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522 Background: Tumor-associated macrophages (TAMs) drive immune evasion and chemotherapy resistance in breast cancer through tumor microenvironment reprogramming. We developed a composite TAM score integrating transcriptional programs with spatial IHC polarization markers to stratify recurrence risk and enrich macrophage-modulating trials, hypothesizing it would improve prognostic accuracy in treatment-naïve disease and predict neoadjuvant chemotherapy (NACT) response. Methods: TAM score was derived from scRNA-seq atlases (n=4), filtering survival-associated genes in METABRIC/TCGA (n=2,509), and weighting IHC markers CD163/CD206 normalized to CD68/CSF1R via Cox coefficients. Validation: treatment-naïve invasive carcinomas (n=83; follow-up 57 months; 24 events). Primary endpoint: recurrence-free survival (RFS); multivariable Cox adjusted for age, tumor size, nodal status, grade, subtype, treatment. Predictive utility assessed in matched primary/post-NACT residual tumors (n=45) correlating TAM dynamics with RCB. Results: High TAM score (≥median) independently predicted worse RFS (HR 3.8, 95% CI 1.6-9.1, p<0.05) and outperformed CD163/CD68 alone (HR 2.1, p<0.05); 5-year RFS was 68% vs 91% (TAM-high vs TAM-low). Prognostic value persisted in node-negative (HR 4.2, p=0.02) and luminal B (HR 3.5, p=0.01) subsets. In the NACT cohort, baseline TAM score inversely correlated with pCR (12% vs 38%, p=0.04). Among residual disease (RCB-II/III, n=34), persistent TAM-high post-NACT identified 3-year RFS 52% vs 85% in TAM-low/normalized cases (HR 4.1, p=0.01), independent of RCB; CD163+/CD206+ expansion occurred in 76% of RCB-III vs 29% of RCB-I (p=0.008). Conclusions: This TAM score predicts recurrence from pre-treatment tissue and identifies macrophage-driven resistance persisting post-NACT, nominating TAM-high residual disease for macrophage-modulating trials. Translational evidence supports this: CSF1R inhibition reduced immunosuppressive TAMs, increased M1-like programs, decreased PD-L1/PD-L2, and enhanced anti-PD-1 efficacy preclinically with ex vivo confirmation. Early-phase data (rebastinib plus chemotherapy in HER2-negative metastatic disease) demonstrate feasibility, supporting prioritization of TAM-high patients with residual disease for trials combining TAM modulation with checkpoint therapy. TAM score performance in treatment-naïve and NACT cohorts. Endpoint TAM-High TAM-Low HR scores (95% CI) p-value Treatment Naïve cohort 5 year RFS (Overall) 68% 91% 3.8 (1.6-9.1) <0.05 RFS (node-negative) 4.0 0.02 RFS (luminal B)-- 3.5 0.01 CD163/CD68 alone 2.1 <0.05 NACT Cohort (n=45) Baseline pCR rate 12% 38%- 0.04 3-year RFS(RCB-II/III n=34) 52% 85% 4.1 0.01 CD163+/CD206+ expansion 76% (RCB-III) 29%(RCB-I)- 0.008

BackgroundStroke etiology is undetermined in approximately one‐sixth to one‐third of patients. The presence of aortic flow reversal and plaques in the descending aorta (DAo) has been identified as a potential retrograde embolic mechanism.PurposeTo assess the relationships between aortic stiffness, wall thickness, and flow reversal in patients with cryptogenic stroke and healthy controls.Study TypeProspective.PopulationTwenty one patients with cryptogenic stroke and proven DAo plaques (69 ± 9 years, 43% female), 18 age‐matched controls (age: 65 ± 8 years, 61% female), and 14 younger controls (36 ± 9 years, 57% female).Field Strength/Sequence1.5T; 4D flow MRI and 3D dark blood T1‐weighted turbo spin echo MRI of the aorta.AssessmentNoncontrast aortic 4D flow MRI to measure 3D flow dynamics and 3D dark blood aortic wall MRI to assess wall thickness. 4D flow MRI analysis included automated quantification of aortic stiffness by pulse wave velocity (PWV) and voxelwise mapping of the flow reversal fraction (FRF).Statistical TestsAnalysis of variance (ANOVA) or Kruskal–Wallis tests, Student's unpaired t‐tests or Wilcoxon rank‐sum tests, regression analysis.ResultsAortic PWV and FRF were statistically higher in patients (8.9 ± 1.7 m/s, 18.4 ± 7.7%) than younger controls (5.3 ± 0.8 m/s, P < 0.0167; 8.5 ± 2.9%, P < 0.0167), but not age‐matched controls (8.2 ± 1.6 m/s, P = 0.22; 15.6 ± 5.8%, P = 0.22). Maximum aortic wall thickness was higher in patients (3.1 ± 0.7 mm) than younger controls (2.2 ± 0.2 mm, P < 0.0167) and age‐matched controls (2.7 ± 0.5 mm) (P < 0.0167). For all subjects, positive relationships were found between PWV and age (R2 = 0.71, P < 0.05), aortic wall thickness (R2 = 0.20, P < 0.05), and FRF (R2 = 0.47, P < 0.05). Patients demonstrated relationships between PWV and FRF in the ascending aorta (R2 = 0.32, P < 0.05) and arch (R2 = 0.24, P < 0.05).Data ConclusionThis study showed the utility of 4D flow MRI for evaluating aortic PWV and voxelwise flow reversal. Positive relationships between aortic PWV, wall thickness, and flow reversal support the hypothesis that aortic stiffness is involved in this retrograde embolic mechanism.Level of Evidence2Technical Efficacy Stage1

Background Blood flow reversal is a possible mechanism for retrograde embolism in the setting of high‐risk atherosclerotic plaques in the descending aorta (DAo). Evidence suggests that pulse wave velocity (PWV) is a determinant of blood flow reversal and can be reduced by the destiffening effect of renin‐angiotensin system inhibitors (RASI). Purpose To evaluate the impact of antihypertensive therapy on in vivo changes in PWV and flow reversal in patients with cryptogenic stroke. Study Type Prospective. Population Sixteen patients (69 ± 9 years; 10 males) included after cryptogenic stroke. Field Strength/Sequence 3T. 4D flow sequence (temporal resolution = 19.6 msec) Assessment Patients underwent aortic MRI at baseline and at 6‐month follow‐up. Patients received standard‐of‐care antihypertensive therapy that were classified as RASI vs. non‐RASI medications (ie, destiffening vs. nondestiffening).We compared aortic PWV, flow reversal fraction (FRF), aortic measurements, cardiac function, and other aortic and cardiac measurements in the antihypertensive therapy groups. Statistical Tests Two‐tailed paired or unpaired Student's t ‐tests (normal distributions) or Wilcoxon tests (nonnormal distribution). Univariate correlations using Pearson correlation coefficients. Results There was a significant decrease in PWV in the RASI ( n = 10) group (9.4 ± 1.6 m/s vs. 8.3 ± 1.9 m/s; P < 0.05), as well as FRF (18.6% ± 4.1% vs. 16.3% ± 4.0%; P < 0.05) between baseline and the 6‐month MRI studies. There were no changes in PWV or FRF in the non‐RASI ( n = 6) group ( P = 0.146 and P = 0.32). A decrease in FRF was significantly correlated with a decrease in PWV ( r = 0.53; P < 0.05). Data Conclusion The findings of our study suggest that RASI therapy after cryptogenic stroke resulted in a decrease of blood flow reversal and aortic stiffness. Evidence Level 1 Technical Efficacy Stage 4