Citations

Abstract Introduction: We aimed to characterize the preclinical pharmacokinetics (PK) of a series of 20 anticancer agents in highly immunodeficient female NOD scid gamma (NSG) mice to provide clearance and exposure data for agents under investigation by the NCI PDX Development and Trial Centers Research Network (PDXNet). Methods: The series of 20 anticancer agents (inhibitors of CDK4/6, PI3K-β/PI3K-δ, ATR, MEK1/2, PI3K, microtubule, EZH2, BCL-2, PARP, histone deacetylase, γ-secretase, FGFR, SHP2, and ERK1/2, as well as a SMAC mimetic) were administered to female NSG mice via IV, PO, or IP routes to characterize plasma exposures under conditions used for PDX efficacy testing. Serial plasma samples were collected 15, 30, 60, 120, 240, 360, 480, and 1440 minutes after dosing. Drug concentrations were quantified using validated LC-MS/MS assays. PK parameters were calculated using non-compartmental analysis. Results: The PK for each agent was determined, and the clearance and half-life values are listed in the table below. The PK metrics for Navitoclax could not be calculated. Due to higher metabolic rates, mice show faster PK processes. They generally had shorter half-lives and higher weight-normalized clearance than humans. Copanlisib, Navitoclax, and Trametinib were exceptions. Conclusion: These PK data are critical for understanding the antitumor activities of agents studied by the PDXNet and will aid investigators in developing new approach methodologies for preclinical safety studies in preparation for human clinical trials. Citation Format: Mohd Beshr Chama, Emily J. Koubek, Sarah A. Buhrow, Renee A. Schoon, Joel M. Reid. Pharmacokinetics of a series of anticancer agents in immunodeficient female NOD scid gamma mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3156.

Abstract Background: Epidemiologic and other studies have identified environmental, occupational, and genetic risk factors for lymphoid and myeloid malignancies, but most studies have been conducted in Western populations. Investigations in populations with differing exposure patterns, distributions of disease subtypes, and genetic architecture are needed to fully understand hematopoietic tumor etiology. Methods: We conducted a large, multicenter, hospital-based case-control study of lymphoid and myeloid neoplasms in East Asia (AsiaLymph), including 5,671 lymphoid cases, 1,879 myeloid cases, and 3,858 controls. Participants completed a computer-assisted personal interview and provided biospecimens. Cases underwent central pathology review and were coded into the WHO Classification. Herein, we describe the study methods in detail and report association results for education, body mass index, and family history. Results: Greater BMI at age 20 but not at age 40 was associated with odds of total lymphoid neoplasm (per 5 kg/m2 increase: OR [95% CI]: 1.18 [1.09-1.27]), total myeloid neoplasm (OR [95% CI]: 1.17 [1.05-1.29]), and several subtypes. Greater educational attainment was associated with increased odds of total lymphoid neoplasm (for college vs. less than primary education: OR [95% CI]: 1.41 [1.21-1.65]) but not myeloid neoplasm (OR [95% CI]: 1.17 [0.95-1.45]; p-heterogeneity=0.02). There were also positive associations between family history of hematologic cancer in first degree relatives and odds of lymphoid neoplasm (OR [95% CI]: 1.53 [1.15-2.03]) and myeloid neoplasm (OR [95% CI]: 1.65 [1.11-2.44]) and specific subtypes. None of the evaluated risk factors were associated with NK/T-cell lymphoma, which supports a distinct etiology for this subtype. Conclusion: The AsiaLymph Study is one of the largest molecular epidemiology studies of both lymphoid and myeloid neoplasms with standardized World Health Organization classification of histopathologic subtypes and will serve as a valuable resource for etiologic investigations into risk factors for these malignancies. Citation Format: Qing Lan, Lauren M. Hurwitz, John K. Chan, Tai Hing Lam, Kexin Chen, Yok Lam Kwong, Xu Caigang, Brian CH Chiu, Raymond Liang, Ip Dennis, Wei Hu, Bryan Bassig, Mark Purdue, Jun Xu, Sarah Locke, Sophia S. Wang, James R. Cerhan, Sonja Berndt, Jonathan N. Hofmann, Jianxin Shi, Kai Yu, Shahinaz Gadalla, Lisa J. McReynolds, Rena Jones, Hongji Dai, Zhangyan Lyu, Lugui Qiu, Wei Liu, Huilai Zhang, Xianhuo Wang, Lindsay M. Morton, Stephen Chanock, Martha Linet, Melissa C. Friesen, Roel Vermeulen, Nathaniel Rothman. A multi-center hospital-based case-control study of lymphoid and myeloid neoplasms (AsiaLymph): Study design and initial findings for education, body mass index, and family history [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5051.

Abstract The detection of genetic abnormalities is required during diagnostic workup and for potential individualization of therapy selection in multiple myeloma (MM) and its precursor conditions. At present, this relies on invasive bone marrow (BM) biopsies, severely limiting early detection, frequent longitudinal monitoring, and the precise selection of therapy. The current standard for detecting genetic alterations in MM is fluorescence in situ hybridization (FISH), which cannot detect point mutations and other clinically relevant alterations. Consequently, the IMS-IMWG guidelines were recently updated to require next-generation sequencing for the classification of high-risk MM. To address these needs, we recently launched GenoPredicta, a CLIA-approved LDT that enables routine monitoring, informing diagnosis, and treatment selection by comprehensively characterizing MM genomes with whole genome sequencing (WGS) from as few as 50 circulating tumor cells (CTCs) isolated from peripheral blood (PB) or tumor cells from BM. Briefly, tumor cells are isolated from samples using fluorescence-activated cell sorting and subjected to WGS, from which copy number alterations, structural variants, and short variants (SNVs/indels) are identified using a fully automated pipeline generating physician-ready clinical reports from raw sequencing data in ∼6h. Analytical validation of GenoPredicta showed complete concordance with FISH results. Identifying alterations in therapeutic targets (e.g., BCMA, GPRC5D) for guiding MM immunotherapies is becoming increasingly important. Here, we describe GenoPredicta results from relapsed/refractory MM patients, highlighting resistance-conferring alterations that can only be detected by WGS, such as deletions in the kilo- to megabase scales that are observed in conjunction with SNVs and indels, leading to biallelic loss/inactivation of the gene, including at subclonal levels. In addition to biallelic loss of BCMA and GPRC5D in response to CAR T or T cell engager therapies, we observed similar resistance mechanisms for targets of immunomodulatory drugs, e.g., CRBN. The observation of these resistance mechanisms was consistent with patients’ clinical histories. In summary, we demonstrate that low input WGS-based characterization of MM from BM or CTCs is a viable replacement for FISH for clinical diagnosis and monitoring, with CTC-based measurements enabling comprehensive profiling of the MM genome. Crucially, this includes genetic alterations that confer resistance to therapy, allowing for both early detection of such alterations and more precise selection and guidance of therapy. The dramatically improved variant calling ability from WGS, especially in low-input CTC applications, extends to other malignancies and will gain wider adoption as sequencing costs continue to decrease. Citation Format: Bruno Paiva, Peter Voorhees, Patricia T. Greipp, Danielle Sookiasian, Julian Hess, Marisa DeMeo, Vicki Pounder, Sarah Calkins, Reid Meyer, Linda B. Baughn, Christine-Ivy Liacos, Meletios-Athanasios Dimopoulos, Alexandra Papadimou, Taouxi Konstantina, Efstathios Kastritis, Jesus Berdeja, Daniel Auclair, Valentina Nardi, Thomas Mullen, Francois Aguet, Shaji Kunnathu Kumar. Whole genome sequencing of multiple myeloma genomes with a novel clinical assay enables identification of genetic alterations underlying immunotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1067.

Abstract Introduction Detecting and estimating blood volume loss are important for the diagnosis and management of life-threatening hemorrhage. There is a direct relationship between percent blood volume loss (BVL%) and falling in stroke volume (SV); furthermore, there is a direct relationship between diminishing SV and the corrected flow time of the carotid artery (ccFT). Therefore, we hypothesized that change in ccFT (ccFTΔ) would directly relate with BVL% in a phlebotomy paradigm. Materials and Methods A prospective, convenience sample of healthy volunteers was studied. Volunteers underwent blood donation protocol in a physiology lab. A wireless, wearable Doppler ultrasound system monitored ccFT during blood donation. Traditional vital signs were also measured throughout. The relationship between traditional vital signs as well as ccFTΔ were compared to BVL% using 2 mixed linear regression models. Results Data from 20 subjects and blood donations comprising 46,123 cardiac cycles are included. On average 413.5 ± 39 mL of blood were drawn representing 8.6 ± 1.6% BVL%. There was a significant and strong linear relationship between BVL% and ccFTΔ during blood draw with the regression slope demonstrating that for every 1 ms reduction in ccFT there was a 0.4% reduction in blood volume. Conclusions In healthy subjects and when blood loss is the sole mechanism for falling SV, we estimate that for every 1 ms reduction in ccFT, there is an approximate 0.4 BVL%. Validation of these results in patients with traumatic hemorrhage is underway.

Abstract Background DDX3X- syndrome is a rare neurodevelopmental disorder characterized by varying degrees of intellectual disability, predominantly affecting females. We present an institutional cohort supplemented by a systematic literature review, expanding the cardiovascular phenotype of DDX3X- syndrome. Methods We conducted a retrospective chart review of patients diagnosed with DDX3X -syndrome at Mayo Clinic. Additionally, we performed a systematic literature review to identify studies reporting cardiovascular abnormalities in patients with DDX3X -syndrome. Results A total of 200 patients with DDX3X -syndrome were analyzed, comprising 14 patients from our institutional cohort and 186 patients identified through a systematic review of 9 published studies. Our institutional cohort included 14 patients (12 females and 2 males) from 13 unrelated families diagnosed with DDX3X -syndrome, at a median age of 4.5 years (IQR 1.2–9.5). Echocardiogram was performed on nine patients, and cardiovascular abnormalities were found in 7 out of 9 patients who underwent echocardiography (78%), two of whom had major congenital heart defect (CHD) requiring surgical intervention. At the time of assessment, 13 individuals were still alive, while one had died at age six due to extracardiac complications. The systematic review included 9 studies involving 186 patients, of whom 32 (17.4%, 25 females and 7 males) had reported cardiovascular abnormalities, ranging from simple CHDs to more complex defects. Conclusion DDX3X -syndrome carries a significant cardiovascular burden, which is possibly higher than previously reported, including complex congenital heart disease requiring surgical repair. A thorough cardiovascular assessment, including an electrocardiogram and echocardiogram, should be universally recommended for all patients at the time of diagnosis.

Abstract Professional identity is defined as the attitudes, behaviors, values, and experiences by which individuals define themselves in a professional role and is influenced by socialization during training and in the workplace. As professional identity develops and is integrated with one's personal identities, it allows an individual to think, act, and feel like a member of their chosen profession and to develop a sense of meaning, confidence, and satisfaction in their work. Conflicts may arise due to perceived differences between one's professional identity and the collective identity of the profession, resulting in stress, burnout, and attrition, all of which can negatively impact patient care and the collective identity of the genetic counseling profession. Using Social Identity Theory (SIT) as a theoretical framework to develop the semi‐structured interview protocol, recorded interviews were conducted with 50 genetic counselors who were purposefully sampled to ensure diversity of personal demographics (gender, race/ethnicity, sexual orientation, disability, and caregiver status), as well as years, settings, and roles in genetic counseling practice. Transcripts were coded and subjected to codebook thematic analysis using NVivo. Genetic counselors described their professional identity in terms of who they are (characteristics and attributes), what they do (actions and skills), and what they have (training and knowledge). The majority of participants had a multidimensional perspective of what it means to be a genetic counselor, noting the transferability of their skills to a broad set of roles and settings, which supported their sense of professional identity, particularly for those who were no longer seeing patients. Yet many expressed tension with the collective identity of the profession. Expanded opportunities for genetic counselors to work in new settings and roles require review and revision of key professional documents to ensure they are reflective of the collective identity of the genetic counseling profession.

ABSTRACT The normal adult male breast has not been characterized at single-cell resolution, leaving the cellular basis of male breast cancer (MBC) biology undefined. Here we present an integrated single-cell RNA sequencing atlas of the adult human breast comprising 174,471 cells from 17 donors (3 male, 14 female), including 18,117 male-derived cells. This revealed that the male breast retains all three epithelial populations, basal (BC), luminal progenitor (LP), and luminal committed cells (LC), but with an increase in LC at the expense of BC and LP across all three male donors. Male LC were distinguished from female by elevated ESR1 and PGR mRNA, enrichment of RNA processing and ribosome biogenesis programs, reduced inflammatory cytokine and growth factor signaling, elevated estradiol gene set enrichment scores, and higher inferred activity of developmental patterning transcription factors. This pattern was observed across differential expression, gene ontology, ligand profiling, and regulon-based analyses, and was not restricted to sex chromosome-linked gene expression. This is consistent with the near-universal estrogen receptor (ER) positivity that characterizes MBC clinically. This atlas provides the first cellular and transcriptional reference for the normal male breast and a resource for investigating sex differences in mammary biology, germline susceptibility variant interpretation, and modeling breast malignancies.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

Abstract Objectives Patients referred for specialized care often arrive with outside medical records (OMRs) compiled into multi-report PDFs that include imaging, pathology, and clinical notes in unstructured formats. Reviewing these records is time consuming and mentally taxing, increasing the risk of delayed care, clinician frustration, and missed information affecting quality of care. This study aimed to automate the segmentation, classification, and date extraction of scanned OMRs, with a focus on records relevant to breast cancer care. Materials and Methods We used optical character recognition (OCR) to extract machine-readable text from 1303 scanned PDF documents from 116 distinct external institutions. Gemini 1.5, a large language model (LLM), was then used to segment multi-report files into individual documents, classify them into clinically meaningful categories such as mammograms and pathology reports, and extract study dates to build diagnostic timelines. Document categories were informed by clinical workflows in a breast cancer center. Results The system achieved an F1 score of 0.95 for segmentation, 0.96 for classification, and 0.90 for date extraction. In a pilot of 45 records reviewed by clinicians, only 2 classification errors and 1 date error were reported. Clinicians estimated that the tool reduced OMR review time by 40%, improved workflow efficiency, and increased satisfaction. Discussion Our findings demonstrate that combining OCR with LLMs can significantly enhance the processing of unstructured medical records, reducing manual burden and supporting timely clinical decision-making. Conclusion This study demonstrates the successful application of OCR and LLMs for organizing scanned OMRs within a specialty clinic. By automating a previously manual process, the approach supports scalable review of incoming outside records and has potential for adaptation to other clinical workflows. Future work will focus on evaluating the system across additional specialties and institutions.