Citations

Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Multimodality imaging plays a pivotal role in ventricular tachycardia (VT) ablation by providing critical insights into arrhythmogenic substrates and guiding procedural strategies. This updated review explores the integration of various imaging techniques, including echocardiography, cardiac magnetic resonance (CMR), multidetector computed tomography (MDCT), electroanatomical mapping (EAM), and nuclear imaging, to optimize VT ablation outcomes. Echocardiography, particularly transthoracic echocardiography (TTE), is an essential first-line tool for evaluating structural heart disease and left ventricular function. Moreover, echocardiography aids in risk stratification and procedural planning by detecting regional wall motion abnormalities and thrombus formation. Meanwhile, intracardiac echocardiography (ICE) enhances ablation precision by providing real-time catheter visualization, improving procedural success, and reducing complications such as cardiac tamponade. Nonetheless, CMR is the gold standard for myocardial tissue characterization, enabling the identification of scar burden and conduction channels critical for VT pathogenesis. Late gadolinium enhancement (LGE) facilitates preprocedural planning by localizing arrhythmogenic substrates, predicting VT recurrence risk, and informing ablation strategies. Additionally, T1- and T2-mapping techniques refine the assessment of myocardial fibrosis and inflammation, further improving patient selection and outcomes. MDCT complements CMR by offering high-resolution anatomical visualization and aids in delineating scar distribution, epicardial fat, and vascular structures, informing safe and effective ablation approaches. The integration of these imaging modalities significantly enhances VT ablation precision, reduces recurrence rates, and improves patient outcomes.

Abstract Background Appendectomy has been proposed to influence ulcerative colitis (UC) outcomes, but its effect based on timing before or after diagnosis and long-term UC outcomes remains unclear. Materials and Methods Using TriNetX U.S. Collaborative Network, we identified adults with UC (2010-2024) who underwent appendectomy before or after diagnosis. Two 1:1 propensity score-matched comparisons were performed: appendectomy-before-UC and appendectomy-after-UC versus controls. The primary outcome was a 5-year composite of oral/intravenous (IV) corticosteroid use or colectomy. Secondary outcomes included individual composite outcomes and advanced therapy initiation in biologic-naive patients. Subgroup analyses stratified by age and biologic exposure were also performed. Results After matching, appendectomy after UC diagnosis showed no association with the composite outcome (aHR 0.98, 95% CI, 0.83-1.16), oral steroids (aHR 0.90, 95% CI, 0.75-1.09), IV steroids (aHR 1.11, 95% CI, 0.87-1.43), colectomy (aHR 1.24, 95% CI, 0.77-1.99), or advanced therapy initiation (aHR 0.97, 95% CI, 0.63-1.48). Appendectomy before UC diagnosis also showed no difference in the composite outcome (aHR 0.91, 95% CI, 0.76-1.09), oral steroids (aHR 0.88, 95% CI, 0.72-1.08), colectomy (aHR 0.99, 95% CI, 0.60-1.63), or advanced therapy initiation (aHR 0.77, 95% CI, 0.53-1.13). However, IV steroid use was reduced (aHR 0.68, 95% CI, 0.51-0.90, P = .006). In subgroup analyses, advanced therapy initiation was lower in patients aged 18-40 years following appendectomy after UC diagnosis (aHR 0.56, 95% CI, 0.33-0.96, P = .03). Conclusion Appendectomy was not associated with improved long-term UC outcomes of oral/IV steroid use, colectomy or initiation of advanced therapy regardless of timing.

Glioblastoma (GBM) is a devastating cancer with a dismal prognosis. Current treatment includes temozolomide (TMZ), which is more effective in about 50% of GBMs that have O 6 - methylguanine DNA methyltransferase ( MGMT ) promoter methylation. MGMT is a DNA repair protein that reverses TMZ-induced DNA damage. EGFR is a prime oncogene in GBM. Here, we report that EGFR inhibition induced the down-regulation of MGMT in GBM cells, revealing a previously unidentified link between EGFR signaling and response to TMZ. EGFR inhibition led to activation of two transcription factors, activator protein-1 (AP-1), which repressed MGMT transcription, and nuclear factor κB (NF-κB), which up-regulated MGMT transcription. EGFR inhibition also induced AP-1–mediated transcription of miR-616. miR-616 inhibited both MGMT translation and NF-κB activation. Thus, the overall effect of EGFR inhibition was down-regulation of MGMT expression. In addition, we provided an explanation for the prior failure of clinical trials that used concomitant EGFR tyrosine kinase inhibitors (TKIs) and TMZ. TMZ up-regulated MGMT, and concomitant treatment with EGFR TKIs and TMZ failed to down-regulate MGMT. However, pretreatment with EGFR TKIs followed by TMZ efficiently down-regulated MGMT and enhanced TMZ sensitivity in experimental models. Posttreatment tumor tissues from two clinical trials were used to validate these findings. We demonstrated that EGFR inhibitors induced down-regulation of MGMT in posttreatment resected tumor tissues from patients with GBM and the failure of EGFR inhibition to down-regulate MGMT if TMZ was used concomitantly. These data support using EGFR TKIs before TMZ treatment as a therapeutic approach in MGMT unmethylated GBM.

Abstract: Cardiovascular disease (CVD) remains the leading cause of death worldwide. While advances in treatment have improved outcomes, the greatest gains in public health will come from primary prevention. Risk stratification is the foundation of CVD prevention. Traditional tools, such as pooled cohort equations (PCEs) and SCORE2, do not capture non-traditional risk factors and individual variability, driving efforts to refine existing approaches. We critically discuss emerging risk determinants for primary CVD prevention. Coronary artery calcium scoring can reclassify CVD risk but has limitations related to cost, access, and unvalidated improvements in clinical endpoints. Biomarkers such as apolipoprotein B and lipoprotein(a) may identify residual risk beyond LDL-C, particularly in patients with lipid discordance, but remain underused due to uncertain thresholds and the lack of prospective triallevel outcome data. Trials of colchicine in primary prevention have yielded mixed results, making the role of targeting inflammation unclear in CVD prevention. Polygenic risk scores can stratify genetic risk but face challenges in sensitivity, specificity, and generalizability. Multiomics approaches, while offering the promise of deeper phenotyping, lack established clinical applications and consensus on when their use is appropriate. Artificial intelligence may allow better prediction across cohorts but requires broader validation. Clonal hematopoiesis of indeterminate potential, a marker of inflammation and age-related CVD risk, lacks evidence supporting routine screening or intervention in younger, asymptomatic individuals. The proliferation of new risk stratification tools poses a key challenge: determining when additional data meaningfully alter clinical decisions. Until robust outcome-based evidence emerges, risk enhancers should guide, but not dictate, therapy in selected patients.

Background: AF in the setting of cardiac amyloidosis is associated with a high risk of TEs, irrespective of CHA2DS2-VASc score. While warfarin has been the traditional anticoagulant, DOACs offer a promising alternative, but their safety in this population remains underexplored. This study aimed to evaluate the prevalence of thromboembolic events (TEs), including stroke and transient ischemic attack (TIA), and major bleeding events in patients with cardiac amyloidosis (CA) and atrial fibrillation (AF) treated with either warfarin or direct oral anticoagulants (DOACs). Additionally, we aimed to explore whether DOACs are at least as effective as warfarin in protecting against TEs in this population. Methods: This retrospective cohort study analyzed 422 patients with confirmed CA and AF from Mayo Clinic, with a median follow-up of 4.3 years. Data on anticoagulation therapy, baseline characteristics, and outcomes (TEs and bleeding) were collected. Statistical analyses included chi-square tests, t-tests, and Cox regression to assess the relationship between anticoagulation and TE. Results: Among 422 patients, 21 experienced a TE. The annual event rate was 0.83% for warfarin and 0.67% for DOACs, with no significant difference (HR 0.66, CI 0.22–2.01, p = 0.5). Patients with anticoagulation interruptions > 5 days had increased TE risk (HR 3.19, CI 0.97–10.5, p = 0.056). The bleeding rate was 9.9% over 4.3 years (2.33% per year), with no significant differences between anticoagulants. Conclusions: Both warfarin and DOACs have similar, low risks of TEs in CA and AF patients. However, anticoagulation interruptions were associated with increased TE risk, emphasizing the challenges in managing anticoagulation in this population.

Abstract Heart failure (HF) is a major cause of hospitalization and mortality worldwide. Ventricular assist devices (VADs) represent an alternative to cardiac transplantation for advanced HF. The main FDA-approved VAD (HeartMate III, Abbott), while effective, requires major cardiac surgery to insert the inflow cannula into the cardiac apex, and is associated with numerous co-morbidities and re-hospitalizations related to continuous flow and an external drive line and power supply. Mi-VAD, Inc. aspires to improve outcomes and quality of life with a miniature, minimally invasive, pulsatile, transcutaneously-powered VAD that is implanted above the aortic valve and/or the pulmonary valve and offering a wide range of hemodynamic support suitable for both advanced-stage and less advanced HF. Through its unique placement, there is the potential for right ventricular and biventricular cardiac assist for patients with restrictive cardiomyopathy and HFpEF for whom current VAD therapy is ineffective. Mi-VAD, Inc. has achieved proof of concept with its prototype, providing pulsatile ECG gated cardiac assist up to 10L/minute. Following initial bench top performance testing and in vivo efficacy and safety studies future work will focus on the development of wireless charging capability and conducting GLP builds for verification, regulatory clearance and commercialization. Additional technical development will focus on AI-driven hemodynamic optimization using multimodal physiologic sensing towards patient-specific digital twin of the Mi-VAD platform.

e20629 Background: Concomitant inhibition of the vascular endothelial growth factor (VEGF) pathway together with PD-1 or PD-L1 immune checkpoint blockade has demonstrated synergistic activity in non-small cell lung cancer (NSCLC). However, comparative evidence across individual immune checkpoint inhibitor (ICI) and anti-VEGF combinations remains limited. This network meta-analysis (NMA) aimed to evaluate and compare the efficacy of available ICI plus anti-VEGF combination strategies in NSCLC. Methods: A systematic search of three electronic databases and two clinical trial registries was conducted to identify randomized controlled trials evaluating combinations of ICIs with anti-VEGF agents. A frequentist NMA framework was applied using the netmeta package in R. Hazard ratios (HRs) were used for overall survival (OS) and progression-free survival (PFS), while odds ratios (ORs) were used for objective response rate (ORR). Treatment ranking was performed using P scores. Results: A total of 24 randomized controlled trials were included in the network. For survival outcomes, the combination of nivolumab plus bevacizumab demonstrated significantly improved OS (HR = 0.66, 95% CI 0.50–0.88) and PFS (HR = 0.46, 95% CI 0.27–0.81) compared with standard chemotherapy. In addition, atezolizumab plus bevacizumab was associated with a significant OS benefit over chemotherapy (HR = 0.79, 95% CI 0.65–0.95). Indirect comparisons showed that nivolumab plus bevacizumab significantly improved PFS compared with pembrolizumab monotherapy, as well as pembrolizumab combined with lenvatinib or chemotherapy. Furthermore, nivolumab combined with sitravatinib demonstrated significantly superior OS and PFS compared with ramucirumab and chemotherapy. For ORR assessed using RECIST 1.1, nivolumab-based combinations could not be incorporated into the network due to insufficient data, and no other combination demonstrated a statistically significant advantage over chemotherapy. However, indirect comparisons showed that pembrolizumab plus lenvatinib was superior to lenvatinib monotherapy (OR = 4.76, 95% CI 1.04–25.0). P-score rankings identified nivolumab plus bevacizumab as the top-ranked regimen for survival outcomes, followed by atezolizumab plus bevacizumab. For ORR, pembrolizumab plus lenvatinib ranked highest, followed by atezolizumab plus bevacizumab. Conclusions: Nivolumab-based ICI and anti-VEGF combinations, particularly with bevacizumab and sitravatinib, demonstrate the most favorable survival outcomes in NSCLC. Evidence for ORR remains limited, and further randomized comparisons are required to better define the relative efficacy of these combinations.

e20139 Background: Extensive-stage small cell lung cancer (ES-SCLC) frequently presents with brain metastases, affecting approximately 20% of the patients at diagnosis. The prognostic impact of baseline brain metastases on survival outcomes in patients treated with contemporary chemo-immunotherapy remains unclear, creating uncertainty in first-line treatment selection for this high-risk population. We conducted a systematic review and meta-analysis to evaluate the impact of baseline brain metastases on treatment outcomes in ES-SCLC. Methods: This PRISMA-compliant systematic review and meta-analysis was prospectively registered in PROSPERO. PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were systematically searched from database inception through January 2026 to identify randomized controlled trials evaluating PD-1/PD-L1-based chemo-immunotherapy versus platinum-etoposide chemotherapy in adults with ES-SCLC. Two reviewers independently screened studies and extracted data, with discrepancies resolved by consensus. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were pooled separately for patients with baseline brain metastases (BM+) and without brain metastases (BM−) using random-effects models with Hartung–Knapp adjustment. Analyses were performed using R. Prespecified subgroup analyses were conducted based on follow-up duration and immunotherapy regimen. Results: Twelve randomized controlled trials were included. Among patients with baseline brain metastases (BM+), pooled OS from seven studies did not show a significant survival benefit (HR 0.84, 95% CI 0.66–1.08, I² = 0.0%, P = 0.145), nor did pooled PFS from five studies (HR 1.03, 95% CI 0.60–1.79, I² = 0.0%). Subgroup analyses revealed no significant heterogeneity. In contrast, among patients without baseline brain metastases (BM−), pooled OS from nine studies demonstrated a significant survival benefit (HR 0.72, 95% CI 0.69–0.76, I² = 0.0%, P < 0.001), with corresponding improvement in PFS (HR 0.70, 95% CI 0.60–0.82, I² = 0.0%). These findings indicate a differential treatment effect according to baseline brain metastasis status. Conclusions: First-line chemo-immunotherapy does not apprear to confer a significant survival benefit in ES-SCLC patients with baseline brain metastases, reflecting a differential treatment effect by brain metastasis status. These findings suggest that baseline brain metastases should be considered in treatment selection and future clinical trial design and highlight the need for optimized systemic strategies for this high-risk population.

603 Background: Accurate prediction of pathologic complete response (pCR) after preoperative therapy for HER2-positive (HER2+) breast cancer can help triage patients to immediate surgery vs additional preoperative therapy. Pre-surgery (i.e., after neoadjuvant therapy) imaging studies may help estimate the likelihood of pCR. In EA1181, patients (pts) with stage II-IIIA HER2+ breast cancer received four cycles of preoperative taxane, trastuzumab, and pertuzumab (THP×4). Pre-surgery imaging was required, though the specific imaging modality was not mandated. Here, we report the accuracy of pre-surgery breast MRI to predict pCR (ypT0/Tis, ypN0). Methods: Among 2,141 pts treated with THPx4, 1,378 had pre-surgery breast MRI and were representative of the overall cohort, although T3 tumors were more common (16% vs 9%). MRI reports were available for 1,351 pts; all reports were centrally reviewed and classified as radiologic complete response (rCR; no residual tumor enhancement and normalization of lymph nodes, if applicable) or radiologic residual disease (rRD). Reports with indeterminate radiologic response were independently reviewed by two study radiologists blinded to pathology outcomes. Among pts with rCR who had pathologic residual disease (pRD), we also assessed the extent of residual disease by residual cancer burden (RCB) score. Among pts with rRD who had a pCR, we determined the proportion who only had residual ductal carcinoma in situ (DCIS). Results: See Table. Conclusions: After neoadjuvant therapy, preoperative MRI accurately predicted pCR in 86% of patients with HER2+/ER− disease and may help identify patients who can proceed directly to surgery. MRI is insufficient to predict pCR for pts with HER2+/ER+ disease, as only 55% with complete response on MRI had a pCR at surgery. A pre-surgery MRI that indicated residual disease was accurate in 80% of pts with HER2+/ER+ disease, but in only 45% of pts with HER2+/ER- cancer. Accurately predicting residual disease after THPx4 allows for consideration of additional therapy that may increase the chance of pCR. Combining imaging like MRI with other biomarkers, such as tissue-based markers or circulating tumor DNA, may improve prediction of pCR and facilitate personalization of treatment decisions in HER2+ breast cancer. All pts with pre-surgery MRI (n=1351)pCR rate overall in this cohort = 47% MRI result Pathology pCR pRD rCR 70.6% (341/483) 29.4%(142/483) 78% had RCB1 rRD 34%(295/868) 21% of 295 had DCIS only 66.01% (573/868) ER- (n=589)*Overall pCR rate in ER- subset = 68% MRI result Pathology pCR pRD rCR 86.1% (205/238) 13.9% (33/238) 85% had RCB1 rRD 55.3% (194/351) 19% of 194 had only DCIS 44.7% (157/351) ER+ (n= 762)*Overall pCR rate in ER+ subset = 31% MRI result Pathology pCR pRD rCR 55.5% (136/245) 44.5% (109/245) 76% had RCB1 rRD 19.5% (101/517) 26% of 101 had only DCIS 80.5% (416/517)