Rath, Shree

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.

e13162 Background: BRCA1/2 mutations impair homologous recombination repair, forcing cancer cells to rely on alternative DNA repair pathways, such as those mediated by poly(ADP-ribose) polymerase (PARP). PARP inhibitors (PARPis), like iniparib, olaparib, talazoparib, niraparib, and veliparib, exploit this dependency, inducing lethality in cells of BRCA-mutated, HER2-negative breast cancers (BRCAm, HER2-BC). Only 2 PARPis, talazoparib and olaparib, are FDA-approved for BRCAm, HER2-BC. However, the treatment with the highest efficacy remains unclear. We conducted a network meta-analysis (NMA) of randomised controlled trials (RCTs) to compare the efficacy of PARPis in treating BRCAm, HER2-BC. Methods: We systematically searched PubMed, Cochrane CENTRAL, SCOPUS, and ClinicalTrials.gov (up to December 2024) for randomized controlled trials (RCTs) following PRISMA-NMA guidelines. Primary outcome was overall survival(OS), with hazard ratios (HRs) and 95% confidence intervals (CIs). Secondary outcome was progression-free survival (PFS). Survival times were converted to HRs under the assumption of exponential distribution. Standard of care (SOC) was defined as taxane/anthracycline-based regimens with additional platinum-based chemotherapy. Physician's choice chemotherapy (PCT) included capecitabine, eribulin, gemcitabine, or vinorelbine. A frequentist approach with random-effects modeling was used to pool estimates, and P-scores ranked treatment efficacy. Heterogeneity and inconsistency were assessed using τ², I², and Q-statistics. Analyses were conducted in R version 4.4.1. Results: 8 studies including 4432 participants incorporating 8 pairwise comparisons and 7 treatments were analyzed for OS. Compared to SOC (reference), HRs of OS were significantly reduced with talazoparib+SOC (HR = 0.49, 95% CI: 0.32–0.74; P = 0.64), olaparib+SOC (HR = 0.46, 95% CI: 0.36–0.59; P = 0.69), niraparib+SOC (HR = 0.44, 95% CI: 0.26–0.76; P = 0.76), and veliparib+SOC (HR = 0.38, 95% CI: 0.29–0.48; P = 0.91). No heterogeneity or inconsistency was detected (τ² = 0; I² = 0; Q = 1.27, p = 0.53). For PFS, iniparib/gemcitabine, talazoparib, olaparib, and niraparib showed significant reduction in HR with increasing order of P-scores, in combination with SOC. Conclusions: Veliparib combined with SOC showed the highest OS improvement, while niraparib ranked highest for PFS, followed by talazoparib and olaparib. Further trials are needed to confirm these findings and refine treatment strategies for BRCAm, HER2-BC.

e17089 Background: Prostate cancer (PC) is often treated with androgen-deprivation therapy (ADT), but progression remains a challenge. Darolutamide, a next-generation androgen receptor inhibitor, may improve outcomes when combined with ADT. This systematic review and meta-analysis evaluates the efficacy and safety of darolutamide plus ADT in hormone-sensitive (HSPC) and castration-resistant prostate cancer (CRPC). Methods: A comprehensive search of PubMed, Cochrane, Clinicaltrials.gov, Embase, and Scopus was conducted through January 11, 2025. Randomized controlled trials (RCTs) comparing darolutamide plus ADT vs. placebo or control in prostate cancer were included. Data on overall survival, metastatic progression, antineoplastic therapy initiation, pain progression, bone fractures, hypertension, adverse events and serious adverse events were analyzed. Outcomes were pooled as risk ratios (RR) with 95% confidence intervals (CI) using a random-effects model. Heterogeneity was assessed via Higgins I², with subgroup analyses for HSPC and CRPC. Results: Four RCTs with 4,992 patients (darolutamide + ADT=3007; control=1985) were further included for quantitative analysis. Our pooled analysis showed a statistically significant decrease in the development of metastatic CRPC across both HSPC and CRPC (RR: 0.38 [0.19, 0.77], p=0.007). Similarly, progression to pain (RR: 0.81 [0.71, 0.92], p=0.001) and the use of antineoplastic therapy (RR: 0.46 [0.38, 0.57], p<0.0001) was significantly delayed across all PC, indicating slower disease progression. While a slightly higher overall survival was noted in the CRPC subgroup (RR: 1.08 [1.01, 1.14], p=0.007), no significant differences were reported on the use of combination therapy across HSPC and overall PC (RR: 0.71 [0.39, 1.31], p=0.28). While a significantly higher risk of developing adverse events (RR: 1.08 [1.03, 1.14], p=0.002) and serious adverse events (RR:1.2 [0.99, 1.45], p=0.07) was noted in the CRPC subgroup, a slight increase was reported in the overall cohort and HSPC, although with statistical insignificance. Bone fractures (RR: 1.52 [1.12, 2.07], p=0.008) and hypertension risk (RR: 1.28 [1.03, 1.59], p=0.03) were elevated, while rates of rash, fatigue, falls, and mental impairment were similar. Conclusions: Combination therapy of darolutamide and ADT reduced metastatic progression and slowed tumor growth but did not significantly improve overall survival. Adverse events were more common, particularly in CRPC cohort. Longer follow-up studies are needed to assess long-term efficacy and weigh tumor control against adverse event risks.

e16001 Background: Esophageal carcinoma ranks among the top 10 malignancies in the world, contributing to high morbidity and mortality. With radiotherapy being one of the most administered treatment options, different variations of administration have evolved. Two such variations include intensity-modulated radiotherapy and 3D conformational radiotherapy. These modalities have been investigated for their efficacy and rate of adverse events. However, conclusions from the trials conducted have been variable. In this systematic review and meta-analysis, we aim to collate these findings to assess the exposure of cancerous cells and rates of adverse events following IMRT or 3D-CRT. Methods: A comprehensive literature search was conducted across three databases for all articles published from inception till September 2024. All primary studies evaluating the comparative efficacy of IMRT vs 3D-CRT were included. Outcomes assessed include dose volume histograms (DVHs) at heart and lung, Dmax at the spinal cord, and irradiation toxicity. Data analysis was conducted in RevMan 5.4 using a random-effects model. Results: A total of twenty records were included in the study, with a sample size of 3090 patients. Radiation dosage, estimated as DVHs, was equal across both regimens at heart (MD: 2.67; 95%CI: –0.15 to 5.48; P = 0.06), except at 40 Gy of radiation, where a lower DVH was noted among patients being administered IMRT (MD: 6.64; 95%CI: 0.25 to 13.03; P = 0.04). At the lung, a higher DVH was noted, especially for doses of 20 Gy or above, on using IMRT. Similarly, a lower dosage in the spinal cord was noted in the IMRT group (MD: 2.87; 95%CI: 1.04 to 4.70; P = .002). Consequently, a lower risk of esophagitis was noted among the IMRT group (OR: 1.54; 95%CI: 1.14 to 2.07; p = 0.009]). While considering patient outcomes, the odds of survival were higher in the IMRT group at 3 years post-treatment (OR: 0.53; 95%CI: 0.31 to 0.92; P = 0.02). Conclusions: IMRT was superior to 3D-CRT in terms of volume of tissue irradiated and lower spinal toxicity. A higher chance of survival was noted in the IMRT group. Further trials are needed to strengthen these findings. Outcome Mean Difference (MD) 95% confidence interval (CI) P value Mean dosage at lung 1.14 0.6, 1.68 <0.0001 Mean dosage at heart 2.67 -0.15, 5.48 0.06 Radiation esophagitis Odds ratio, OR: 1.38 1.09, 1.76 0.009 Radiation pneumonitis OR:1.37 0.62, 3.01 0.43 3-year OS OR: 0.69 0.56, 0.84 0.0003 5-year OS OR: 0.53 0.31, 0.92 0.02 Maximum dosage at spinal cord 2.87 1.04, 4.7 0.0002

e19022 Background: Chronic lymphocytic leukemia (CLL) is a common adult leukemia that originates by dysfunctional development of the lymphocytes. Acalabrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, has demonstrated promising outcomes as a targeted therapy alternative to chemoimmunotherapy for treating CLL. The objective of this retrospective analysis was to compare the safety profiles of acalabrutinib and chemoimmunotherapy in patients with CLL and to evaluate the potential of acalabrutinib as an alternative therapeutic option. Methods: We conducted a retrospective cohort analysis using the TriNetX platform analyzing data of patients diagnosed with CLL from January, 2000 to January, 2025. Data was classified into cohorts on the basis of treatment with either acalabrutinib or chemoimmunotherapy. Propensity score matching analysis was carried out to balance their demographic and clinical characteristics. Demographic factors included age (≥18 years), sex, race, and ethnicity. Outcomes assessed included all cause death, atrial fibrillation, hypertension, acute heart failure, ventricular arrythmias, and bleeding. Kaplan-Meier survival analysis was employed. Results: A total of 4,006 patients were included in the analysis, 847 received acalabrutinib and 3,172 underwent chemoimmunotherapy, with a mean age of 70±11 and 69±14 years respectively. Participants were mostly male, with the majority of the patients being non-Hispanic Whites. Median period of follow up was 578 and 925 days respectively, incidence and risk of mortality and adverse events were assessed. A lower risk of mortality was noted with acalabrutinib (RR: 0.407; 95%CI: 0.32, 0.51; p<0.0001). Additionally, atrial fibrillation developed in fewer than 10 patients on use of acalabrutinib, thus carrying significantly lower odds (odds ratio (OR):0.3; 95%CI: 0.16, 0.58; p=0.001) than chemoimmunotherapy, which reported atrial fibrillation in 120 patients. Similarly, significantly lesser incidence of hypertension was noted on use of acalabrutinib, implying safer drug profile. Bleeding risk was also reduced in the acalabrutinib cohort and was statistically significant (OR:0.36, 95%CI: 0.24, 0.52; p<0.0001). The odds of acute heart failure (OR:1.25, 95%CI: 0.61, 2.57; p=0.54) and ventricular arrhythmia (OR:1.5, 95%CI: 0.72, 3.14; p=0.2) were statistically nonsignificant. Conclusions: The use of acalabrutinib in patients with CLL was associated with statistically significant better safety profile, with lesser risk of mortality, bleeding events and atrial fibrillation. Clinicians may consider using acalabrutinib as a superior treatment modality in the treatment of CLL. Further research maybe required to optimize treatment protocols in the best interest of patients.