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Background Tumor-infiltrating lymphocytes (TILs) are established determinants of clinical outcomes in breast cancer. 1–6 While stromal TILs (sTILs) are commonly evaluated due to easier scoring and higher interobserver reproducibility, intraepithelial TILs may provide additional insights into anti-tumor immunity. 7 We aimed to comprehensively characterize immunotype-associated cellular landscapes in triple-negative breast cancer (TNBC) and identify features associated with clinical outcomes. Methods 212 TNBC tumors were classified into three immunotypes based on immune infiltrate location and density: immune desert (ID), immune excluded (IE), and immune inflamed (IN). 8 Single-cell spatial transcriptomics was performed on 75 tumors to define the cellular composition and functional states of the tumor microenvironment across immunotypes. Findings were validated and integrated with bulk RNA sequencing data and clinical outcome datasets from FinXX, CALGB-40603, I-SPY 2, and Real-World Clinico-Genomic Data (RWCGD) cohorts. Results Patients with IN tumors had significantly improved outcomes compared with ID tumors. Despite high sTILs, IE tumors showed poor outcomes similar to ID tumors. Single-cell spatial analysis revealed that ID and IE tumors exhibited reduced major histocompatibility complex I/II expression and fewer tumor-resident plasmacytoid dendritic cells (pDCs) compared with IN tumors, which were enriched for interferon-alpha (IFNα) and interferon-gamma (IFNγ) responses. High IFN response scores were associated with favorable outcomes across multiple therapy types in independent datasets. Deconvolution of RWCGD bulk RNA-seq data confirmed that pDC abundance correlated with improved outcomes specifically in hormone receptor–negative subtypes. Conclusions Our study highlights pDCs and IFN signaling as hallmarks of effective anti-tumor immunity in TNBC. Immunotype-based profiling underscores the limited prognostic value of sTILs alone in immune-excluded tumors and supports pDCs and IFN pathways as potential biomarkers for prognosis and therapeutic development in TNBC.

1591 Background: The 21-gene OncotypeDX (ODX) recurrence score (RS) is the standard for chemotherapy decision-making in HR+/HER2- early breast cancer (EBC), but cost limits accessibility in resource-constrained settings. The Magee equations (MEs) use routine pathology features (Nottingham grade and IHC; ER/PR/HER2/Ki-67) to estimate RS. We performed a meta-analysis to validate MEs performance as a triage tool for ODX testing and a qualitative synthesis to identify sources of discordance, highlighting the transition toward objective digital pathology AI models. Methods: A systematic review identified validation studies comparing MEs with RS in HR+ EBC. Studies with sufficient data to construct a 2X2 contingency table were included; neoadjuvant trials were excluded. Primary outcomes were Negative Predictive Value (NPV) for identifying low-risk cases (RS <26 for the current TAILORx cutoff and RS<31 for the historical cutoff) and ODX test sparing rate (TSR). Data were pooled using random-effects models. Qualitative themes regarding interpretation variability were extracted from study results and discussion sections. Results: Thirteen studies met the inclusion criteria, representing 5396 patients in global cohorts from the USA, Mexico, Colombia, Jordan, France, Belgium, and Canada. For RS >26, Magee <18 achieved pooled NPV of 0.96 (95% CI: 0.94-0.97) and TSR 61% (95% CI:51%-69%). For RS >31, NPV increased to 0.99 (95% CI: 0.97-1.00) and TSR 52% (95% CI: 44%-59%). Pooled diagnostic performance for Magee <18 predicting RS <26 demonstrated 83% sensitivity and 71% specificity (AUC 0.81, LR+:2.53, LR-:0.28). Qualitative analysis of discordance identified: (1) Inter-observer variability: Nottingham mitotic counts and Ki-67 scoring were the primary drivers of score fluctuations. (2) IHC quantification: Variations in H-score calculation and Allred-to-H-score conversion introduced heterogeneity (3) Pre-analytical and biological factors: Inflammation and stromal proliferation occasionally inflated genomic RS; selection of non-representative blocks and intratumor heterogeneity further contributed to discordance (4) Technological solutions: Digital pathology and AI models emerge as solutions to standardize these variables. Conclusions: Magee-based triage provides a safe and cost-effective strategy for HR+ EBC risk stratification, with NPV up to 99% for excluding high-risk disease and sparing up to 61% of ODX testing. These results confirm a robust histopathological signal. Transitioning to objective digital pathomics provides a pathway to reduce manual subjectivity and democratize precision oncology globally. Pooled diagnostic accuracy of Magee equations by cutoff. Magee score and RS cutoff Number of studies Total patients Pooled NPV (95% CI) ODX test sparing rate (95% CI) Magee <18/ RS>26 8 4153 0.96 (0.94-0.97) 61% (51%-69%) Magee <18/ RS>31 5 1243 0.99 (0.97-1.00) 52% (44%-59%)

12122 Background: Aromatase Inhibitors (AI) have become the standard of care to reduce breast cancer recurrence in hormone receptor-positive (HR+) breast cancer patients. AIs have been shown to be effective in reducing the risk of breast cancer recurrence by 47%. However, up to 52% of patients prematurely discontinue their use due to AI-associated musculoskeletal pain symptoms called Aromatase Inhibitor-associated musculoskeletal pain syndrome (AIMSS). No effective treatment exists to treat AIMSS. The present study examined the effectiveness of a multicomponent pain treatment program in reducing symptoms of AIMSS with the goal of improving adherence to AI medication. Methods: This trial enrolled breast cancer survivors with AIMSS in an intensive multicomponent pain treatment program. Pain, impact on functioning, fatigue, and mood were assessed with the Brief Pain Inventory, Center for Epidemiologic Studies of Depression- Revised Questionnaire, Pain Catastrophizing Scale, Symptom Impact Questionnaire Revised, and Fatigue Questionnaire at baseline, 3-month, 6-month, 9-month, and 12-month intervals. Adherence to AI medication was obtained from patients’ self-reports. The treatment program consisted of a two-day structured intervention focused on Cognitive-Behavioral skills to address strategies to improve pain control, fatigue, sleep disturbance, and stress while educating patients on the efficacy of Aromatase Inhibitors in prolonging cancer-free survival. Results: A total of 73 patients were enrolled, with a median age of 63 years (range 31-79). Participants were primarily white, married, and highly educated. The measures showed elevated levels of pain, fatigue, and psychological distress at baseline with decrements in self-reported levels of functioning. Significant improvements across all measures were observed at the 3-month follow-up after participation in the multicomponent pain treatment program. Significant improvements in painrelated outcomes were observed at 3 months (WPI Δ −1.6; SS Δ −4.0; both p < 0.001), with sustained reductions in symptom severity through 6-month, 9-month, and 12-month follow-up. Self-report of AI medication adherence at one year showed that 77.9% of patients were still taking their prescribed medication. Conclusions: Patients with AIMSS experienced substantial emotional distress, pain, fatigue, and functional impairment at baseline. Following the intervention, significant improvements were observed across pain, physical functioning, fatigue, and psychological distress, with benefits sustained at one year. Importantly, the intervention was associated with high long-term adherence at one-year follow-up, highlighting its potential to improve both quality of life and treatment persistence.

Objective To quantitatively examine immune cell markers and spatial distribution in human diabetic kidney disease (DKD) to enhance understanding of the inflammatory landscape contributing to injury. Maladaptive inflammation is an underrecognized contributor to DKD pathogenesis and progression and remains undertreated. Patients and methods NanoString GeoMx™ Digital Spatial Profiling technology targeted antibodies labeled with unique oligonucleotide barcode in kidney biopsy [DKD (n=5), tubulointerstitial nephritis (TIN; n=4), and normal (n=2)] with regions of interest selection of compartments (glomeruli, tubules, interstitium). Inflammation-related proteins were analyzed with differential expression through linear mixed modeling. Results Compared to normal tissue, inflammatory cell surface protein markers were increased in DKD tubules and interstitium. Markers of T cells (CD4, CD44), macrophages (CD68; proinflammatory), and antigen-presenting cells (APCs; CD40 and CD11c) were increased across all DKD compartments (vs. normal). Macrophage (CD163; prorepair) marker was increased in DKD tubules and interstitium (vs. normal). Fewer differences were observed in glomeruli for normal vs. DKD or TIN vs. DKD groups. CD66b+ (granulocytes) cell marker was higher in DKD (vs. TIN). As expected, TIN had higher levels of T cell and macrophage markers in tubules and interstitium (vs. DKD). Interestingly, CD34, a hematopoietic stem cell and endothelial cell marker, was lower in DKD tubules and interstitium (vs. normal) but higher in DKD (vs. TIN). Conclusion NanoString GeoMx DSP technology may fulfil a role in enhancing the understanding the inflammatory landscape engaged in DKD pathogenesis as well as measuring response to therapy. Moreover, additional investigations of CD34 progenitor cell depletion in DKD may be warranted.

Background: Older adults with severe aortic stenosis (AS) are at high risk of mortality unless treated by aortic valve replacement (AVR). The Society of Thoracic Surgery (STS) score is primarily used clinically to determine mortality risk from surgical AVR. Due to geriatric comorbidities unique to older adults, traditional methods of risk stratification with STS may have significant shortcomings. Administratively derived risk scores that have prognostic significance in the geriatric population may prove valuable. Methods: We reviewed patients at our hospital system with AS undergoing AVR (surgical and transcatheter) and administratively derived an Elder Risk Assessment (ERA) score from the health record. The ERA score is a composite of age, marital status, number of hospitalized days in previous 2 years, and comorbidities (diabetes, coronary artery disease (CAD), heart failure, stroke, pulmonary disease, cancer, and dementia). Kaplan-Meier method was used to estimate survival by ERA score tertile. Cox regression was used to determine association between ERA and survival after accounting for STS predicted risk. Results: There were a total of 228 patients that underwent AVR (TAVR: 59 (26.1 %); SAVR 167 (73.9%) and had ERA scores derived. The average age was 79.6 (SD 7.6) years) and there were 93 (40.8%) women. Patients were stratified by ERA score tertiles: low (≤6), mid (6-13), or high (≥14). Over a mean follow up of 5.8 (SD 3.1) years, lower ERA scores were associated with better long-term survival (p<0.001). After accounting for age, sex, and STS score, mid ERA (HR 1.61; 95% CI 1.00-2.59; p<0.001) and high (HR 2.90; 95% CI 1.79-4.69; p<0.001) were associated with mortality (reference: low ERA). For every 10-point increase in the ERA, there was a 2-fold increase in adjusted mortality risk (HR 2.14; 95% CI 1.58-2.90; p<0.001). Conclusions: Older adults undergoing AVR for severe AS have specific geriatric comorbidities that may be better characterized using the ERA score. This administratively derived score was independently associated with survival after accounting for the widely used STS risk score.

Abstract The highest risk for liver allograft rejection is within the first weeks to months after a liver transplant; however, while later-stage mechanisms are well described, the initial window at the moment of alloantigen influx (e.g., ~ 1 h post-reperfusion) remains unmapped. T-cell priming is initiated in lymph nodes, yet these sites are rarely profiled in humans and their relationship to rejection risk is unclear. To address this gap, we profiled paired pre- and ~ 1 h post-reperfusion hepatic draining lymph nodes from liver transplant recipients using multiplexed immunofluorescence and GeoMx whole-transcriptome profiling to identify features that predict rejection versus non-rejection. Early after reperfusion, CD4 + and CD8 + T cells became proximal to macrophages in rejection compared to dendritic cells in non-rejection, which also displayed an immunoregulatory-leaning profile marked by PD-1, IDO1, and CD39, suggesting that macrophages and dendritic cells differentially influence early T-cell alloimmunity. These results provide nodal targets for precise immune modulation.

Background: Coronary artery disease (CAD) is common among liver transplantation (LT) candidates, yet whether pre-transplant percutaneous coronary intervention (PCI) improves post-LT outcomes remains uncertain. Methods: We conducted a single-center, Institutional Review Board-approved cohort study of adults undergoing LT from 2005 to 2025. Asymptomatic candidates with significant stenosis on invasive angiography were included; prior coronary artery bypass grafting was excluded. The primary endpoint was major adverse cardiovascular events (MACE: myocardial infarction [MI], stroke/transient ischemic attack, new systolic dysfunction, post-LT coronary revascularization, or all-cause death). Results: Among 111 patients (median age 65 years; 84% male), 66 (59%) underwent PCI and 45 (41%) were managed medically. Over a median 32 months of follow-up, 61 patients (55%) experienced MACE. Composite MACE did not differ between PCI and non-PCI groups (52% vs. 60%, p = 0.40; log-rank p = 0.59). Fine–Gray modeling showed no association of PCI with MACE; independent predictors were prior MI (HR 1.81, 95% CI 1.01–3.24) and pre-transplant dialysis (HR 2.13, 95% CI 1.07–4.24). Major bleeding occurred in 7%. Matched and era-stratified analyses were concordant. Conclusions: In asymptomatic LT candidates with angiographically severe CAD, pre-LT PCI was not associated with a lower incidence of post-LT MACE.

ABSTRACT Background Sulfa antibiotic allergy labels (SALs) are encountered frequently in kidney transplant recipients (KTs). This often results in patients receiving second‐line prophylaxis for both Pneumocystis jiroveci and urinary tract infections (UTIs). The effect of SAL on outcomes including UTIs after KT is unclear. Methods In our single‐center retrospective cohort study, we investigated the effect of SALs on bacteriuria after KT. We identified patients with pre‐KT SALs from 2011 to 2022. A matched cohort was then created using KT with no pretransplant SALs. The groups were compared using proportional analysis and univariable and multivariable Cox proportional regression models. The primary outcome of interest was the proportion of individuals experiencing one or more episodes of bacteriuria within 1 year posttransplant. Secondary outcomes included bacteremic UTIs, acute kidney injury, and opportunistic infections. Results We found that the proportion of individuals experiencing bacteriuria within the first‐year posttransplant was significantly greater in the SAL group versus the control group ( n = 21, 28% vs. n = 22, 14.7%, p = 0.012). This result was also seen in univariable and multivariable survival analysis. In addition, episodes of UTI with associated bacteremia ( n = 11, 14.7% vs. n = 5, 3.3%, p = 0.002) were statistically significantly higher in the SAL group. Conclusion There was a significantly greater number of episodes of bacteriuria in the first‐year posttransplant in subjects with pretransplant SAL. Based on our findings, we suggest that all KTs with pretransplant SALs undergo evaluation and intervention prior to transplantation. image