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ABSTRACT Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

PURPOSE Tumor treating fields (TTFields) use alternating electric fields to disrupt cancer cell proliferation. Feasibility of TTFields therapy with gemcitabine/nab-paclitaxel was previously demonstrated in patients with advanced pancreatic adenocarcinoma. PANOVA-3 was designed to confirm safety and efficacy of TTFields in patients with unresectable locally advanced pancreatic adenocarcinoma (LA-PAC). METHODS In this global phase III trial, 571 patients with newly diagnosed LA-PAC were randomly assigned to receive gemcitabine 1,000 mg/m 2 and nab-paclitaxel 125 mg/m 2 by intravenous infusion once a day on days 1, 8, and 15 of a 28-day cycle with or without TTFields. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), local PFS, pain-free survival, and overall response rate (ORR). Distant PFS was analyzed post hoc. RESULTS OS was significantly prolonged using TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel (median, 16.2 months [95% CI, 15.0 to 18.0] v 14.2 months [95% CI, 12.8 to 15.4]; hazard ratio [HR], 0.82 [95% CI, 0.68 to 0.99]; P = .039). PFS, local PFS, and ORR were not improved. Pain-free survival was significantly prolonged with TTFields with gemcitabine/nab-paclitaxel (median, 15.2 months [95% CI, 10.3 to 22.8] v 9.1 months [95% CI, 7.4 to 12.7]; HR, 0.74 [95% CI, 0.56 to 0.97]; P = .027), as was distant PFS (median, 13.9 months [95% CI, 12.2 to 16.8] v 11.5 months [95% CI, 10.4 to 12.9]; HR, 0.74 [95% CI, 0.57 to 0.96]; P = .022). Device-related skin adverse events (AEs) were experienced by 76.3% of patients. Most device-related skin AEs were mild to moderate, with 7.7% of patients reporting a grade 3 AE. CONCLUSION This study demonstrated significant OS, pain-free survival, and distant PFS benefits for TTFields with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in patients with unresectable LA-PAC, with no additive systemic toxicity.

e20615 Background: Patients with Stage IV NSCLC have a poor prognosis, with approximately 25-30% succumbing to the disease within the first three months. However, survival outcomes can vary significantly depending on individual factors and advancements in treatment options. Therefore, it is crucial to identify patients at high risk of poor survival outcomes to tailor personalized treatment strategies and optimize clinical management. An international study has been conducted to generate prognostic scores for patients with Stage IV NSCLC. Methods: A retrospective observational study was conducted using real-world data (RWD) from South Korea (ROOT-HEALTH database from Samsung Medical Center), the USA (COTA NSCLC dataset) and France (CIAN lung cohort from Centre Léon Bérard). Patients with stage IV NSCLC between January 2008 and December 2023 were included. The study's primary objective was to learn from patients ‘baseline characteristics affecting overall survival (OS) and progression-free survival (PFS) to derive a prognostic score reflecting relative risk of death for given patient. A partition strategy was used, with 70% of the cohort for training and 30% for validation. Data-driven feature elimination has been applied to avoid overfitting of the models. Nested cross-validation reduced selection bias in hyperparameter tuning and model selection. Results: A total of 7,805 patients with NSCLC were included in the final analysis (USA: n=610, France: n=271, Korea: n=6,924). In the Korean dataset, the model achieved a C-index of 0.872 for OS using 35 selected variables. For the USA dataset, the model, based on 15 selected variables, demonstrated a C-index of 0.707 for OS. For PFS, the Korean dataset demonstrated a C-index of 0.823, the USA dataset achieved a C-index of 0.664, and the French dataset reported a C-index of 0.64, using 15 selected variables. The important predictors for OS included albumin, neutrophil/lymphocyte ratio, bilirubin, and druggable mutations. For PFS, important predictors included LDH, albumin, hemoglobin, MET mutation, bilirubin, and BMI. The prognostic scores derived from these models allowed to identify patients with higher risk of death, than average, in each country. Conclusions: This study generates prognostic scores for OS and PFS in stage IV NSCLC using longitudinal international data from the USA, France, and South Korea throughout the cancer journey. It has the potential to support better treatment strategy for severe patients in clinical practice and early decision-making in clinical studies. Further research utilizing diverse international cohorts is essential to refine prognostic scores and enhance personalized treatment strategies for stage IV NSCLC patients.

e14555 Background: Natural killer (NK) cells are innate lymphocytes that engage in direct cytotoxic responses against malignant cells and promote pro-inflammatory tumor microenvironments. While studies have predominantly focused on conventional NK cell subsets, recent findings uncovered adaptive and tissue-resident (TR) subsets with unique functional properties. The influence of distinct NK cell subsets on tumor immunobiology and clinical outcomes remains unknown. Methods: Single-cell RNA-sequencing (scRNA-seq) of primary, therapy-naïve tumors from 276 patients across 14 cancer types, as well as 39 patients treated with immune checkpoint blockade (ICB), was accessed through publicly available datasets. We employed systematic computational analyses to phenotype and examine intra-tumoral NK cells. Gene signatures for NK cell subsets were applied to bulk RNA-sequencing from 212,105 tumor samples to delineate their associations with clinical outcomes using the Caris CODEai database. Results: Six main subsets of NK cells were identified in solid tumors, including conventional CD56 dim and CD56 bright NK cells, alongside adaptive, TR adaptive, TR CD56 bright , and TR CD56 bright /adaptive subsets. Across cancer, TR adaptive NK cells emerged as the most prognostic subset, with high infiltration conferring significantly longer overall survival (HR[95% CI] = 0.68[0.66-0.69], p < 0.001) than conventional CD56 dim and CD56 bright subsets. This was also observed in cohorts of head and neck, non-small cell lung, and esophageal cancers, particularly those treated with ICB. Notably, elevated TR adaptive NK cell infiltration was more prognostic than high tumor mutational burden in these settings. This was most apparent in ICB-treated head and neck cancers (HR = 0.48[0.41-0.57], p < 0.001 vs HR = 0.90[0.76-1.04], p = 0.16). Additionally, TR adaptive NK cells were strongly correlated to the infiltration of CD8 + T cells and B cells in tumors. Underlying these observations, our scRNA-seq analyses demonstrated that TR adaptive NK cells exhibit the highest immunomodulatory activity of all subsets, expressing high levels of pro-inflammatory cytokines ( CCL3 , CXCL13 , and IFNG ) and low levels of immunosuppressive cytokines ( TGFB1 ). Mechanistically, this activity was linked to the upregulation of transcription factors associated with NK cell activation, function, and persistence and downregulation of genes related to stress response and exhaustion. Interestingly, scRNA-seq from paired pre- and post-ICB-treated tumors revealed a unique expansion of cytotoxic GZMB + TR adaptive NK cells after treatment. Conclusions: TR adaptive NK cells represent a novel subset of NK cells that may drive anti-tumor immune responses, particularly in the context of ICB treatment. Features of this unique population may be harnessed to design more effective NK cell-based therapies against solid tumors.

5073 Background: B7-H3 ( CD276 ) is an immunomodulatory protein overexpressed in prostate cancer (PC), representing a promising therapeutic target. However, expression of B7-H3 across PC disease states (hormone sensitive [HSPC], castration resistant [CRPC], neuroendocrine [NEPC]) and across races is poorly understood. We analyzed PC samples from a large clinico-genomic database to comprehensively characterize B7-H3 expression and elucidate its therapeutic potential in PC patients. Methods: We analyzed 7,682 PC samples with paired DNA/RNA profiling from Caris Life Sciences. Using CD276 mRNA expression measured by transcripts per million (TPM), samples were stratified into B7-H3-high (>75% centile) or low (<25% centile) groups. Annotations of HSPCs and CRPCs were based on time of biopsy collection relative to first use of androgen deprivation therapies. NEPC was defined histologically (Epstein, AJSP 2014). Transcriptomic alterations were compared using Mann-Whitney U tests. Overall survival (OS) was obtained from insurance claims data and assessed by Kaplan-Meier and Cox proportional hazards analyses. Results: B7-H3 was expressed at similar levels across specimen sites (prostate, lymph node, bone, liver, lung). HSPCs and CRPCs had similar levels of B7-H3 expression, but was reduced in NEPCs (TPM = 5.07, 4.96, 4.48; q<0.0001). While B7-H3-high was associated with worse OS in HSPCs (HR 1.32, 95CI 1.14-1.53, p=0.0002), it was associated with better OS in CRPC (HR 0.82, 95CI 0.69-0.97, p=0.018). B7-H3 expression was comparable in white, African American (AA), and Asian patients. However, Asian patients with high B7-H3 had worse outcomes (HR 4.08, 95CI 2.10-7.93, p<0.0001) while AA patients had improved outcomes (HR 0.74, 95CI 0.57-0.97, p=0.027). In co-expression analyses, B7-H3 was positively correlated with AR transcriptional co-factors ( HOXB13 , FOXA1 ) (R=0.59, 0.47; q<0.0001) but had weaker correlations with lineage plastic factors ( EZH2 , SOX2 , ASCL1 ) (R=0.26, 0.11, -0.02). Further, B7-H3-high correlated with high AR-score and low-NEPC. Given emergent bi-specific therapeutics in PC, we examined co-expression of B7-H3 with other cell surface targets. TROP2 ( TACSTD2 ) and NECTIN-4 ( PVRL4 ) exhibited the greatest correlation with B7-H3 (R=0.42, 0.40; q<0.0001); whereas PD-L1 ( CD274 ), CTLA4 , DLL3 , and CEACAM5 had weaker correlations (R=0.18, 0.08, 0.14, 0.09). Conclusions: High B7-H3 expression worsens prognosis in HSPC but improved prognosis in CRPC. Outcomes differed by race, with B7-H3-high Asian patients exhibiting worse OS while AA patients had better OS. The positive correlation between B7-H3 and AR co-factors suggests that B7-H3 is AR-regulated, at least in CRPC. Lastly, bi-specific approaches may be valuable against B7-H3-high tumors, with co-targeting of TROP2 and/or NECTIN-4.

4545 Background: The treatment landscape of front-line nccRCC has evolved with recent trials demonstrating the efficacy of combination systemic therapy. However, the efficacy of treatment after combination therapy is unknown. This study evaluates the efficacy of VEGF-based regimens in nccRCC patients (pts) previously treated with combination regimens. Methods: ORACLE is a real-world, multi-center, retrospective database that includes nccRCC patients that received combination systemic therapies (IO+IO, IO+VEGF and VEGF+ mTOR) in any line. Subsequent treatments were categorized as VEGF only regimens (cabozantinib vs other VEGF), IO+ VEGF and VEGF+ mTOR. The primary endpoint was objective response rate (ORR) assessed by investigator review using RECIST 1.1. Secondary endpoints included disease control rate (DCR), defined as the proportion of patients achieving complete or partial responses or stable disease, time to treatment progression (TTP), calculated from the date of VEGF-based initiation to progression or last follow-up using the Kaplan-Meier method. Differences between groups were estimated with the log-rank test, and categorical outcomes were compared with the chi-square test. Results: 105 pts who received VEGF – based regimens after combination therapy were included in the analysis. Baseline characteristics: median age: 59years, 71 % male, 58% white, 25% black, 87% ECOG 0-2. IMDC-risk categories included:21% favorable, 59% intermediate and 20% poor risk. Histology included papillary (40%), unclassified (32%), chromophobe (16%) and other rare subtypes (12%). Prior combination therapies included IO+IO: 62%, IO+ VEGF: 34% and VEGF+ mTORi:4%. 70% pts received combination therapy in the first line setting while the remainder received combination therapy in a second or later line. Outcomes with subsequent treatments are described in Table1. IMDC risk score correlated with TTP. Conclusions: Modest antitumor activity was observed with VEGF- based approaches in combination therapy refractory nccRCC. Optimal management of nccRCC remains an unmet need. Outcomes of nccRCC patients by treatment and histologic type. Outcomes per Treatment n ORR (%) DCR (%) mTTP (mo.) Cabozantinib 56 18 47 3.6 VEGF/mTOR 19 16 42 9.3 IO+VEGF 17 29 47 5.6 Other VEGF 13 15 46 5.5 Outcomes per Histology Papillary 42 19 43 6.5 Unclassified 33 21 42 6.1 Chromophobe 17 29 59 8.9 Other * 13 0 46 NR

Importance Nontraumatic subarachnoid hemorrhage (SAH) represents the third most common stroke type with unique etiologies, risk factors, diagnostics, and treatments. Nevertheless, epidemiological studies often cluster SAH with other stroke types leaving its distinct burden estimates obscure. Objective To estimate the worldwide burden of SAH. Design, Setting, and Participants Based on the repeated cross-sectional Global Burden of Disease (GBD) 2021 study, the global burden of SAH in 1990 to 2021 was estimated. Moreover, the SAH burden was compared with other diseases, and its associations with 14 individual risk factors were investigated with available data in the GBD 2021 study. The GBD study included the burden estimates of nontraumatic SAH among all ages in 204 countries and territories between 1990 and 2021. Exposures SAH and 14 modifiable risk factors. Main Outcomes and Measures Absolute numbers and age-standardized rates with 95% uncertainty intervals (UIs) of SAH incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) as well as risk factor–specific population attributable fractions (PAFs). Results In 2021, the global age-standardized SAH incidence was 8.3 (95% UI, 7.3-9.5), prevalence was 92.2 (95% UI, 84.1-100.6), mortality was 4.2 (95% UI, 3.7-4.8), and DALY rate was 125.2 (95% UI, 110.5-142.6) per 100 000 people. The highest burden estimates were found in Latin America, the Caribbean, Oceania, and high-income Asia Pacific. Although the absolute number of SAH cases increased, especially in regions with a low sociodemographic index, all age-standardized burden rates decreased between 1990 and 2021: the incidence by 28.8% (95% UI, 25.7%-31.6%), prevalence by 16.1% (95% UI, 14.8%-17.7%), mortality by 56.1% (95% UI, 40.7%-64.3%), and DALY rate by 54.6% (95% UI, 42.8%-61.9%). Of 300 diseases, SAH ranked as the 36th most common cause of death and 59th most common cause of DALY in the world. Of all worldwide SAH-related DALYs, 71.6% (95% UI, 63.8%-78.6%) were associated with the 14 modeled risk factors of which high systolic blood pressure (population attributable fraction [PAF] = 51.6%; 95% UI, 38.0%-62.6%) and smoking (PAF = 14.4%; 95% UI, 12.4%-16.5%) had the highest attribution. Conclusions and Relevance Although the global age-standardized burden rates of SAH more than halved over the last 3 decades, SAH remained one of the most common cardiovascular and neurological causes of death and disabilities in the world, with increasing absolute case numbers. These findings suggest evidence for the potential health benefits of proactive public health planning and resource allocation toward the prevention of SAH.

AbstractPersons Living with Dementia (PLWD), diagnosed or undiagnosed, have high Emergency Department (ED) use. Identification of such patients poses significant challenges for emergency clinicians with considerable downstream implications on patients, care partners, and healthcare systems. With the advent of Geriatric Emergency Departments (GEDs) there is an opportunity to understand and improve care of PLWDs in EDs with effective allocation of resources and the development of novel techniques to better support detecting those at risk, communicating findings, and coordinating care for such patients. Advances have been made leveraging Electronic Health Record (EHR) data to risk stratify patients for dementia in the hope that those at high‐risk may benefit from further evaluation. The promise of multiple blood‐base biomarkers (BBM) as a future modality to improve detection of those at risk of dementias, will also have the potential to advance the delivery of care of PLWD and their care partners in EDs.Highlights EDs have an integral role in delivering care for Person Living with Dementia and their care partners. High acuity and fast paced ED environment and other barriers makes it difficult to identify Person Living with Dementia. EHR‐based risk stratification algorithms can identify patients at risk for Dementia in ED and outpatient settings. Use of Blood‐Based Biomarkers in the ED setting is novel and considerations of its use and implications need to be studied. EHR based risk stratification algorithm and Blood Based Biomarkers when used judiciously have the potential to overcome some of the known barriers to identify and improve care for Person Living with Dementia as they transition through EDs.

ABSTRACTA core tenant of the Geriatric Emergency care Applied Research Network 2.0—Advancing Dementia Care (GEAR 2.0‐ADC) is the inclusion of community members during all stages of clinical research. As such, we deliberately integrated and supported patient and public involvement in the evaluation and selection of GEAR 2.0‐ADC Pilot Research Grants by developing and adapting traditional grant application review structures, with input from community members, to create the GEAR 2.0‐ADC Community Review Committee approach. Community members, including persons living with dementia, effectively participated in all three rounds of research grant application review and selection, complementing the traditional scientific review process. The structure and flexibility of the GEAR 2.0‐ADC Community Review Committee approach serve as a model for patient and public grant application review involvement with strong potential for applications across grant reviews in other medical specialties.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the first-line treatment of unresectable hepatocellular carcinoma (HCC). The prognostic value of immune-related adverse events (irAEs) in these patients remains controversial. We aimed to investigate the association between irAEs and clinical outcomes in patients with HCC treated with ICIs. METHODS: We searched the PubMed, Scopus, Web of Science, and Central Register of Controlled Trials databases for articles published from inception to June 2024, using keywords including ICI, HCC, and irAEs. Statistical analysis was performed with a random effects model. RESULTS: Of 3,028 studies, 24 (4,127 patients) met the criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n = 10 studies). IrAEs were associated with an increased objective response rate (pooled relative ratio: 1.73; 95% confidence interval [CI]: 1.36–2.21, I 2 = 41%), a higher disease control rate (pooled relative ratio: 1.45; 95% CI: 1.21–1.74, I 2 = 74%), and longer progression-free survival (pooled hazard ratio [HR]: 0.66; 95% CI: 0.52–0.84, I 2 = 71%). There was a trend toward longer overall survival for patients with irAEs compared with those without (pooled HR: 0.84; 95% CI: 0.63–1.12, I 2 = 73%). Subgroup analysis indicated a survival benefit for patients with grade 1–2 irAEs (pooled HR: 0.50; 95% CI: 0.36–0.67, I 2 = 0%) and for those with endocrine irAEs (pooled HR: 0.63; 95% CI: 0.48–0.83, I 2 = 12%). DISCUSSION: The development of irAEs is associated with favorable clinical outcomes in HCC, including improved progression-free survival and higher objective response rate. Overall survival benefit was noted in patients with mild irAEs but not those with severe irAEs.