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Abstract Background Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. Methods Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. Results Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. Conclusion This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

8534 Background: Immunotherapy (IO) has transformed treatment for non–small cell lung cancer (NSCLC), but not all patients (pts) benefit, underscoring the need for predictive biomarkers to guide IO versus chemotherapy (Ch). CheckMate 227 (CM227; NCT02477826) showed a survival benefit of first-line nivolumab plus ipilimumab (nivo+ipi) over Ch in stage IV NSCLC. CD8⁺ T cells are key mediators of antitumor immunity and are associated with IO benefit. We developed an artificial intelligence (AI)–based pipeline (VIGOR-CD8) that predicts spatial CD8⁺ immune signatures from routine baseline H&E whole-slide images using histopathology foundation model embeddings (H-Optimus-0) and virtual gene expression modeling (HE2Gene), and evaluated its ability to identify pts who do and do not derive IO benefit over Ch in CM227. Methods: 1,598 pts with advanced NSCLC were analyzed, including multi-institutional retrospective cohorts (n = 487; 65 for patch-level CD8⁺ prediction and overall survival (OS), 422 for patient-level OS) and a blinded CM227 validation subset (n = 1,111). For orthogonal validation, 86,470 H&E patches were co-registered with quantitative CD8⁺ immunofluorescence. H-Optimus-0 and HE2Gene immune-related embeddings were used to train a random forest classifier to predict patch-level CD8⁺ probability. Patch-level probabilities were aggregated into a patient-level CD8⁺ signature and dichotomized into biomarker-positive (B⁺) and biomarker-negative (B⁻) groups by the training-set median. Cox models assessed the impact of VIGOR-CD8 on OS. In CM227, prognostic and predictive utility were evaluated using treatment-specific analyses; investigators were blinded to outcomes, and models were trained on independent, non-overlapping cohorts. Results: VIGOR-CD8 was associated with longer OS in the testing cohort (n = 422; HR 0.68, 95% CI 0.53–0.87, p = 0.00163) and CM227 (n = 1,111; HR 0.8, 95% CI 0.67–0.96, p = 0.016), irrespective of treatment type and PD-L1 expression. Among pts with evaluable PD-L1, B⁺ pts treated with nivo+ipi had superior OS versus Ch (n = 617; HR 0.72, 95% CI 0.58–0.90, p = 0.003), while in B⁻ pts there was no significant OS difference between treatment arms (n = 130; HR 1.18, 95% CI 0.79–1.75, p = 0.436), supporting a predictive rather than purely prognostic role for VIGOR-CD8. Conclusions: An AI-derived CD8⁺ immune signature from routine baseline H&E slides was associated with favorable OS in CM227 and predicted differential benefit from nivo+ipi versus Ch. VIGOR-CD8 may help identify advanced NSCLC pts most likely to benefit from first-line dual IO, but further validation in independent and prospective trials is warranted.

3118 Background: Improved risk stratification is critically needed across multiple cancers to guide treatment decisions. This includes reducing overtreatment in Ductal Carcinoma in Situ (DCIS), addressing late recurrence risk in estrogen receptor-positive/lymph node-negative (ER+/LN-) breast cancer (BC), and refining prognosis in head & neck squamous cell carcinomas (HNSCC), and high-grade serous ovarian carcinoma (HGSOC). Tumor-infiltrating lymphocytes (TILs) reflect anti-tumor immunity, whereas tumor-associated macrophages (TAMs) polarize toward anti-tumor M1-like (CD68+) or immunosuppressive M2-like (CD163+) phenotypes. Integrating TILs with TAM polarization markers may better capture inflammatory balance and improve outcome prediction. We developed a hematoxylin and eosin (H&E)-only AI method (VAIP) to quantify TILs and virtual CD68/CD163 TAMs to develop multi-cancer based potential prognostic models. Methods: TILs were detected on H&E with HoVer-UNet, and virtual CD68 and CD163 macrophages were inferred with VISTA. In cancer regions, we computed cell densities and immune-balance ratios and trained cancer-specific Cox models with compact feature sets (DCIS 6; HGSOC 7; ER+ 4; HNSCC 4). Prognostic stratification used disease-free survival (DFS) for DCIS (N=273), HGSOC (training N=165, independent test N=220), and ER+ BC (training N=144, test N=622), and overall survival (OS) for HNSCC (N=77), reflecting clinical endpoints. Evaluation used cross-validation for cohorts without an external test set (DCIS, HNSCC) and independent training and testing when independent cohort was available (HGSOC, ER+). Results: Risk stratification performance across cancer types is in Table 1. The DCIS model used 6 features, largely TIL-macrophage contrast ratios (TIL/M2, TIL/M1). HGSOC used 7 features with a similar ratio-heavy immune-balance signature, plus macrophage-normalized density and polarization metrics (e.g., M1/N, M/N). In contrast, ER+ BC and HNSCC achieved best performance with 4 features dominated by macrophage measures, particularly M2 density and the M1/M2 ratio. Across sites, CD163-related macrophage metrics and immune-balance ratios were consistently informative. Conclusions: Integrating H&E-visible TILs with virtual CD68/CD163 TAMs enables fully automated, H&E-only prognostic biomarkers that stratify OS and DFS across multiple cancers, demonstrating consistent prognostic value in DCIS, ER+ BC, HGSOC, and HNSCC. These findings support further study of this histomorphometric risk classifier through broader external and prospective validation. Performance across cancer types. Cancer Type Cohort C-index HR [95% CI] p-value DCIS All 0.616 1.76 [1.20-2.59] <0.001 DCIS RT/No-treatment 0.624 1.94 [1.15-3.26] 0.003 HGSOC Test 0.553 1.38 [1.02-1.87] 0.030 ER+ BC Test 0.577 1.51 [1.00-2.28] 0.004 HNSCC All 0.603 1.92 [1.03-3.36] 0.012

Abstract Introduction Sickle cell disease (SCD) disproportionately affects African Americans(AA), comprising over 90% of cases. Acute pulmonary embolism (APE) is a serious complication in SCD patients due to increased thromboembolic risk from chronic inflammation, endothelial dysfunction, and hypercoagulability. Although recent studies have demonstrated sex-based differences in APE outcomes, data remain limited for SCD patients. We evaluated sex-based differences in outcomes among AA SCD patients with APE. Methods AA adults with SCD hospitalized for APE were queried from the 2016-2022 National Inpatient Sample. COVID-19 positive patients, patients younger than 18 years, and cases missing data were excluded. Demographics, treatment patterns, and in-hospital outcomes were compared between males and females using appropriate statistical tests with survey-weighted analysis. Results We studied 3635 SCD patients who were treated for APE, consisting of 60.66% (3635)females and 39.34%(2205) males. The overall mean age was 38.40 years, with no differences between the two sexes(mean age of 38.71 in males and 38.20 years in females, p = 0.620). While males reported a higher comorbidity burden with a Charlson Comorbidity Index(CCI) score of 1.03 (vs. 0.92 in females), it was not statistically significant(p = 0.345). In total, 23.43% of males and 22.68% of females had a prior history of PE(p = 0.815). Medicare constituted 31.82% of primary payers among males and 38.36% among females, while Medicaid and private insurance accounted for 32.52% and 24.83% of males, and 32.19% and 25.11% of females, respectively(p = 0.015). After adjusting for confounders, we found that females demonstrated higher odds of receiving transfusion to males. No statistically significant differences were seen for mortality, major cardiovascular complications including cardiac arrest, acute kidney injury, acute liver injury, ventricular tachycardia, or cardiogenic shock. In addition, treatment modalities such as mechanical ventilation, vasopressors or thrombolytic interventions(systemic thrombolysis, catheter-directed thrombolysis, mechanical thrombectomy) were comparable between males and females. We further did not find any differences in sepsis, bleeding events, acute ischemic stroke, or acute myocardial infarction(Table 1). Similarly, although females stayed longer(mean: 5.46 days vs. 4.90 days, p = 0.121), and had higher inflation-adjusted charges($61106 vs. $58810, p = 0.688), they were comparable. Conclusion Our study revealed that sex-based differences in outcome disparities among AA SCD patients admitted for APE are limited, with female transfusion requirements differing significantly, which warrants further investigation. This abstract is funded by: None

Abstract Introduction Chronic Lymphocytic Leukemia(CLL) is the most common leukemia in adults in the United States. CLL patients are at higher risk of bacterial infections, and Pseudomonas aeruginosa is a notable pathogen. Limited data is available comparing the demographics and outcomes of pseudomonas sepsis in CLL. Our study aims to analyze the patient characteristics and mortality between intensive care unit (ICU) and non-ICU admissions for pseudomonas sepsis among CLL patients. Methods Adults with active CLL admitted with a primary diagnosis code of pseudomonas sepsis(ICD-10 code: A41.52) were identified via the National Inpatient Sample(NIS)(2016-2022), excluding COVID-19 cases. Admissions to ICU were estimated if the patients required mechanical ventilation , vasopressors or central venous catheter placement, as per prior NIS-based studies. The predictors of ICU admissions were identified using multivariable regression models, with further analyses focused on estimating the in-hospital mortality. All analysis incorporated adjustments for weight, cluster, and strata, as advised by the data source. Results A total of 1,650 admissions were identified, of which 335 (20.3%) required intensive care. The intensive care cohort was younger (mean age: 73.19 vs. 76.86 years), yet age was not a significant predictor for the need for intensive care. Significant racial disparities were observed, with Black patients demonstrating significantly higher odds of intensive care use than White patients. In contrast, Hispanic patients had comparable odds to White patients. Sex, weekend admission status, private insurance coverage versus Medicare, and income quartiles did not significantly impact intensive care utilization. Among comorbidities, liver cirrhosis and palliative care encounters predicted higher ICU admission rates. Paradoxically, hypertension was associated with lower odds. Other comorbidities showed no significant association with intensive care admission (Table 1). Intensive care patients demonstrated an in-hospital mortality rate of 40.91% versus 8.75% in non-intensive care patients (aOR: 6.690, 95% CI: 2.648-16.906, p &lt; 0.01). Furthermore, intensive care had a substantially greater resource utilization, longer stays (mean: 16.49 vs. 8.83 days, p &lt; 0.01) and markedly higher hospitalization charges (mean: $314,311 vs. $89,614, p &lt; 0.01). Conclusions Our study revealed that black race, comorbidities like liver cirrhosis and palliative care encounters were key predictors for ICU admissions. ICU utilization was associated with higher inpatient mortality, length of stay and hospitalization costs. These findings highlight the disparities and resource burden, and warrants strategic interventions to address them. This abstract is funded by: None

Abstract Introduction Catheter-directed thrombolysis (CDT) has emerged as a safer interventional option for acute pulmonary embolism (APE) compared to systemic thrombolysis, with reduced rates of hemorrhage and mortality. However, comparative outcomes between first-time and recurrent APE patients undergoing CDT remain inadequately documented. This study aims to compare complications, mortality, and readmissions following CDT in recurrent versus first-time PE to provide evidence-based guidance for treatment optimization. Methods We explored the 2016-2022 Nationwide Readmissions Database(NRD) for APE admissions treated with CDT and stratified our sample by history of prior pulmonary embolism. Our cases excluded patients with COVID-19 and those younger than 18 years. We compared differences in their demographics, in-hospital complications during the index admission, and 30-day readmission rates. Adjustments were made to account for the complex design of the NRD via STATA 18.0. Results Of 37,952 patients identified, 9.27% had a history of prior PE. The groups had comparable mean age, sex distribution, and hospital status, with varying comorbidities as shown in Tables 1a-1b. Patients with first-time PE were more likely to experience in-hospital complications including sepsis, transfusion requirement, invasive mechanical ventilation, shock, acute encephalopathy, acute kidney injury, and all-cause mortality during the index hospitalization(Table 2). However, hospital length of stay and charges were similar between groups(Table 1b). Following discharge, 30-day readmission rates were comparable (6.25% vs. 6.41% for first-time versus recurrent PE, respectively; hazard ratio 0.948, 95% CI 0.765-1.17, p = 0.626). Conclusion First-time APE patients who underwent CDT reported higher rates of various in-hospital complications, and all-cause mortality, despite having comparable 30-day readmission rates. There were certain limitations to our study, such as the lack of laboratory data, imaging findings, APE severity scores on admissions, and medication history. Prospective studies with detailed clinical parameters will help validate our findings and elucidate the different causes of death. This abstract is funded by: None

Abstract Introduction Pneumocystis jirovecii pneumonia (PJP) is a significant opportunistic infection in immunocompromised patients. While cancer patients experience significant immunosuppression that increases their susceptibility to PJP, outcomes of this infection stratified by specific tumor types remain poorly characterized. Methods This retrospective study identified adults with PJP and either solid or hematologic malignancies using the National Inpatient Sample (2016-2022). Exclusion criteria included age &lt;18 years, COVID-19 positivity, concurrent solid and hematologic malignancies, HIV positivity, or missing data. Baseline characteristics were compared between the two cancer groups. Multivariable regression analyses, adjusting for potential confounders, were conducted to estimate adjusted odds ratios for adverse events, treatments, and mortality. All analyses accounted for the complex survey design of the dataset. Results We found 11565 admissions involving PCP matching our selection, with 55.6%(6430) liquid and 44.4%(5135) solid cancers. Both groups contained an elderly population (mean age in solid: 64.25 years, vs. mean age in liquid: 63.36 years, p = 0.139), and mostly males( 51.32% of solid and 66.33% of liquid cancers, p &lt; 0.01). The adjusted Deyo Charlson Comorbidity Index Scores were also comparable(1.65 in solid vs. 1.55 in liquid cancers, p = 0.195). Majority of patients in both groups (73.97% of solid and 72.55% of liquid) were Whites(p = 0.155), insured via Medicare(52.98% of solid and 54.60% of liquid,p=0.580), and hospitalized at urban teaching centers(85.69% of solid and 87.17% of liquid, p = 0.341). Among patients with solid tumors, 32.03% were respiratory/thoracic cancers, 11.88% were breast cancers, 11.10% were gastrointestinal cancers. Among patients with hematologic malignancies, the most common diagnoses were lymphoma (48.4%) followed by leukemia (37.2%). Patients with hematologic malignancies recorded reduced rates of acute respiratory failure, mechanical ventilation requirements, and intubation. In contrast, no significant differences were observed between groups for cardiovascular complications including cardiac arrest and septic shock. Acute kidney injury odds were similarly comparable between the two cohorts(Table 1). Our analysis demonstrated significantly lower mortality in hematologic malignancy patients compared to solid tumor patients, but with longer lengths of stay (15.4 days vs 13.2 days) and higher hospital charges ($234,616 vs $188,792). Conclusions Our findings demonstrate that solid malignancies may pose a bigger threat to PJP outcomes as compared to hematological cancers, warranting further investigation to set up appropriate preventive strategies and treatment protocols. This abstract is funded by: None

Abstract Introduction Minimally invasive surgical techniques including Robotic-Assisted thoracoscopic surgery (RATS) have advanced the treatment of lung cancer and enhanced patient outcomes from early recovery to improved quality of life. The “July effect” hypothesizes that morbidity and mortality outcomes worsen during the beginning of academic year when new residents and fellows begin training. We investigated the impact of the same on outcomes of RATS among lung cancer patients. Methods Using the National Inpatient Sample (2016-2019), we identified adults(ages≥18 years) with lung cancer who underwent RATS(lobectomy/sublobar resection) at urban teaching centers(UTC). Patients were stratified by surgical timing: July-September versus other months. Multivariable logistic regression compared perioperative outcomes between groups, adjusting for confounders. Results We analyzed 25,480 RATS procedures, with 25.59% performed during July-September. Baseline characteristics were comparable between groups regarding sex, race (White, Hispanic), insurance type, comorbidity burden, and age; however, fewer Black patients underwent surgery during July-September (Table 1a). Multivariable logistic regression revealed no significant differences in perioperative outcomes between the July-September and other months of the year. Evaluated outcomes included thoracic complications like pneumonia (aOR 0.89, 95% CI 0.62-1.28, p = 0.526), pneumothorax (aOR 1.07, 95% CI 0.85-1.34, p = 0.583), air leak (aOR 0.98, 95% CI 0.79- 1.22, p = 0.873), respiratory failure (aOR 0.9, 95% CI 0.50-1.63, p = 0.729) , atelectasis (aOR 1.12, 95% CI 0.88-1.42, p = 0.372), thromboembolic events like pulmonary embolism (aOR 0.63, 95% CI 0.13-2.97, p = 0.557), deep venous thrombosis (aOR 1.01, 95% CI 0.65-1.57, p = 0.952), bleeding complications like transfusion (aOR 0.95, 95% CI 0.55-1.64, p = 0.866), hemothorax/hemoperitoneum/hematoma (aOR 0.58, 95% CI 0.22-1.52, p = 0.264), renal complications (aOR 1.00, 95% CI 0.32-3.17, p = 0.994), conversion to open surgery (aOR 0.53, 95% CI 0.11-2.47, p = 0.417), extended length of stay (&gt;7 days) (aOR 0.96, 95% CI 0.78-1.17, p = 0.667), and in-hospital mortality (aOR 0.57, 95% CI 0.21-1.50, p = 0.250)(Table 1b). Conclusions Our study suggested no “July effect” in the perioperative outcomes of RATS. This demonstrates the robust hospital support systems ensuring the safe transition of resident classes without affecting the patient care negatively. This abstract is funded by: None

Abstract Introduction The lung is the most commonly affected organ in sarcoidosis, present in over 90% of cases. However, cardiac involvement may also occur and can significantly complicate patient outcomes. We propose to explore further. Methods Adults with isolated pulmonary sarcoidosis and combined pulmonary-cardiac sarcoidosis were identified using ICD-10 codes from the National Inpatient Sample (2016-2022). Patients with any additional organ involvement beyond lung or heart were excluded to ensure distinct comparison groups. We compared age, sex, race, insurance type, hospital characteristics, comorbidities, and healthcare burden between groups. Results Over the seven-year study period, we identified 154,125 hospitalizations of patients with either isolated pulmonary or combined pulmonary-cardiac sarcoidosis. Of these, 2.41% (n = 3,715) were combined pulmonary-cardiac cases, while the remainder were isolated pulmonary sarcoidosis. Patients with combined pulmonary-cardiac sarcoidosis were significantly younger(mean age: 58.2 vs. 62.0 years, p &lt; 0.001), but had a higher mean Charlson Comorbidity Index (CCI) score (3.49 vs. 2.77, p &lt; 0.001) compared to those with isolated pulmonary disease. Multiple demographic differences were found: isolated pulmonary cases were predominantly female(59.5%), with a higher proportion of White patients(46.7%), whereas combined cases were predominantly male(60.4%), with a higher proportion of Black patients(53.0%). Both groups were primarily covered by Medicare(58.1% of isolated vs. 48.1% of combined), with a higher proportion of combined pulmonary-cardiac sarcoidosis cases treated at urban teaching centers(92.3% vs. 78.9%, p &lt; 0.001). Patients with combined pulmonary-cardiac sarcoidosis demonstrated a higher prevalence of multiple comorbidities, including chronic kidney disease, prior myocardial infarction, complete atrioventricular block, obstructive sleep apnea, congestive heart failure, peripheral vascular disease, and valvular disease. Conversely, the prevalence of chronic obstructive pulmonary disease was lower in this group. Hospitalization burden was substantially greater among patients with combined pulmonary-cardiac sarcoidosis (Charlson Comorbidity Index 2.77±0.01 vs. 3.49±0.07), evidenced by longer mean length of stay (6.1±0.05 vs. 7.6±0.32 days) and significantly higher total hospital charges ($82,987±1,121 vs. $122,460±6,991) (Table 1). Conclusions Combined pulmonary-cardiac sarcoidosis affected younger patients with greater comorbidity and hospitalization burden, with notable racial disparities. As cardiac sarcoidosis is frequently underdiagnosed, systematic cardiac screening protocols in high-risk sarcoidosis patients are essential for earlier detection and improved management. This abstract is funded by: None