Citations

Abstract Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of liquid tumors but faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous TCR using an oncolytic virus (OV) enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to CAR T cells that do not undergo TCR priming. Single cell RNA-sequencing showed clonal expansion of anti-VSV CAR T cells, selective avoidance of exhaustion, and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in both the generation and polarization of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of intravenous administration of oncolytic viruses with separate applications from their direct oncolytic activity and for directly exploiting the TCR and its endogenous interactions as tools for fine tuning the phenotype and function of CAR T cells, with particular efficacy against solid tumors.

The primary purpose of this study was to examine the acute effects of a multi-ingredient preworkout supplement (MIPS) on isometric, concentric, and eccentric peak torque and electromyographic (EMG) responses of the leg extensors during a fatiguing isokinetic protocol. Thirteen male subjects (mean age ± SD = 22.9 ± 2.2 years) were assigned in crossover fashion to ingest an MIPS or placebo before an isokinetic protocol that consisted of 30 maximal, concentric and eccentric muscle actions with EMG signals recorded from the vastus lateralis, rectus femoris, and vastus medialis muscles. Immediately before (PRE) and after (POST) the isokinetic fatigue protocol, subjects were assessed for isometric peak torque. The MIPS condition resulted in greater isometric (205 ± 48 vs. 185 ± 44 N·m, p = 0.04) and concentric (121 ± 34 vs. 103 ± 27 N·m, p = 0.015) torque values versus placebo (collapsed across time). For eccentric peak torque as well as EMG amplitude and frequency values, there were no significant (p > 0.05) interactions or main effects for each condition. These findings indicated that acute ingestion of the MIPS enhanced isometric and concentric peak torque of the leg extensors, which was not explained by changes in the EMG signal.

Abstract BACKGROUND Post-operative prognostication in glioma patients remains a clinical challenge, particularly given the heterogeneity in tumor biology and patient outcomes. We evaluated whether image-derived features from post-operative imaging improve survival modeling beyond established clinicopathologic factors. METHODS We analyzed a cohort of 71 post-surgical glioma patients treated at Princess Margaret Cancer Centre with known clinicopathologic features including age, histological classification, IDH mutation status, MGMT methylation status, extent of resection, and performance status. A baseline Cox proportional hazards model was fit to clinical variables. Radiomic features were extracted using PyRadiomics from post-operative CT and MRI across three regions of interest: whole brain, tumor bed, and peritumoral ring. Features underwent stepwise unsupervised reduction (variance filtering, exclusion of volume-correlated features, and removal of remaining collinear features), followed by dimensionality reduction via principal component analysis. Combined clinical and imaging models were evaluated in the overall cohort and stratified by IDH mutation status. RESULTS In the overall cohort, the clinical model was highly prognostic (C-index 0.74, p ~ 3.2×10⁻⁶). Adding imaging features improved performance (C-index 0.79) but was not significant (p ~ 0.31). Subset analysis revealed differential effects by IDH status. In IDH-mutant gliomas (n=24), neither clinical nor combined models were significant. In IDH wild-type glioblastoma (n=47), the clinical model achieved C-index 0.75 (p=0.04). The addition of imaging features significantly improved model performance (C-index 0.83, p=0.03), with selected imaging components contributing independent prognostic value after adjustment for clinical variables. Post-hoc analysis of radiomic feature importance (random forest ranking) revealed that top contributing features were drawn from both CT and MRI modalities, with most sourced from the whole brain region. CONCLUSIONS In post-surgical patients with IDH wild-type glioblastoma, image-derived features from post-operative imaging can significantly enhance prognostic modeling beyond known clinicopathologic factors. These preliminary findings support the potential role of radiomic biomarkers in refining risk stratification for this patient subgroup.

Abstract Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is marked by profound immune suppression. Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of this immunosuppressive environment. In this study, we examined the tumor-immune microenvironment using ultrasonic aspirate samples from GBM patients (n = 14). Several immune checkpoint molecules, including PDL1, B7-H3, and VISTA, were notably elevated. TIGIT, a receptor typically associated with T cells, was widely expressed across multiple myeloid subsets, including monocytic myeloid-derived suppressor cells (mMDSCs; 64.27 ± 7.99%) and non-classical monocytes (NCM; 39.8 ± 4.37%). Co-culture of healthy donor monocytes (n=10) with TEVs replicated similar effects (control 11.69±1.87 vs EV treated 23.32±2.0). We found CD155, the primary TIGIT ligand, to be heavily enriched in TEVs and co-expressed with TIGIT in co-culture, suggesting the TIGIT/CD155 axis may be involved in promoting immune suppression. Additionally, induced MDSCs significantly inhibit T cell proliferation (30.65±5.97% proliferation, v/s control 86.47±2.94, p=0.0001), concomitant with a surge in Th2 immune responses via TIGIT+ monocytes along with an increase in NLRP3 and IL-1β expressing cells. Interestingly, TIGIT knockdown did not affect NLRP3 expression but did restore T cell proliferation (64.13 ± 1.33%; p = 0.02) and pro-inflammatory cytokine production. However, the restoration of T cell proliferation was lost when NLRP3 was also silenced, indicating its essential role in mediating immune rescue. Overall, our findings highlight a crucial role of TIGIT in driving myeloid-mediated immune suppression in GBM. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue.

Background: Orthopaedic sports medicine fellowships are highly competitive, yet objective data defining characteristics of successful applicants remain limited. Hypothesis: It was hypothesized that greater academic productivity, top-tier residency training, and certain demographic factors would be associated with matching into a top-ranked orthopaedic sports medicine fellowship. Study Design: Cross-sectional study. Methods: We retrospectively reviewed applicants who matched into one of the top 10 orthopaedic sports medicine fellowships from 2020 to 2025, as identified by previous applicant preference rankings. Applicant data were obtained from publicly available sources and verified by 2 independent reviewers. Variables included sex, degree type, residency program ranking, geographic region, and research productivity (total publications, primary publication count, H-index, and sports-related publications). Multivariate logistic regression assessed predictors of matching into top 5 versus 6th- to 10th-ranked programs. Results: Among 226 matched applicants, 87.7% were male and 99.1% held a doctorate in medicine degree. The mean total publication count was 12.4, mean H-index was 8.2, and 30.5% trained at a top 20 orthopaedic residency. Applicants matching into top 5 programs had significantly higher research metrics than those in the 6th- to 10th-ranked programs: total publications (20.1 vs 4.7), primary publication count (6.2 vs 1.6), and sports-related publications (11.4 vs 1.9). On regression analysis, total publications, H-index, and residency ranking were independent predictors of matching into a top 5 program. Conclusion: Matching into a top orthopaedic sports medicine fellowship is associated with higher academic productivity and training at a top-tier residency program.

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 Pulmonary hypertension due to interstitial lung disease (PH‐ILD) is associated with high morbidity and mortality. Real‐world patients initiating inhaled treprostinil are not well‐characterized. This retrospective cohort study aimed to evaluate healthcare resource utilization in patients with PH‐ILD who initiated treatment with inhaled treprostinil vs patients who remained untreated. Adult patients diagnosed with PH‐ILD were indexed on initiation of inhaled treprostinil and patients who remained untreated were indexed on first observed PH diagnosis (31 March 2021–30 September 2024). Patients were excluded if they were ever treated with any pulmonary arterial hypertension therapy. Inhaled treprostinil patients were matched to up to four untreated patients. All‐cause per‐patient per‐month (PPPM) hospitalizations and ICU‐related hospitalizations were the primary outcomes of interest. 294 patients treated with inhaled treprostinil and 736 untreated patients were identified. Mean all‐cause PPPM hospitalizations remained unchanged in the pre‐index vs post‐index periods in the inhaled treprostinil cohort (0.11 vs 0.12; p = 0.42) but significantly increased in untreated patients (0.12 vs 0.23; p < 0.01). ICU utilization also remained unchanged in the pre‐index vs post‐index periods for the inhaled treprostinil cohort (0.06 vs 0.07; p = 0.11) compared to the untreated cohort (0.06 vs 0.13; p < 0.01). Untreated patients had significantly higher post‐index PPPM hospitalizations ( p < 0.01) and ICU utilization ( p < 0.01) compared to inhaled treprostinil patients. Patients who initiated inhaled treprostinil had a 30% decreased risk of hospitalization compared to untreated patients (relative risk: 0.70; 95% CI: 0.59–0.83; p < 0.01). Among real‐world patients with PH‐ILD, treatment with inhaled treprostinil is associated with fewer all‐cause hospitalizations and ICU‐related hospitalizations compared to untreated patients with PH‐ILD.

Abstract Background Coagulation markers are used to guide clinical anticoagulation decisions. We aimed to identify circulating metabolites that are associated with coagulation markers in children with congenital heart disease (CHD). Methods Plasma samples were separated from whole blood under consistent conditions. Untargeted metabolomic data were measured in plasma from up to 203 young patients (age range: 0 days-24 years) with CHD before cardiac surgery. Coagulation markers included activated partial thromboplastin time (aPTT), prothrombin time (PT), and activated clotting time (ACT). Weighted Gene Co-expression Network Analysis (WGCNA) was performed to explore metabolite modules (clusters). Associations of metabolites with the coagulation markers were assessed cross-sectionally with regression models, with false discovery rate (FDR) correction for multiple comparison. Associations between coagulation markers and ‘eigenmetabolites’ from WGCNA modules were assessed by correlation analysis. Results A total of 776 metabolites were included in the final analysis. Among these, 20 metabolites were associated with PT and one (valine) with ACT (FDR q value < 0.05). Among the metabolites associated with PT, the top three were retinol, 1-palmitoyl-GPI (16:0), and X-25371 (identity unknown). One module from WGCNA with metabolites from the lipid super pathway was correlated with PT (P = 0.004). Conclusion In this first attempt to identify novel metabolites for coagulation markers, we report 21 metabolites associated with PT or ACT in children with CHD. Future studies are needed to replicate these findings in independent cohorts and to elucidate the biological mechanisms linking these metabolites to hemostatic regulation.

Abstract Background Central nervous system (CNS) tumors are a significant cause of morbidity and mortality in sub-Saharan Africa (SSA). To date, no large-scale efforts have focused on brain tumor genetics within this region. This study aimed to assess and map the current neuro-oncology capacity in SSA, including workforce availability and existing services for brain tumor registries and biobanks. The results represent the final analysis representing respondents from 70 healthcare institutions. Methods This cross-sectional study utilized an online survey to collect data from healthcare professionals involved in CNS tumor care across SSA through the Society for Neuro-Oncology SSA (SNOSSA). The survey gathered information on the availability of neuro-oncology practitioners, neuropathology and molecular diagnostic capacity, brain tumor management, cancer registries, and biobanking of specimens. Purposive sampling was used to identify participants, with the questionnaire provided in English, French, and Swahili. Results A total of 145 respondents from 22 countries and 70 healthcare institutions participated. Among the 70 institutions, neurosurgery was available in 89%, anatomic pathology in 74%, and medical oncology in 71%. For radiologic evaluation, 64% of institutions reported having both CT and MRI, while 17% had CT only. Molecular testing through IHC or NGS was available in 46% of institutions. Multidisciplinary tumor boards for CNS cases were present in 86% of institutions. General cancer registries were available in 66% of institutions, while 29% had brain tumor-specific registries, and 10% maintained brain tumor biorepositories. Conclusion This study provides a comprehensive summary of the neuro-oncology capacity in SSA. Next steps are to reach out to institutions who have registries and determine what data are being collected, with the hopes of defining a set of common elements to expand registry efforts across SSA. Similarly, to reach out to institutions that have ongoing brain tumor biobanks and CT/MRI capacity to determine what infrastructure exists.