Showing papers by "Ralph B. D'Agostino published in 2023"

Predictive Accuracy of Stroke Risk Prediction Models Across Black and White Race, Sex, and Age Groups.

Abstract: Importance Stroke is the fifth-highest cause of death in the US and a leading cause of serious long-term disability with particularly high risk in Black individuals. Quality risk prediction algorithms, free of bias, are key for comprehensive prevention strategies. Objective To compare the performance of stroke-specific algorithms with pooled cohort equations developed for atherosclerotic cardiovascular disease for the prediction of new-onset stroke across different subgroups (race, sex, and age) and to determine the added value of novel machine learning techniques. Design, Setting, and Participants Retrospective cohort study on combined and harmonized data from Black and White participants of the Framingham Offspring, Atherosclerosis Risk in Communities (ARIC), Multi-Ethnic Study for Atherosclerosis (MESA), and Reasons for Geographical and Racial Differences in Stroke (REGARDS) studies (1983-2019) conducted in the US. The 62 482 participants included at baseline were at least 45 years of age and free of stroke or transient ischemic attack. Exposures Published stroke-specific algorithms from Framingham and REGARDS (based on self-reported risk factors) as well as pooled cohort equations for atherosclerotic cardiovascular disease plus 2 newly developed machine learning algorithms. Main Outcomes and Measures Models were designed to estimate the 10-year risk of new-onset stroke (ischemic or hemorrhagic). Discrimination concordance index (C index) and calibration ratios of expected vs observed event rates were assessed at 10 years. Analyses were conducted by race, sex, and age groups. Results The combined study sample included 62 482 participants (median age, 61 years, 54% women, and 29% Black individuals). Discrimination C indexes were not significantly different for the 2 stroke-specific models (Framingham stroke, 0.72; 95% CI, 0.72-073; REGARDS self-report, 0.73; 95% CI, 0.72-0.74) vs the pooled cohort equations (0.72; 95% CI, 0.71-0.73): differences 0.01 or less (P values >.05) in the combined sample. Significant differences in discrimination were observed by race: the C indexes were 0.76 for all 3 models in White vs 0.69 in Black women (all P values <.001) and between 0.71 and 0.72 in White men and between 0.64 and 0.66 in Black men (all P values ≤.001). When stratified by age, model discrimination was better for younger (<60 years) vs older (≥60 years) adults for both Black and White individuals. The ratios of observed to expected 10-year stroke rates were closest to 1 for the REGARDS self-report model (1.05; 95% CI, 1.00-1.09) and indicated risk overestimation for Framingham stroke (0.86; 95% CI, 0.82-0.89) and pooled cohort equations (0.74; 95% CI, 0.71-0.77). Performance did not significantly improve when novel machine learning algorithms were applied. Conclusions and Relevance In this analysis of Black and White individuals without stroke or transient ischemic attack among 4 US cohorts, existing stroke-specific risk prediction models and novel machine learning techniques did not significantly improve discriminative accuracy for new-onset stroke compared with the pooled cohort equations, and the REGARDS self-report model had the best calibration. All algorithms exhibited worse discrimination in Black individuals than in White individuals, indicating the need to expand the pool of risk factors and improve modeling techniques to address observed racial disparities and improve model performance.

Prevalence, Progression, and Modifiable Risk Factors for Diabetic Retinopathy in Youth and Young Adults With Youth-Onset Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth Study.

Abstract: OBJECTIVE To determine the prevalence, progression, and modifiable risk factors associated with the development of diabetic retinopathy (DR) in a population-based cohort of youth-onset diabetes. RESEARCH DESIGN AND METHODS We conducted a multicenter, population-based prospective cohort study (2002-2019) of youth and young adults with youth-onset type 1 diabetes (n = 2,519) and type 2 diabetes (n = 447). Modifiable factors included baseline and change from baseline to follow-up in BMI z score, waist/height ratio, systolic and diastolic blood pressure z score, and A1C. DR included evidence of mild or moderate nonproliferative DR or proliferative retinopathy. Prevalence estimates were standardized to estimate the burden of DR, and inverse probability weighting for censoring was applied for estimating risk factors for DR at two points of follow-up. RESULTS DR in youth-onset type 1 and type 2 diabetes is highly prevalent, with 52% of those with type 1 diabetes and 56% of those with type 2 diabetes demonstrating retinal changes at follow-up (mean [SD] 12.5 [2.2] years from diagnosis). Higher baseline A1C, increase in A1C across follow-up, and increase in diastolic and systolic blood pressure were associated with the observation of DR at follow-up for both diabetes types. Increase in A1C across follow-up was associated with retinopathy progression. BMI z score and waist/height ratio were inconsistently associated, with both positive and inverse associations noted. CONCLUSIONS Extrapolated to all youth-onset diabetes in the U.S., we estimate 110,051 cases of DR developing within ∼12 years postdiagnosis. Tight glucose and blood pressure management may offer the opportunity to mitigate development and progression of DR in youth-onset diabetes.

Plasma Progerin in Patients With Hutchinson-Gilford Progeria Syndrome: Immunoassay Development and Clinical Evaluation

Abstract: Background: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin’s quantity, response to progerin-targeted therapy, and relationship to patient survival. Methods: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children’s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. Results: The assay’s dynamic detection range was 59 to 30 000 pg/mL (R2=0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2–71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1–17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children (P<0.0001). Progerin levels did not differ by sex (P=0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P<0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival (P<0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration. Conclusions: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00879034 and NCT00916747.

Association of Elevated Arterial Stiffness With Cardiac Target Organ Damage and Cardiac Autonomic Neuropathy in Young Adults With Diabetes: The SEARCH for Diabetes in Youth Study.

Abstract: OBJECTIVE Adults with diabetes are at risk for cardiovascular (CV) events, possibly due to increased arterial stiffness (AS) and cardiac autonomic neuropathy (CAN). We sought to determine whether 1) AS is associated with cardiac target organ damage in young adults with youth-onset diabetes, 2) whether CAN is associated with AS, as one possible etiology for increased AS in this cohort, and 3) whether these relationships differ by type of diabetes. RESEARCH DESIGN AND METHODS Participants from the SEARCH for Diabetes in Youth Study (type 1 diabetes [T1D], n = 222; type 2 diabetes [T2D], n = 177; mean age 23 years) had clinical, echocardiographic, AS, and CAN assessed. Linear regression was performed to determine whether AS was associated with cardiac changes and CAN and whether relationships differed by diabetes type. RESULTS AS was significantly associated with cardiac structure (left ventricular mass index, P < 0.0001), systolic function (ejection fraction, P = 0.03) and diastolic function (transmitral peak early [E]/atrial [A] wave velocities ratio, P = 0.008; early [e']/atrial [a'] waves, P = 0.02) after adjustments for CV risk factors. The association between AS and CAN was not significant when other important covariates were added. These relationships were mostly similar in both T1D and T2D. CONCLUSIONS AS is associated with cardiac changes in young adults with diabetes. CAN-induced AS does not appear to be an etiology for cardiac abnormalities in this cohort.

Diabetes Stigma and Clinical Outcomes in Adolescents and Young Adults: the SEARCH for Diabetes in Youth Study.

Abstract: OBJECTIVE To examine the association between diabetes stigma and HbA1c, treatment plan and acute and chronic complications in adolescents and young adults (AYAs) with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS The SEARCH for Diabetes in Youth study is a multicenter cohort study that collected questionnaire, laboratory, and physical examination data about AYAs with diabetes diagnosed in childhood. A five-question survey assessed frequency of perceived diabetes-related stigma, generating a total diabetes stigma score. We used multivariable linear modeling, stratified by diabetes type, to examine the association of diabetes stigma with clinical factors, adjusting for sociodemographic characteristics, clinic site, diabetes duration, health insurance, treatment plan, and HbA1c. RESULTS Of 1,608 respondents, 78% had type 1 diabetes, 56% were female, and 48% were non-Hispanic White. The mean (SD) age at study visit was 21.7 (5.1) years (range, 10-24.9). The mean (SD) HbA1c was 9.2% (2.3%; 77 mmol/mol [2.0 mmol/mol]). Higher diabetes stigma scores were associated with female sex and higher HbA1c (P < 0.01) for all participants. No significant association between diabetes stigma score and technology use was observed. In participants with type 2 diabetes, higher diabetes stigma scores were associated with insulin use (P = 0.04). Independent of HbA1c, higher diabetes stigma scores were associated with some acute complications for AYAs with type 1 diabetes and some chronic complications for AYAs with type 1 or type 2 diabetes. CONCLUSIONS Diabetes stigma in AYAs is associated with worse diabetes outcomes and is important to address when providing comprehensive diabetes care.

Prognostic Mutational Signatures of NSCLC Patients treated with chemotherapy, immunotherapy and chemoimmunotherapy

Abstract: Different types of therapy are currently being used to treat non-small cell lung cancer (NSCLC) depending on the stage of tumor and the presence of potentially druggable mutations. However, few biomarkers are available to guide clinicians in selecting the most effective therapy for all patients with various genetic backgrounds. To examine whether patients' mutation profiles are associated with the response to a specific treatment, we collected comprehensive clinical characteristics and sequencing data from 524 patients with stage III and IV NSCLC treated at Atrium Health Wake Forest Baptist. Overall survival based Cox-proportional hazard regression models were applied to identify mutations that were "beneficial" (HR < 1) or "detrimental" (HR > 1) for patients treated with chemotherapy (chemo), immune checkpoint inhibitor (ICI) and chemo+ICI combination therapy (Chemo+ICI) followed by the generation of mutation composite scores (MCS) for each treatment. We also found that MCS is highly treatment specific that MCS derived from one treatment group failed to predict the response in others. Receiver operating characteristics (ROC) analyses showed a superior predictive power of MCS compared to TMB and PD-L1 status for immune therapy-treated patients. Mutation interaction analysis also identified novel co-occurring and mutually exclusive mutations in each treatment group. Our work highlights how patients' sequencing data facilitates the clinical selection of optimized treatment strategies.

Abstract OT2-01-05: The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor

Abstract: Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) therapy to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in the non-cancer population is associated with CV disease, including atherosclerosis and coronary artery disease, which can be detected pre-clinically by myocardial perfusion imaging and coronary artery plaques. This, together with the CV morbidity associated with other aspects of BC treatment and future life-years of these women, warrants further investigation with the goal of identifying pre-clinical markers of myocardial compromise. We seek to do this with the following specific aims: 1. Characterize and quantify the extent of coronary microvascular injury and perfusion changes experienced during early NCED therapy. 2. Characterize and quantify the extent of structural and functional alterations to the aorta and left ventricle while on NCED therapy. 3. Identify potential biomarkers and additional risk factors for CV morbidity in patients receiving NCEDTrial Design: This is a federally funded (NHLBI) prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary outcome is myocardial perfusion reserve (MPR) as measured by CMR imaging stress studies. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors, including an emphasis on racial disparities, on study outcomes, and dynamic change in modifiable and treatment related risk factors. Statistical Methods: We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group) for Aims 1 and 2. Comparisons will be made using longitudinal mixed models to examine effects on outcomes measured. The second analyses, for Aim 3, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with MPR. The sample size allows 80% power to address specific aims for between and within group comparisons, including a between group difference of 2.8% in our primary outcome, MPR. Present Accrual: 0 Target Accrual: 90 Contact information: Emily Douglas, MD; edouglas@wakehealth.edu Table 1: Study Procedures Citation Format: Emily Douglas, Nathaniel O’Connell, Mary Hackney, Wendy Bottinor, John Grizzard, Igor Klem, Carolyn Park, Sujethra Vasu, Karl Richardson, Susan Dent, Ralph D’Agostino, Gregory Hundley, Jennifer Jordan, Alexandra Thomas. The CROWN Study (CaRdiac Outcomes With Near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women treated with ovarian suppression and an aromatase inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-05.

c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities

Abstract: Simple Summary Multiple non-cancerous cells are known to be involved in brain metastasis, and the roles of neutrophils during this event are poorly understood. We aim to understand how tumor-infiltrated neutrophils promote breast cancer brain metastasis and how tumor cells affect the properties of neutrophils. Utilizing patient-based analyses together with our unique animal models, we discovered that several c-Met mediated inflammatory cytokines, including CXCL1/2 and G/GM-CSF, are critical to the neutrophil recruitment and activity in the metastatic lesions. In return, neutrophils activated by those factors secrete a high level of lipocalin 2 (LCN2), which in turn enhances the stemness of tumor cells. Our study revealed novel interactions between neutrophils and brain metastatic cells, which may offer new insight into treating brain metastasis. Abstract The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.

Family History of Modifiable Risk Factors and Association With Future Cardiovascular Disease.

Abstract: Background A parental history of cardiovascular disease (CVD) confers greater risk of future CVD among offspring. Whether the presence of parental modifiable risk factors contribute to or modify CVD risk in offspring is unclear. Methods and Results We studied 6278 parent-child trios in the multigenerational longitudinal Framingham Heart Study. We assessed parental history of CVD and modifiable risk factors (smoking, hypertension, diabetes, obesity, and hyperlipidemia). Multivariable Cox models were used to evaluate the association of parental history and future CVD among offspring. Among 6278 individuals (mean age 45±11 years), 44% had at least 1 parent with history of CVD. Over a median follow-up of 15 years, 353 major CVD events occurred among offspring. Parental history of CVD conferred 1.7-fold increased hazard of future CVD (hazard ratio [HR], 1.71 [95% CI, 1.33-2.21]). Parental obesity and smoking status were associated with higher hazard of future CVD (obesity: HR, 1.32 [95% CI, 1.06-1.64]; smoking: HR, 1.34 [95% CI, 1.07-1.68], attenuated after adjusting for offspring smoking status). By contrast, parental history of hypertension, diabetes, and hypercholesterolemia were not associated with future CVD in offspring (P>0.05 for all). Furthermore, parental risk factors did not modify the association of parental CVD history on future offspring CVD risk. Conclusions Parental history of obesity and smoking were associated with a higher hazard of future CVD in offspring. By contrast, other parental modifiable risk factors did not alter offspring CVD risk. In addition to parental CVD, the presence of parental obesity should prompt a focus on disease prevention.

A Visual Diagnostic Tool for Causal Inference

Abstract: Abstract:Rosenbaum and Rubin (1983) suggested a visual representation, that can be used as a diagnostic tool, for examining whether the relationships between confounders and outcomes are sufficiently controlled, or whether there is a more complex relationship that requires further adjustment. This short commentary highlights this simple tool, providing an example of its utility along with relevant R code.

Intensity Modulated Radiation Therapy for Early Stage Squamous Cell Carcinoma of the Glottic Larynx: A Systematic Review and Meta-Analysis.

Abstract: Early stage squamous cell carcinoma of the glottic larynx is commonly treated with 2-dimensional or 3-dimensional conventional radiation therapy (CRT). Despite its use in other head and neck cancers, intensity modulated radiation therapy (IMRT) remains controversial in this patient population.A systematic review was performed by querying 3 databases (Pubmed, Embase, Web of Science) for articles published between December 1, 2000 and September 2, 2022. Included studies reported outcomes in at least 10 patients treated with IMRT for early stage glottic cancer. Data were extracted and reported following PRISMA standards. Pooled outcomes were estimated using random-effects models. Primary outcome was the rate of local failure (LF) following IMRT. Secondary outcomes included rates of regional failure (RF) following IMRT and rates of LF and RF following CRT.A total of 15 studies (14 retrospective, 1 prospective) consisting of 2083 patients were identified. IMRT was used in 873 patients (64% T1, 28% T2). Multiple treatment (partial larynx, single vocal cord carotid sparing) and image-guided radiation therapy techniques were used. The pooled crude rate of LF was 7.6% (95% confidence inverval [CI], 3.6%-11.5%) and actuarial LF rates at 3 and 5 years were 6.3% (95% CI, 2.2%-10.3%) and 9.0% (95% CI, 4.4%-13.5%), respectively. The pooled crude rate of RF after IMRT was 1.5% (95% CI, 0.5%-2.5%). On metaregression analysis, increased rate of LF was significantly associated with T2 disease (P < .001) and grade 2 to 3 histology (P < .001). Treatment with CRT was reported in 738 patients (76% T1, 22% T2). Among the studies reporting outcomes of both modalities, there was no significant difference in LF (log odds ratio; P = .12) or RF (log odds ratio; P = .58) between IMRT or CRT.In patients with early stage glottic cancer, retrospective data suggests local and regional control are similar for patients treated with IMRT and CRT. Additional prospective studies with uniform methods of volume delineation and image guidance are needed to confirm the efficacy of IMRT.

Favourable mid-term outcomes following unicompartmental knee arthroplasty with wider patient selection: A single-centre experience

Abstract: Objective: The purpose of this study was to determine surgical outcomes of robotic-assisted UKAs utilizing a wider set of indications than traditionally utilized. Additionally, we seek to determine alternate predictive factors as potential surgical indications and contraindications. Methods: A prospectively maintained institutional joint registry was queried at a single academic centre for all patients that underwent robotic-assisted UKA between January 2010–December 2016. Surgical indication included isolated medial or lateral compartment degenerative disease with a stable knee based on physical exam. In 2013, haemoglobin A1C levels over 7.5% were considered contraindications, which was lowered to 7.0% in 2015. Preoperative alignment, age, activity level and degree of pain were not contraindications for surgery. Preoperative demographics, Oxford scores, radiographic (joint space), comorbidities and operative data were collected and reviewed to determine factors related to conversion to TKA and survivorship of the primary implant. Results: In total, 1878 cases were performed; however, excluding multi-joint knees, there were a total of 1186 knees in 1014 patients with a minimum 4-year follow-up. The mean age was 63.4 10.7 years and mean follow-up was 76.4 17.4 months. Mean BMI was 32.3 6.5 kg/m2. (52.9% females, 47.1% males). There were 901 patients undergoing medial UKA, 122 patients undergoing lateral UKA and 69 patients undergoing patellofemoral UKA. In total, 85 (7.2%) knees underwent conversion to TKA. Preoperative factors such as the degree of preoperative valgus deformity (p 1⁄4 0.01), greater operative joint space (p 1⁄4 0.04), previous surgery (p 1⁄4 0.01), inlay implant (p 1⁄4 0.04) and pain syndrome (p 1⁄4 0.01) were associated with increased risk of revision surgery. Factors associated with decreased implant survivorship included patients with history of previous surgery (p < 0.01), history of pain syndrome (p < 0.01) and greater preoperative joint space (>2 mm) (p < 0.01). There was no association of BMI to conversion to TKA. Conclusion: Robotic-assisted UKA with wider patient selection demonstrated favourable outcomes at 4 years with survivorship greater than 92%. The present series agree with emerging indications that do not exclude patients based on age, BMI, or degree of deformity. However, increased operative joint space, inlay design, history of surgery and coexistence of pain syndrome are factors that increase risk of conversion to TKA. Level of evidence: Level III. What are the new findings Increased preoperative joint space predicts failure after UKA Unexplained pain or a pain syndrome predicts failure after UKA Patient age, BMI and degree of deformity should not preclude patients from a UKA dic Surgery, Wake Forest Medical tig), poehling@wakehealth.edu 17 February 2023; Accepted 11 evier Inc. on behalf of Internation nse (http://creativecommons.org urable mid-term outcomes foll S, https://doi.org/10.1016/j.j

Exploring Racial and Ethnic Differences in Arterial Stiffness Among Youth and Young Adults With Type 1 Diabetes

Abstract: Background We examined arterial stiffness in individuals with type 1 diabetes, and explored whether differences between Hispanic, non‐Hispanic Black (NHB), and non‐Hispanic White (NHW) individuals were attributable to modifiable clinical and social factors. Methods and Results Participants (n=1162; 22% Hispanic, 18% NHB, and 60% NHW) completed 2 to 3 research visits from ≈10 months to ≈11 years post type 1 diabetes diagnosis (mean ages of ≈9 to ≈20 years, respectively) providing data on socioeconomic factors, type 1 diabetes characteristics, cardiovascular risk factors, health behaviors, quality of clinical care, and perception of clinical care. Arterial stiffness (carotid–femoral pulse wave velocity [PWV], m/s) was measured at ≈20 years of age. We analyzed differences in PWV by race and ethnicity, then explored the individual and combined impact of the clinical and social factors on these differences. PWV did not differ between Hispanic (adjusted mean 6.18 [SE 0.12]) and NHW (6.04 [0.11]) participants after adjustment for cardiovascular risks (P=0.06) and socioeconomic factors (P=0.12), or between Hispanic and NHB participants (6.36 [0.12]) after adjustment for all factors (P=0.08). PWV was higher in NHB versus NHW participants in all models (all P<0.001). Adjustment for modifiable factors reduced the difference in PWV by 15% for Hispanic versus NHW participants; by 25% for Hispanic versus NHB; and by 21% for NHB versus NHW. Conclusions Cardiovascular and socioeconomic factors explain one‐quarter of the racial and ethnic differences in PWV of young people with type 1 diabetes, but NHB individuals still experienced greater PWV. Exploration of pervasive inequities potentially driving these persistent differences is needed.

Association of Unilateral Radiotherapy With Contralateral Lymph Node Failure Among Patients With Squamous Cell Carcinoma of the Tonsil

Abstract: Key Points Question What is the risk of lymph node failure within the contralateral nonirradiated neck when irradiating only the ipsilateral neck in patients with tonsil cancer? Findings In this systematic review and meta-analysis of 17 studies with 1487 unique patients with tonsil cancer who received ipsilateral neck radiotherapy, the rate of contralateral nodal failure was 2%. Meaning These findings suggest that ipsilateral neck radiotherapy is associated with a low risk of contralateral nodal failure and should be considered in patients with small, lateralized tonsil cancers.

Estimating incidence of type 1 and type 2 diabetes using prevalence data: the SEARCH for Diabetes in Youth study

Abstract: Abstract Background Incidence is one of the most important epidemiologic indices in surveillance. However, determining incidence is complex and requires time-consuming cohort studies or registries with date of diagnosis. Estimating incidence from prevalence using mathematical relationships may facilitate surveillance efforts. The aim of this study was to examine whether a partial differential equation (PDE) can be used to estimate diabetes incidence from prevalence in youth. Methods We used age-, sex-, and race/ethnicity-specific estimates of prevalence in 2001 and 2009 as reported in the SEARCH for Diabetes in Youth study. Using these data, a PDE was applied to estimate the average incidence rates of type 1 and type 2 diabetes for the period between 2001 and 2009. Estimates were compared to annual incidence rates observed in SEARCH. Precision of the estimates was evaluated using 95% bootstrap confidence intervals. Results Despite the long period between prevalence measures, the estimated average incidence rates mirror the average of the observed annual incidence rates. Absolute values of the age-standardized sex- and type-specific mean relative errors are below 8%. Conclusions Incidence of diabetes can be accurately estimated from prevalence. Since only cross-sectional prevalence data is required, employing this methodology in future studies may result in considerable cost savings.

Abstract P1-12-01: Impact of Anti-Estrogen Therapy on Early Vascular Referrals, Tests and Medications in Premenopausal Women with Operable Breast Cancer

Abstract: Introduction: Premenopausal women with high-risk hormone receptor-positive (HR+) breast cancer (BC) undergo abrupt menopause induction with anti-estrogen therapy (AE) and ovarian function suppression (OFS). This treatment improves recurrence-free survival but may increase cardiovascular (CV) risk associated with early hypoestrogenemia. as observed in women with non-cancerous reasons for premature menopause. We sought to identify patterns of CV actions including referrals, tests and medication by type of AE therapy in premenopausal women in early follow-up for operable BC as a possible surrogate for early CV disease. Methods: Consecutive premenopausal women ≤ 50 years (mean age 42.6 years; sd 5.9) with Stage I-III HR+ or triple negative breast cancer (TNBC) diagnosed between 02/2013-06/2020 were identified by retrospective review. Mean follow-up was 4.9 years (sd 2.1 years.) Women were placed into 3 treatment groups based on initial AE approach: HR+ on OFS+AE (HR+OFS), HR+ not on OFS (HRnoOFS), and TNBC. Patient demographics, cancer treatment and CV risk factors as well as post-diagnosis adverse CV events (myocardial infarction, transient ischemic attack) and CV-related clinical actions (CV actions) including referrals, (cardiology, neurology (vascular)), tests (stress test, angiogram, ECHO, EKG, Carotid US) and medications (statin, ACEi, ARB, betablocker, calcium channel blocker, antiarrhythmic, and anti-platelet agents) were recorded. For each CV outcome (events, total actions, referrals, tests, medications) we created an “any” vs “none” dichotomous variable as well as a variable for number of CV outcome per year of follow-up. Categorical variables were compared among the 3 groups using chi-square and Fisher’s exact tests; continuous outcomes (including the “per year” variables) were compared among the 3 groups using ANOVA. For the ANOVAs we report the global null hypothesis p-value. A two-tailed alpha of 0.05 was used throughout. Results: 80, 78, and 48 (total n=206) women were identified in the HR+OFS, HRnoOFS and TNBC groups respectively. Mean follow-up was longest in the HRnoOFS group (Table 1). Mean number of CV actions per year were highest in the HR+OFS group compared with HRnoOFS and TNBC (0.41 vs 0.22 and 0.35, respectively; p=0.008.) The HR+OFS group had significantly more referrals during follow-up, as well as more referrals per year than the other two groups. This group also had significantly more tests per year than the other two groups. CV medication initiation did not differ among the groups. The proportion with >3 CV actions during follow-up was 62% higher in women in the HR+OFS group compared to other groups. Experiencing >3 CV actions was associated with having diabetes, hypertension, and hyperlipidemia, being a current smoker, and receipt of left-sided radiation (Table 2). Conclusions: In this early follow-up period, women on OFS+AE experienced more CV actions per year suggesting concern for CV sequela in this patient group. Future work should seek to further understand the impact of OFS+AE on the CV health of premenopausal women, try to identify who is at greatest risk and test strategies to mitigate cardiotoxicity. Table 1. Patient Characteristics and CV outcomes by Breast Cancer Treatment Group. Table 2. Patient Characteristics by number of CV Actions. Citation Format: Ahmer Ansari, Beverly Levine, Emily Douglas, Katherine Ansley, Susan Melin, Carolyn Park, Karl Richardson, Ralph D’Agostino, Jennifer Jordan, Alexandra Thomas. Impact of Anti-Estrogen Therapy on Early Vascular Referrals, Tests and Medications in Premenopausal Women with Operable Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-01.

Quad-shot-immunotherapy: quad-shot radiotherapy with pembrolizumab for advanced/recurrent head and neck cancer.

Abstract: Effective treatments for advanced/recurrent head and neck squamous-cell carcinoma are limited. For cases not curable by conventional local therapies, the immune checkpoint inhibitor pembrolizumab shows modest response rates. Quad-shot, a hypofractionated palliative radiotherapy regimen (14.8 Gy in four twice-daily fractions), can provide symptomatic relief, contributes to local control and may potentiate the effects of immune checkpoint inhibitors. In this study, 15 patients with advanced/recurrent head and neck squamous-cell carcinoma will be treated with pembrolizumab combined with up to three administrations of quad-shot before cycles four, eight and 13. Outcomes include disease response, survival and treatment toxicity. Correlative multiomics analysis of blood and saliva will identify molecular biomarkers of response to immune checkpoint inhibitor and the immune-related impact of quad-shot. Clinical trial registration: This study (WFBCCC 60320) is registered on NCT04454489 (ClinicalTrials.gov).

Abstract 150: A 515 tumor specimens collection from surgery to benchtop: the WFORCE organoid experience in personalized research

Abstract: Introduction: Patient tumor organoids (PTOs) are a new and developing preclinical model in cancer research. However, there is variation in protocols between centers and lack of consistency in important variables, impacting PTO culture success. In this study, we analyzed factors in clinical data and tumor tissue processing to determine optimal conditions for cell isolation and PTO success. Methods: Under IRB approval, tumor tissues from primary and metastatic sites were procured in clinically indicated surgeries then dissociated using a standardized protocol. PTOs were fabricated using collagen-hyaluronic acid ECM and underwent drug screening at 10 days post fabrication, where viability was assessed. Clinical and tissue processing inputs such as type of primary, peritoneal carcinomatosis index (PCI), prior surgery or neoadjuvant chemotherapy, presence of mucin, tissue digestion time, specimen mass, digestion time, and the diameter of isolated cells were analyzed. These factors were assessed by calculating the Pearson Correlation Coefficient (r) and best fit modeling to determine the effect on outputs including tissue viability as measured by % of viable cells using an automated cellular counter, viable cells per mg tissue, and PTO log10 viability by Promega 3D Cell Titer Glo assay. Results: From December 2018-July 2022, 515 tumors from 286 patients with 25 primary types were processed for cellular isolation and PTO fabrication. 407 (79%) provided PTOs for therapeutic testing, with 354 (69%) providing sufficiently viable PTOs for therapeutic interrogation. The most common primary tumor type accrued was appendiceal cancer (n=223, 43%). Tissues processed at 24 hours did not differ in viability outputs when compared to tissues processed immediately (p>0.05). Tissue % viability was better maintained in larger specimens (r=.18, p<0.001), resulting in more viable cells per mg of tissue (r=.12, p=0.009) while it was negatively related to larger cell diameter (r=-.32, p<0.001). The number of viable cells per mg of tumor correlated to higher post-processing cell counts (r=.49, p<0.001) while it was decreased by longer digestion times (r=-.11, p=0.017). Finally, PTO log10 viability, correlated with higher burden of disease as measured by PCI scores (r=.35, p<0.001), larger specimens (r=.19, p<0.001), mucinous tumors (PTO log10 viability 5.46 vs 5.17, p=0.01), and tissues with higher cellular viability (r=.31, p<0.001), while it was negatively impacted by neoadjuvant chemotherapy (5.06 vs 5.41, p<0.001). Conclusions: Higher rates of successful PTO fabrication are obtained in patients with untreated tumors, more aggressive biologic behavior, and increased tumor burden. Creating a unified protocol for tissue processing, agnostic to tumor type, will facilitate incorporation of tissue from the operating room to research protocols with wider translational implications. Citation Format: Steven Donald Forsythe, Richard A. Erali, Preston Laney, William Meeker, Salomat Abdulkhuseynova, Nadeem Wajih, Nicholas Edenhoffer, Cecilia R. Schaaf, Hemamyammal Sivakumar, Aleksander Skardal, Roy E. Strowd, Stephen B. Tatter, Clancy J. Clark, Reese W. Randle, Perry Shen, Edward A. Levine, Ralph B. D'Agostino, Shay Soker, Konstantinos I. Votanopoulos. A 515 tumor specimens collection from surgery to benchtop: the WFORCE organoid experience in personalized research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 150.

Increased Risk of Hypertension Onset Among Patients With Narcolepsy Newly Treated With High-Sodium Oxybate (P5-13.002)

Abstract:

Objective:

This study compared intermediate-term risk (≤180 days) of new-onset hypertension among normotensive patients with narcolepsy initiating high-sodium oxybate (SXB cohort) with those not initiating high-sodium oxybate (controls).

Background:

High-sodium oxybate, a recommended narcolepsy treatment, contains a high-sodium content warning in its US Food and Drug Administration–approved labeling. The sodium-hypertension relationship is well established.

Design/Methods:

MarketScan^® claims (1/2014 to 2/2020) were analyzed. Eligible adults had continuous enrollment and ≥1 narcolepsy claim or prescription for sodium oxybate. Patients with a history of hypertension, use of antihypertensives, and prior use of sodium oxybate were excluded. In a sensitivity analysis, patients with a history of cardiovascular disease (CVD) were also excluded. Two endpoints were assessed: 1) a composite of new-onset hypertension diagnosis or initiation of antihypertensive medication and 2) new-onset hypertension diagnosis alone. Propensity-score 1:2 matching was applied to balance baseline characteristics. Risk per 100 patients and adjusted odds ratios (ORs) were reported with 95% confidence intervals (CIs).

Results:

A total of 954 and 1906 patients were included in the SXB and control cohorts, respectively. Risk of the composite endpoint per 100 patients was higher in SXB (6.60) than control (4.20) cohorts (OR=1.61; 95% CI, 1.15–2.27); risk of new-onset hypertension per 100 patients was higher in SXB (0.94) than control (0.52) cohorts (OR=1.81; 95% CI, 0.73–4.46). In the sensitivity analysis, risk of the composite endpoint per 100 patients was higher in SXB (6.22) than control (4.06) cohorts (OR=1.57; 95% CI, 1.10–2.24); risk of new-onset hypertension per 100 patients was higher in SXB (0.89) than control (0.44) cohorts (OR=2.01; 95% CI, 0.75–5.36).

Conclusions:

This study showed increased risk of new-onset hypertension among normotensive patients with narcolepsy treated with sodium oxybate, even among patients without history of CVD. Clinicians should consider the cardiovascular risk associated with high-sodium oxybate. Disclosure: Dr. Ben-Joseph has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Ben-Joseph has stock in Jazz Pharmaceuticals. Virend Somers has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Jazz Pharmaceuticals . Virend Somers has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Respicardia. Virend Somers has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer . Virend Somers has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Baker Tilly. The institution of Virend Somers has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sleep Number . Virend Somers has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for National Institutes Health . The institution of Virend Somers has received research support from National Institutes Health. The institution of Virend Somers has received research support from Sleep Number . Jed Black, MD has stock in Jazz Pharmaceuticals. Jed Black, MD has stock in . Dr. Dagostino has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Jazz Pharmaceutical . Dr. Dagostino has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Dagostino has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Exelixis. Dr. Dagostino has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MEI Pharma. Dr. Dagostino has received research support from NIH. Mr. Saad has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Mr. Saad has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Evidinno Outcomes Research Inc.. Mr. Saad has received stock or an ownership interest from Jazz Pharmaceuticals. Mat D. Davis has received personal compensation for serving as an employee of Teva pharmaceuticals. Mat D. Davis has received stock or an ownership interest from Teva Pharmaceuticals. Dr. Macfadden has received personal compensation for serving as an employee of Jazz pharma. Dr. Macfadden has stock in Jazz pharma. Dr. Mues has received personal compensation for serving as an employee of Aetion. Ms. Jackson has received personal compensation for serving as an employee of Aetion. Ms. Jackson has stock in Aetion. Dr. Ni has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Ni has stock in Jazz Pharmaceuticals. Dr. Cook has received personal compensation for serving as an employee of Jazz Pharmaceuticals. Dr. Cook has stock in Jazz Pharmaceuticals. Miss Pitino has received personal compensation for serving as an employee of Aetion, Inc. Miss Pitino has stock in Aetion, Inc. Ms. Latimer has received personal compensation for serving as an employee of Aetion. Ms. Latimer has stock in Aetion. Ms. Dabrowski has received personal compensation for serving as an employee of Aetion, Inc.. Ms. Dabrowski has received stock or an ownership interest from AbbVie Inc.. Ms. Dabrowski has received stock or an ownership interest from BioMarin Pharmaceutical Inc.. Ms. Dabrowski has received stock or an ownership interest from CVS Health Corporation . Ms. Dabrowski has received stock or an ownership interest from Moderna Inc.. Ms. Dabrowski has received stock or an ownership interest from Walgreens Boots Alliance. Dr. White has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for JAZZ Pharmaceuticals.

The CROWN study (CaRdiac outcomes with near complete estrogen deprivation): A multicenter, prospective cohort study of cardiovascular outcomes in premenopausal women with hormone receptor positive breast cancer treated with ovarian suppression and an aromatase inhibitor.

Abstract: TPS12142 Background: Treatment for premenopausal women with high or intermediate risk hormone receptor (HR)+ breast cancer (BC) now includes the concurrent use of ovarian function suppression (OFS) and an aromatase inhibitor (AI) to induce near complete estrogen deprivation (NCED). The long-term cardiovascular (CV) sequela for women treated with NCED is unknown. Premature menopause in non-cancer populations is associated with CV disease. Taken together with the CV morbidity associated with other aspects of BC treatment and the future life-years of these women, the CV impact of NCED warrants further study. The CROWN study will use sophisticated imaging assessments of cardiac dysfunction to understand the evolution of CV injury, as well as biomarker and demographic correlates, with the goal of developing tools to assess and mitigate CV risk. Methods: This is a NIH funded prospective cohort study conducted at 3 regional NCI-supported Cancer Centers (Atrium Health Wake Forest Baptist, Virginia Commonwealth and Duke) that will include premenopausal women, age ≤ 55, with Stage I-III BC following completion of planned chemotherapy, surgery and radiation with an ECOG 0-1. HR+ BC patients will receive an AI and OFS. Women with HR- BC are included as comparators. CV imaging and biomarkers will be obtained at baseline, 1 year and 2 years (Table 1). These assessments will include serial cardiac magnetic resonance (CMR) and coronary computed tomography angiography (CCTA) imaging as well as laboratory measurements, including exploratory biomarkers. The primary objective is to determine the 24-month difference in stress myocardial blood flow as measured by adenosine CMR imaging in both groups. We will correlate CMR imaging with CCTA to provide complementary detail of coronary plaque changes. The study will also assess the relevance of pre-existing risk factors on study outcomes, including an emphasis on racial disparities, and dynamic change in modifiable and treatment related risk factors. We plan to enroll 90 women, 67 in the NCED group and 23 in the HR-group, allowing for a 10% drop out rate. There are two primary types of statistical analyses. The first includes testing hypotheses between group (NCED vs HR-) and within group (longitudinal changes within the NCED group). The second analyses, involve developing predictive equations utilizing a stepwise linear regression approach to determine if patient demographics, clinical parameters and serum biomarkers are associated with cardiovascular changes over time. Present accrual is 4. Clinical trial information: NCT05309655 . [Table: see text]

Transcranial ultrasonography to detect intracranial pathology: A systematic review and meta‐analysis

Abstract: Transcranial ultrasonography (TCU) can be a useful diagnostic tool in evaluating intracranial pathology in patients with limited or delayed access to routine neuroimaging in critical care or austere settings. We reviewed available literature investigating the diagnostic utility of TCU for detecting pediatric and adult patient's intracranial pathology in patients with intact skulls and reported diagnostic accuracy measures.

Patterns of Failure Outcomes for Combination of Stereotactic Radiosurgery and Immunotherapy for Melanoma Brain Metastases

Abstract: BACKGROUND: Previous series have demonstrated central nervous system activity for immune checkpoint inhibitors (ICIs) and shown improved local control between stereotactic radiosurgery (SRS) and ICI for lung cancer brain metastases. OBJECTIVE: To assess whether the addition of ICI to SRS for melanoma brain metastasis improves outcomes when compared with historical control group treated in the era before ICI availability. METHODS: In this single institution retrospective series, outcomes of 24 patients with melanoma receiving concurrent ICI and SRS were compared with 111 historical controls treated before ICI era. Overall survival (OS) was estimated using the Kaplan-Meier method. Cumulative incidence of local and distant failures was estimated using a competing risk model that accounted for baseline differences using propensity score adjustments. RESULTS: The median OS time was improved in patients receiving ICI compared with the historical control group (17.6 vs 6.6 months, hazard ratio [HR] = 0.056, P = .0005). Cumulative incidence at 1 year for local failure in the historical control and ICI groups was approximately 12.5% and 6.5%, respectively (HR = 0.25, P = .19), while cumulative incidence of distant brain failure in the historical control and ICI groups was approximately 48% and 28%, respectively (HR = 0.326, P = .015) CONCLUSION: Distant brain failure and OS were improved in patients receiving concurrent ICI with SRS compared with historical controls. Local failure trended in the same direction; however, owing to small sample size, this did not reach statistical significance. While these data remain to be validated, they suggest that patients with brain metastasis may benefit from concurrent use of ICI with SRS.

Association of ipsilateral radiation therapy with contralateral lymph node failure in patients with squamous cell carcinoma of the oral cavity: A systematic review and meta‐analysis

Abstract: Ipsilateral neck radiotherapy (INRT) is controversial in some patients with oral cavity cancer due to concern for contralateral neck failure (CNF).

Diabetes Complications and Cognitive Function in Young Adults with Youth-Onset Type 1 or Type 2 Diabetes: The SEARCH for Diabetes in Youth Study

Abstract: Aims/Hypotheses. People with type 1 (T1D) or type 2 diabetes (T2D) who also have diabetes complications can have pronounced cognitive deficits. It remains unknown, however, whether and how multiple diabetes complications co-occur with cognitive dysfunction, particularly in youth-onset diabetes. Methods. Using data from the SEARCH for Diabetes in Youth Study cohort, a prospective longitudinal cohort, we examined clustering of complications and their underlying clinical factors with performance on cognitive tests in young adults with youth-onset T1D or T2D. Cognition was assessed via the NIH Toolbox Cognition Battery. The main cognitive variables were age-corrected scores for composite fluid cognition and associated cognitive subdomains. Diabetes complications included retinopathy, microalbuminuria, and peripheral neuropathy (PN). Lipids, systolic blood pressure (SBP), hemoglobin A1c, and other clinical factors were included in the analyses. Clustering was applied separately to each group (T1D = 646; T2D = 165). A three-cluster (C) solution was identified for each diabetes type. Mean values and frequencies of all factors were compared between resulting clusters. Results. The average age-corrected score for composite fluid cognition differed significantly across clusters for each group ( p < 0.001 ). People with T1D and the lowest average fluid cognition scores had the highest frequency of self-reporting at least one episode of hypoglycemia in the year preceding cognitive testing and the highest prevalence of PN. Persons with T2D and the lowest average fluid cognition scores had the highest SBP, the highest central systolic and diastolic blood pressures, and highest prevalence of PN. Conclusions/Interpretations. These findings highlight shared (PN) and unique factors (hypoglycemia in T1D; SBP in T2D) that could be targeted to potentially mitigate cognitive issues in young people with youth-onset diabetes.

Abstract 952: Prioritizing mutations associated with smoking as a variable in lung cancer precision medicine with immunotherapies

Abstract: Background: In 2022, 230,000 new lung cancer cases will be diagnosed in the United States. The treatment regimen for non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects of immunotherapies. Immune checkpoint inhibitors (ICI) and chemo-immunotherapy (chemo-ICI) are the first-line treatments for NSCLC. Tumor Mutation Burden (TMB) and PD-L1 expression in tumor cells are potential biomarkers in predicting a patient’s survival and response to ICI. However, emerging data have shown that TMB and PD-L1 may no longer be an adequate biomarkers in predicting a patient’s response to ICI or chemo-ICI. We hypothesize that by using tumor-sequencing data and taking into effect a patient’s smoking status, we can identify biomarkers that predict survival to either ICI or chemo-ICI. Methods: To identify biomarkers, we collected genomic sequencing data and comprehensive clinical characteristics on 424 NSCLC patients who received ICI or chemo-ICI treatment at Atrium Health Wake Forest Baptist. Cox-proportional hazard regression models were fit to identify mutations that were “beneficial” (HR < 1) or “detrimental” (HR > 1) for patients on different treatment regimens, followed by the generation of mutation composite scores (MCS) for each treatment. Co-occurrence analysis was performed to identify novel co-occurring and mutually exclusive mutations in each treatment and smoking group by mutation interaction analysis. Results: We identify beneficial and harmful mutations in patients that received ICI or chemo-ICI treatment. We also identified unique biomarkers based on smoking statues. We then created an MCS for each smoking statues group and treatment type to assist personalize treatment. Future directions: We will validate these results in other institute cohorts and add other clinical characteristics to personalize treatment based on MCS for an individual patient. Citation Format: Margaret Rose Smith, Yuezhu Wang, Ralph D’Agostino, Yin Lin, Jimmy Ruiz, Thomas Lycan, Umit Topaloglu, Mohammed Abdulhaleem, Michael Chan, Fei Xing. Prioritizing mutations associated with smoking as a variable in lung cancer precision medicine with immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 952.