Citations

Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger’s MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] < 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p<5×10-8; MAF>0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p<2.4×10-6) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2), BRCA2 (OR=2.0, 95% CI=1.7-2.3), CHEK2 (OR=1.6, 95% CI=1.5-1.8), ATM (OR=1.6, 95% CI=1.4-1.9), FAM111A (OR=1.4, 95% CI=1.3-1.5), BIK (OR=1.4, 95% CI=1.2-1.6), SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB390.

OBJECTIVE Dural arteriovenous fistulas (dAVFs) are rare cerebrovascular anomalies. Tentorial dAVFs (TDAVFs) have more aggressive features, making them prone to symptomatic presentations and hemorrhage. TDAVFs are heterogenous and require tailored surgical approaches. Presented is a multicenter analysis of TDAVF surgical outcomes. METHODS The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) consortium compiled data on dAVFs from 16 international centers from 1990 to 2021 retrospectively. Microsurgical treatment success was defined as angiographically confirmed complete obliteration of the fistula or discontinuation of cortical venous drainage (CVD) in high-grade TDAVFs. TDAVF subtypes and tailored surgical approaches were reviewed. RESULTS Of 1360 patients in CONDOR, 161 had TDAVFs and 27% (44/161) of these patients underwent surgical management, with the majority (52% [23/44]) receiving surgery as a salvage treatment following failed embolization. The mean age (SD) of this cohort was 56 (15) years, and 68% (30/44) were male. In total, 91% (40/44) of surgically treated patients presented with aggressive symptoms: 64% (28/44) presented with hemorrhage and 27% (12/44) with nonhemorrhagic neurological deficit (NHND). The median (IQR) duration from symptom onset to diagnosis was 1 (1–4) day. The median time (IQR) between diagnosis and surgery was 15 (3–80) days. Surgical approaches varied across the cohort, with the retrosigmoid being the most common (44% [18/41]), followed by the midline suboccipital (24% [10/41]) and occipital (15% [6/41]) approaches. Perioperative complications occurred in 11% (5/44) of cases, as well as permanent neurological deficits in 2% (1/44). Surgical success was achieved in 90% of patients (38/42). During the mean 3-year follow-up, 2 patients experienced a recurrence of their fistula including representation of CVD (2/38 [5%]) and 1 patient had a new NHND (1/43 [2%]). Shorter symptom duration was significantly associated with success (15.6 vs 181.5 days, p = 0.001). Primary versus salvage microsurgery showed no difference in outcomes. Both patients with recurrent fistula were effectively treated with Gamma Knife radiosurgery. CONCLUSIONS Resection is safe and durable for the treatment of TDAVF not otherwise amenable to embolization. It can achieve a high degree of success with a low rate of perioperative complications and permanent neurological deficits, benefits far exceeding the risks associated with TDAVF natural history or management with less effective modalities.

Abstract Purpose Spatial distribution of coronary artery calcium (CAC) may provide additional prognostic value in patients undergoing SPECT and PET myocardial perfusion imaging (MPI). We aimed to automatically identify CAC in proximal segments from attenuation correction CT (CTAC) scans using artificial intelligence (AI) and to evaluate prognostic significance in two large international multicenter registries. Methods From hybrid MPI/CT imaging (N=43,099) across 15 sites, we included 4,552 most relevant patients with 1) no prior coronary artery disease; 2) AI-derived mild CAC scores (1-99); and 3) normal perfusion (stress total perfusion deficit <5%). The independent associations between AI-identified proximal CAC and major adverse cardiovascular events (MACE) and all-cause mortality (ACM) were evaluated using multivariable Cox regression, likelihood ratio test (LRT), and continuous net reclassification index (NRI). Results Among the patients with mild CAC and normal perfusion (mean age 65±12 years, 51% male), 1,730 (38%) had proximal CAC. Over 3.6 (inter-quartile interval 2.1, 5.2) years follow-up, 599 (13%) and 444 (10%) patients had MACE or ACM, respectively. Proximal CAC was associated with an increased risk of MACE (adjusted hazard ratio [HR] 1.24, 95% CI 1.03–1.48, P=0.02) and ACM (adjusted HR 1.25, 95% CI 1.01–1.53, P=0.04) after the adjustment of CAC score and density, clinical risk factors, and perfusion deficit. Proximal CAC improved the risk stratification of MACE (LRT P=0.02; NRI 12%) and ACM (LRT P=0.04; NRI 12%). Conclusion In patients with mild CAC and normal perfusion, AI detection of proximal CAC identified a higher-risk group for adverse outcomes, highlighting its prognostic utility. Graphical Abstract From patients who underwent hybrid myocardial perfusion imaging (MPI) from 15 sites, we analyzed those without prior coronary artery disease (CAD), mild coronary artery calcium (CAC) scores (1-99), and normal perfusion (stress total perfusion deficit <5%). A previously developed AI model was used to identify CAC lesions in proximal coronary segments on CT attenuation correction maps (CTAC). We evaluated associations with major adverse cardiovascular events (MACE) and all-cause mortality (ACM), showing risk stratification of proximal CAC and improvement by net reclassification index (NRI). CAC lesion color: green, left anterior descending artery (LAD) with left main artery; red, left circumflex artery (LCX); yellow, right coronary artery (RCA). Adjusted hazard ratios (HRs) are shown with 95% confidence intervals.

BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

Abstract Background Red cell alloimmunization complicates sickle cell disease (SCD) management despite current widespread prophylactic Rh/K matching in the United States (US). Regional antibody patterns remain poorly characterized. Study Design and Methods We conducted a retrospective analysis of 2965 SCD patients from 9 US sites (2010–2022). All hospitals prophylactically match for Rh and K antigens. Each site collected demographics, antigen status, antibody histories, and antibody screen results from their laboratory information system. Results Overall antibody prevalence was 29.7% with dramatic institutional variation (17.9%–56.0%). Alloantibody prevalence was 27.5%. Most autoantibody‐positive patients (74.23%) also had alloantibodies, identifying a high‐risk population. A third of patients with positive antibody histories had negative screens. Pediatric patients showed markedly different antibody profiles than adults. Hospitals’ antibody patterns clustered by patient age rather than geography. Rh and K antibodies were the most common and also most likely to co‐occur, followed by S, Fya, and Jkb antibodies. Antibodies against Jsa (1.82%), V (1.75%), and Kpa (1.69%) were more prevalent than anti‐Jka (1.28%). Despite regional antibody variation, antigen frequencies remained overall consistent. In antigen–antibody pairwise comparisons, 3.15% were antigen‐negative and antibody‐positive reflecting alloimmunization; 0.47% were both antibody‐ and antigen‐positive, suggesting partial/variant antigens. Discussion Substantial institutional variation in antibody prevalence suggests need for site‐specific approaches to testing and prophylactic matching. High co‐occurrence of auto‐ and alloantibodies, antibody immunogenicity patterns, and antigen–antibody discordances support the need for further research and consideration of refined testing and/or matching strategies beyond the current Rh and K standard.

Background Acute kidney injury (AKI) is associated with high morbidity and mortality in critically ill patients. Multicenter analyses describing the epidemiology of AKI in the cardiac intensive care unit (CICU) are scarce. Here, we describe the prevalence, predictors, and outcomes associated with AKI in a contemporary multicenter CICU population. Methods The Critical Care Cardiology Trials Network (CCCTN) is a collaboration of CICUs in North America coordinated by the TIMI Study Group (Boston, MA). We evaluated patient and hospital-level outcomes as a function of creatinine-only Kidney Disease: Improving Global Outcomes (KDIGO) AKI stage within the CCCTN registry. Logistic regression was used to assess associations with in-hospital mortality. Results Among 21 603 admissions, the overall prevalence of AKI was 23.7%, which was composed of KDIGO stage 1: 12.7%, stage 2: 1.7%, and stage 3: 9.2%. A higher prevalence and severity of AKI were seen in patients with baseline kidney disease, hypertension, or diabetes and in admissions with heart failure, cardiogenic shock, and cardiac arrest ( P < .001 for all). There was a stepwise increase in hospital mortality across AKI stages (stage 1: 23%, stage 2: 39%, stage 3: 42%; P < .0001). The increased risk of death associated with progressive AKI stage persisted after multivariate adjustment (adjusted OR: stage 1: 2.1, stage 2: 3.7, stage 3: 3.4). Conclusions AKI occurs in 1 in 4 admissions to the CICU, and a higher AKI stage is incrementally associated with in-hospital mortality, highlighting a need to develop strategies to mitigate AKI and its complications.

These NCCN Guidelines for Distress Management discuss the identification and treatment of psychosocial problems in patients with cancer. They are intended to assist oncology teams to identify patients who require referral to psychosocial resources and to give oncology teams guidance on interventions for patients with significant distress. These guidelines also provide guidance for social workers, certified chaplains, and mental health professionals by describing treatments and interventions for various psychosocial problems as they relate to patients with cancer. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding standards of care for distress management in patients with cancer and implementation of these standards, including application of evidence-based care delivery models, such as the collaborative care model.