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.

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.

Abstract Peritoneal Carcinomatosis (PC) is a metastatic cancer of the lining of the abdominal cavity, most often originating from the gastrointestinal or gynecological tracts. PC occurs in approximately 20% of colorectal cancer and 60% of ovarian cancer cases, with estimated 5-year survival rates as low as 6%. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a locoregional drug delivery modality administered via a minimally invasive laparoscopic approach. PIPAC shows promise in the treatment of peritoneal metastasis in early trials on colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery. The spatial organization of the tumor microenvironment (TME) and the complex cellular interactions within profoundly shape biology and treatment response. Spatial transcriptomics offers an opportunity to characterize TME heterogeneity in its native architecture, allowing the identification of biomarkers, interactions, and gene expression programs as well as resistance mechanisms and new potential targets. We performed image-based spatial transcriptomic profiling of 152 tissue samples, including 50 pre-treatment and 65 post-treatment metastatic tumors and 17 pre-treatment and 20 post-treatment tumor-adjacent normal tissue samples from 19 patients who participated in a Phase I trial on Oxaliplatin PIPAC. Through a comprehensive characterization of transcriptional profiles of a total of 1,249,711 cells, as well as cellular neighborhood and ligand-receptor interactions, we describe the heterogeneity of PC in its spatial context. We have further characterized treatment-driven changes in pre- and post-treatment tumors of a subset of 7 patients who underwent PIPAC with mitomycin IP. Through cell-based niche and proximity analyses, we identify distinct shifts in the composition and architecture of treated tumors. Most notably, treatment resulted in an 87% decrease in the number of malignant cells, as well as an expansion of the plasma-barrier niche and an increased number of immune infiltrates. Further analysis revealed distinct differences in the abundance of specific cancer-associated fibroblast and immune subsets, demonstrating changes in TME architecture. Overall, our results provide an invaluable characterization of PC in CRC and AC, garnering new insight into their architecture, cellular composition, and cell-cell interactions at baseline and in response to regional chemotherapy. Further analyses and follow-up studies can identify and validate new, actionable biomarkers to target these hard-to-treat tumors. Citation Format: Heini Maaret Natri, Arianna L. Williams-Katek, Muhammad Talha Waheed, Tiana Li, Marwan Fakih, Mingye Feng, Amit Merchea, Sue Chang, Richard L. Whelan, Danielle Deperalta, Thanh H. Dellinger, Nicholas Banovich, Mustafa Raoof. Spatial transcriptomic profiling of peritoneal metastases identifies multicellular programs in patient tumors undergoing pressurized intraperitoneal aerosol chemotherapy (PIPAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3958.

Abstract Background: Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia among adults in Western populations, disproportionately affecting the elderly, with a median age at diagnosis of approximately 70 years. Over the past two decades, significant advancements in therapeutic options, including Bruton tyrosine kinase (BTK) inhibitors, BCL-2 antagonists, and monoclonal antibodies, have improved clinical outcomes. However, despite these advances, limited data exist on long-term mortality trends and disparities in CLL outcomes among older adults in the United States. Understanding such patterns is critical to guiding geriatric oncology care, identifying gaps in healthcare delivery, and informing public health strategies. Methods: We conducted a population-based analysis using the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Underlying Cause-of-Death database. We identified all deaths among individuals aged ≥65 years from 1999 to 2020 in which CLL (ICD-10 code C91.1) was listed as the underlying cause. Mortality data were stratified by sex, age group (65–74, 75–84, ≥85), U.S. Census region, urban-rural classification, state, and place of death. We calculated crude mortality rates (CMRs) and age-adjusted mortality rates (AAMRs) per 100,000 persons, standardized to the U.S. 2000 population. Joinpoint regression analysis was used to assess temporal trends in AAMRs and compute annual percent changes (APCs) and average annual percent changes (AAPCs), with statistical significance set at p<0.05. Results: Between 1999 and 2020, a total of 85,371 CLL-related deaths occurred among U.S. adults aged ≥65 years. The overall AAMR declined from 11.18 per 100,000 in 1999 to 7.75 in 2020, reflecting a significant downward trend (AAPC: -1.86%; 95% CI: -2.18 to -1.54; p<0.0001). Men consistently exhibited higher mortality rates (AAMR: 13.48) than women (AAMR: 6.45), though the mortality decline was more pronounced among women (AAPC: -2.10% vs. -1.65%, respectively; both p<0.0001). Regional disparities were evident, with the Midwest reporting the highest AAMR (10.63), and the West the lowest (8.71). Urbanization analysis revealed higher mortality in non-metropolitan areas (AAMR: 10.33) than metropolitan ones (AAMR: 9.08), though both experienced significant declines over time. Age-stratified analysis showed the steepest declines in the 65–74 age group (AAPC: -3.91%; p<0.0001), followed by those aged 75–84 years (AAPC: -1.96%) and ≥85 years (AAPC: -0.25%). States with the highest mortality included Minnesota, Iowa, and South Dakota, while Hawaii, Nevada, and New Mexico had the lowest. Most deaths occurred in medical facilities (43.8%), followed by home (26.7%), nursing homes/long-term care (19.5%), and hospice (5.6%). Conclusion: CLL-related mortality among the U.S. geriatric population declined significantly between 1999 and 2020, likely reflecting the impact of therapeutic innovations and improved disease management. However, substantial disparities persist across sex, age, region, urbanization, and state-level subgroups. These findings underscore the importance of equitable access to modern CLL treatments and the need for targeted interventions to reduce mortality in high-risk, underserved older populations. Efforts to close these gaps will be essential in optimizing outcomes in the era of personalized cancer care for aging Americans.

Abstract Disclosure: R. Haider: None. M. Waqas: None. S. Khan: None. A. Ullah: None. M. Khawar: None. A. Qadeer: None. M. Talha: None. A. Batool: None. A. Khan: None. M.Z. Haider: None. R.W. Kirchoff: None. Background: Hypothyroidism and heart failure (HF) contribute significantly to mortality among older adults. Understanding mortality trends, including demographic, geographic, and socio-economic disparities, is crucial to inform healthcare policies and resource allocation. Methods: This study analyzed age adjusted mortality rates (AAMRs) from 1999 to 2022 for adults aged 55-85+ years. Age adjusted mortality rates (AMRs) per 1,000,000 population were stratified by gender, race, geographic location, and urbanicity. Trends were evaluated using Average Annual Percentage Change (APC) with 95% confidence intervals (CI), examining periods of decline and increase. Results: Between 1999 and 2022, 105,008 deaths were recorded among older adults (55-85+ years) due to hypothyroidism and heart failure (HF). The age-adjusted mortality rate (AAMR) initially declined from 1999 to 2016, marked by a significant drop between 2005 and 2008 (APC = -6.0, 95% CI: -7.6 to -3.0). However, mortality trends reversed post-2016, with a sharp increase (APC = 6.7, 95% CI: 5.5 to 8.4). Age-specific trends revealed declining crude mortality rates (CMR) across all groups until 2016, followed by increases, particularly in the 65-74 and 75-84 age brackets, with APCs of 14.1 (95% CI: 7.8 to 27.8) and 8.9 (95% CI: 3.8 to 21.8), respectively. Gender disparities showed men and women had similar trends, with declines until 2015-2016 followed by surges, with APCs of 6.8 (95% CI: 5.2 to 9.1) and 6.6 (95% CI: 4.6 to 11.1), respectively. Racial disparities highlighted steady declines until 2016, followed by increases in non-Hispanic Whites (APC = 10.4, 95% CI: 5.2 to 23.2) and Hispanics (APC = 7.5, 95% CI: 6.0 to 10.1). Geographically, the Midwest exhibited the highest AAMR (71.1), while the Northeast showed the lowest (51.4). State-level disparities revealed North Dakota with the highest AAMR (129.5), contrasting with Nevada, which had the lowest (20.4). Urban-rural differences showed similar trends, with notable AAMR increases in both settings post-2016. These results underscore significant demographic and regional disparities in hypothyroidism and HF-related mortality. Conclusion: While mortality from hypothyroidism and HF among older adults declined until 2016, trends have since reversed across all demographic and geographic strata. Addressing these rising rates require targeted interventions focusing on high-risk groups and areas. Presentation: Monday, July 14, 2025

AbstractBackgroundGastric cancer with synchronous peritoneal metastases is a debilitating disease with limited treatment options. This article describes an update of the 2018 Chicago Consensus guidelines addressing the management of gastric cancer with synchronous peritoneal metastases in line with the most recent evidence.MethodsA clinical management pathway was updated through two rounds of a Delphi consensus to assess agreement levels with pathway blocks. Supporting evidence underwent evaluation using a rapid literature review. Meta‐analyses were performed as appropriate.ResultsOverall, the level of evidence in this disease subset was low to moderate. Of 124 participants in the first round, 109 (88%) responded in the second round. Strong consensus (>90%) was achieved in six of eight blocks (75%) in rounds 1 and 2. A multidisciplinary preoperative assessment and diagnostic laparoscopy should be offered to all patients, whereas patients with a high burden of disease or progression should undergo nonsurgical management. Patients with stable/responsive disease and a low peritoneal carcinomatosis index should subsequently be offered treatment with regional therapeutic interventions and cytoreductive surgery. In patients who are cytology‐positive, systemic therapy can be used to convert them to cytology‐negative, with subsequent surgery offered according to the patient's goals of care. Meta‐analysis of observational and randomized control trials revealed a survival benefit with the addition of intraperitoneal chemotherapy to cytoreductive surgery (hazard ratio, 0.52).ConclusionsThe consensus‐driven clinical pathway for gastric cancer with synchronous peritoneal metastases offers vital clinical guidance for practitioners. There is a growing body of high‐quality evidence to support management strategies, and future clinical trials are eagerly awaited.

Background: Peripheral artery disease (PAD) is a prevalent condition affecting one in four patients with end stage renal disease (ESRD). Intermittent pneumatic compression (IPC) has proven benefits in PAD. We are conducting a trial testing the utility of IPC in the ESRD population by assessing the improvement in quality of life (QOL), functional limitation and walking performance from PAD-related symptoms. We aim to present our pilot results. Methods: Prospective single cohort study undergoing recruitment of outpatients at the hemodialysis (HD) unit of John H. Stroger Hospital. The calculated sample size is 78. PAD is confirmed by ankle-brachial index (ABI) and demographics obtained from interview and chart review. At baseline and post intervention, a Six-minute Walk Test (6MWT), Peripheral Artery Questionnaire (PAQ) and Walking Impairment Questionnaire (WIQ) are administered. The IPC device (Bio Arterial Plus) is used for intervention during HD. We present continuous variables as median (IQR) and categorical variables as percentage. Wilcoxon signed rank test was performed for comparison of results. Results: So far, 9 patients have completed intervention for the pilot study, 44% are men, the majority hispanic (66%), with age 48 (41-63) years. At baseline 66% of ABI were abnormal, all due to non-compressible PAD 1.46 (1.20-1.62). All patients have HTN, 44% diabetes, 33% hyperlipidemia and 33% heart failure. The median time of intervention is 70 (60-83) days. There was a significant difference in QOL measured by the WIQ (Fig.1), PAQ physical limitation (p=0.011), and PAQ social limitation (p=0.018). Although there was a trend towards benefit, no statistical difference was found on rest of objective and subjective measured parameters (p>0.05) Conclusions: Preliminary, IPC shows to improve many subsets of QOL in patients with ESRD and PAD. Given the small sample, improvement of walking distance remains elusive but with trends towards benefit.

AbstractBackgroundOptimal timing of cardiovascular implantable electronic device (CIED) re‐implantation following device removal due to infection is undefined. Multinational guidelines reflect this and include no specific recommendation for this timing, while others have recommended waiting at least 14 days in cases of CIED related infective endocarditis (CIED‐IE). The current work seeks to clarify this issue.MethodsWe retrospectively reviewed institutional data at Mayo Clinic, Minnesota of patients aged ≥ 18 years who developed CIED‐IE from January 1, 1991 to February 1, 2016. CIED‐IE was defined as echocardiogram reported device lead or valvular vegetation. Regression analyses were used to relate the risk of clinical outcomes to the interval between CIED removal and re‐implantation and the location of vegetations.ResultsA total of 109 patients met study inclusion criteria. A majority (68.8%) of patients were men and the median age was 68.0 years. Transoesophageal echocardiogram (TEE) was performed in 95.4% of patients, with valve vegetations detected in 33.9% (n = 37). Survival analysis comparing patients in whom device re‐implantation was < 14 days vs. ≥14 days, and further categorized by those with and without valve vegetation, showed a significant difference (P = 0.028); patients with valve vegetation and reimplantation interval < 14 days had the lowest (58.7%) 12‐month survival. When adjusted for valve vegetation, longer time interval for reimplantation trended toward increased hospital length of stay (P = 0.079).ConclusionOur findings suggest that the recommended 14‐day delay between CIED extraction and re‐implantation in CIED‐IE patients is associated with a survival benefit, but longer length of hospital stay following re‐implantation.