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Abstract Intro: The 70-gene MammaPrint (MP) assay is prognostic for distant recurrence and predictive of benefit from adjuvant chemotherapy (CT) benefit established on surgical tissue of systemically untreated patients (pts). The MP index range is from -1 to +1 with higher index indicating lower risk of early recurrence. Risk is categorized as MP High Risk, MP Low Risk, and MP UltraLow Risk, and results can guide treatment decisions. Pts with MP index >0 are classified as Low Risk and derive little benefit from CT. There are clinical scenarios in which the only available tissue for MP or other genomic testing has been exposed to neoadjuvant endocrine therapy (NET). Few studies have investigated the impact of ET exposure on MP index. Methods: Pts were identified through the I-SPY Low Risk Registry (LRR), an observational sub-study which enrolled pts with hormone receptor positive (HR+)/HER2-negative early breast cancer ineligible for the I-SPY2 trial due to MP Low Risk or UltraLow Risk status, between 2010-2020. Pts were treated at the discretion of their provider. We conducted a retrospective analysis of MP index from paired tumor tissue obtained from systemically untreated diagnostic core biopsies and surgical specimens after NET. MP categories and index before and after NET were compared. Change in MP index was assessed for an association with changes in clinicopathologic factors obtained through the LRR using the paired-t test. Results: 28 pts with paired tumor samples were included in the analysis. Median age was 48 (range 31-75) and 18 (64%) were premenopausal. At baseline, 13 (46%) were clinically node-positive and 22 (76%) had ductal histology. Tumor grade was 1 in 6 pts (21%), 2 in 20 pts (71%), and 3 in 2 pts (7%). ER expression was >95% in 25 pts (range 60-100%) and PR expression was >90% in 14 pts (range 0-100%). NET regimens included tamoxifen +/- ovarian function suppression (OFS) in 3 pts (10.7%), aromatase inhibitor (AI) +/- OFS in 15 pts (53.6%), tamoxifen followed by or in combination with AI +/- OFS in 8 pts (28.6%), fulvestrant in 1 pt (3.6%) and OFS alone in 1 pt (3.6%). 11 (61%) of premenopausal pts received OFS. 96% (27/28) of pts were classified as Low Risk both pre- and post-NET. Only one pt had MP change from Low Risk to High Risk. Three pts had change from Low Risk to UltraLow Risk or vice versa. As a continuous variable, a small average increase in MP index was observed after NET; but, there was a range of responses. 19 pts (68%) had an increase in MP index after NET, while 9 pts (32%) had a decrease. In those with a decrease in MP index, the average ER expression decreased by -13.6%, whereas in those with an increase in MP index, ER expression was unchanged (-0.18%) (p=0.049). There was no significant difference in changes in PR expression between tumors with increased vs decreased MP indices. At a median follow-up of 35 months, 4 distant recurrences were observed. Of the 9 pts with a decrease in MP index, 3 pts (33%), including the one who changed from Low Risk to High Risk, experienced a distant recurrence. In contrast, in those with an increase in MP index, 1 of 19 (5%) experienced a distant recurrence. Conclusion: In pts with early-stage HR+/HER2- MP Low Risk or UltraLow Risk breast cancer, NET had minimal impact on the tumor MP classification. These data suggest that the MP assay could be used for tissue exposed to NET if untreated tissue is not available. Further investigation in larger cohorts is needed to validate these findings. The observation that there were more distant recurrences in pts with tumors that had an increase in MP after NET is hypothesis generating, and potentially clinically relevant if validated in a larger study. The potential of MP as a dynamic risk marker to stratify recurrence risk following NET is being evaluated in the ongoing I-SPY2 Endocrine Optimization Pilot. Citation Format: S. Jacob, C. Wu, A. Glas, C. Yau, L. Brown-Swigart, G. Hirst, T. Haddad, K. Giridhar, A. Elias, R. Mukhtar, L. Huppert, K. Albain, D. Yee, L. van’t Veer, L. Esserman, J. Chien. Impact of Neoadjuvant Endocrine Therapy on MammaPrint Index in Hormone Receptor-Positive, HER2-Negative MammaPrint Low Risk Early-Stage Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-05-28.

Abstract Background Invasive lobular carcinoma (ILC) differs from invasive ductal carcinoma (IDC) in its estrogen receptor (ER) signaling pathways, response to systemic therapy, and imaging features. We evaluated differences in early change in the proliferation marker Ki67 and features on magnetic resonance imaging (MRI) after novel endocrine based neoadjuvant therapy in lobular versus non-lobular cases on the I-SPY2 EOP Trial. Methods EOP is a prospective, randomized NET trial enriched for patients with ILC. Patients with stage II-III ER positive HER2 negative breast cancer with low molecular risk (Mammaprint low or Mammaprint Hi1 plus high Sensitivity to Endocrine therapy Index) were randomized to one of several endocrine therapy-based arms. Treatment arms include novel oral SERDS with or without CDK4/6 inhibitor, aromatase inhibitors, and SERMs with or without ovarian function suppression in pre-menopausal patients. Patients undergo repeat core needle biopsy with central Ki67 assessment after 3 weeks of treatment and serial breast MRI. Here, we compare endocrine therapy responsiveness as measured by change in Ki67 at 3 weeks and functional tumor volume (FTV) on pre-surgical MRI in lobular versus non-lobular cases. Results We evaluated 253 patients of whom 148 (58.5%) had non-lobular cancer (93.9% IDC), and 105 (41.5%) had lobular cancer (17.1% mixed ILC/IDC). Overall, mean age was 53.3 years, 63.8% of tumors were grade 2, and 86.5% were Mammaprint (MP) Low with the remaining being Hi1, with higher rates of MP Low in the lobular versus non-lobular cohorts (92.4% versus 83.4%, p=0.0358). At baseline, tumors in the lobular cohort had significantly lower mean Ki67 than those in the non-lobular cohort (11.2% [SD 12.8] versus 16.4% [SD 14.4%], p=0.0038). Consistent with this, the proportion with baseline tumor Ki67 <10% was significantly higher in the lobular cohort than the ductal cohort (60.4% versus 39.3%, p=0.001). At 3-week biopsy, mean Ki67 remained lower in the lobular versus non-lobular group (3.4% versus 5.4%, respectively, p=0.0415). The proportion of patients with Ki67 <10% at 3 weeks did not differ significantly between lobular and non-lobular cases (88.6% versus 79.7%, respectively, p=0.08). Among the 40 lobular cases and 88 non-lobular cases with baseline Ki67 ≥10%, week 3 Ki67 decreased to <10% in 90% of lobular cases and 72.7% of non-lobular cases (p=0.07). On MRI, mean FTV at baseline was similar among lobular and non-lobular cases (21 cc3 versus 16.3 cc3). On pre-surgical MRI, patients in the lobular cohort had significantly higher mean residual FTV than those in the non-lobular cohort (5.7 cc3 versus 3.8 cc3, p=0.034). Interestingly, when splitting the lobular cohort into mixed lobular and pure lobular, mean residual MRI FTV was 7.5 cc3 in mixed cases and 3.8 cc3 in pure lobular cases, reflecting that FTV decreased the least in mixed lobular cases (decrease of 51.1% in mixed cases, 69.7% in pure lobular cases, and 73.9% in non-lobular cases, p=0.0255). Conclusions These results highlight differences in lobular versus non-lobular breast cancer. Lobular cases had lower baseline Ki67, and similar rates of decrease in Ki67 after 3 weeks of NET than non-lobular cases. Despite this, mean FTV after completion of 6 months of NET was higher in lobular tumors. These findings may reflect differences in early versus late indicators of response to NET, or differential response patterns by histology. Alternatively, standard response measures such as Ki67 and FTV may need lobular-specific modifications. Ongoing work includes central assessment of Ki67 from surgical specimens, analysis of changes in gene expression signatures, and evaluation of surgical outcomes such as breast conservation rates by histologic subtype. Citation Format: R. Mukhtar, P. Norwood, A. Borowsky, S. Alkhafaji, K. Giridhar, C. Vaklavas, A. Elias, M. Wei, M. Goetz, N. Onishi, O. Olopade, L. Van 't Veer, L. Huppert, W. F. Symmans, L. Brown Swigart, C. Wu, C. Yau, D. Yee, M. Magbanua, E. Price, N. Hylton, L. Esserman, J. Chien. Differential early response to neoadjuvant endocrine therapy in lobular versus non-lobular breast cancer on the Endocrine Optimization Pilot (EOP) of the I-SPY2 Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-02-01.

Abstract Background: Combinations of antibody-drug conjugates and immunotherapy, such as trastuzumab deruxtecan (T-DXd) and rilvegostomig (rilve), respectively, offer promising efficacy but are associated with a heightened risk of drug-induced interstitial lung disease (ILD)/pneumonitis. Early detection and management are critical for optimizing patient safety, yet there are no standard protocols for real-time evaluation. We hypothesized that vigilant monitoring would enable early detection, prevent symptoms, and minimize the chance of treatment delays while testing novel therapeutic combinations that have a potential risk of ILD. Methods: We tested the combination of T-DXd and rilve administered every 3 weeks in the I-SPY2.2 phase 2 platform trial (NCT01042379), which enrolls patients with clinical stage II/III breast cancer commencing neoadjuvant systemic therapy. Given the potential risk of overlapping pulmonary toxicity of these two agents, we added rigorous monitoring with pulmonary function tests (PFTs), six-minute walk test (6MWT), and high-resolution chest CT (HRCT) scanning pretreatment and every 6 weeks thereafter. A real-time safety workflow was implemented, with pre-specified criteria for halting treatment and escalation to the next block of treatment. All abnormal findings reported on chest CT by site radiologist were centrally reviewed in real time by the study pulmonologist (T.K.) and cases of suspected ILD were adjudicated promptly by a safety committee consisting of the pulmonologist and several medical oncologists, enabling early study drug interruption and therapeutic interventions. Toxicity data were evaluated in the first 51 patients treated with T-DXd plus rilve, and a preplanned hold was initiated until safety was ascertained by the data and safety monitoring board. Results: Safety data were evaluated in the first 51 patients receiving T-DXd plus rilve. Eight ILD events were confirmed (15.68% incidence): 5 grade 1, 2 grade 2, and 1 grade 3. One patient had an early chest CT scan because of dyspnea. All cases were identified by HRCT scans; PFTs and 6MWT did not enhance early detection and were subsequently dropped from the monitoring protocol. No patient was symptomatic for more than 24 hours. Radiographic findings resolved within 14-55 days. Patients with grade 2 & 3 ILD were treated with corticosteroids. No cases of ILD required intensive care or escalated therapy beyond steroids. Early treatment escalation to the subsequent block of therapy occurred in 3 patients; all 3 patients were subsequently able to receive appropriate therapy. At the meeting, safety data from all 100 patients treated with this combination will be reported. Conclusion: Real-time, centralized monitoring and adjudication allowed for early detection and prompt management of ILD, which both mitigated severity and supported timely therapeutic management. Among the monitoring tools studied, HRCT scanning performed every 6 weeks proved most effective for early ILD identification; PFT and 6MWT did not enhance early detection. This approach offers a potential framework for future studies assessing pulmonary safety in regimens combining agents that have a known risk for inducing ILD. Citation Format: T. Kulkarni, R. Nanda, H. S. Rugo, C. C. OSullivan, K. M. Kalinsky, J. C. Boughey, P. R. Pohlmann, J. Perlmutter, D. Yee, A. Borowsky, F. Symmans, N. Hylton, L. Van ‘t Veer, C. Yau, L. Esserman. Real-time monitoring for drug-induced interstitial lung disease with Trastuzumab Deruxtecan and Rilvegostomig combination therapy prevents persistent, symptomatic disease: Safety insights from the I-SPY2.2 platform trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-01-09.

Abstract Introduction: AC plus a taxane is standard neoadjuvant therapy for high-risk early breast cancer, but AC may be unnecessary for pathologic complete response (pCR) in many patients. I-SPY2 is a phase 2 trial evaluating the use of 12 weeks of paclitaxel +/- an investigational drug followed by AC. Serial measurements of Functional Tumor Volume (FTV) by MRI, inter-regimen biopsies and pathology from surgery were used to determine the contribution of AC to reduction in FTV or pCR. Methods: 1187 patients enrolled between 2010-2022 had serial measurements of FTV. 150 patients received an inter-regimen biopsy. The primary endpoint of I-SPY2 is pCR. To determine how much AC contributed to the reduction in FTV, we calculated the total FTV decrease between pre-treatment and pre-surgery, and then computed the percentage (%) of the total FTV decrease seen after 12 weeks of paclitaxel regimen. We attributed pCRs observed among patients for whom taxane contributed <90% FTV reduction to AC and estimated the % patients achieving pCR from AC. For the subset with inter-regimen biopsy, we estimated the percentage achieving pCR from those patients with invasive cancer present at inter-regimen biopsy. Results: We found that by week 12 (end of taxane), 64% (763/1187) of patients had achieved ≥90% of their total FTV reduction. In 424/1187 (36%) patients had with taxane <90% response, and subsequent AC contributed to more than 10% of the total decrease in FTV. 90 pCRs (21%) were observed among these 424 patients or, overall, approximately 8% of patients achieved pCR from AC after taxane. Of note, 54/1187 (4.5%) patients had no response to a taxane regimen and had decreased in FTV due to AC alone. Of the 54/1187 responding to AC only, there were 11 pCRs. These results varied by response predictive subtypes as shown. When the subpopulation with post-paclitaxel biopsy was examined, 63/150 (42%) patients had invasive cancer at this timepoint. 47 patients received AC and 4/47 (8.5%) achieved a pCR after AC. 13/47 (28%) achieved RCB 0/1. Conclusions: Serial measurements of FTV identifies patients who had a favorable response to a taxane regimen. For those with a suboptimal response, AC provided some contribution to further decrease in tumor volume. However, only a small fraction achieved a complete response. Immune positive and HER2+ (non-luminal) had the biggest benefit, with only 3-6% of other subtypes achieved pCR. Thus, AC can be reserved for those patients with suboptimal response to the initial taxane therapy. I-SPY2.2 utilizes these data to avoid AC by allowing patients to proceed to surgery after serial MRI and biopsy predict a pCR at an early timepoint. While AC remains the standard of care in many neoadjuvant regimens, the low response rates seen in I-SPY2 suggests that more active regimens need to be developed for patients with disease resistant to a taxane based therapy. Citation Format: D. Yee, C. Yau, P. Norwood, D. M. Wolf, P. R. Pohlmann, N. Onishi, L. van 't Veer, A. Borowsky, W. F. Symmans, J. Perlmutter, J. C. Boughey, E. Price, W. Li, I-SPY Investigators, N. Hylton, L. J. Esserman. Quantifying the Contribution of Doxorubicin and Cyclophosphamide (AC) to Pathologic Response Following Neoadjuvant Taxane Therapy: Analysis of the I-SPY2 TRIAL [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD6-09.

Abstract BACKGROUND: EOP is an I-SPY2 sub-study designed to test novel endocrine-based strategies in patients (pts) predicted to have modest benefit from chemotherapy. Vepdegestrant is a selective oral PROTAC estrogen receptor (ER) degrader that has demonstrated efficacy in mutant ER+ HER2-negative MBC. METHODS: EOP eligibility included pts with Stage 2/3 HR+ HER2-negative, MammaPrint (MP) Low Risk BC. Patients with MP High1 signatures were eligible if clinically node-negative or SET 2,3 High. Pts were randomized to one of 3 oral treatment (tx) arms: vepdegestrant 200 mg/d (V), vepdegestrant 200 mg/d +letrozole (VL), vepdegestrant 200 mg/d + abemaciclib 150 mg bid (VA). Pts received tx for six 28-day cycles followed by surgery. Premenopausal (PreMN) pts received ovarian function suppression (OFS) starting C1D1 in the VL arm, and C2D1 in the V and VA arms. The primary endpoint was feasibility, defined as >75% of pts completing >75% of study therapy. Breast MRI functional tumor volume (FTV) and ctDNA (tumor-informed assay) were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). Ki67 and ER/PR by IHC were centrally assessed from tumor biopsies at T0, T1, and the surgical specimen. Results: Between 4/2023 and 1/2025, 121 pts were enrolled: 40 in V, 41 in VL, and 40 in VA. Median age was 54 years, 50% preMN. 60% of pts had ductal, 35% lobular, 5% mixed histology. 55% were cN+, and 59% were not breast conservation surgery (BCS) candidates at baseline. Mean baseline Ki67 was 12.5%, 85.1% had MP Low Risk signature, 79.3% were SET 2,3 High. All 3 tx arms met the primary endpoint with 88%, 88%, and 83% completing > 75% study therapy in V, VL, and VA (thus far), respectively. Most common all grade (AG) TRAEs in V and VL arms include fatigue (53% V, 71% VL), hot flashes (48% V, 71% VL), arthralgias (33% V, 49% VL), all G1 or G2 except for 1 G3 fatigue in VL arm. G2 and G3 neutropenia was seen in 1 pt each in V and VL arms. The most common AG TRAEs in VA include diarrhea (80%), fatigue (65%), nausea (58%), hot flashes (50%), neutropenia (43%). High grade TRAEs in VA include neutropenia (23% G3, 5% G4), ovarian cyst requiring surgery (5% G3), diarrhea (15% G3), nausea (3% G3), transaminitis (3% G3), thromboembolic event (8% G3), acute kidney injury (3% G3). Table 1 summarizes key response endpoints by tx arm. CONCLUSION: Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy. Citation Format: J. Chien, R. M. Mukhtar, C. Yau, A. D. Elias, A. M. Wallace, N. Chan, C. Omene, N. Chen, J. Tseng, M. S. Trivedi, E. Stringer-Reasor, D. Yee, A. S. Clark, A. Thomas, H. Han, M. Arora, C. Nangia, K. Albain, C. Falkson, C. Isaacs, A. Zimmer, M. Rozenblit, L. van't Veer, L. Brown Swigart, G. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, S. Alkhafaji, K. V. Giridhar, C. Vaklavas, M. Wei, M. P. Goetz, O. Olopade, L. Huppert, C. Wu, L. J. Esserman. I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD10-02.

Abstract The human X chromosome accounts for ∼5% of the genome. Despite its size, the role of X-chromosomal variants in human diseases is not well understood, mainly due to its distinct inheritance pattern and the frequent omission of sex chromosomes from genome-wide association studies. This study used whole-genome sequencing data from 888 multiple system atrophy (MSA) cases and 7128 controls to perform an X-chromosome-wide common variant association study. Our analyses revealed two sex-differential risk loci: one located at Xq28, associated with increased risk for MSA in females [index variant: rs4898389, odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.40–2.03, P-value = 2.43 × 10⁻⁸], and another at Xp22.2 within the TBL1X gene, identified in males (index variant: rs6638956, OR = 1.48, 95%CI = 1.26–1.73, P-value = 9.92 × 10⁻⁷). In the Xq28 locus, colocalization analyses pointed to FAM3A and PLXNA3 as genes of interest. These findings emphasize the vital role of sex-differential genetic factors in the pathogenesis of MSA.

Abstract Background Immune checkpoint inhibitors can result in serious, long-lasting immune-related adverse events (irAEs). Early identification of symptoms predictive of irAEs could enhance monitoring and timely intervention. This study assessed whether symptoms within the first 8 weeks of treatment could predict subsequent development of immune-related adrenal insufficiency(AI) or hypothyroidism. Methods This retrospective cohort study analyzed prospectively collected data from the I-SPY2 trial, a phase 2 platform trial for high-risk stage II/III breast cancer across 30 U.S. sites. The cohort included 482 women treated with experimental immunotherapy agents concurrent with weekly paclitaxel neoadjuvant chemotherapy. The primary outcomes were grade ≥ 1 hypothyroidism or AI, adjudicated by an independent safety group, up to 1-year post-treatment. Symptoms and irAEs were assessed using the Common Terminology Criteria for Adverse Events. Symptom burden was quantified as area under the curve (AUC) based on symptom grade and duration. Predictive modeling was performed using logistic regression and ROC analysis; symptom enrichment between cases and controls was evaluated using Fisher’s exact tests. Results Among 482 participants, 107 (22.2%) developed irAEs, with hypothyroidism (n = 61, 12.7%) occurring more frequently than AI (n = 38, 7.9%) at medians of 99 and 105 days from treatment initiation, respectively. Symptom enrichment analysis identified early predictive symptoms. Fatigue (17.2% vs 6.8%, p = 0.011) and rash (20.7% vs 7.8%, p = 0.0037) were predictive of hypothyroidism, while diarrhea (45.9% vs 31%, p = 0.048), constipation (5.4% vs 0.2%, p = 0.018), and taste changes (5.4% vs 0.5%, p = 0.034) were associated with AI. A predictive model demonstrated moderate performance (AUC 0.65 for AI, p < 0.0001; AUC 0.61 for hypothyroidism, p = 0.012). Model accuracy in an external validation cohort was 72.8% for AI and 74.7% for hypothyroidism. Conclusions This study presents a predictive framework to identify patients at risk for adrenal insufficiency and hypothyroidism as irAEs, enabling personalized care and proactive intervention to improve treatment outcomes and safety.

Abstract Background Emerging evidence suggests that premature ventricular contractions (PVCs) may influence atrial electrophysiology and remodeling, potentially leading to higher rates of atrial fibrillation (AF) recurrence. However, existing data is limited to small-scale studies. Therefore, we conducted a retrospective study to evaluate the potential association between PVCs and AF ablation outcomes, which may suggest the need for more aggressive management of ventricular ectopy in this population. Objective This study aims to assess the 5-year outcomes of catheter ablation for AF in patients with and without a diagnosis of PVCs. Methods Using the TriNetX Analytics Research Network, we included patients aged ≥ 18 years who underwent AF catheter between January 1, 2014, and January 1, 2020. Patients were further categorized into two groups based on the presence of a diagnosis of PVCs. Propensity score matching (PSM) was performed using patient demographics, left ventricular ejection fraction (LVEF), cardiac comorbidities, and medications. Study outcomes included all-cause mortality & hospitalization, acute heart failure (HF), and rhythm control interventions during a 5-year follow-up. Results A total of 15,987 patients with PVCs and 40,605 patients without PVCs were identified. After PSM, 15,152 patients from each group were included for further analysis. Compared to control group, patients with PVCs had significantly higher odds of all-cause mortality (odds ratio [OR], 1.138; 95% confidence interval [CI], 1.034–1.253), all-cause hospitalization (OR, 1.300; 95% CI, 1.243–1.360), acute heart failure (HF) (OR, 1.223; 95% CI, 1.162–1.287), and cardiogenic shock (OR, 2.059; 95% CI, 1.751–2.420) following catheter ablation for AF at 5-year follow-up. Additionally, higher odds of AF requiring cardioversion (OR, 1.135; 95% CI, 1.074–1.199) or repeated ablation (OR, 1.164; 95% CI, 1.085–1.249) were observed in the PVCs group. Conclusion Premature ventricular contractions were associated with poorer clinical outcomes and a higher odds of requiring additional rhythm control intervention following catheter ablation for AF. These findings suggest that PVCs may be a marker for worse outcomes after AF ablation.

Complex bidirectional interactions between the nervous and cardiovascular systems are integrated through the heart–brain axis, a physiological pathway that governs both neural regulation of cardiovascular function and cardiovascular influences on brain health. Emerging evidence indicates that even in the absence of overt disease, subclinical changes in the heart, aortic arch, and extracranial arteries contribute to brain injury and cognitive vulnerability. This review synthesizes current knowledge on how subclinical heart–brain axis dysfunction affects brain structure and function, highlighting the roles of central and autonomic neural pathways as well as hormonal signaling in driving neurological decline. Key biomarkers linked to silent brain injury, cognitive decline, and dementia are discussed, emphasizing their potential for early risk stratification and as targets for preventive interventions. We also outline mechanistic pathways connecting subclinical heart–brain axis dysfunction to adverse brain outcomes, identify major gaps in current evidence, and propose priorities for future research and clinical trials aimed at early detection and risk reduction to preserve brain health.

Abstract Introduction The Hunger Vital Sign (HVS) is a two‐item, validated food insecurity screener recommended by the American Academy of Pediatrics. Given its brevity, HVS could be useful in assessing food insecurity in pregnant populations, for whom high‐quality nutrition and food access is essential. However, the HVS has not been evaluated in obstetric settings. Thus, we aimed to evaluate the performance of the HVS compared to the gold standard, the 18‐item US Household Food Security Survey Module (HFSSM) among low‐income, urban pregnant people. Methods We conducted a prospective study at a multi‐hospital tertiary health system (September 2023 to April 2024) in the United States. English‐ or Spanish‐speaking individuals from zip codes in which ≥10% of households were under the federal poverty line or who had publicly funded antenatal care completed a 20‐min self‐administered survey, which included the HFSSM and HVS. Food insecurity was defined as marginal, low, or very low food insecurity on the HFSSM; the prevalence of food insecurity was assessed and evaluated by participant characteristics. A positive screen on the HVS was defined as a “often true” or “sometimes true” to either item. Descriptive statistics were performed to characterize the performance of the HVS compared to the HFSSM. Results Of 713 potentially eligible participants based on medical record review, 192 (27%) completed an eligibility screener and were found to be eligible. Of these, 171 (89%) completed the survey. Nearly half (41%) of participants ( n = 70; of whom 74% received publicly funded care) screened positive for food insecurity on the HFSSM. HVS sensitivity was 83%, while specificity was 96%. The positive predictive value of the HVS was 94% and negative predictive value was 89%. Conclusion The two‐item HVS had relatively high accuracy for detecting food insecurity in this low‐income, urban obstetric population. Incorporating this brief screener into prenatal care may enable efficient, clinically useful food insecurity detection and intervention to address this need.