Pharmacokinetic Analysis of Carboplatin and Fluorescein Brain Retention following Ultrasound-Based Blood-Brain Barrier Opening.

Purpose: The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving parenchymal drug penetration. Parenchymal drug retention following short-lived BBB opening is unknown.

Dual αVβ8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Glioma Immunity.

Background: Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune checkpoint blockade efficacy. In glioblastoma (GBM), tumor B-cells are driven into a regulatory B-cell state that suppresses immune activation and T-cell function.

Targeting CHEK2-YBX1&YBX3 regulatory hub to potentiate immune checkpoint blockade response in gliomas.

Although GBM's immunosuppressive environment is well known, the tumor's resistance to CD8+ T cell killing is not fully understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as the key driver of CD8+ T cell resistance in mouse glioma through an in vivo CRISPR screen and demonstrated that Chk2 inhibition, combined with PD-1/PD-L1 blockade, significantly enhanced CD8+ T cell-mediated tumor killing and improved survival in preclinical model. Here, we aimed to elucidate the immunosuppressive function of Chek2.

Pharmacokinetic analysis of carboplatin and fluorescein brain permanence following ultrasound-based blood-brain barrier opening.

Background: The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving parenchymal drug penetration. Parenchymal drug permanence upon short-lived BBB opening is unknown.

Endothelial response to blood-brain barrier disruption in the human brain.

Cerebral endothelial cell (EC) injury and blood-brain barrier (BBB) permeability contribute to neuronal injury in acute neurological disease states. Preclinical experiments have used animal models to study this phenomenon, yet the response of human cerebral ECs to BBB disruption remains unclear. In our phase I clinical trial (ClinicalTrials.

MAPK/ERK signaling in gliomas modulates interferon responses, T cell recruitment, microglia phenotype, and immune checkpoint blockade efficacy.

Background: Glioblastoma (GB) remains a formidable challenge in neuro-oncology, with immune checkpoint blockade (ICB) showing limited efficacy in unselected patients. We previously recently established that MAPK/ERK signaling is associated with overall survival following anti-PD-1 and anti-CTLA-4 treatment in recurrent GB. However, the causal relationship between MAPK/ERK signaling and susceptibility to ICB, as well as the mechanisms underlying this association, remain poorly understood.

Navigating the Neurosurgery Match Process: Insights from the National Resident Matching Program - Program Director Surveys.

Objective: Neurosurgery is one of the most competitive specialties, and navigating the match process is often challenging for aspiring applicants. Here, we analyze insights from the National Resident Matching Program Director Surveys, illustrating evolving trends in applicant selection for interviews and for the ranking process, and providing a comparison with other specialties.

Methods: We evaluated 7 surveys administered from 2012 to 2022.

Prohibitin Expression in Antigen-Presenting Cells: Implications for Inciting Trigger in CNS IgG4-Related Disease.

Immunoglobulin G4-related disease (IgG4-RD) is a rare autoimmune disorder with an unknown etiology. Using orthogonal immune profiling and automated sequential multiplexing, we found an enhanced frequency of activated circulating B cells, antigen-presenting myeloid cells in peripheral blood, and a distinct distribution of immune cells within the CNS lesions. Prohibitin-expressing CD138+ plasma B cells and CD11c+ dendritic cells have been found interacting with T cells resulting in irmnune cell activation within the lesion.

Real-World Experience in Hispanic Patients With Breast Cancer and Brain Metastases Using Different Prognostic Tools.

Purpose: Only a small percentage of Hispanic patients have been included in studies that developed prognostic models for breast cancer and brain metastases. Therefore, there is a clear need for tools tailored to this demographic. This study assesses the efficacy of common prognostic tools in a Hispanic population.

Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.

We recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680).

The CXCL16-CXCR6 axis in glioblastoma modulates T-cell activity in a spatiotemporal context.

Introduction: Glioblastoma multiforme (GBM) pathobiology is characterized by its significant induction of immunosuppression within the tumor microenvironment, predominantly mediated by immunosuppressive tumor-associated myeloid cells (TAMCs). Myeloid cells play a pivotal role in shaping the GBM microenvironment and influencing immune responses, with direct interactions with effector immune cells critically impacting these processes.

Methods: Our study investigates the role of the CXCR6/CXCL16 axis in T-cell myeloid interactions within GBM tissues.

Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.

Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM).

ERK1/2 Phosphorylation Predicts Survival in Recurrent Glioblastoma Following Intracerebral and Adjuvant PD-1/CTLA-4 Immunotherapy: A REMARK-guided Analysis.

Purpose: Evidence suggests that MAPK pathway activation, as measured by ERK1/2 phosphorylation (p-ERK), predicts overall survival (OS) in patients with recurrent glioblastoma receiving anti-PD-1 therapy. We aimed to validate these findings in independent cohorts.

Experimental Design: In a 24-patient clinical trial on recurrent glioblastoma and high-grade gliomas, we examined the link between p-ERK levels and OS.

Metixene is an incomplete autophagy inducer in preclinical models of metastatic cancer and brain metastases.

A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes.

Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial.

Background: Low-intensity pulsed ultrasound with concomitant administration of intravenous microbubbles (LIPU-MB) can be used to open the blood-brain barrier. We aimed to assess the safety and pharmacokinetics of LIPU-MB to enhance the delivery of albumin-bound paclitaxel to the peritumoural brain of patients with recurrent glioblastoma.

Methods: We conducted a dose-escalation phase 1 clinical trial in adults (aged ≥18 years) with recurrent glioblastoma, a tumour diameter of 70 mm or smaller, and a Karnofsky performance status of at least 70.

IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM.

Introduction: The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME.

Immune checkpoint blockade in glioblastoma: from tumor heterogeneity to personalized treatment.

Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance.

Myeloid Cell Classification and Therapeutic Opportunities Within the Glioblastoma Tumor Microenvironment in the Single Cell-Omics Era.

The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies.

Translocon-associated Protein Subunit SSR3 Determines and Predicts Susceptibility to Paclitaxel in Breast Cancer and Glioblastoma.

Purpose: Paclitaxel (PTX) is one of the most potent and commonly used chemotherapies for breast and pancreatic cancer. Several ongoing clinical trials are investigating means of enhancing delivery of PTX across the blood-brain barrier for glioblastomas. Despite the widespread use of PTX for breast cancer, and the initiative to repurpose this drug for gliomas, there are no predictive biomarkers to inform which patients will likely benefit from this therapy.