Citations

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 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: The cellular balance between saturated and monounsaturated fatty acids is a defining feature of tumor lipid metabolism, with SCD1 functioning as a key modulator through the production of MUFAs. Elevated SCD1 activity and MUFA accumulation have been documented in hepatocellular carcinomas, although the consequences of restricting MUFA synthesis have not been fully clarified. Methods: A selective SCD1 inhibitor, SSI-4, was evaluated across established human HCC cell lines and xenograft models. Measurements included cell viability, lipid compositional analyses, and characterization of stress response pathways at both molecular and biochemical levels. The effects of MUFA depletion were studied in vitro and in vivo, with attention to ER stress, apoptosis, ferroptosis markers, and autophagy induction. Results: SSI-4 treatment led to marked reduction in cellular MUFA content and an increase in saturated fatty acid pools. The resulting metabolic stress correlated with activation of unfolded protein response components, caspase-mediated cell death, and the upregulation of ferroptosis-associated genes. Triglyceride and MUFA levels declined precipitously, as confirmed by mass spectrometry-based lipidomics. Tumor growth was suppressed in PDX models and evidence of autophagic flux was apparent in sensitive cell lines. Variability in response highlights metabolic heterogeneity in HCC. Conclusions: Targeted disruption of MUFA biosynthesis inflicts metabolic vulnerability on HCC cells, precipitating membrane alterations and activation of multiple cell death programs. These findings recommend further investigation into metabolic interventions exploiting MUFA depletion, with consideration for stratifying patients according to lipid metabolic phenotypes. Funding: This work is supported by Mayo Clinic Comprehensive Cancer Center and the Jay and Deanie Stein Career Development Award for Cancer Research at Mayo Clinic Jacksonville and the Mayo Clinic Translational Hepatobiliary Cancer SPORE P50CA210964 Career Enhancement Program (CEP) and Florida Department of Health/Florida Cancer Innovation Fund C25C23. Citation Format: Justyna J. Gleba, Victoria N. Rios, Brian M. Necela, Skyeler M. Klinge, Matt L. Pawlush, Mike J. Redig, Aylin Alasonyalilar-Demirer, Han W. Tun, John A. Copland III, . Disrupting tumor lipid homeostasis by MUFA depletion drives cell death in HCC [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 7333.

Abstract Introduction: Ewing sarcoma (EwS) is a FET::ETS family member-driven primary bone cancer demonstrating vast heterogeneity. Between a patient’s primary diagnosis and disease progression, tumor cell state adaptation, microenvironment changes, and the landscape of evolving therapeutic vulnerabilities remain poorly understood. To address these gaps, the Sean Karl Cohort was established in 2025 to conduct the largest single-cell transcriptomic analysis of retrospective paired tumor samples from patients with EwS. Here, we present data from the five analytic teams, and through shared SOPs now expand this cohort to Europe. Methods: Common sample processing SOPs were established to isolate cells from FFPE material from paired patient EwS samples. Single-cell (sc) RNAseq was generated using the GEM-X Flex Gene Expression protocol (10x Genomics). Alex’s Lemonade Stand Foundation (ALSF) Data Lab established a common data processing and integration pipeline with an EwS-specific cell annotation workflow to create a harmonized dataset for downstream analyses. Analytic teams were created to define tumor cell subpopulations and their therapeutic vulnerabilities and to characterize the tumor microenvironment. Data: We demonstrate the feasibility of generating high-quality scRNAseq profiles from retrospective FFPE-preserved EwS tumors. To date, 116 samples have yielded ∼800,000 cells. Integrated analysis reveals reproducible EwS tumor cell states shared across patients with regulatory network analyses nominating candidate therapeutic vulnerabilities. The scale of this international cohort enables saturation analysis for rare cell populations. Paired and longitudinal samples further allow correlation of emergent cell states with therapy resistance and metastatic progression. For example, immune-focused analyses show increases in T cell and macrophage populations in post-therapy samples. A novel, standardized EwS-specific cell annotation workflow has been developed to harmonize analyses and findings. These data will be openly shared with the community through the ALSF Single-cell Pediatric Cancer Atlas Portal. Conclusion: Large-scale international collaborative sample sharing, standardized processing pipelines, and harmonized EwS-specific annotations now enable deep single-cell analyses to characterize tumor heterogeneity in this rare pediatric and adolescent cancer. An in vivo expansion of the Sean Karl Cohort is underway to assess conservation of EwS tumor cell states and regulatory vulnerabilities identified in human tumors pre- and post-therapy in preclinical models, further supporting translation of these findings toward therapeutic strategies. Citation Format: Abbe Pannucci, Elina Mukherjee, Jessica D. Daley, Shireen Sita Ganapathi, Elissa Boguslawski, Lea Surrey, Lauren Gutstein, Patrick Azar, Emily Stockfisch, Azfar Neyaz, Ivy John, Jennifer Picarsic, Yutaro Tanaka, Byron Butaney, Riaz Gillani, Brian D. Crompton, Katherine A. Janeway, Jaclyln Taroni, Jessica Davis, Damon Reed, Adam Shlien, Theodore W. Laetsch, Rajen Mody, Clémence Henon, Thomas G. Grünewald, Elizabeth R. Lawlor, Filemon Dela Cruz, Patrick J. Grohar, Jovana Pavisic, Ally Hawkins, Anthony R. Cillo, Kelly M. Bailey. The Sean Karl Cohort: An international single-cell RNAseq study of paired patient Ewing sarcoma specimens [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 643.

ABSTRACT BACKGROUND Increasing evidence suggests that accurate prediction of Alzheimer’s disease (AD) symptom onset requires more than amyloid- and tau-centric biomarkers such as cerebrospinal fluid (CSF) Aβ42/40, total tau and p-tau181 and plasma p-tau217. Autosomal dominant AD (ADAD), caused by pathogenic PSEN1, PSEN2 and APP mutations with predictable age at symptom onset, presents a unique opportunity to characterize the chronological changes in proteins beyond amyloid and tau and clarify them as early biomarkers of disease onset or as biomarkers related to disease staging and progression monitoring. METHODS We measured 972 CSF samples corresponding to 484 participants of the Dominantly Inherited Alzheimer Disease Network (DIAN) using the NULISASeq 120 CNS Disease Panel. We first benchmarked the technology against gold-standard measurements followed by the identification of proteins that were differentially abundant in relation to mutation status and symptomatology. Next, we determined the chronological emergence of protein changes in relation to the estimated years to onset (EYO). Finally, we assessed whether specific protein measures improved the prediction of EYO in the ADAD. FINDINGS NULISA measurements were comparable to those previously published. We demonstrated that known early alterations in CSF amyloid and tau were followed by inflammatory and neurodegenerative responses suggesting that clinical manifestation of AD happens before the inflammatory processes is fully developed. Finally, we found a multi-protein composite approach for predicting EYO that outperformed single biomarker values. INTERPRETATION Our results suggest that the main CSF proteomic landscape changes in ADAD are due to the presence of a pathogenic mutation and occur prior to symptom onset. Improved performance of multi-protein composite to predict EYO compared to single biomarker values highlights the added value of multiplex proteomic signatures for biomarker panel development. FUNDING National Institute on Aging, Alzheimer’s Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea, Spanish Institute of Health Carlos III.

Background: Hepatorenal syndrome–acute kidney injury (HRS-AKI) is associated with high mortality in cirrhosis. Recent FDA approval of terlipressin and updated clinical guidance have expanded management options, but real-world practice patterns remain unknown. Methods: We conducted a nationwide survey of U.S. hepatology providers regarding HRS-AKI management practices. The 33-question survey assessed provider demographics, vasoconstrictor selection, treatment timing, and adherence to guideline recommendations. Results: Among 162 respondents, most were hepatologists (94%) at academic centers (83%). Only 11% obtained a nephrology consultation at AKI detection, with 44% waiting until worsening renal function. Terlipressin was available at 80% of institutions but more commonly at academic centers (84% vs. 53%, p =0.003). Consistent with guideline recommendations, 77% of providers initiate vasoconstrictors only after completing a trial of volume expansion (if no renal improvement), particularly in academic centers (80% vs. 60% non-academic, p =0.03). Terlipressin (49%) and midodrine/octreotide (44%) were preferred first-line treatments, with providers at academic centers more likely to use midodrine/octreotide (46% vs. 30%, p =0.008). Mean arterial pressure was used by 62% of providers to guide vasoconstrictor dosing. Most providers (73%) discontinued vasoconstrictor treatment after 4 days if no improvement. Conclusions: Significant variations exist between guideline recommendations and real-world HRS-AKI management, especially first-line treatment choice, treatment monitoring, and nephrology consultation. These findings highlight opportunities to improve guideline implementation and identify areas where practice patterns might inform provider education and future guidance updates.

Background: A 2-stage approach is most commonly used to treat periprosthetic joint infection (PJI). Some successful studies of the 1-stage approach were underpowered, lacked a 2-stage comparative group, and excluded patients with draining sinuses, comorbidities, and/or antibiotic-resistant organisms. Given the morbidity and expense associated with 2-stage treatment, we conducted a prospective, multicenter, randomized trial to compare the results of 1- and 2-stage PJI treatment, specifically including patients with draining sinuses, comorbidities, and resistant organisms. Methods: Patients presenting for surgical treatment of a chronic PJI with a known organism following primary total hip or knee arthroplasty were included (with infection defined by Musculoskeletal Infection Society [MSIS] criteria). Patients with prior revision, culture-negative infection, or fungal infection, or who were immunosuppressed or had soft-tissue involvement precluding wound closure, were excluded. Patients were classified according to the McPherson host staging system. Clinical success was defined as (1) no clinical failure or reinfection with the same or new organism; (2) no reoperation for PJI; and (3) no PJI-related death. A double-instrument setup was used for all patients, as were similar irrigation and antibiotic protocols. A total of 323 patients (166 one-stage; 157 two-stage) were randomized. Groups were similar with respect to demographics and host classification. After excluding patients who died or were lost to follow-up, 258 of the 323 patients had 2-year follow-up (135 one-stage and 123 two-stage). The rate of patient loss to follow-up was similar between the treatment groups. Results: Sixteen patients in the 1-stage group and 9 patients in the 2-stage group died prior to 2-year follow-up. Overall, the 2-year success rate of 1-stage treatment was 97% (131 of 135), while the success of 2-stage treatment was 91% (112 of 123) (p = 0.04). Compared with the 2-stage group, the 1-stage group had 3-times the odds of overall success in a regression analysis (unadjusted odds ratio = 3.22 [95% confidence interval = 1.0 to 10.38]). After adjusting for specific variables (McPherson host grade, resistant organism, and draining sinuses), 1-stage treatment also had 3-times the odds of success. Conclusions: The results of this prospective randomized trial indicated that 1-stage treatment (97% success) was statistically noninferior to 2-stage treatment (91% success) when treating chronic PJI following primary total hip or knee arthroplasty, provided the protocols described here are explicitly followed. Extrapolation to other patient cohorts and clinical situations should be avoided. Level of Evidence: Therapeutic Level I . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background Women with severe aortic stenosis (AS) are diagnosed later and experience poorer outcomes than men, partly because clinical approaches rely on 2D, valve-centric thresholds derived from male-predominant cohorts that underutilize information from 3D left ventricular (LV) geometry. We hypothesize that a sex-specific computational framework integrating statistical shape analysis (SSA) of pre-TAVR CT with machine learning would improve prediction of 1-year LV mass regression (LVMR). Objective To develop a computational framework leveraging 3D LV geometry and evaluate whether it improves sex-specific prediction of 1-year LVMR after TAVR. Methods We studied 339 patients with severe AS who underwent TAVR from 2013 to 2020 and had pre-TAVR CT and 1-year post-TAVR echocardiography. LV geometries were segmented into digital twins, and shape modes predictive of LVMR were extracted using SSA and partial least squares. These modes were incorporated into support vector regression models and compared with conventional echocardiographic predictors, including pre-TAVR LVEF, LVMI, and E/A ratio. Performance was assessed using RMSE and R 2 . Results After one year, 65% of patients showed positive LVMR, with median regression of approximately 10%; regression was significant overall and within each sex ( p < 0.001) and similar between sexes ( p = 0.99). Predictive shape modes differed by sex ( p < 0.01), with women showing more localized variation and men broader geometric gradients. Sex-specific shape modes outperformed general modes and clinical metrics, particularly in women (R 2 = 0.80, RMSE = 0.09 vs. R 2 = 0.59, RMSE = 0.13; clinical-only baseline R 2 = 0.16, RMSE = 0.22). In men, sex-specific modes also performed strongly (R 2 = 0.89, RMSE = 0.08). Conclusion In severe AS, 3D LV geometry predicts post-TAVR reverse remodeling more accurately than conventional metrics and may improve risk stratification, particularly in women.

Importance Alzheimer disease (AD) biomarker and genetic testing results are increasingly disclosed to cognitively unimpaired adults in research and could in the future inform clinical treatment decisions in this population. Objectives To assess psychological outcomes after returning 3 categories of amyloid biomarker results as well as apolipoprotein E ( APOE ) genotypes. Design, Setting, and Participants This cohort study was a secondary analysis of data collected as part of screening for the multisite AHEAD preclinical AD trial. Participants were individuals aged 55 to 80 years undergoing screening from July 14, 2020, to October 15, 2024. Exposure Participants were informed whether they had not-detected, intermediate, or elevated amyloid positron emission tomography levels, as well as their APOE genotype, which were categorized as noncarrier, ε4 heterozygote, or ε4 homozygote. Main outcomes and measures Impact of Events Scale (IES; 15 items to assess intrusive thoughts and avoidance; each item is scored as not at all [0], rarely [1], sometimes [3], or often [5]; total range, 0-75), collected 24 to 72 hours after disclosure, and change in a scale measuring concerns about AD dementia (adapted scale using 6 items in which participants indicated their level of agreement with statements related to their perceived probability of developing AD dementia; items scored as strongly disagree [1] through strongly agree [5]; total range, 6-30), calculated by subtracting the score collected before biomarker testing from 1 collected after biomarker and genetic test results disclosure. Results Among 3414 included individuals, the mean (SD) age was 68.8 (6.0) years and 2116 (62%) were female. Group mean IES scores were below clinically significant thresholds. Nevertheless, across genetic groups, learning an elevated amyloid result (1184 participants) was associated with higher IES (mean [SD], 10.5 [10.9]) than intermediate amyloid (482 participants; mean [SD] IES, 8.8 [9.8]), and intermediate amyloid was associated with higher scores than not-detected amyloid (1748 participants; mean [SD] IES, 6.5 [8.4]). Across amyloid groups, learning APOE ε4 homozygosity (337 participants) was associated with higher mean (SD) IES (12.7 [11.6]) than heterozygosity (1609 participants; 9.1 [10.2]), and heterozygosity was associated with higher IES than noncarrier status (1468 participants; mean [SD] IES, 6.2 [8.1]). Both types of information were significant in an analysis of covariance model; no interaction effect was observed. In contrast, only biomarker disclosure was associated with differential change in concerns about AD dementia. Those with elevated amyloid showed a mean (SD) increase in concern (0.8 [3.5]), those with intermediate amyloid showed a smaller increase (0.4 [3.7]), and those with not-detected amyloid showed decreased concerns (−1.1 [4.2]). Conclusions and Relevance In this cohort study of cognitively unimpaired adults, associations with intrusive thoughts were observed to differ among genetic and biomarker subgroups; such associations were limited to biomarker subgroups for measures of perceived dementia risk.

Abstract Background The clinical use and interpretation of cardiac troponins (cTn) in pediatric patients is heterogeneous. Content This review is based on an appraisal and synthesis of the available literature and discussions between International Federation of Clinical Chemistry and Laboratory Medicine Committee on Clinical Application of Cardiac Biomarkers members and pediatricians, cardiologists, emergency department physicians, and laboratorians. It aims to summarize current knowledge and best practices related to cTn measurements in pediatric patients, including which percentile should be applicable as the upper reference limit, and the influence of age, sex, and physiology on circulating concentrations. Preanalytical and analytical precautions, and a consensus on optimal interpretation of the reported results are discussed. Summary Current studies report high cTn concentrations in healthy infants and newborns. The nadir is reached at 1–3 years at which time concentrations gradually increase, reaching adult levels through puberty. The incidence of myocardial injury is reported to be low and dependent on whether the 97.5th or 99th percentile is chosen as the upper reference limit. The main clinical indication for testing appears to be suspicion of myo/pericarditis or traumatic chest injury. On occasion, cTn is measured in cases of possible heart failure and/or myocardial ischemia. There is heterogeneity among the limited clinical studies published. Most of the data are retrospective, and the current suggestions for clinical practice are thus largely based on expert opinion. More research is needed regarding all aspects of cTn testing in children, and suggestions for future research are included at the end of this review.