Citations

Background Mortality in adults with congenital heart disease (CHD) is strongly driven by disease complexity. Social determinants of health (SDOH) influence adult CHD (ACHD) health outcomes but their impact on mortality is unclear. This study examined the influence of clinical factors and SDOH on all‐cause mortality in patients with ACHD. Methods Single‐center retrospective cohort study of patients with ACHD in the Mayo ACHD Registry who had a verifiable residential address between January 1, 2004 and December 31, 2023. Clinical and SDOH indicators were extracted, including insurance type, language, rural–urban commuting area code, and a housing‐based socioeconomic index, an individual‐level measure of socioeconomic status derived from 4 objective housing characteristics and categorized into quartiles (Q1–Q4). Cox proportional‐hazards models were fitted to evaluate associations with mortality, incorporating CHD severity, arrhythmias, SDOH indicators, and other comorbidities. County of residence was included as a random effect, and model discrimination was assessed using the concordance statistic. Results Among 6134 patients with ACHD, the mean age was 38±16 years; 51% were male; 78.7% were White and 44.9% had rural residence. Independent predictors of mortality included cyanotic CHD (adjusted hazard ratio [aHR], 5.70 [95% CI, 2.90–11.23]), Fontan palliation (aHR, 4.98 [95% CI, 2.56–9.70]), ventricular tachycardia (aHR, 1.71 [95% CI, 1.16–2.52]), older age at first visit (aHR, 1.05 per year [95% CI, 1.04–1.05]), male sex (aHR, 1.19 [95% CI, 1.03–1.39]), public insurance (aHR, 1.60 [95% CI, 1.35–1.90]), rural residence (aHR, 1.25 [95%, CI 1.06–1.47]), and non‐English language (aHR 1.75 [95% CI 1.38–2.23]). The housing‐based socioeconomic index quartile was not associated with mortality. The final model achieved a concordance statistic of 0.77. Conclusions Mortality in patients with ACHD is strongly influenced by both clinical factors and SDOH, independent of socioeconomic status. Addressing barriers to care such as language, insurance, and geography is essential for improving ACHD survival particularly in those at increased mortality risk.

Functional neurological disorder (FND) is a prevalent neurologic condition, yet existing treatment approaches yield inconsistent outcomes. We propose a unifying framework that conceptualizes FND as a disorder triggered and perpetuated by individuals lacking targeted tools to reconcile the cumulative impact of intolerance of uncertainty (IU) and multidimensional allostatic overload. Expanding upon predictive coding and IU theories from neuroscience and psychology research, we argue that during times of uncertainty, individuals with FND exhibit a higher rate of prediction error but lack the energy, resources, and adaptive capacity to respond. This sustained hyperactivation of the brain and body trigger and perpetuate FND. We propose that FND treatment requires a strategic and progressively tiered behavioral approach. First, the individual with FND must be taught behavioral skills to gain immediate symptom control and shift automatic, hyperactive processes into conscious awareness. Only then, can practices from Acceptance and Commitment Therapy, Dialectical Behavioral Therapy, and Mindfulness Therapy be leveraged. These practices help explicitly identify sources of uncertainty and teach how to effectively respond to hyperactive processes with skills that optimize function, commitment to values, and well-being. This framework offers testable hypotheses and a pathway to more effective, individualized care for FND.

Abstract Background: Stromal tumor infiltrating lymphocytes (sTILs) are associated with improved response to chemotherapy and better overall survival (OS) in triple-negative breast cancer (TNBC). Quantification of sTILs via hematoxylin and eosin (H&E) tumor slides offers a widely available method to define a simple, effective surrogate for host anti-tumor immunity. Digitization of H&E slides has rapidly gained acceptance for use in diagnostic pathology and research, opening the door for image-based computational approaches to enumerate sTILs, among other features. Methods: We describe QuTILs - a multilayer perceptron-based framework to detect/enumerate TILs trained on >700,000 cells via The Cancer Genome Atlas Program (TCGA) slide images, implemented in the widely used open-source QuPath digital pathology suite. QuTILs was applied to digital H&E images using standard computing in primary breast tumors from phase 3 breast cancer clinical trials - CALGB 40502 (testing), CALGB 40601 and 40603 (validation) - in total 1,729 total images from 962 unique patients. The aims of this investigation were: 1) to assess the relationship between TIL patterns with overall or event-free survival outcomes; 2) to benchmark diverse image-based characteristics of TIL abundance and spatial architecture; and 3) to evaluate the association between image-based TIL levels and RNA-seq-based immune deconvolution metrics (CIBERSORT, EPIC, quanTIseq). Results: QuTILs average processing time was 7.9 minutes for whole-slide total TIL count and area density on a standard laptop workstation. In CALGB 40502, there was positive but modest correlation between pathologist TILs and QuTILs total TILs %, higher in the TNBC subgroup of CALGB 40502 (Pearson r = 0.55). In Cox proportional hazards models, the CALGB 40502 TNBC cohort showed significant univariate association for total TILs % with increasing decile (higher total TIL%) associated with reduced hazard (hazard ratio [HR]: 0.712, 95% CI: 0.559-0.906; P = 0.006), which remained significant in multivariable model incorporating age, race, and treatment arm (HR: 0.713, 95% CI: 0.556-0.915; P = 0.008). In validation TNBC clinical trial CALGB 40603, marginal TILs % was significant in the univariable Cox model (HR: 0.786, 95% CI: 0.639-0.966). Evaluation of TILs % by QuTILs with RNAseq-based deconvolution metrics in cohort-stratified and deconvolution method-stratified multivariable models showed that decile total TILs % by QuTILs was shown to significantly predict outcome in the EPIC (HR: 0.668, 95% CI: 0.466-0.957) and quanTIseq (HR: 0.646, 95% CI: 0.446-0.936) sets, with a similar magnitude as in clinical Cox, suggesting that RNA-based deconvolution estimates may not supplement the prognostic power of image-based TIL estimates. Exploratory analyses of pre- versus post-neoadjuvant therapy H&E images in CALGB 40603 and CALGB 40601 revealed a significant decrease in QuTILs total TIL% in CALGB 40603 for all pairs (n = 118 pairs, pre-median=9.52%, post-median=6.33%; Wilcoxon signed rank P < 0.001) but no significant change in QuTILs total TIL% among all pairs in CALGB 40601 (n = 82 pairs, pre-median=15.92%, post-median=15.10%; P = 0.886). Conclusions: QuTILs provides a computationally efficient open-source workflow for sTIL identification from digital H&E images that can be deployed on a standard laptop. We present the first evaluation of digital sTIL enumeration in CALGB 40502, CALGB 40603, and CALGB 40601 phase III breast cancer clinical trials and demonstrate significant prognostic association with QuTIL total TIL % among TNBCs across studies. Citation Format: M. Vater, R. Salgado, E. Blige, H. Lefebvre, A. Strahan, M. Gatti-Mays, H. Rugo, K. Ballman, M. Watson, Y. Wen, R. Leon-Ferre, K. Niazi, W. Symmans, L. Carey, K. AbdulJabbar, Z. Li, D. Stover. Qutils: open-source image-based infiltrating immune cell detection and outcomes in calgb 40502, calgb 40603, and calgb 40601 phase iii breast cancer clinical trials [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 PS2-07-27.

Abstract Background: PALLAS (PALbociclib CoLlaborative Adjuvant Study, NCT02513394) is a randomized phase III trial comparing two years of the CDK4/6 inhibitor palbociclib combined with the physician’s choice of adjuvant endocrine therapy, versus endocrine therapy alone for patients with Stage II-III hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer. Molecular residual disease (MRD) detection via circulating tumor DNA (ctDNA) testing was a predefined biomarker analysis to identify patients at highest risk of recurrence. Methods: PALLAS participants with available tumor block, at least a baseline (pre-study treatment) plasma sample, and either whole blood or buffy coat were randomly selected from the overall study population. Plasma samples on cycle 1 day 1 (C1D1), cycle 6 day 1 (C6D1), and at the end of treatment (EOT) were collected, processed, and stored. Nucleic acids were extracted from primary tumor tissue or, when primary tissue was insufficient, from post-neoadjuvant tumor tissue, provided the sample had sufficient material and tumor cellularity (>25 mm2 tissue area with ≥20% tumor nuclei). Data from next generation sequencing of tumor tissue and matched normal DNA were used to create a personalized ctDNA SignateraTM assay (Natera, Inc.) for MRD assessment in the peripheral blood. ctDNA was reported as mean tumor molecules/mL (MTM/mL) of plasma. The primary endpoint was distant recurrence-free interval (DRFI) based on ctDNA status. Cox Proportional Hazards models were used to evaluate prognosis and predictive interactions. To minimize bias, the biorepository and laboratory teams were blinded to participant identity. Results: In total, 1280 participants were randomly selected for inclusion in this preplanned ctDNA sub-study. WES and WGS are being conducted on tissue, and Signatera results will be generated. Results for association of MRD status (positive/negative) and MTM/mL with DRFI in the context of 7 year median follow up of this study cohort will be reported. Conclusions: The planned analysis is ongoing and the presented work will provide data from the first randomized phase 3 adjuvant study in HR+/HER2- breast cancer to report MRD status by treatment arm. Citation Format: H. A. Parsons, K. Ballman, E. Heitzer, M. Watson, M. Balic, D. Hlauschek, D. Renner, E. Kalashnikova, G. Steger, J. M. Balko, Y. Novik, M. Martin, A. A. Rodriguez, Z. Dayao, A. Chan, E. Nili Gal-Yam, M. C. Liu, C. Isaacs, M. Los, M. Gil Gil, B. Felder, C. Denkert, P. Fasching, F. Liu, T. O'Donnell, E. L. Mayer, M. Gnant, W. F. Symmans, A. DeMichele. Tumor-informed circulating tumor DNA analysis to assess molecular residual disease for prognosis and prediction of benefit from palbociclib in the PALLAS 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 RF3-04.

Abstract Background PALLAS trial compared palbociclib plus endocrine therapy (ET) vs. ET alone in stage II-III HR+/HER2- breast cancer. SETER/PR index quantifies transcriptional activity related to estrogen and progesterone receptors and serves as a measure of endocrine sensitivity. In CALGB 9741, low SETER/PR (< 0.75) - reflecting endocrine resistance - predicted survival benefit from adjuvant anthracycline/taxane-based treatment. In PALLAS low SETER/PR was associated with worse prognosis and early recurrence. Early recurrences driven by endocrine-resistant tumors may obscure the benefit of palbociclib by disproportionately contributing events from a more resistant population. We hypothesized that palbociclib efficacy might vary by endocrine sensitivity and prior chemotherapy regimen, with greatest benefit in patients with intermediate SETER/PR index. Methods Invasive disease-free survival (iDFS) was summarized with Kaplan-Meier plots and the treatment arms were compared with a log-rank test. Cox models estimated the hazard ratio (HR) with 95% confidence interval (95%CI) (significance level used was a two-sided 0.05). SETER/PR index was successfully obtained for 3,090 PALLAS patients (TransPALLAS ITT cohort, Metzger et al. ASCO 2024). SETER/PR index cut points (0.75 and 1.50) were proposed from previous studies comparing different adjuvant chemotherapy regimens. Results Table 1 summarizes the efficacy of adjuvant palbociclib by prior (neo)adjuvant chemotherapy regimen. Palbociclib was associated with longer iDFS in the group who received prior anthracycline-paclitaxel chemotherapy (AC-P), though the chemo regimen x palbociclib interaction term was not significant (Table 1). In the 1,132 patients from the TransPALLAS cohort who received AC-P chemotherapy, the 518 (46%) patients with intermediate SETER/PR (0.75≤ SETER/PR <1.50) had longer iDFS with palbociclib (HR 0.58; 95% CI: 0.40-0.84; p=0.004; 7-yr iDFS 80.2% vs. 68.4%), but this subset did not predict palbociclib benefit relative to all others, i.e., 206 (18%) patients with low SETER/PR (<0.75) and 408 (36%) high SETER/PR (≥1.50); P interaction=0.11. Exploratory analysis of SETER/PR index as a continuous variable in patients who received prior AC-P chemotherapy revealed a non-linear relationship with the hazard ratio favoring palbociclib observed in the subset with SETER/PR values between 1.1 and 1.8, compared to all others (P interaction=0.01). Conclusions In PALLAS, we observed a numerical benefit favoring palbociclib among pts treated with adjuvant AC-P; in this subset a moderate level of endocrine transcriptional activity (SETER/PR index between 1.1 and 1.8) predicted palbociclib benefit. These results are hypothesis-generating. Citation Format: O. Metzger, P. O'Brien, K. Ballman, M. Gnant, M. Watson, E. Chen, K. Tran, D. Hlauschek, M. Martin, J. Balko, Z. Nowecki, O. Hahn, C. Denkert, C. Curtis, F. Liu, A. Dueck, C. Fesl, E. Mayer, A. De Michele, W. Symmans. Exploratory analysis of palbociclib benefit in the PALLAS trial by SETERPR index and prior chemotherapy regimens (ABCSG-42/AFT-05/BIG-14-13) [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 PS3-08-13.

Abstract Background: Microtubule inhibitors remain a standard chemotherapy in the management of HER2-negative metastatic breast cancer (MBC). CALGB (Alliance) 40502 was a phase 3 randomized study involving 799 patients with MBC receiving first-line chemotherapy, to determine the optimal chemotherapeutic agent among paclitaxel, nab-paclitaxel, or ixabepilone (with or without bevacizumab). Secondary analysis suggested inferior PFS with nab-paclitaxel specifically among patients with hormone receptor positive (HR+)/HER2-negative breast cancer. Correlative analysis demonstrated significant association of stromal tumor infiltrating lymphocytes (sTILs) with improved progression-free (PFS) and overall survival (OS) in CALGB40502. We hypothesized that immune activation would be associated with differential benefit among distinct microtubule agents. To address this, we evaluated the sTILs and RNA-based immune features association with clinical outcomes, including evaluation of nab-paclitaxel versus paclitaxel. Methods: To limit heterogeneity, analyses focused on pre-treatment primary tumor breast samples with central review/pathologist-enumerated sTILs in accordance with International TILs Working Group methods and RNAseq (n = 280). PAM50 molecular subtypes were assigned based on transcriptomic features. RNAseq data were used to generate immune deconvolution estimates from 5 distinct algorithms (CIBERSORT, xCell, ABIS, ConsensusTME, ImmuCellAI). 1,018 curated breast cancer gene expression signatures GES) were derived from previously published studies. Associations between sTILs and GES were evaluated with sTILs being a categorical variable with the thresholds <5% (low) and (≥5%) high. Results: In the evaluable population, basal-like PAM50 subtype was enriched for high sTILs category (p=1e-4), as anticipated. T-cell and B-cell immune signatures and immune deconvolution estimates were among most highly associated with sTILs. In addition to the expected prognostic association of high T-cell GES, high B-cell-related IgG signature score was also significantly associated with improved overall survival (OS) among triple-negative breast cancer (TNBC) in CALGB 40502 (HR = 0.50,95% CI:0.30-0.86, log-rank p=0.01) but not in HR+/HER2-. In an exploratory analysis of young patients (age at study entry <50 years), high sTILs were associated with improved OS among TNBC patients but worse OS among those with HR+/HER2- MBC (HR = 2.19, 95% CI:1.10-4.36, log-rank p=0.022). High (above median) RNA-based Xcell total immune score was significantly associated with worse OS in both CALGB 40502 and a validation dataset of primary breast cancers, METABRIC (OS HR = 2.12, 95% CI:1.01-4.45, log-rank p=0.042). To further investigate the clinical trial finding of inferior PFS for nab-paclitaxel compared with paclitaxel in patients with HR+/HER2- MBC, there was a significant enrichment of T-cell signatures associated with poor outcome in patients receiving nab-paclitaxel (Fisher exact p<0.001). Conclusion: In this translational analysis of sTILs and RNAseq from a large phase III clinical trial, sTILs and immune signatures were not uniformly associated with better outcome. Rather, high sTILs or immune signatures were associated with worse OS in young patients with HR+/HER2- breast cancer and higher T-cell signatures were associated with inferior PFS with nab-paclitaxel among HR+/HER2- MBC patients. These data reinforce the importance of context/subtype-specific interrogation of the tumor-immune microenvironment Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. Bristol Myers Squibb (BMS); Clinicaltrials.gov Identifier: NCT00785291 Citation Format: E. K. Blige, K. V. Ballman, A. Michmerhuizen, M. Vater, L. A. Carey, A. H. Partridge, W. F. Symmans, M. A. Watson, C. M. Perou, D. G. Stover, H. S. Rugo. Rna-based immune features associated with benefit from distinct microtubule inhibitor therapy for metastatic her2-negative breast cancer: a post hoc analysis of the calgb 40502 (alliance) phase iii randomized clinical 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 PS1-13-17.

OBJECTIVE Spinal ultrasound is used to investigate occult dysraphism in neonates with sacrococcygeal dimples. Inappropriate imaging studies may be performed despite the Choosing Wisely Canada guidelines. The objective of this study was to assess the appropriateness of spinal ultrasounds performed in 2 Canadian provinces and to compare the diagnostic accuracy of spinal ultrasound and MRI in predicting the need for neurosurgical intervention. METHODS This multicenter retrospective cohort study identified spinal ultrasounds in neonates younger than 6 months of age from January 1, 2017, to December 30, 2018, in Alberta and British Columbia, Canada. The authors collected data on patient demographic characteristics, reasons for requested imaging, the presence of any imaging abnormalities, and the ultimate need for intraspinal surgery. Ultrasounds were deemed appropriate if the Choosing Wisely guidelines were followed for ordering. The authors compared high-risk findings on spinal ultrasound and MRI to the need for surgery using sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV). RESULTS A total of 1043 ultrasounds were ordered in 1042 neonates, most commonly by pediatricians (49%), family doctors (27%), and neonatologists (16%). Three hundred eighty-three ultrasounds (37%) were deemed inappropriately ordered. Sixty-nine infants (7%) of the cohort received an MRI and 11 (1%) ultimately underwent neurosurgical intervention. None of the patients who had an inappropriately ordered ultrasound underwent surgery. Spinal ultrasound, compared to surgery, had a sensitivity of 36%, specificity of 98%, PPV of 17%, and NPV of 99%. Spinal MRI, compared to surgery, had a sensitivity of 73%, specificity of 76%, PPV of 38%, and NPV of 94%. CONCLUSIONS Although spinal ultrasound has an acceptable specificity in predicting surgery, it remains a poor screening test (36% sensitivity). Given that approximately 37% of spinal ultrasounds were inappropriately ordered in this study period, the authors estimate that if physicians followed the Choosing Wisely Guidelines more closely, it would result in an estimated potential cost savings of CAD$1,856,769 over a decade for Canada with minimal surgical impact and a very low risk of missing surgically relevant spinal dysraphism.

Abstract This publication represents the first part of an update to the clinical practice guideline on the diagnosis and management of group A streptococcal (GAS) pharyngitis, developed by the Infectious Diseases Society of America (IDSA). Diagnosis of GAS pharyngitis by clinician judgment alone is unreliable, and universal testing incurs cost and inconvenience for individuals at low risk of having GAS infection. Clinical scoring systems have been used to quantify the probability of a positive GAS throat culture based on standardized criteria such as the presence of fever, tonsillar enlargement or exudate, tender and enlarged anterior cervical lymph nodes, and the absence of cough. The goal of this manuscript is to review the evidence and provide a recommendation as to whether a scoring system should be used to decide which patients should have a GAS diagnostic test (ie, rapid antigen test [RADT], molecular method, and/or throat culture) performed. We performed a systematic review of randomized and nonrandomized studies that compared the use of a clinical scoring system to clinician judgment alone in predicting the result of a throat culture. Evidence from studies in children and adults suggests the diagnostic accuracy is comparable or slightly higher using a scoring system compared to clinician judgment alone. Although the studies are limited due to small size, lack of uniformity in outcome measures, and incomplete data, the consensus of the panel is that the balance of benefits and harms favors incorporation of a clinical scoring system as part of the evaluation of patients with sore throat and suspected GAS pharyngitis.

Abstract Background Reference sets are needed to evaluate performance of multi-cancer detection (MCD) assays. The National Cancer Institute funded the Alliance reference set study to assess MCDs for use in future trials. Methods Individuals with cancer and controls were recruited; blood specimens were collected prior to cancer treatment. A performance evaluation study was designed utilizing reference set samples. Companies (n = 6) were selected to participate based on review of performance data and ability to utilize the blood collection tube. Companies received samples from cancer types their assay was designed to detect (“targeted”), plus additional “non-targeted” and control samples. Companies reported positive/negative calls, risk scores, and tissue-of-origin (TOO) predictions. Sensitivity was computed for early (I-II) and late (III-IV) stage cases, based on positive/negative calls (SEPN) and at fixed 98% specificity (SE98). Specificity and TOO accuracy were computed. Results Five hundred and forty nine cases (encompassing 13 cancer types) and 413 controls from the reference set were included in the study. Companies assessed samples from median 6 (range 5-9) targeted cancer types and median 8 (range: 7-11) overall cancer types. Median (range) specificity was 92.3% (76.5%-98.5%). Median (range) SEPN was 32% (25%-42%) for early stage and 73% (48%-89%) for late stage; while median (range) SE98 was 19% (8%-35%) for early stage and 66% (13%-79%) for late stage. Median sensitivity for non-targeted types was 40% (early stage) and 52% (late stage). Median (range) TOO accuracy (primary predicted site) was 75% (64%-78%). Conclusions Sensitivity and specificity varied widely across assays with early-stage sensitivity substantially lower than late-stage sensitivity. Clinical Trial Registration Number ClinicalTrials.gov identifier NCT05334069.