Citations

Abstract Background: The Breast Cancer Index (BCI) is clinically validated to stratify patients with hormone receptor-positive (HR+), early-stage BC based on the risk of overall (0-10 years [y]) and late (5-10 y) distant recurrence (DR) with N0/N1 lymph node involvement. Validation of BCI in patients with HR+ HER2+ BC has been limited, especially in patients treated with adjuvant trastuzumab-based chemotherapy. The HOXB13 and IL17BR genes constitute the predictive component of BCI and are known to exhibit an ER-dependent correlation pattern with HER2. We evaluated the prognostic performance of BCI in patients with HR+ HER2+ disease enrolled in the NCCTG N9831 (Alliance) trial treated with the combination of chemotherapy and trastuzumab. Methods: All available tumor specimens from patients with HR+ HER2+ N0/N1 BC in arms B (sequential trastuzumab) and C (concurrent trastuzumab) of the trial were included. BCI testing was performed blinded to clinical outcomes. The primary endpoint was distant recurrence-free interval (DRFI). BCI (N0) and BCIN+ (N1) risk groups were calculated based on prespecified cut points. Kaplan-Meier analysis and log-rank testing were used to assess the prognostic significance of BCI/BCIN+ risk groups based on DR. Cox proportional hazard models with and without clinical covariates were used to estimate hazard ratios (HRs), and the associated 95% confidence intervals (CIs). Results: A total of 454 HR+ patients (234 arm B, 220 arm C), including 69 N0 and 385 N1 patients, were analyzed (median age was 47 y, 85% N1, 55% T2, 63% G3). BCIN+ scores were available for 378 of the 385 N1 patients due to missing tumor grade for 7 patients. The median follow-up was 12.7 years. In the overall cohort, BCI/BCIN+ stratified 51 (11%), 24 (5%) and 372 (83%) patients as low-, intermediate- and high-risk with 10-y DRFI rates of 96% (95% CI: 84-99%), 100% (100-100%) and 89% (86-92%), respectively. Since the low and intermediate risk groups had few patients and a similar risk of 10-y DRFI, they are combined into a single low-risk group hereafter. Thus, for overall 10-y DR, 75 (17%) and 372 (83%) of patients were classified by BCI/BCIN+ as low and high risk with 10-y DRFI rates of 97% (95% CI: 89-99%) and 89% (95% CI: 86-92%), respectively (HR=4.50, 95% CI: 1.09-18.61; p = 0.038). BCI/BCIN+ remained statistically significant in the multivariable analysis, adjusting for age, treatment, and nodal status (HR=7.54, 95% CI: 1.34-42.64; p = 0.022). For 69 N0 patients, BCI stratified 54 (78%) and 15 (22%) patients as low and high risk with 10-y DRFI rates of 100% (95% CI, 100-100%) and 77% (95% CI, 44-92%), respectively (p = 0.012). For 378 N1 patients, BCIN+ stratified 21 (6%) and 357 (94%) of patients as low and high risk with 10-y DRFI of 90% (95% CI, 66-97%) and 90% (95% CI, 86-93%), respectively (p = 0.07). Of the 21 patients classified as BCIN+ low-risk, two had BCIN+ scores of 6.75 and 6.73 in close proximity to the cut point (6.93) and experienced DR after 5 years, resulting in the same 10-y DRFI for both BCIN+ low- and high-risk patients. Conclusions: BCI is significantly prognostic for the risk of overall DR (0-10 y) in patients with HR+ HER2+ disease treated with adjuvant trastuzumab-based chemotherapy. Optimization of BCI cut points may further improve prognostic performance in HR+ HER2+. Additional validation in other HR+ HER2+ cohorts treated in the modern setting with anti-HER2-based therapy is warranted, given the small sample size of N0 patients and relatively low DR rate in the late recurrence cohort. In summary, these results provide further evidence of BCI’s utility to support clinical decision-making for adjuvant endocrine therapies for HR+ HER2+ BC. Support: U10CA180821, U10CA180882, U24CA196171, Genentech; Clinicaltrials.gov Id: NCT00005970; https://acknowledgments.alliancefound.org. Citation Format: S. Chumsri, E. Liu, K. Edwards, Y. Wen, Y. Zhang, A. K. Anderson, A. H. Partridge, L. Carey, K. Ballman, E. Perez, K. Treuner, M. Goetz, E. Thompson. Prognostic performance of Breast Cancer Index in patients with early-stage HR+ HER2+ breast cancer (BC) treated with adjuvant trastuzumab: NCCTG N9831 (Alliance) [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 PS3-08-08.

Objectives: Cerebral hemodynamic impairment in patients with asymptomatic high-grade internal carotid artery (ICA) stenosis confers a risk of stroke and cognitive decline, but correlations between degree of stenosis and hemodynamic impairment are derived from small case series only. Using baseline data from 282 participants in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis – Hemodynamics (CREST-H) study, we hypothesized that degree of stenosis, measured by peak systolic velocity (PSV) and end diastolic velocity (EDV) in the ipsilateral ICA, would correlate with time-to-peak (TTP) delay using MR (n=275) or CT (n=7) perfusion scans, adjusting for demographic and cardiovascular risk variables. Methods: Using a 7-10MHz Doppler probe, ICA PSV and EDV were assessed. Doppler results were adjudicated centrally. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using sequential T2*-weighted time-sequence scanning (e.g. TR=1500, TE=25ms, flip angle=60deg, phase=128, slice thickness=5mm for GE 3T magnet). CTP was acquired with standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral MCA/ACA territories using OLEA software. Linear regression used TTP delay as the outcome variable and PSV and EDV as predictor variables, adjusting for covariates.The 282 with complete data for all variables were included in the analysis. Results: Among 392 CREST-H participants, 63% were men, 7% Black, 3% Hispanic, 33% with less than college education. Tables 1a/b show the regression results for PSV and EDV as main predictor variables. PSV and EDV on the index side significantly correlated with TTP delay (p=0.004, p=0.002 respectively). Neither PSV nor EDV on the non-index side correlated with TTP delay (p=0.49, p=0.82). Compared with moderate exercise, vigorous exercise correlated with lower TTP delay in both models (p=0.05. p=0.04). Compared with college graduates, those with HS education had longer TTP delays in both models (p=0.03. p=0.02). Conclusions: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher flow velocities correlated with greater TTP delays, suggesting an increasing hemodynamic impairment with greater degree of stenosis above 70%. Our findings have implications for management of asymptomatic carotid stenosis which are being tested in the CREST-H and CREST-2 studies. Exercise and education may independently impact cerebral hemodynamics.

BACKGROUND: Cerebral hemodynamic impairment in patients with asymptomatic high-grade (>70%) internal carotid artery (ICA) stenosis is associated with risk of stroke and cognitive decline, but correlations between the degree of stenosis and hemodynamic impairment are derived from small case series. Using baseline data from 242 participants in the CREST-H study (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics), we hypothesized that the degree of stenosis in the ICA would correlate with time-to-peak (TTP) delay in ipsilateral cerebral blood flow using MR/CT perfusion scans, adjusting for demographic and cardiovascular risk variables. METHODS: From all participants, ICAs were insonated using a 7 to 10 MHz probe for peak systolic velocity (PSV) and end diastolic velocity. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using standard sequential T2*-weighted perfusion imaging. CT perfusion used standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral hemispheres. In cross-sectional analysis, linear regression was used to model TTP delay as the outcome variable and PSV, end diastolic velocity, and PSV ICA/common carotid artery ratio on the index and nonindex side as primary predictor variables in 6 separate models, adjusting for covariates, followed by automated backward elimination model reduction. RESULTS: Among 392 CREST-H participants, the 242 with complete data for all variables were included in the regression analysis (age, 70±7.6; 62% M). End diastolic velocity on the index side correlated with TTP delay (β=0.003, P =0.005). PSV had a similar correlation but did not reach significance (β=0.001, P =0.099), nor did ICA/common carotid artery ratio (β=0.003, P =0.126). Nonindex side PSV, end diastolic velocity, and ICA/common carotid artery ratio showed no correlation with TTP delay ( P =0.268, P =0.495, P =0.380, respectively). Circle of Willis completeness did not correlate with TTP. CONCLUSIONS: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher end-diastolic flow velocities correlated with greater TTP delays, supporting a definition of hemodynamically significant stenosis. Our findings have implications for the management of asymptomatic carotid stenosis, which will be tested in the CREST-H study. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03121209.

Abstract Aims Heart failure (HF) with preserved (HFpEF) and mildly reduced (HFmrEF) ejection fraction are prevalent, yet frequently underdiagnosed syndromes associated with high morbidity and mortality, impaired quality of life, and escalating healthcare expenditures. Although guideline-directed medications like SGLT2 inhibitors have been shown to reduce the risk of hospitalization and cardiovascular death, their use remains limited and substantial residual risk persists. This trial aims to evaluate the safety and performance of a novel left-atrium-to-coronary-sinus shunt (Edwards APTURE transcatheter shunt system) in HFpEF and HFmrEF patients. Methods ALT-FLOW II is a prospective multi-centre, randomized, sham-controlled, double-blinded (patient and assessor) trial. Approximately 100 symptomatic HF patients aged ≥18 years with left ventricular ejection fraction >40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mm Hg with a PCWP to right atrial pressure gradient ≥8 mm Hg will be randomized 1:1 to the APTURE shunt vs sham control. Key exclusion criteria include severe HF, significant valvular disease, and more than mild right ventricular dysfunction. The primary endpoints are the safety of the APTURE device at 30 days and change in workload-corrected PCWP normalized to bodyweight at 6 months. Secondary endpoints include changes in patient-reported outcomes, and hemodynamic and echocardiographic parameters through 5 years. The trial will also explore the impact of the device on short-term cardiac remodelling and intra-cardiac flow patterns using multi-modality imaging. Conclusions The ALT-FLOW II trial will evaluate the safety and performance of the APTURE system in symptomatic HFpEF and HFmrEF patients with elevated left atrial pressure.

Multiplex immunofluorescence and immunohistochemistry (mIF/IHC) are increasingly employed antibody-based technologies that use tissue sparingly and facilitate the detection of co-localized or neighboring biomarkers. Specifically, these platforms enable spatial analyses of the tumor microenvironment as well as extended applications, for example, describing normal tissue anatomy, autoimmunity, infectious diseases, etc. mIF/IHC has greatly enhanced biomarker discovery efforts, and a growing number of studies suggest superiority to traditional IHC. Standardization of staining approaches, reporting of image analysis strategies and resultant data is critical for facilitating cross-study comparisons, validation, deployment, and generalization of findings. To address this challenge, The Society for Immunotherapy of Cancer (SITC) previously published two articles providing best practice guidelines for mIF/IHC staining, image analysis, and data sharing. Here, SITC convened stakeholders to develop the third article in the series, a consensus checklist for scientific reporting of mIF/IHC data to support and complement the best practice guidelines. The checklist includes critical components of mIF/IHC applications to be defined within publications such as detailed descriptions of analytical validation; image acquisition, selection, and registration methods; and cell clustering and spatial analysis strategies, amongst others. Such information will help with data reproducibility and comparison across studies towards future drug and assay development.

Abstract Zieve's syndrome is a rare and often overlooked complication of alcohol misuse, likely under-recognized due to limited physician awareness. We present a unique case with an atypical and misleading clinical presentation that initially raised concern for a hepatic mass. Despite the diagnostic uncertainty, the astute clinical vigilance and thoughtful evaluation by the treating team led to the correct diagnosis of Zieve's syndrome. This case highlights the importance of maintaining a broad differential and considering alcohol-related syndromes even when initial findings suggest alternative etiologies. We present the case of a 29-year-old man with a history of essential tremor managed on propranolol, who was transferred for further evaluation of worsening jaundice following a brief, self-resolving viral-like illness. He denied abdominal pain, ongoing gastrointestinal symptoms, intravenous drug use, or alcohol intake. Initial CT abdomen/pelvis showed hepatic steatosis and a 4.5 × 2.5 × 7.0 cm lobulated hypodense lesion in the right hepatic lobe, raising concern for pyogenic abscess versus neoplasm. Gallbladder wall was mildly thickened (5 mm) without pericholecystic fluid or biliary dilation. He was transferred for further evaluation. Laboratory evaluation revealed macrocytic anemia (Hb 9.9 g/dL, MCV 102 fL), thrombocytopenia (PLT 148), markedly elevated bilirubin (total 12.9 mg/dL, direct 6.8 mg/dL), transaminitis (ALT 93 U/L, AST 217 U/L), and evidence of hemolysis with low haptoglobin (30 mg/dL), elevated LDH (339 U/L), and a low reticulocyte count (0.39%). Sodium was 127 mmol/L, and INR was normal. Hepatitis viral panel, urine drug screen, and urinalysis were negative. Lipid panel revealed extreme hyperlipidemia with triglycerides 1500 mg/dL, LDL 687 mg/dL, and total cholesterol 1300 mg/dL. Peripheral smear showed macrocytic anemia with mild anisocytosis, slight polychromasia, and mild red blood cell agglutination. RUQ ultrasound showed hepatic steatosis with no focal lesion. MRI liver protocol revealed hepatomegaly and diffuse hepatic steatosis with sparing in the falciform ligament, gallbladder fossa, and portions of the right hepatic lobe explaining the CT “lesion” as focal fat sparing rather than a true mass. Although the patient denied alcohol misuse, phosphatidylethanol (PEth) testing was positive, confirming recent heavy alcohol consumption. The clinical picture was consistent with alcohol-associated liver injury, hemolysis, and secondary hyperlipidemia. In conclusion, Zieve's syndrome is characterized by a triad of hemolytic anemia, cholestatic jaundice, and transient hyperlipidemia. Prompt recognition of this underdiagnosed condition is crucial, as it can prevent unnecessary invasive interventions and shift the clinical focus toward supportive care and alcohol cessation, which remains the cornerstone of treatment.