Citations

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

Abstract Stress injuries of the lunate are rare and have been occasionally described in tennis players. Previously reported cases typically involve bone marrow edema or incomplete stress reactions. We report two elite tennis players presenting with advanced lunate stress fractures that were initially interpreted as Kienböck disease. A retrospective review was performed of patients presenting with lunate fractures in association with competitive tennis playing. Presenting symptoms, imaging studies, treatment, and outcomes were evaluated. Healing was assessed on serial computed tomography (CT) scans by the treating surgeon and was defined as osseous continuity across the fracture site on sagittal and axial slices. A literature review was performed of the world English literature. Magnetic resonance imaging (MRI) demonstrated lunate abnormalities in both athletes. CT imaging revealed a distinct fracture line involving the dorsal aspect of the lunate with associated fragment sclerosis. Conservative management failed to resolve symptoms. Surgical treatment consisted of fragment excision in one case and internal fixation in the other. Both patients returned to play. Lunate stress fractures should be considered in tennis players presenting with long-standing dorsal wrist pain. These lesions may mimic Kienböck disease on MRI, and CT can provide valuable information for diagnostic confirmation in advanced stages. Conservative treatment may be inadequate to return patients to competitive tennis. IV.

Background New antiamyloid therapies (AAT) for treating patients with early Alzheimer disease (AD) have become available in the past 3 years. Although AAT can be beneficial in slowing progression of AD, they also come with potentially serious side effects, particularly for patients requiring anticoagulation or thrombolysis for cardiovascular conditions. Given that most patients with AD are older and likely to have cardiovascular risk factors, there is urgent need for additional guidance for clinicians about potential risks and benefits associated with AAT for patients with cardiovascular comorbidities, best practices for management of these patients, and special considerations with respect to emergency evaluation and treatment of patients on AAT who develop acute neurological symptoms. Methods The American Heart Association convened 75 multidisciplinary experts for the Amyloid‐Related Imaging Abnormalities Summit: Cardiovascular and Stroke Considerations for β‐Amyloid Immunotherapy in AD in July 2025. These experts were divided into 8 work groups to evaluate the current evidence related to AAT usage in patients with cardiovascular risk factors and conditions and develop consensus‐based guidance for clinicians. Results This statement outlines the outcomes of the Summit, including considerations for prescribers, primary care professionals, emergency personnel, and health care system stakeholders. These considerations are intended to improve identification of patients as appropriate candidates for AAT, management of patients with co‐occurring AD and cardiovascular conditions, and their emergency evaluation and treatment. The statement also includes guidance for shared decision‐making, implementation of system changes for improving dementia care, and recommendations for future research and data collection to add to the body of evidence for treating patients with concomitant AD and cardiovascular conditions. Conclusions Building on lessons learned from the establishment of stroke systems of care, the consensus‐based considerations outlined in this document can serve as a foundation for AD systems of care aimed at ensuring optimal use of these ground‐breaking therapies.

Abstract Objective Surgery is an effective, yet underutilized treatment for children with drug‐resistant epilepsy. Although predictors of surgical outcomes are well described, the decision to recommend surgery varies by institution. We aim to evaluate the rates of not recommending surgery, identify associated patient characteristics, and quantify variability across centers. Methods We queried the Pediatric Epilepsy Research Consortium Surgery database, a prospective multicenter cohort of children (0–18 years) undergoing initial evaluation for epilepsy surgery. Patients with documented surgical decisions were included. Demographic, clinical, and presurgical evaluation variables were compared by surgical recommendation status. Logistic regression identified factors associated with not recommending surgery. Mixed‐effects models quantified between‐center variability. Results Among 2480 patients across 29 centers, 532 (21%) were not recommended epilepsy surgery (median center rate 17%, interquartile range [IQR] 10%–28%). After accounting for patient characteristics associated with surgical candidacy, substantial variation in decision‐making remained across centers, with a median twofold difference in the odds of not recommending surgery between otherwise similar patients evaluated at different institutions (Median Odds Ratio = 2.25; Intraclass Correlation Coefficient = .18). The clinical characteristics most strongly associated with not recommending surgery included monthly or less frequent seizures (odds ratio [OR] 2.17, 95% confidence interval [CI] 1.75–2.69), non‐structural etiology (OR 2.02, 95% CI 1.56–2.61), and taking ≤2 anti‐seizure medications (ASMs) (OR 1.67, 95% CI 1.34–2.08, all p 's < .01). These characteristics showed minimal clustering across centers (ICCs < .05). Significance One in five children evaluated for epilepsy surgery are not recommended to pursue surgical treatment. Although clinical factors influence decision‐making, they do not explain the substantial variation in recommendations across pediatric epilepsy centers. Similar children evaluated at different institutions had significant differences in the odds of not being recommended surgery, suggesting that institutional decision‐making contributes importantly to surgical candidacy.

ACCESS is a prospective, multicenter phase II trial evaluating peripheral blood stem cell (PBSC) transplantation using 4-7/8 HLA-mismatched unrelated donors (MMUD) with post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate. Adults undergoing first HCT with myeloablative (MAC) or reduced-intensity/nonmyeloablative (RIC/NMA) conditioning were enrolled, with donors aged 18-35 years and matched at 4/8-7/8 HLA loci by high-resolution typing. This expanded analysis includes all enrolled adult PBSC recipients, including the protocol-specified RIC/NMA cohort expansion, to improve precision of outcome estimates and provide descriptive analyses by HLA match level. Among 268 adults, 183 received 7/8 and 85 received &lt;7/8 MMUD grafts; 82.4% of the &lt;7/8 cohort received 6/8 grafts. Median follow-up among survivors was 11.9 months. At 1-year, overall survival was 78.6% (95% CI, 71.9-83.9) in the 7/8 cohort and 85.6% (95% CI, 76.0-91.5) in the &lt;7/8 cohort. One-year relapse, non-relapse mortality, and GVHD-free relapse-free survival were 17.1%, 13.7%, and 51.1% versus 22.8%, 8.4%, and 54.6%, respectively. The cumulative incidence of grade II-IV and grade III-IV acute GVHD by day 100 was 36.6% and 7.7% in the 7/8 cohort versus 28.3% and 5.9% in the &lt;7/8 cohort. Moderate-to-severe chronic GVHD at 1 year was 11.3% versus 7.7%, respectively. Among adult ACCESS recipients treated on a uniform young-donor PBSC/PTCy platform, short-term outcomes with predominantly 6/8 MMUD transplantation were encouraging. Because donor match level was not prospectively assigned and between-group comparisons were exploratory, these findings are descriptive and should not be interpreted as establishing equivalence with 7/8 MMUD transplantation. (Registered as NCT04904588 at CT.gov)

Abstract Glioblastoma (GBM) remains the most lethal primary brain cancer due to its remarkable metabolic plasticity and therapeutic resistance. Here, we identify cholesterol dependency as a therapeutically exploitable vulnerability in GBM using two FDA-approved drugs: the H1 histamine antagonist clemastine and the retinoid X receptor agonist bexarotene. Combined treatment induces potent synergistic anti-tumor activity across patient-derived glioma models, suppressing proliferation, stemness, and survival at sub-IC50 concentrations. Mechanistically, this therapy disrupts cholesterol biosynthesis, transport, and homeostasis, triggering endoplasmic reticulum stress and activation of the unfolded protein response, ultimately leading to autophagy and apoptotic cell death. Orthotopic patient-derived glioma models recapitulate these mechanisms in vivo, where local intracranial administration significantly reduces tumor progression and prolongs survival using fourfold lower doses than systemic intraperitoneal delivery. Single-cell RNA sequencing revealed activation of regeneration and plasticity programs, accompanied by immune microenvironment remodeling and enhanced inflammatory signaling. Importantly, syngeneic models preserved immune cell composition, supporting future integration with immunotherapeutic strategies. Together, these findings establish cholesterol dysregulation–induced metabolic collapse as a promising therapeutic approach for GBM.

Abstract General anesthesia increasingly facilitates asleep deep brain stimulation (DBS) surgery but suppresses spontaneous electrophysiological signals used to guide lead placement. Here, we investigated whether evoked resonant neural activity (ERNA), a stimulation-evoked biomarker of basal ganglia circuitry, remains informative during asleep DBS. We analyzed intraoperative recordings from a multisite cohort of 45 patients (86 hemispheres) undergoing subthalamic nucleus or globus pallidus internus DBS under awake and anesthetized conditions. Anesthesia markedly attenuated spontaneous beta and high-frequency oscillatory activity. Although ERNA amplitude was reduced at matched stimulation intensities, increasing stimulation current restored high-amplitude, spatially localized responses while preserving anatomical specificity. Across both targets, ERNA spatial distributions remained stable across awake and anesthetized states, co-localized with established motor-network biomarkers, and retrospectively identified electrode levels associated with the greatest postoperative therapeutic window. These retrospective findings position stimulation-evoked circuit interrogation as a complement to imaging for physiology-guided asleep DBS and as a candidate signal for contact prioritization. Prospective studies are warranted to determine whether ERNA-guided decisions improve placement, programming efficiency and clinical outcomes.

Purpose: To measure the computed tomography (CT) attenuation of acute pulmonary embolism (PE) and establish an upper Hounsfield unit (HU) threshold above which it is unlikely to occur. Materials and Methods: This retrospective study analyzed CT pulmonary angiography (CTPA) exams in patients with acute PE (2018–2023) who had a prior negative CTPA in the preceding 2 weeks. Clot and artifact attenuation were measured on the positive and prior negative CTPA respectively. Analysis of variance with post hoc tests and linear regression analysis were performed to determine the effects of technical and other parameters on clot and artifact attenuation. Results: A total of 60 patients were included, each with 1 record or a pair of CTPA exams, yielding 105 clots and 41 artifacts. Mean attenuation for acute PE was 50±40 HU, and for artifact was 110±146 HU. A threshold of 125 HU achieved 97% (102/105) sensitivity for acute PE below it and the same specificity for artifact above it. Specificity for acute PE below this threshold was 37% (15/41). Subsegmental clots had a lower attenuation than all other clots as a group. Kilovoltage peak (kVp) and proximal vessel attenuation were poor predictors of clot attenuation . Conclusions: Most acute PE demonstrated a CT attenuation ≤125 HU on standard CTPA, an upper threshold higher than previously reported, while artifacts demonstrated both lower and higher attenuation. An attenuation >125 HU on standard CTPA, favoring artifact rather than acute PE, may be a useful adjunct to morphologic differentiation between these entities.

The kinesin-5 motor protein KIF11 is crucial for mitotic spindle assembly, driving the separation of spindle poles through microtubule sliding. Src-family kinases phosphorylate KIF11 at multiple tyrosine residues within its motor domain, but the mechanistic consequences of these modifications remain unclear. Here, we dissect the role of phosphorylation at Y211 using phospho-mimetic (Y211E) and nonphosphorylatable mutants (Y211F) in biochemical, biophysical, and cellular assays. Optical trapping and Förster resonance energy transfer analyses reveal that Y211 phosphorylation slows neck-linker docking, reducing motor velocity and force generation under load. In human cells, Y211E expression impairs bipolar spindle formation and decreases spindle pole separation velocity, while Y211F shortens steady-state spindle length. Fluorescence recovery after photobleaching analyses show that Y211E accelerates motor turnover on spindle microtubules, consistent with the mutant motor’s heightened load sensitivity. Together, these findings support a model in which Src-mediated phosphorylation at Y211 acts as a rheostat to tune KIF11 mechanochemistry and spindle assembly dynamics, linking cancer-relevant kinase signaling to mitotic force generation.

ABSTRACT Background Radiotherapy is a cornerstone of treatment for pediatric central nervous system (CNS) tumors, but dose selection remains uniform despite interpatient variability in tumor radiosensitivity. This is consequential in children, for whom toxicity can have lifelong effects. Genomic-adjusted radiation dose (GARD) integrates tumor genomics with delivered radiation dose to quantify the biological effect of radiotherapy and has been validated across adult malignancies. Its relevance in pediatric CNS tumors is unknown. Methods We performed a cohort study using gene expression and data from 246 pediatric patients with high-grade glioma, medulloblastoma, or ependymoma from the Children’s Brain Tumor Network. GARD was calculated using a sequencing-adapted radiosensitivity index integrated with radiation dose through the linear–quadratic model. Associations of GARD and physical radiation dose with event-free and overall survival were evaluated using Cox proportional hazards models stratified by tumor type and anatomic location. Patients who did not receive radiotherapy comprised a negative control cohort (sham-GARD). Results Among patients receiving radiotherapy, physical dose was uniform, whereas GARD showed substantial interpatient variability in biological effect. Higher GARD was associated with improved event-free survival (hazard ratio [HR] 0·90, 95% CI 0·83–0·97; p=0·004) and overall survival (HR 0·90, 95% CI 0·83–0·99; p=0·018). Physical dose was not associated with either endpoint. Among patients who did not receive radiotherapy, sham-GARD was not associated with outcomes, supporting GARD as a treatment-specific predictor rather than a prognostic biomarker. Conclusions In pediatric CNS tumors, the biological effect of radiotherapy quantified by GARD was associated with outcomes, whereas physical dose was not. These findings challenge uniform radiotherapy dosing and support genomically informed dose individualization. Prospective evaluation of GARD-guided radiotherapy is warranted to optimize tumor control while minimizing long-term toxicity in children.