Background While studies to date have broadly shown that cardiovascular disease (CVD) increases cognitive and physical impairment risk, there is still limited understanding of the magnitude of this risk among relevant CVD subtypes or age cohorts. Methods We analyzed longitudinal data from 16,679 U.S. Health and Retirement Study (HRS) participants who were age ≥65 years at study entry. Primary endpoints were physical impairment (ADL impairment) or cognitive impairment (Langa-Weir Classification of dementia). We compared these endpoints among participants who developed incident CVD versus those who were CVD-free, both in the short-term (<2 years post diagnosis) and long-term (>5 years), controlling for sociodemographic and health characteristics. We then analyzed effects by CVD subtype (atrial fibrillation, congestive heart failure, ischemic heart disease, stroke) and age-at-diagnosis (65-74, 75-84, ≥85). Results Over a median follow-up of 10 years, 8,750 participants (52%) developed incident CVD. Incident CVD was associated with a significantly higher adjusted odds [aOR] of short-term and long-term physical and cognitive impairment. The oldest (≥85) age-at-diagnosis subgroup had the highest risk of short-term physical (aOR 3.01, 95% confidence-interval [CI] 2.40-3.77) and cognitive impairment (aOR 1.96, 95% CI 1.55-2.48), as well as long-term impairment. All CVD subtypes were associated with higher odds of physical and cognitive impairment, with the highest risk for patients with incident stroke. Conclusions Incident CVD was associated with increased risk of physical and cognitive impairment across CVD subtypes. Impairment risk after CVD was highest among the oldest patients (≥85 years) who should therefore remain a target for prevention efforts.

e21571 Background: We previously reported on the biological relevance of melanoma histologic subtypes (Lattanzi et al, JNCI 2019). However, a substantial percentage of primary melanoma is histologically subtyped as NOS. The impact of this designation on clinical outcome is untested but casually believed not to have an impact considering the increasing reliance of molecular subclassification of melanoma tumor that might eliminate the need for histologic characterization. We also reported our data that supported a role for melanoma germline prognostic factors independent of known prognostic criteria (Chat et al, Front Oncol 2023). In this study, we sought to determine if NOS represents phenotypically and genetically distinct subtype or its clinical behavior is determined by AJCC criteria. Methods: We studied primary melanoma patients prospectively accrued and followed up using an IRB approved protocol at NYULH. We tested the association between NOS and baseline characteristics (e.g. thickness, ulceration, stage, Mitotic Index, TIL) and its association with recurrence free survival (RFS), and overall survival (OS) using Kaplan-Meier and multivariable Cox regression analyses. We also performed Principal Component Analysis (PCA) to test the clustering of NOS compared to other subtypes. We then examined the association between germline genetic variants and the development of NOS melanoma. Analyzing imputed SNP data generated using global screening array (GSA) from blood DNA we compared NOS (cases) with other histologic melanomas (controls) controlling for clinical and demographic variables. Results: NOS were identified in 550/2,891 (19%) of patients (median follow up of 4.44 years). PCA revealed clustering of NOS melanoma and superficial spreading melanoma (SSM) with similar favorable prognostic criteria (thinner, less ulcerated, earlier stage) compared to other subtypes (P < 0.001) However, NOS patients had a significantly shorter RFS compared to SSM (median RFS 8.83 years compared to 17.5 years, respectively; HR = 1.79 (95% CI: 1.37-2.33), P < 0.001 in multivariate analysis Genetic analysis of 919 cases (NOS = 127 versus all others n = 792) revealed a cluster of four genetic variants defining a linkage disequilibrium (LD) block mapping in the region of annotated microRNA 924 (LD-MIR924; OR = 1.844, p = 2.72E-06, 95% CI = 1.40-2.43), associating with ~1.8-fold increased risk of developing NOS compared to other melanoma subtypes. Conclusions: Our data suggest NOS melanoma might be a distinct genetic subtype that require further analysis considering the significant association with worse clinical outcome. The genetic variants associated with the risk of developing NOS melanoma point to MIR924, a microRNA previously linked to cancer progression. Our findings support the integration of studying patients’ genetics in addition to tumor somatic mutations to better understand the heterogeneous behavior of melanoma.

12087 Background: Aging is a nebulous concept with several definitions, but they all generally include physical and cognitive decline in function as a key component. We hypothesized that following cancer diagnosis, patients decline in physical and cognitive function would correspond with accelerated and/or accentuated aging trajectories. The magnitude of the functional changes could inform strategies to minimize impact of cancer diagnosis on trajectory of aging. Methods: We analyzed 32,935 participants >50 years enrolled between 1995-2018 in the Health and Retirement Study (HRS), a population-based, biennial longitudinal health interview survey of older adults in the United States. We assessed the changes in physical and cognitive function among cancer patients controlling for their pre-cancer trajectories and comparing it with aged population with no cancer diagnosis as control. The primary outcomes were change in physical function (Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL): range 0–11) and global cognitive function (Telephone Interview for Cognitive Status (TICS): range 0–27). The secondary outcome was change in self-rated health (SRH: range 1-5). We estimated the effect of acute change based on the immediate post-cancer outcome measurements compared to the trajectories before cancer; and the long-term effect as the per-year change in outcome decline post cancer compared to aging of cancer-free respondents adjusting covariates by linear mixed models. Results: 5,101 developed incident cancer: 1,514 in the 50-64 age group, 1,901 in the 65-74 age group, and 1,686 in the 75+ age group. 27,834 participants were cancer-free throughout. Cancer was associated with acute declines in physical function (0.06 [0.01– 0.10] and 0.25 [0.14– 0.36] points), cognitive function (0.22 [0.04–0.39] and 0.24 [0.01– 0.46] points), and SRH (0.19 [0.14–0.23] and 0.22 [0.12–0.33] points) for age of onset groups 50- and 75+ respectively. Moreover, participants with cancer demonstrated accelerated decline in physical function (0.02 [0.01–0.03], and 0.06 [0.05–0.07] points per year faster for 50-74 and 75+ age-of-onset groups respectively) compared to cancer-free participants, but not in cognitive and SRH. Lung, colorectal & breast cancer were associated with the highest acute and accelerated decline in functions, while prostate cancer was associated with moderate and insignificant decline. Conclusions: Using 24 years of nationally representative longitudinal data, this study provides, for the first time, evidence for the heterogeneous aging trajectories of cancer patients across varying age-of-onset and cancer types. Our results supported an accelerated aging trajectory of physical function with increased acceleration with increasing age-of-onset compared to the non-cancer population. It also provides evidence for accentuated aging trajectories of cognitive function and self-rated health.