AD2) and pre-therapy (C2AD) models are simple, easy to use and effective tools to stratify breast and lung cancer patients undergoing chest radiation for post-RT MACCE.

Distal radioulnar joint instability is commonly seen after surgical fixation of a distal radial fracture, and surgeons’ ability to reliably determine stability on examination is poor. Debate remains regarding whether to fix the ulnar styloid or reinsert the triangular fibrocartilaginous complex. Four surgeons with Level 5 expertise were asked to respond to questions surrounding this debate.

Abstract Heterotopic ossification (HO), often arising in response to traumatic challenges, results from the aberrant osteochondral differentiation of mesenchymal stem cells (MSCs). Nevertheless, the impact of trauma‐induced inflammatory exposure on MSC fate determination remains ambiguous. In this study, the cellular diversity within inflammatory lesions is elucidated, comprising MSCs and several innate and adaptive immune cells. It is observed that quiescent MSCs transition into cycling MSCs, subsequently giving rise to chondrogenic (cMSC) and/or osteogenic (oMSC) lineages within the inflammatory microenvironment following muscle or tendon injuries, as revealed through single‐cell RNA sequencing (scRNA‐seq), spatial transcriptome and lineage tracing analysis. Moreover, these investigations demonstrate that neutrophils and natural killer (NK) cells enhance transition of quiescent MSCs into cycling MSCs, which is also controlled by M1 macrophages, a subpopulation of macrophages can also stimulate cMSC and oMSC production from cycling MSCs. Additionally, M2 macrophages, CD4 + and CD8 + T lymphocytes are found to promote chondrogenesis. Further analysis demonstrates that immune cells promotes the activation of signaling transducers and activators of transcription (STAT) pathway and phosphoinositide 3 (PI3K)/protein kinase B (AKT) pathway in MSC proliferation and osteochondral progenitors’ production, respectively. These findings highlight the dynamics of MSC fate within the inflammatory lesion and unveil the molecular landscape of osteoimmunological interactions, which holds promise for advancing HO treatment.

Introduction: The Mindfulness-Based Stress Reduction (MBSR) Program for breast cancer survivors (BCS) is designed to enhance cognitive training through formal and informal meditational practices. This randomized clinical trial (RCT) aimed to evaluate if BCS assigned to either the MBSR(BC), Breast Cancer Education Support (BCES), or Usual Care (UC) regimens experienced greater improvements at 6, 12, and 26 weeks on objective and subjective cognitive performance. Methods: BCS ( n = 212) randomized to a three-group RCT: MBSR(BC) ( n = 91), BCES ( n = 90), or UC ( n = 31) were assessed on cognitive performance and symptoms at baseline, 6, 12, and 26 weeks. Linear mixed models were fit to evaluate the effects of the MBSR(BC) program, hypothesizing ordered effect improvements: (MBSR[BC] highest, BCES intermediate, UC lowest) along with baseline characteristics evaluated as moderators. Results: Of the BCS (mean age of 57), 73% were White, and non-Hispanic, and 77% received both chemotherapy (CT) and radiation. Cognitive performance improved in all groups. Although there were no statistically significant between-group differences in cognitive outcomes, significant symptom reductions occurred for the MBSR(BC) group ( p = 0.003). Within-group effect size analysis at 26 weeks showed substantial improvements in all three groups (effect sizes >0.50) in subjective impairments and quality of life (effect size >0.50) and objective measures of cognitive performance. MBSR(BC) showed the largest within-group effect size in the reduction of fatigue (effect size = 0.81). Effect sizes occurred in the hypothesized direction for 10 of the 18 outcomes. Discussion: Although the MBSR(BC) program did not show significant differences in cognitive performance compared with BCES and UC, all groups improved and reductions in fatigue were beneficial for MBSR(BC). Results suggest that cognitive performance may improve after CT over time considering one’s natural history. Furthermore, BCS enrolled in RCTs may be more motivated to improve their health status (NCT02786797).

Abstract Background: Medium vessel occlusion (MeVO) strokes, particularly affecting the M2 segment of the middle cerebral artery, represent a critical proportion of acute ischemic strokes, posing significant challenges in management and outcome prediction. The efficacy of mechanical thrombectomy (MT) in MeVO stroke may warrant reliable predictors of functional outcomes. This study aimed to investigate the prognostic value of follow-up infarct volume (FIV) for predicting 90-day functional outcomes in MeVO stroke patients undergoing MT. Methods: This multicenter, retrospective cohort study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, covering patients with acute ischemic stroke due to M2 segment occlusion treated with MT. We examined the relationship between 90-day functional outcomes, measured by the modified Rankin Scale (mRS), and follow-up infarct volume (FIV), assessed through CT or MRI within 12–36 h post-MT. Results: Among 130 participants, specific FIV thresholds were identified with high specificity and sensitivity for predicting outcomes. A FIV ⩽5 ml was highly specific for predicting favorable and excellent outcomes. The optimal cut-off for both prognostications was identified at ⩽15 ml by the Youden Index, with significant reductions in the likelihood of favorable outcomes observed above a 40 ml threshold. Receiver Operator Curve (ROC) analyses confirmed FIV as a superior predictor of functional outcomes compared to traditional recanalization scores, such as final modified thrombolysis in cerebral infarction score (mTICI). Multivariable analysis further highlighted the inverse relationship between FIV and positive functional outcomes. Conclusions: FIV within 36 h post-MT serves as a potent predictor of 90-day functional outcomes in patients with M2 segment MeVO strokes. Establishing FIV thresholds may aid in the prognostication of stroke outcomes, suggesting a role for FIV in guiding post intervention treatment decisions and informing clinical practice. Future research should focus on validating these findings across diverse patient populations and exploring the integration of FIV measurements with other clinical and imaging markers to enhance outcome prediction accuracy.