Citations

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and rare B-cell non-Hodgkin lymphoma with poor prognosis, even with treatment. Despite its clinical importance, the etiology of MCL remains largely unknown. Some studies have reported a positive association with family history, suggesting that genetic factors could contribute to risk. Methods: To identify germline genetic variants associated with risk, we conducted the first genome-wide association studies (GWAS) and GWAS meta-analysis for MCL, comprising 1,163 cases and 61,271 controls. The most significant loci were taken forward for replication in three independent studies, including 576 cases and 771,773 controls. To identify potential target genes and pathways of discovered loci, we conducted F-MAGMA, colocalization, and transcriptome-wide association study (TWAS) analyses. To gain insight into underlying regulatory mechanisms, we performed integrative epigenomic analyses using DNase I hotspots and histone mark ChIP-seq data across diverse cell types applying the FORGE2 framework. Results: In the joint analyses, we identified eight genome-wide significant loci (P<5x10-8) associated with MCL risk, several of which were located near genes with known DNA repair (ATM), telomere (TERT), or RNA-binding functions (RBM20). Further analyses using F-MAGMA, which uses DNase-seq data to prioritize genes from GWAS, identified genes that were significantly associated with risk, including SP140, a chromatin reader and immune regulator of pathogen response. This gene also displayed strong colocalization with our lead variant in whole blood (COLOC posterior probability PP4=0.97). TWAS demonstrated significant associations with SP140 and ACTA2, which has been linked to cell proliferation (P<3x10-6). Enrichment for DNase I hotspots was observed in B and T lymphocytes (q-value<0.05), providing evidence for a role in immune cell-specific regulatory regions. Enrichment for enhancer-associated histone mark H3K4me1 was observed in B cells (q-value<0.01), highlighting a role for immune cell-specific enhancers. Transcription factor (TF) motif enrichment analysis pointed to TFs critical for B-cell development and differentiation, notably TCF3 and EP300 (q<0.01 for both), suggesting an association between B-cell lineage regulation and MCL risk. Finally, genome-wide SNP-based heritability was estimated to be 17%, underscoring the importance of common variants in MCL risk. Conclusion: Our study provides novel insight into the inherited susceptibility of MCL by identifying eight significant loci and estimating substantial common variant heritability. These findings highlight a role for several distinct biological pathways -specifically DNA repair, telomerase function, and B-cell differentiation- in the etiology of MCL, offering new targets for mechanistic investigation. Citation Format: Charles E. Breeze, Alyssa Clay-Gilmour, Hanla A. Park, Ólafur B. Davíðsson, Angelica Macauda, Brenda M. Birmann, Elizabeth E. Brown, Murat Güler, Michelle A. T. Hildebrandt, Alexandra Nieters, Krystle Ong, Jojo Biel-Nielsen Dietz, Karin E. Smedby, Karl Smith-Byrne, Rosalie Griffin, Sophia S. Wang, Susan Slager, James R. Cerhan, Jonathan N. Hofmann, Qing Lan, Nathaniel Rothman, Ingrid Glimelius, Henrik Hjalgrim, James Mckay, Sonja I. Berndt. Genome-wide association study of mantle cell lymphoma identifies novel loci suggesting a critical role for B-cell chromatin readers and DNA repair mechanisms [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 3602.

Abstract Introduction: The National Cancer Institute estimated almost 317,000 new breast cancer and over 13,000 new cervical cancer cases in 2025. While the National Breast and Cervical Cancer Early Detection Program has served millions of women over the past two decades, inequities in cancer screening, subsequently delayed diagnosis, and timely and appropriate treatment remain a public health challenge in the United States. Despite the substantial impact of social determinants of health (SDOH) on cancer screening, few studies have accounted for SDOH at the individual level when assessing breast and cervical cancer screening adherence. The primary objective of this study is to examine whether the individual-level SDOH, measured using HOUsing-based SocioEconomic Status (HOUSES) index, is associated with breast and cervical cancer screening non-adherence (not current on respective USPSTF recommendations for age and frequency). Methods: In this retrospective study, patients were identified as those receiving primary care in the Mayo Clinic Health System and Mayo Clinic (Rochester, MN). The Midwest Quality Metrics panel was then used to assess patients due for screening for breast or cervical cancer in July 2023. The HOUSES, using home address and publicly available data on the residence which measures and categorizes housing status into quartiles, was obtained using the electronic health records (EHRs)-linkable patient-level information. Logistic regression analyses were conducted, controlling for Census block group-level adverse social exposome from the Area Deprivation Index, age, and comorbidities. Results are presented as odds ratios (OR) with corresponding 95% confidence intervals (CI). Results: For breast cancer, among 128,462 eligible patients, 20.1% (n= 25,857) were non-adherent. Compared to the highest HOUSES quartile (Q4), lower HOUSES groups showed significantly higher odds of non-adherence: Q3 OR=1.20 (95% CI=1.15, 1.25), Q2 OR=1.45; (95% CI=1.40, 1.53), and Q1 OR=1.90 (95% CI=1.81, 1.99). For cervical cancer, among 175,712 eligible patients, 29.9% (n=52,533) were non-adherent. Compared to the highest HOUSES quartile (Q4), lower HOUSES groups showed significantly higher odds of non-adherence: Q3 OR=1.07 (95% CI=1.03, 1.10), Q2 OR=1.16; (95% CI=1.12, 1.20), and Q1 OR=1.36 (95% CI=1.31, 1.41). Conclusions: A clinically meaningful association between the HOUSES index and cancer screening adherence was observed. A lower HOUSES index was associated with higher odds of non-adherence for both breast and cervical cancer screening, even after accounting for neighborhood-level risk, age, and comorbidities. Incorporating HOUSES into EHRs can be a practical “screening-for-screening” tool that enables close monitoring of higher-risk patients without additional burden of surveys. Citation Format: Eunice Y. Park, Madison Beenken, Dave Watson, Chung Il Wi, Tufia Haddad, Gladys Asiedu, Karla BALLMAN, James R. Cerhan, Carolyn Flock, Brian Lynch, Folakemi T. Odedina, Scott H. Okuno, Young J Juhn, . HOUSES as a screening tool for cancer screening: Patient-level housing-based socioeconomic status and breast and cervical cancer screening adherence [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 7599.

Abstract Background: Digital access, health literacy, and confidence in obtaining cancer information are well-known factors that influence cancer beliefs and behaviors. However, less is understood about whether these information-related factors vary across regions within a cancer center's catchment area and how they collectively relate to cancer beliefs in large community samples. This study investigated regional differences in digital access, health literacy, and confidence in seeking information, and examined the connections between these factors and cancer risk perceptions, fatalistic beliefs, prevention confusion, and willingness to participate in cancer clinical trials. Methods: Data (N=2,334) from the 2023 Mayo Clinic Comprehensive Cancer Center’s Cancer-Focused Needs Assessment, conducted across catchment areas in Arizona, Florida, and the Midwest (Minnesota, Wisconsin, Iowa). Regional differences in digital access (Internet use and device ownership), health literacy, and confidence in obtaining cancer information were analyzed using multivariable ANCOVAs and logistic regressions, adjusting for sociodemographic covariates. Follow-up models examined whether these information precursors are associated with perceived cancer risk, fatalistic beliefs, confusion about recommendations, and willingness to participate in cancer clinical trials, adjusting for the same covariates. Results: Regions showed minimal differences in digital access and health literacy. Health literacy was instead associated with ethnicity, age, gender, and education (all p<.001). Confidence in obtaining cancer information followed similar trends, with significant influences of ethnicity and gender (p<.01). Internet use was strongly associated with sociodemographic factors (all p<.01). Additionally, the information precursors consistently correlated with cancer beliefs across the full sample: Higher health literacy and greater confidence in obtaining cancer information were associated with increased perceived cancer risk, reduced cancer fatalism, and less confusion regarding prevention guidelines (ps < .001). Internet use and device access were significantly related to a greater willingness to participate in clinical trials (ps < .01). These relationships persisted even after controlling for sociodemographic covariates. Conclusions: Regional differences in digital access and health literacy were minimal, indicating a consistent information environment. Within this context, individual sociodemographic and information-related factors played a larger role, strongly shaping cancer beliefs. These findings underscore technology access and information empowerment as key targets for enhancing cancer prevention knowledge and research engagement, and indicate that the effects of information empowerment are primarily driven at the individual rather than the geographic level. Citation Format: Tingyu Zou, Monica L. Albertie, Emelina Asto-Flores, Manisha Salinas, Farhia Omar, Adeline Abbenyi, Noreen Stephenson, Nuwanthi Heendeniya, James R. Cerhan, Kathleen J. Yost, Folakemi T. Odedina. Digital access, health literacy, and cancer beliefs: Findings from a multi-region community survey [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 7553.

Abstract Background: MHC class II molecules are normally restricted to professional antigen-presenting cells. Prior TNBC studies have focused on immune-compartment MHC-II. Using spatial transcriptomics, we recently identified aberrant tumor-cell MHC-II expression. Here, we characterized the immune architecture surrounding HLA-DRA-expressing tumor cells. Methods: High-plex single-cell spatial transcriptomics (CosMxTM SMI) was performed on treatment-naïve TNBC (Mayo TMA, n=65) and two neoadjuvant pembrolizumab cohorts (Mayo n=8; Emory n=4). Spatial neighborhoods were mapped relative to HLA-DRA-high tumor cells. Differential expression and adaptive immune gene-set scores were evaluated. Clinical relevance was assessed using FinXX (n=114), I-SPY2 (n=364), and Caris CODEai (n=3,662). Results: HLA-DRA-high tumor regions showed significant enrichment of adaptive immune subsets within ≤50 μm, including B cells, CD8+ T cells, NK cells, macrophages, and plasmacytoid dendritic cells. In pembrolizumab-treated cohorts, responders exhibited higher proportions of HLA-DRA-high tumor cells and greater numbers of B cells, plasmablasts, CD4+ and CD8+ T cells, and macrophages near tumor cells. Responders’ tumors showed upregulation of antigen-presentation machinery, B-cell/plasma-cell programs, CXCL13, and NOTCH3/DLL1. Across I-SPY2 and FinXX, higher HLA-DRA correlated with pathologic complete response and improved survival. In CODEai TNBC, high HLA-DRA expression correlated with higher CXCL13 (median TPM 7.5 vs. 1.1, q<0.05) and longer overall survival (24.2 vs. 18.5 months, HR 0.77, 95% CI 0.71-0.83, p<0.0001). This association was TNBC-specific. High CXCL13 also predicted improved survival (26.6 vs. 16.5 months, HR 0.64, 95% CI 0.59-0.69, p<0.0001). Conclusions: Tumor-cell HLA-DRA expression defines a highly organized adaptive immune niche enriched with B cells and activated T-cell populations in close proximity. Adaptive immune programs—including enhanced antigen presentation and CXCL13-mediated B-cell/plasma-cell pathways—consistently associate with improved outcomes across TNBC cohorts treated with chemotherapy and immune checkpoint blockade. Aberrant tumor-cell MHC-II expression may contribute to antitumor immunity and warrants further investigation as a potential therapeutic target. Citation Format: Yi Liu, Sachin Kumar Deshmukh, Thiti Susiriwatananont, Panuch Eiamprapaporn, Bogang Wu, Heikki Joensuu, Roberto A. Leon-Ferre, David Zahrieh, Judy C. Boughey, James Newell Ingle, Fergus J. Couch, Sharon Wu, Shipra Gandhi, Maryam Lustberg, George W. Sledge, Matthew P. Goetz, Keith L. Knutson, E Aubrey Thompson, Jodi Carter, Saranya Chumsri. Spatially resolved tumor-cell MHC class II shapes adaptive immunity and therapeutic response in triple-negative breast cancer [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 1200.

BACKGROUND: Subtotal cholecystectomy is increasingly recommended as a bailout strategy for the difficult gallbladder, yet its long-term durability and the risk profile of subsequent completion cholecystectomy remain incompletely defined. STUDY DESIGN: We performed a population-based retrospective cohort study of adults undergoing laparoscopic or open subtotal cholecystectomy for acute cholecystitis from 2012 to 2021 using Healthcare Cost and Utilization Project state databases from New York and Florida. The primary endpoint was remnant cholecystitis, defined as a postoperative emergency, inpatient, or outpatient diagnosis of cholecystitis or need for subsequent cholecystectomy. Kaplan–Meier analysis estimated cumulative incidence. Secondary outcomes included completion cholecystectomy and bile duct injury requiring surgical repair. RESULTS: Among 2,682 patients (98.7% laparoscopic), the cumulative incidence of remnant cholecystitis was 13.3% during a median follow-up of 2 years (interquartile range [IQR] 0.7 to 4.1). The median time to developing remnant cholecystitis was 28 days (IQR 13 to 91), with 79.7% occurring within 6 months. Only 70 patients (2.6%) underwent completion cholecystectomy at a median of 103 days (IQR 43 to 202). Completion cholecystectomy was performed via open surgery in 47.1% of patients and was associated with a 7.1% bile duct injury rate and median length of stay of 3 days (IQR 1 to 7), compared with a 0.9% bile duct injury rate for subtotal cholecystectomy overall. CONCLUSIONS: Although remnant cholecystitis occurred in 13.3% of patients after subtotal cholecystectomy, few required completion cholecystectomy. When necessary, completion cholecystectomy was frequently open and associated with a substantially higher bile duct injury rate, supporting referral to experienced hepatobiliary centers for reoperation.

ABSTRACT Background Academic departments in medicine face increasing pressure to balance clinical productivity with their broader academic missions, including education, scholarship, mentorship, and service. While clinical work is routinely quantified through relative value units (RVUs), non‐clinical academic contributions are inconsistently measured and often undervalued. Academic Value Unit (AVU) systems have emerged as frameworks to quantify these activities, but adoption remains limited due to inconsistent funding models, lack of standardized frameworks, and minimal evidence demonstrating outcomes such as faculty satisfaction, retention, or return on investment (ROI). Methods This concept paper synthesizes current AVU implementation strategies in emergency medicine and proposes an evidence‐informed six‐step framework for AVU design, funding, and sustainability. The framework was informed by a literature review, analysis of institutional dashboards, and multi‐institutional input from the Society for Academic Emergency Medicine (SAEM) community, including feedback from a national didactic session at the 2025 SAEM Annual Meeting. Results The proposed framework outlines practical steps for AVU implementation: defining mission‐aligned domains, identifying measurable academic activities, establishing transparent weighting systems, integrating real‐time tracking dashboards, developing sustainable blended funding models, and engaging leadership and faculty through iterative review. The model incorporates customizable templates, adaptable activity menus, and suggested ROI metrics that departments can tailor to local institutional priorities and resources. Conclusions AVU systems offer a structured approach to recognizing and incentivizing non‐clinical academic contributions in emergency medicine. A transparent, mission‐aligned framework supported by sustainable funding and measurable ROI metrics may enhance faculty engagement, equity, and long‐term departmental sustainability. Future work should focus on establishing validated benchmarks for AVU weighting, integrating AVUs with faculty development and wellness initiatives, and evaluating longitudinal outcomes such as retention, satisfaction, and equity.

Abstract Background. Pain drives disability and medication use in autoimmune rheumatic diseases (ARDs), even when inflammation is controlled. The extent of pain-related polypharmacy across ARDs and chronic overlapping pain conditions (COPCs) remains poorly characterized. We aimed to quantify first-year pain medication burden following ARD diagnosis and examine variations by disease, COPC status, and time. Methods. Using the Merative MarketScan Commercial Claims database, we identified adults newly diagnosed with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriatic arthritis, Sjögren’s disease, or systemic sclerosis (2008–2021). We analyzed pain-related medications across ten pharmacologic categories during the first year post-diagnosis. Polypharmacy measures included distinct medication counts, medication categories, ≥ 5 and ≥ 10 medication thresholds, and the Medication Quantification Scale. Findings. Among 149,742 adults with newly diagnosed ARDs, 57.6% had at least one COPC. During the first year after diagnosis, patients filled a mean of 9.0 distinct pain medications and 47.9% met criteria for ≥ 5 medications; 30.5% met criteria for ≥ 10 medications. Ankylosing spondylitis demonstrated the highest medication burden (mean 11.6 medications; 57.5% with ≥ 5 medications; 37.9% with ≥ 10 medications). Patients with fibromyalgia had consistently higher medication burden across ARDs and were the only COPC group in whom prescribing increased after 2015. Overall medication burden rose from 2008 to 2014–2015 and declined thereafter; however, absolute levels remained high. Interpretation. Pain-related polypharmacy is common early after ARD diagnosis and varies substantially by disease and pain phenotype. Despite modest declines after 2015, medication burden remains high, underscoring the need for phenotype-informed, nonpharmacologic, and deprescribing strategies in rheumatology. Funding. NIAMS (K01AR079039).

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 Background This exploratory analysis of the NEURO‐TTRansform Phase 3 trial evaluated the efficacy of eplontersen in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy by genetic variant. Methods Changes from baseline in NEURO‐TTRansform primary endpoints serum transthyretin (TTR) at Week 65, modified Neuropathy Impairment Score+7 (mNIS+7) composite score, and Norfolk Quality of Life‐Diabetic Neuropathy (Norfolk QoL‐DN) total score at Week 66 were evaluated in patients with early‐onset (aged < 50 years) and late‐onset (aged ≥ 50 years) Val30Met (p.Val50Met) or non‐Val30Met ATTRv amyloidosis with polyneuropathy. Secondary endpoints from NEURO‐TTRansform were also evaluated by genetic variant. Results In total, 144 patients with early‐onset ( n = 54) or late‐onset ( n = 31) Val30Met or non‐Val30Met ( n = 59), ATTRv amyloidosis with polyneuropathy were randomized to eplontersen. A further 60 patients from NEURO‐TTR with early‐onset ( n = 16) or late‐onset ( n = 17) Val30Met or non‐Val30Met ( n = 27), served as a historical placebo group. The mean percentage difference (95% confidence interval) in serum TTR was −79.9 (−87.8, −72.0), −85.0 (−93.3, −76.6), and −70.6 (−77.7, −63.5) with eplontersen versus placebo in the early‐ and late‐onset Val30Met, and non‐Val30Met groups, respectively. Across subgroups, the change from baseline to Week 66 in mNIS+7 composite score was generally well maintained, and the Norfolk QoL‐DN total score improved with eplontersen versus worsening with placebo. The Polyneuropathy Disability score was maintained in most patients. From baseline to Week 65, the modified body mass index was maintained with eplontersen compared to a marked reduction (worsening) for placebo. Conclusions Findings were suggestive of consistent benefits in reducing neuropathy impairment and improving QoL with eplontersen versus historical placebo, across TTR variants. Trial Registration ClinicalTrials.gov: NCT04136184, NCT01737398