Citations

The NCCN Guidelines for Prostate Cancer provide a framework on which to base decisions for patients with prostate cancer across the disease spectrum. The Guidelines sections included in this article focus on metastatic castration-sensitive prostate cancer (mCSPC), nonmetastatic castration-resistant prostate cancer (CRPC), and metastatic CRPC (mCRPC). For patients with mCSPC, disease characteristics, such as whether metastases arose synchronously or metachronously and the degree of metastatic burden, impact therapy decisions, including how much treatment intensification is appropriate and when prostate-directed and/or metastasis-directed therapy should be considered. In the mCRPC setting, androgen deprivation therapy is continued with the sequential or concurrent addition of certain androgen receptor pathway inhibitors, chemotherapies, immunotherapies, radiopharmaceuticals, and/or targeted therapies. The NCCN Prostate Cancer Panel emphasizes a shared decision-making approach in all disease settings based on patient preferences, prior treatment exposures, biomarkers, the extent and location of metastases, symptoms, and potential side effects.

Abstract Background Adolescent and young adult (AYA) patients remain underrepresented in neuro-oncology research. Despite being the second most common primary brain tumor in this population, meningiomas have not been studied using age-specific molecular analyses. DNA methylation-based classification and prognostic tools have transformed meningioma care. This study aimed to evaluate the performance of these tools across age groups. Methods We analyzed 1,568 meningiomas with DNA methylation and clinical data, including 18 pediatric patients (<15 years), 195 AYA patients (15-39 years), and 1,355 adult patients (>39 years). Pediatric and AYA (P/AYA) tumors were combined and compared with adult tumors. The performance of established molecular classifiers and recurrence predictors, as well as differences in chromosomal copy number alterations were compared across age groups. Results While histologic grading was comparable between cohorts, P/AYA tumors displayed significantly fewer aggressive molecular groups and lower frequencies of chromosomal arm losses, including 1p, 6q, and 14q. The adult-trained recurrence predictor failed in the P/AYA population (AUC 0.57), despite similar score distributions. Retraining the model on an age-specific cohort using an identical analytic framework improved performance (AUC 0.79) and enabled effective stratification of progression-free survival (P = 0.00054). Importantly, 1p loss retained prognostic significance within the P/AYA group, supporting its clinical utility. Conclusions Molecular tools developed in adult-dominant cohorts do not generalize to younger patients due to both biological divergence and exclusion from model development. These findings underscore the need for age-specific molecular frameworks and highlight the imperative of including P/AYA populations in precision neuro-oncology research to ensure lifespan-equitable care.

Background: Previously, we discovered that DENND3, a guanine nucleotide exchange factor regulating Rab GTPases, influences cardiac ion channel trafficking. Both electrophysiological dysfunction and arrhythmic events were identified in variant inserted inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) expressing DENND3-p.R534S. This was a novel missense variant identified in a patient with familial idiopathic ventricular fibrillation (IVF). Notably, augmented membrane retention of key cardiac ion channels was observed in both DENND3-p.R534S expressing TSA201 cells and variant inserted iPSC-CMs. To further study the mechanisms underlying arrhythmogenesis associated with IVF, intracellular calcium handling was characterized in these re-engineered heart cells with DENND3-p.R534S. Methods: Here, iPSC-CMs expressing DENND3-p.R534S and isogenic controls (IC) were studied. Optical action potentials were recorded using the FluoVolt voltage-sensitive dye at a constant pacing rate of 1 Hz. Multi-electrode array (MEA) recordings assessed beat period and conduction dynamics. Intracellular calcium dynamics were analyzed using Fluo-4 calcium imaging. Results: DENND3-p.R534S iPSC-CMs exhibited frequent arrhythmic activity, including irregular beating patterns (78%, n=28/36), alternans (25%), early afterdepolarizations (EADs, 8%), and delayed afterdepolarizations (DADs, 8%) versus 0% in IC lines (n=0/36, p<0.05). MEA recordings revealed significantly prolonged and irregular beat periods (2.59±0.26s vs. 1.37±0.10s, p<0.05), indicating electrical instability. Calcium imaging further showed significantly reduced calcium transient amplitude in DENND3-p.R534S iPSC-CMs compared to ICs (0.035±0.039ΔF/F 0 vs. 0.302±0.099ΔF/F 0 , p<0.05), and slowed upstroke velocity (0.170±0.212 ΔF/F 0 ●s -1 vs. 1.340±0.463ΔF/F 0 ●s -1 ) suggesting impaired intracellular calcium release. Conclusion: The DENND3-p.R534S variant not only disrupts ion channel distribution as shown previously but also markedly perturbs intracellular calcium handling, contributing to electrophysiological instability and arrhythmogenic cellular phenotypes. These findings highlight DENND3’s novel and emerging role in maintaining cardiac cellular homeostasis and rhythm stability.

Abstract Background Carbon ion radiotherapy (CIRT), characterized by its Bragg peak and a reduced lateral scattering compared to proton radiotherapy (PT), offers excellent dose conformity in radiation treatment. Meanwhile, compared to PT, CIRT causes more complex and severe DNA damage in tumor cells, which results in a higher relative biological effectiveness (RBE), making it particularly advantageous in treating radioresistant and hypoxia tissues than conventional radiotherapy. However, CIRT's high RBE and the nuclear fragmentation dose tail outside the target presents challenges in sparing organ at risk (OARs). Combining PT and CIRT offers a potential hybrid modality that leverages the biological effectiveness of carbon ions while minimizing normal tissue toxicity with high biological damage. Purpose Despite the potential of combining PT and CIRT, balancing their respective advantages while mitigating disadvantages remains a significant challenge. This study aims to develop an optimized treatment approach that automatically adjusts the relative contributions of protons and carbon ions, improving target dose conformity while minimizing biological impact on OARs. Methods We propose a biological optimization framework for multi‐modality combining PT and CIRT (CCIPRT). The biological dose is modeled as the product of the physical dose and RBE. Through iterative Jacobian‐based linearization, the biological dose of carbon ion is expressed in a linear model, enabling the formulation of a linear least‐square objective. The biological dose of proton is formulated as a linear model using the physical dose and dose‐averaged linear energy transfer (LET). The joint optimization problem is then solved using iterative convex relaxation and the alternating direction method of multipliers. For comparison, single‐modality PT and CIRT were also implemented. Results When the target dose of CCIPRT is prescribed in terms of the physical dose, compared to PT, CCIPRT increased the mean biological dose in the target by 37.7%, 29.6%, and 31.1% for brain, lung, and abdomen, respectively; compared to CIRT, CCIPRT reduced the biological dose in CTV1cm (ring surrounding CTV with 1 cm width) by 47.2%, 32.3%, and 40.4% for brain, lung, and abdomen, respectively. When the target dose of CCIPRT is prescribed in terms of the biological dose, compared to PT, CCIPRT achieved higher conformity index (CCIPRT: 0.96 and 0.97; PT: 0.93 and 0.96 for brain and liver cases, respectively) and reduced the dose in CTV1cm by 9.5% and 7.0% for brain and liver cases, respectively; compared to CIRT, CCIPRT enhanced healthy tissue sparing, reducing the dose to the body by 7.5% and 9.2% for brain and liver cases, respectively. Conclusions A novel multi‐modality CCIPRT treatment planning is developed with demonstrated superior performance over single‐modality PT or CIRT, with enhanced biological effectiveness and dose conformity compared to PT and reduced OAR dose compared to CIRT.

Importance Many patients are diagnosed with benign breast lesions; however, evidence- and consensus-based guidelines for the management of benign breast disease (BBD) are limited. Observations The American Society of Breast Surgeons (ASBrS) and the Society of Breast Imaging (SBI) developed guidelines for the management of benign fibroepithelial lesions (FELs) using a modified Delphi consensus methodology and public comment. There was strong consensus that core biopsy–proven concordant fibroadenomas without atypia only require excision if they were symptomatic, patient preferred, attained a certain size, or demonstrated substantive growth over time on clinical examination. There was strong consensus that when removing a fibroadenoma, complete excision without transection of the mass is recommended and surgeons should consider aesthetics, sensation, and other factors when selecting incision placement. Patients with core biopsy–proven concordant fibroadenomas do not require imaging follow-up and may return to age-appropriate screening. Many benign phyllodes tumors (BPTs) present as an FEL on core biopsy, and these lesions along with any lesions with suspicion of or concern for phyllodes tumors (PTs) require surgical excisional biopsy with complete excision of the mass. Re-excision of a BPT is not required for patients with a positive margin for BPT, but a margin re-excision may be considered if the mass was transected or there is concern of residual disease after excisional biopsy. Patients with BPT who have undergone excision do not require follow-up imaging and may return to age-appropriate screening. Conclusions and Relevance Evidence-informed, consensus and expert opinion-based guidelines for the management of benign FELs of the breast were developed. These guidelines provide clarification on the controversial management of benign FELs of the breast. Any practicing clinicians who treat patients with benign FELs should integrate these guidelines into treatment of their patients.

Importance An estimated 70% to 80% of older adults develop delirium in the intensive care unit (ICU). Objective To determine if a slow-tempo music (60-80 beats/min) listening intervention decreases delirium duration, delirium severity, pain, or anxiety in older adults undergoing mechanical ventilation. Design, Setting, and Participants This multicenter randomized clinical trial with concealed outcomes assessments was conducted in older adults undergoing mechanical ventilation from February 2020 to December 2023. Patients were enrolled from the ICUs of 2 hospitals affiliated with the Indiana University School of Medicine and from the Mayo Clinic in Rochester, Minnesota. Intervention A music intervention comprising classical and contemporary tracks, delivered twice daily through noise-canceling headphones and tablets for up to 7 days, was compared to active control listening to a silence track delivered under identical conditions. Main Outcomes and Measures The primary outcome was delirium/coma-free days during the 7-day intervention period assessed by the Confusion Assessment Method for the ICU (CAM-ICU) and the Richmond Agitation-Sedation Scale. The secondary outcomes were delirium severity assessed by the CAM-ICU-7, pain assessed by the Critical Care Pain Observation Tool, and anxiety assessed by the visual analog scale for anxiety (VAS-A). Results A total of 158 patients were randomized (mean [SD] age, 68 (9.2) years; 72 [45.5%] female and 86 [54.4%] male). In an intention-to-treat analysis, no differences were found in the number of delirium/coma-free days in the music intervention group compared with control (median [IQR] days, 2.5 [0-5] vs 3 [0-5]; P = .66). There were also no statistically significant differences in the mean CAM-ICU-7 scores, mean pain scores, or mean VAS-A scores over the 7-day intervention period. By end of the 7-day period, both music intervention and control groups had similar mean (SD) CAM-ICU-7 scores (2.72 [2.80] vs 2.56 [2.72]), Critical Care Pain Observation Tool scores (0.20 [0.55] vs 0.61 [1.29]), and VAS-A scores (43.6 [24.7] vs 28.8 [38.4]). Conclusions and Relevance In this randomized clinical trial among older adults undergoing mechanical ventilation, a slow-tempo music intervention did not demonstrate a statistically significant decrease in delirium duration, delirium severity, pain, or anxiety symptoms. Trial Registration ClinicalTrials.gov Identifier: NCT04182334

Background Postoperative atrial fibrillation occurs in ~40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We evaluated the association of preoperative MRA use with postoperative atrial fibrillation and investigated atrial cell types modulated by MRAs during cold preservation. Methods We studied 19 042 cardiac surgery patients at Mayo Clinic. Propensity 1:3 matching identified 298 MRA users and 894 non‐users. A subgroup analysis of patients on any preoperative diuretic was performed to isolate cardiac‐specific effects of MRAs, matching 298 MRA users to 894 non‐MRA diuretic users. AF recurrence was assessed for up to 6‐years. Single‐nucleus RNA sequencing (snRNA‐seq) was performed on human donor atria exposed to canrenone (a water‐soluble MRA) during cold preservation with ex‐vivo reperfusion, and expression profiles were compared with atria from patients with AF. Results After matching, preoperative MRA use was associated with a lower incidence of postoperative atrial fibrillation (19.8% versus 31.8%, P <0.001). In the diuretic‐only subgroup, MRA users also had lower postoperative atrial fibrillation (19.8% versus 33.2%, P <0.001). MRA use was associated with a reduced incidence of paroxysmal and chronic AF at 6‐years. snRNA‐seq identified a cardiomyocyte subpopulation, CM2, with high mineralocorticoid receptor expression where canrenone suppressed cold preservation‐induced mineralocorticoid receptor target gene expression, which was conversely elevated in chronic AF. Canrenone also attenuated stress‐response in atrial macrophages and pericytes. Conclusions Preoperative MRAs were associated with reduced postoperative and long‐term AF after cardiac surgery. Mechanistically, our ex‐vivo human atrial model revealed that MRAs suppress mineralocorticoid receptor ‐driven atrial stress responses, particularly in conduction‐relevant cardiomyocytes.

Background: Heart transplantation is the gold standard treatment for end-stage heart failure patients. However, only about half of patients will receive a transplant, and hearts from donors >55 years of age are often not transplanted due to concerns about primary graft dysfunction (PGD). The molecular mechanisms behind the increased risk of PGD in old donor age are not well-known. Methods: We examine the chromatin architecture changes in old and young human donor hearts via HiC. We determine the effects of Brd4 inhibition on the on old mouse donor heart cold preservation quality via ex vivo perfusion. Results: we found that older human donor hearts are associated with upregulated BRD4 expression and increased chromatin accessibility. We also identified that human cardiac aging is associated with altered 3D chromatin architecture at BRD4 sites at baseline. Unexpectedly, the cold preservation process in older donor hearts further intensifies chromatin looping at BRD4 sites. Functionally, we showed that old murine donor hearts are more susceptible to cold preservation-reperfusion injury. Importantly, Brd4 inhibition with JQ1 improved the function of ex vivo cold-preserved old donor hearts, restoring them to levels comparable to young donor hearts. Moreover, AAV9-mediated Brd4 knockdown in cardiomyocytes similarly improved ex vivo old donor heart function after cold preservation. Conclusions: Brd4-associated 3D chromatin reorganization plays a critical role in the vulnerability of old donor hearts to cold preservation injury. Therefore, Brd4 could be a potential target for aging-associated PGD.

Ischemic cardiomyopathy (ICM) is a leading cause of heart failure characterized by extensive remodeling of the cardiac extracellular matrix (ECM). While initially adaptive, ECM deposition following ischemic injury eventually turns maladaptive, promoting adverse cardiac remodeling. The strong link between the extent of fibrosis and adverse clinical outcomes has led to growing interest in ECM-targeted therapies to prevent or reverse maladaptive cardiac remodeling in ICM; yet, the precise composition of the ECM in ICM remains poorly defined. In this study, we employed sequential protein extraction enabled by the photocleavable surfactant Azo to enrich ECM proteins from left ventricular tissues of patients with end-stage ICM and nonfailing donor hearts. High-resolution mass spectrometry–based quantitative proteomics identified and quantified over 6,000 unique protein groups, including 315 ECM proteins. We discovered significant upregulation of key ECM components, particularly glycoproteins, proteoglycans, collagens, and ECM regulators. Notably, LOXL1 , FBLN1 , and VCAN were among the most differentially expressed. Functional enrichment analyses revealed enhanced TGFB signaling, integrin-mediated adhesion, and complement activation in ICM tissues, suggesting a feedback loop driving continued ECM deposition in the end-stage failing heart. Together, our findings provide a comprehensive proteomic landscape of ECM alterations in the end-stage ICM myocardium and identify promising molecular targets for therapeutic intervention.

Abstract Chronic widespread pain (CWP) remains challenging due to its heterogeneous causes and complex mechanisms. A total of 2920 plasma proteins are analyzed from 29,254 UK Biobank participants. A total of 256 proteins are identified as cross‐sectionally correlated with CWP. A simple (top 10 proteins) and comprehensive (all significant proteins) proteomic‐based score (ProtS) is created for CWP diagnosis, both outperforming and improving the existing clinical score (area under the curve, AUC: 0.801, 0.723, and 0.791 alone, and 0.856 and 0.880 in combination). In addition, the protein score predicted 13‐years risk of pain‐related traits over the body, including pain onset, progression, and intensity; Moreover, it has stronger associations with nociplastic pain and fibromyalgia compared to nociceptive and neuropathic pain, implying a unique protein signature of different pain mechanisms. Finally, among 434 candidate proteins prioritized in the observational analysis, 18 are corroborated with causal relevance by Mendelian randomization, and importantly, four (CA14, DPEP1, LGALS3, and TNF) showed potential as novel drug targets repurposed for treating CWP.