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Importance The Breast Cancer Index (BCI) previously identified premenopausal patients with tumors in which the ratio of expression of HOXB13 relative to IL17BR (hereafter, BCI [H/I]–low tumors) as likely to derive greatest benefit from ovarian function suppression (OFS)–containing adjuvant therapy in the Suppression of Ovarian Function Trial (SOFT) trial. Objectives To assess BCI as a predictive biomarker of benefit from exemestane plus OFS vs tamoxifen plus OFS and to validate BCI as a prognostic biomarker for premenopausal patients. Design, Setting, and Participants This prognostic study used a prospective-retrospective translational design within the Tamoxifen and Exemestane (TEXT) and SOFT trials (enrolled November 2003 to April 2011). Blinded BCI testing in all available tumor samples was completed in March 2024. Premenopausal women with hormone receptor–positive breast cancer randomized to tamoxifen plus OFS or exemestane plus OFS who had BCI assessed were included. Analysis occurred from March to August 2024. Exposure 5 years of adjuvant tamoxifen plus OFS or exemestane plus OFS. Main Outcomes and Measures The primary outcomes were breast cancer-free interval (BCFI) for predictive analyses and distant recurrence-free interval (DRFI) for prognostic analyses after a median follow-up of 13 years in the TEXT cohort. Secondary objectives examined the predictive performance of BCI (H/I) in the combined TEXT and SOFT cohort overall and in prespecified clinical subgroups. Results Of 1782 patients in the TEXT study, 1034 (58.0%) had BCI (H/I)–low tumors; 915 (51.3%) of patients had N0 disease and 1077 (60.4%) were younger than 45 years. Patients with BCI (H/I)–low tumors had a 6.6% absolute benefit in 12-year BCFI (HR, 0.61; 95% CI, 0.44-0.85) for exemestane plus OFS vs tamoxifen plus OFS, while those with BCI (H/I)–high tumors had a 6.3% absolute benefit (HR, 0.78; 95% CI, 0.57-1.07; P for interaction = .29). Results were consistent in the combined TEXT plus SOFT cohort (2896 patients) and adjusting for clinicopathological variables. Clinical subgroup analyses consistently showed benefit of exemestane plus OFS vs tamoxifen plus OFS for BCI (H/I)–low tumors, and more variable relative treatment effects among BCI (H/I)–high tumors, including by age. Post hoc exploratory time-varying estimates suggested the treatment × BCI associations may differ in years 0 to 5 vs greater than 5 years. BCI and BCI N+ as continuous indices were prognostic for distant recurrence in N0 (HR, 1.27; 95% CI, 1.11-1.44; P < .001) and N1 (HR, 1.58; 95% CI, 1.21-2.05; P < .001) cancers. The 12-year DRFI was 96.3%, 90.3%, and 84.9% for BCI low-, intermediate-, and high-risk N0 cancers, respectively. Conclusions and Relevance In this study of premenopausal women with hormone receptor–positive breast cancer, BCI (H/I) status did not clearly predict greater benefit of adjuvant exemestane plus OFS vs tamoxifen plus OFS for women with BCI (H/I)–low tumors than for those with BCI (H/I)–high tumors; BCI continuous indices were reconfirmed as prognostic for premenopausal women. These findings support prior results of SOFT, which compared tamoxifen-alone vs OFS with either exemestane or tamoxifen, indicating premenopausal patients with BCI (H/I)–low tumors may benefit from more intensive endocrine therapy.

Brain tumor-related epilepsy (BTRE) is a common and debilitating symptom of central nervous system (CNS) tumors. The epileptogenic zone, defined as cortex responsible for seizure generation, is located at the peritumoral region for most tumors, and lower-grade intrinsic brain tumors have the highest seizure incidence. Surgery is often the most effective treatment for the reduction in seizures in BTRE. However, surgical decisions have historically often been made exclusively for oncologic reasons, with less emphasis on seizure control. Surgical approaches for all tumor types are reviewed, highlighting relevant risk factors. Adjunctive tools during surgery, such as intraoperative electrocorticography (ECoG), may help identify and remove surrounding brain areas which are epileptogenic. Minimally invasive surgery is also gaining traction, given its utility in treating seizures deep-seated tumors. This review explores epileptogenic brain tumors, surgery for BTRE, and emerging strategies to better achieve seizure control.

Introduction: The use of intravascular ultrasound (IVUS) to guide lower extremity deep venous stent placement is associated with improved identification of the degree of maximal vessel stenosis, vessel obstruction, and thrombus burden, compared to venography alone. As the US medical system moves towards value-based care, the financial impact of interventional tools requires close consideration. Currently, there are limited evaluations of the cost effectiveness of IVUS during venous procedures. Research Question: This study seeks to examine the cost-effectiveness of IVUS in lower extremity deep venous interventions. Methods: Medicare fee-for-service claims data from 2016 through 2021 for beneficiaries aged ≥ 65 years undergoing lower extremity venous interventions with stent placement, thrombolysis, and/or thrombectomy were analyzed. Cost ratios between IVUS-guided and non-IVUS-guided procedures were assessed using gamma regression, adjusting for demographic and clinical variables. Results: A total of 52,610 patients were included, with 42.6% undergoing IVUS-guided procedures. IVUS utilization varied by setting, with higher usage in hospital-based outpatient centers (75.3%) and ambulatory surgical centers/outpatient-based laboratories (ASC/OBL; 86.4%) compared to inpatient hospitalizations (10.4%). Among inpatient procedures, IVUS-guided venous intervention was associated with greater cost than non-IVUS procedures at 90 days, with an adjusted cost ratio of 1.04 (95% CI 1.01-1.07), yet was associated with an average 0.6-day shorter hospitalization (p < 0.001; Figure 1, Figure 2 ). There were marginal increased costs associated with use of IVUS in inpatient procedures persisting through one- and three-years follow-up, with adjusted cost ratios of 1.05 (95% CI 1.02-1.08) and 1.05 (95% CI 1.02-1.09), respectively. In contrast, IVUS use was associated with significant cost savings in outpatient settings, with adjusted cost ratios of 0.71 (95% CI 0.69-0.73) in hospital-based outpatient settings and 0.75 (95% CI 0.73-0.78) in ASC/OBL at 90 days. These cost savings persisted at one- and three-year follow-up. Conclusions: IVUS-guided venous intervention was associated with cost savings in outpatient and ASC/OBL settings, while maintaining near cost equivalence in inpatient settings. These findings suggest that in addition to the clinical benefit of IVUS for venous intervention, IVUS is a cost-effective strategy, particularly in the outpatient setting.

Introduction: Semaglutide 2.4 mg has been shown to reduce the risk and severity of cardiometabolic comorbidities (CMCs) and to improve cardiometabolic biomarkers in patients with overweight or obesity in clinical trials. However, real-world evidence in these areas is limited. Research Question: This study compared the incidence rates of CMCs and 12-month changes in biomarkers between adults with overweight/obesity with and without once-weekly subcutaneous semaglutide 2.4 mg use. Methods: A retrospective cohort study using a large U.S. claims database linked with clinical data evaluated patients with semaglutide 2.4 mg use for ≥12 months (June 2021–June 2023) and those without. For each CMC, including hypertension, T2D, dyslipidemia, HF, prediabetes, ASCVD, and CVD, patients were excluded from analysis of each individual CMC if they had claims indicating the corresponding CMC during the 12-month baseline. For each biomarker, patients were required to have the corresponding biomarker measurements at both baseline and 12-month follow-up. For each CMC and biomarker, propensity score weighting was used to balance patient characteristics between semaglutide 2.4 mg users and non-users. Time to CMCs were compared using weighted Cox proportional hazards models and biomarker changes were compared using weighted linear regression. Results: Sample sizes ranged from 14,067 to 25,490 in semaglutide 2.4 mg users and 4,271,926 to 8,578,948 in non-users across CMCs. After balancing, baseline characteristics were similar between users and non-users. Mean age ranged from 44.4 to 47.2 years among users and 44.4 to 47.4 years among non-users; 77%–83% of users and 75%–82% of non-users were women. Compared to non-users, semaglutide 2.4 mg users had significantly lower risk of incident hypertension (Hazard ratio [HR]: 0.62, 95% confidence intervals [CI]: 0.57; 0.68), T2D (HR: 0.45, 95% CI: 0.39; 0.51), HF (HR: 0.48, 95% CI: 0.38; 0.61), prediabetes (HR: 0.75, 95% CI: 0.70; 0.80), ASCVD (HR: 0.65, 95% CI: 0.58; 0.72), and CVD (HR: 0.69, 95% CI: 0.64; 0.75) (all p<0.001). The risk of dyslipidemia was similar between users and non-users (HR: 1.05, 95% CI: 1.00; 1.11, p=0.05). Semaglutide 2.4 mg use was also associated with significant improvements in cardiometabolic biomarkers specified in Table 1 and slower decline in eGFR. Conclusion: In adults with overweight/obesity, semaglutide 2.4 mg was associated with lower risk of specified CMCs and greater improvements in cardiometabolic biomarkers.

Introduction/Background: CHIP is a risk factor for cardiovascular (CV) disease, cancer, and all-cause mortality. Previous work has shown that CHIP, and particularly larger CHIP clones, are associated with adverse CV outcomes, yet the molecular pathways through which CHIP impacts CV risk are poorly defined. Hypothesis/Research Question: We hypothesize that the integration of whole blood transcriptomics and methylomics will provide novel insights into the pathophysiology of CHIP. Methods/Approach: Whole blood DNA methylation profiling, transcriptomics, and whole exome sequencing with CHIP calling for variant allele frequencies (VAF) of ≥2% (CHIP) and ≥10% (large CHIP) were performed for 507 ISCHEMIA and ISCHEMIA-CKD participants with moderate-severe ischemia. We identified transcriptomic and methylomic differences between participants with CHIP and large CHIP vs no CHIP using DESeq2 and limma, adjusted for age, sex, and race/ethnicity. Gene set enrichment analysis (GSEA) and probe set enrichment analysis (PSEA) were performed to identify pathway-level alterations in transcription and methylation, respectively. Results/Data: Clinical characteristics of study participants are described in Fig 1A . Compared to no CHIP (n=391), transcriptomics identified 6 differentially expressed genes (DEGs) in CHIP (n=116) and 27 DEGs in large CHIP (n=35) (p-adj<0.05; abs(logFC)>0.25) (Fig 1B) . Compared to no CHIP, methylation identified no differentially methylated probes in CHIP and 6 in large CHIP (padj<0.20, abs(logFC)>0.03). GSEA identified 137 pathways significantly different in both CHIP and large CHIP vs. no CHIP (padj<0.05), while PSEA identified 724 and 2356 pathways (padj<0.20), respectively. Given its stronger relationship with methylation and transcription, downstream analyses focused on large CHIP. Integrating these data, we found 58 pathways to be both hypomethylated and transcriptionally upregulated in large CHIP, including azurophil granule-related pathways implicated in neutrophil degranulation (Fig 1C) . Further investigation into the gene-probe pairs driving the azurophil granule pathway enrichment in large CHIP revealed hypomethylation and increased transcription of genes implicated in neutrophil extracellular trap formation, including ELANE, PTRN3, AZU1, and CTSG (Fig 1D) . Conclusions: Integration of the methylome and transcriptome suggests large CHIP is linked to neutrophil-mediated immune pathways in patients with stable coronary artery disease.

Background: Pre-clinical animal studies have demonstrated improved cerebral blood flow and neurological survival with Automated Head Up Position (AHUP) cardiopulmonary resuscitation (CPR) as compared to flat conventional (C) CPR. AHUP CPR consists of 1) automated head and thorax elevation 2) active compression decompression CPR and 3) an impedance threshold device. Subsequently, observational propensity-matched studies of out-of-hospital cardiac arrest (OHCA) patients demonstrated a time-dependent association between survival with intact neurological function (SNF) and application of AHUP CPR. However, comparison of AHUP CPR outcomes with contemporaneous C-CPR controls is lacking. Hypothesis: Use of AHUP CPR for OHCA by first responder agencies will demonstrate a higher incidence of SNF compared to C-CPR outcomes from a national registry Methods: Data from the previous 5 years (2020-2024) from an AHUP-CPR Registry comprised of OHCA patients routinely treated by first responders with AHUP CPR were compared with data from the Cardiac Arrest Registry to Enhance Survival (CARES). Patient demographics, arrest characteristics, ROSC, SHD, and SNF were recorded. SNF was defined as a Cerebral Performance Category 1 or 2 at hospital discharge. A two-sample test of proportions was used for outcome comparisons. Results: Nine AHUP registry sites (MN, FL, TN, IL, OK, VA, AL, IA, MI) were included. Summary 5-year demographics (Table 1) and clinical outcomes (Table 2) are presented. For 2020-2024 AHUP sites, the average time (mm:ss, SD) from 9-1-1 call to start of CPR was 9:09 (4:37) and time to start of AHUP CPR was 12:46 (5:57). The AHUP registry had a higher 5-yr incidence of SNF versus the CARES registry (difference 2.8%, 95% CI 1.8-3.8, p < 0.00001). This difference was consistent year over year (Figure 1). Secondary outcomes of sustained return of spontaneous circulation and survival to hospital discharge in the AHUP registry were also significantly higher than CARES registry data (Table 2). Conclusions: Over a 5-year period, an unadjusted analysis of aggregate data from two OHCA patient registries demonstrated that the incidence of survival with intact neurological function was higher in patients treated with AHUP CPR as part of first responder care versus patients treated with more conventional CPR methods.

Background: MARVEL-HCM is a US multicenter study assessing the safety and effectiveness of mavacamten in real-world academic and community practices. Mavacamten is a first-in-class cardiac myosin inhibitor (CMI) and the only CMI currently approved in over 50 countries for use in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Modest evidence exists describing the effectiveness and safety of mavacamten monotherapy. Aims: To describe the real-world outcomes of patients using mavacamten as monotherapy for oHCM. Methods: Patient-level data from medical records at 5 sites were analyzed to describe mavacamten monotherapy, defined as monotherapy at baseline or after background HCM therapy (beta-blockers [BB], calcium channel blockers [CCB], disopyramide) discontinuation within 12 weeks(wks) of mavacamten initiation and without reinitiation, up to 60 wks. A minimum of 12 wks follow-up was required for inclusion. Patient characteristics, echocardiographic data, and safety are reported at baseline and follow-up visits. Results: The monotherapy cohort comprised 13.4% (32/239) of patients: 24 were on mavacamten monotherapy at initiation, and 8 discontinued background therapy. Baseline characteristics included: NYHA Class II (46.9%) and III (53.1%), female (66%), hypertension (50%), and atrial fibrillation (AF) (18%) (Table 1). Median follow-up and duration of mavacamten monotherapy were 48 wks (range 12-60 wks) and 57 wks (range 14-60 wks), respectively. Resting left ventricular outflow tract gradient (LVOTg) was ≤ 30 mmHg in 93%, 91% and 100% of patients at Wk 24, 36, and 60. Valsalva LVOTg was ≤ 30 mmHg in 61%, 77% and 86% of patients at Wk 24, 36, and 60 (Fig 1). No patients were in NYHA Class III at wk 60, and ~50% of patients were NYHA Class I by wk 48 (Fig 2). Mean reduction in LVEF was 4.8% over 60 wks. One patient had LVEF < 50% at Wk 20, resulting in a dose reduction (10 to 7.5 mg). Safety events included 3 hospitalizations due to AF ablation (n=1), viral gastrointestinal illness (n=1) and heart failure (n=1). Demographic, clinical characteristics, and outcomes were similar across the mavacamten monotherapy cohort, mavacamten in combination with background HCM therapy (n=207), and the overall cohort of MARVEL-HCM (N=239). Conclusions: Mavacamten monotherapy was effective, safe, and consistent with the overall MARVEL cohort, as well as previously reported monotherapy cohorts from pivotal, long-term, and real-world evidence.

Introduction: Acoramidis, an oral transthyretin (TTR) stabilizer achieving near-complete (≥90%) TTR stabilization, is now approved in the USA, EU, Japan, and UK for the treatment of TTR amyloid cardiomyopathy (ATTR-CM). In the 30-month phase 3 ATTRibute-CM study, acoramidis reduced all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH) vs placebo. Through Month 42 (M42) of the open-label extension (OLE; 30 months ATTRibute-CM + 12 months OLE), the clinical benefit of acoramidis was sustained, resulting in a 36% and 43% risk reduction in ACM and ACM/first CVH, respectively, compared with the placebo to acoramidis group Research Question: Are the long-term clinical benefits of acoramidis on ACM and ACM/first CVH in ATTR-CM over 42 months consistent across patient subgroups? Methods: ATTRibute-CM study design has been previously described. At the end of the 30-month double-blind period, patients enrolled into OLE continued acoramidis or switched from placebo to acoramidis; all patients received open-label acoramidis HCI 800 mg BID. Data cut was performed after 12 months in OLE. Subgroup analysis for ACM and ACM/first CVH through M42 were conducted for randomization stratification factors (genotype, NT-proBNP, and eGFR levels) and other pre-specified subgroups. ACM included death due to any cause, cardiac mechanical assist device placement, and heart transplant. CVH included CV hospitalizations (≥24 h) and urgent visits (<24 h) for decompensated heart failure requiring IV diuretics and was adjudicated by an independent Clinical Events Committee. Results: Overall, 389 patients enrolled in the OLE (263 continuous acoramidis and 126 placebo to acoramidis). The analyses of ACM/first CVH ( Figure 1 ) and ACM ( Figure 2 ) through M42 consistently favored patients initially randomized to acoramidis across all patient subgroups, including those based on sex, age, country, ATTR-CM genotype, baseline NT-proBNP, baseline eGFR, NYHA class, and NAC stage. The largest effect size for the reduction in ACM/first CVH (HR <0.50) was observed in the following subgroups: female, non-Caucasian patients, variant ATTR-CM, or NAC stage 2. Conclusions: The long-term benefit of acoramidis was consistently shown in patients initially randomized to acoramidis treatment compared with placebo to acoramidis switch after 30 months across multiple clinically relevant subgroups, underscoring the importance of early initiation of acoramidis to reduce the long-term risk of ACM or CVH.

Introduction: Higher mtDNA-CN reflects better mitochondrial function, while lower levels indicate mtDNA release and increased inflammation. Although mtDNA-CN serves as a marker of cardiovascular health, the importance and mechanism of risk associated with mtDNA in high-risk individuals with chronic coronary artery disease (CAD) remains poorly understood. To address this gap, we leveraged the ISCHEMIA Biorepository to: (1) evaluate the association between mtDNA-CN and all-cause death (ACD); and (2) define a transcriptomic profile associated with high mtDNA-CN and ACD risk for high-risk patients with CAD. Hypothesis: Higher mtDNA-CN is associated with reduced ACD risk and inflammation in high-risk patients enrolled in the ISCHEMIA Biorepository. Methods: Low pass whole genome sequencing and whole blood RNA-Seq were performed on 594 ISCHEMIA and ISCHEMIA-CKD participants with moderate-severe ischemia. Data were processed using the NYU deciphEHR pipeline and mtDNA was quantified using mitoAnalyzer. mtDNA-CN was median split, with samples having values ≤ median classified as the 'low' group and those > median as the 'high' group. Unadjusted group differences were assessed using Chi-squared tests. Survival analysis was performed using Cox proportional hazard models, adjusted for age, sex, diabetes, eGFR, dialysis status, ischemia severity, and left ventricular ejection fraction. Adjusted differential gene expression (DGE) and gene set enrichment analysis (GSEA) were performed to explore molecular mechanisms underlying mtDNA-CN. Results: Median age was 67 (IQR: 57–78); 19% were female, 84% white, and 6% Hispanic. Hypertension (84%), diabetes (43%), and obesity (45%) were common; 26% had eGFR <60 mL/min/1.73 m 2 . Median mtDNA-CN was 153 counts per sample. After multivariate adjustment , mtDNA-CN > median was associated with a 48% reduction in ACD (aHR = 0.52, 95% CI: 0.30–0.90; P = 0.020) (Figure 1A) . DGE revealed downregulation of inflammatory genes in the mtDNA-CN group, including S100A9 (FC=-.41, p=3.32e-10) and S100A12 (FC=-.56, p=3.32e-10). Inflammatory pathways such as the inflammasome complex (NES=-2.17, p=9.32e-03) and interleukin-1 production (NES= -2.02, p=6.60e-03) were downregulated among participants in the high mtDNA-CN ( Figure 1B) . Conclusion: Higher mtDNA-CN is associated with lower risk of ACD and reduced inflammasome activity, suggesting that enhanced mitochondrial health may mitigate inflammasome-related pathology linked to ACD in patients with CAD.