Minimizing pneumocephalus during deep brain stimulation surgery.

BACKGROUND: Deep brain stimulation (DBS) surgery is an effective treatment for movement disorders. Introduction of intracranial air following dura opening in DBS surgery can result in targeting inaccuracy and suboptimal outcomes. We develop and evaluate a simple method to minimize pneumocephalus during DBS surgery. METHODS: A retrospective analysis of prospectively collected data was performed on patients undergoing DBS surgery at our institution from 2014 to 2022. A total of 172 leads placed in 89 patients undergoing awake or asleep DBS surgery were analyzed. Pneumocephalus volume was compared between leads placed with PMT and leads placed with standard dural opening. (112 PMT vs. 60 OPEN). Immediate post-operative high-resolution CT scans were obtained for all leads placed, from which pneumocephalus volume was determined through a semi-automated protocol with ITK-SNAP software. Awake surgery was conducted with the head positioned at 15-30°, asleep surgery was conducted at 0°. RESULTS: PMT reduced pneumocephalus from 11.2 cm3±9.2 to 0.8 cm3±1.8 (P<0.0001) in the first hemisphere and from 7.6 cm3 ± 8.4 to 0.43 cm3 ± 0.9 (P<0.0001) in the second hemisphere. No differences in adverse events were noted between PMT and control cases. Lower rates of post-operative headache were observed in PMT group. CONCLUSION: We present and validate a simple yet efficacious technique to reduce pneumocephalus during DBS surgery.

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. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.

Cellular senescence in glioma.

INTRODUCTION: Glioma is the most common primary brain tumor and is often associated with treatment resistance and poor prognosis. Standard treatment typically involves radiotherapy and temozolomide-based chemotherapy, both of which induce cellular senescence-a tumor suppression mechanism. DISCUSSION: Gliomas employ various mechanisms to bypass or escape senescence and remain in a proliferative state. Importantly, senescent cells remain viable and secrete a large number of factors collectively known as the senescence-associated secretory phenotype (SASP) that, paradoxically, also have pro-tumorigenic effects. Furthermore, senescent cells may represent one form of tumor dormancy and play a role in glioma recurrence and progression. CONCLUSION: In this article, we delineate an overview of senescence in the context of gliomas, including the mechanisms that lead to senescence induction, bypass, and escape. Furthermore, we examine the role of senescent cells in the tumor microenvironment and their role in tumor progression and recurrence. Additionally, we highlight potential therapeutic opportunities for targeting senescence in glioma.

Biological principles of adult degenerative scoliosis.

The global aging population has led to an increase in geriatric diseases, including adult degenerative scoliosis (ADS). ADS is a spinal deformity affecting adults, particularly females. It is characterized by asymmetric intervertebral disc and facet joint degeneration, leading to spinal imbalance that can result in severe pain and neurological deficits, thus significantly reducing the quality of life. Despite improved management, molecular mechanisms driving ADS remain unclear. Current literature primarily comprises epidemiological and clinical studies. Here, we investigate the molecular mechanisms underlying ADS, with a focus on angiogenesis, inflammation, extracellular matrix remodeling, osteoporosis, sarcopenia, and biomechanical stress. We discuss current limitations and challenges in the field and highlight potential translational applications that may arise with a better understanding of these mechanisms.

Initiating a Magnetic Resonance-Guided Focused Ultrasound Program: Comprehensive Workflow and Lessons Learned from the Initial 116 Cases.

INTRODUCTION: Magnetic resonance-guided focused ultrasound (MRgFUS) represents an incisionless treatment option for essential or parkinsonian tremor. The incisionless nature of this procedure has garnered interest from both patients and providers. As such, an increasing number of centers are initiating new MRgFUS programs, necessitating development of unique workflows to optimize patient care and safety. Herein, we describe establishment of a multi-disciplinary team, workflow processes, and outcomes for a new MRgFUS program. METHODS: This is a single-academic center retrospective review of 116 consecutive patients treated for hand tremor between 2020 and 2022. MRgFUS team members, treatment workflow, and treatment logistics were reviewed and categorized. Tremor severity and adverse events were evaluated at baseline, 3, 6, and 12 months post-MRgFUS with the Clinical Rating Scale for Tremor Part B (CRST-B). Trends in outcome and treatment parameters over time were assessed. Workflow and technical modifications were noted. RESULTS: The procedure, workflow, and team members remained consistent throughout all treatments. Technique modifications were attempted to reduce adverse events. A significant reduction in CRST-B score was achieved at 3 months (84.5%), 6 months (79.8%), and 12 months (72.2%) post-procedure (p < 0.0001). The most common post-procedure adverse events in the acute period (<1 day) were gait imbalance (61.1%), fatigue and/or lethargy (25.0%), dysarthria (23.2%), headache (20.4%), and lip/hand paresthesia (13.9%). By 12 months, the majority of adverse events had resolved with a residual 17.8% reporting gait imbalance, 2.2% dysarthria, and 8.9% lip/hand paresthesia. No significant trends in treatment parameters were found. CONCLUSIONS: We demonstrate the feasibility of establishing an MRgFUS program with a relatively rapid increase in evaluation and treatment of patients while maintaining high standards of safety and quality. While efficacious and durable, adverse events occur and can be permanent in MRgFUS.

Endoplasmic Reticulum Stress in the Brain Tumor Immune Microenvironment.

Immunotherapy has emerged as a powerful strategy for halting cancer progression. However, primary malignancies affecting the brain have been exempt to this success. Indeed, brain tumors continue to portend severe morbidity and remain a globally lethal disease. Extensive efforts have been directed at understanding how tumor cells survive and propagate within the unique microenvironment of the central nervous system (CNS). Cancer genetic aberrations and metabolic abnormalities provoke a state of persistent endoplasmic reticulum (ER) stress that in turn promotes tumor growth, invasion, therapeutic resistance, and the dynamic reprogramming of the infiltrating immune cells. Consequently, targeting ER stress is a potential therapeutic approach. In this work, we provide an overview of how ER stress response is advantageous to brain tumor development, discuss the significance of ER stress in governing antitumor immunity, and put forth therapeutic strategies of regulating ER stress to augment the effect of immunotherapy for primary CNS tumors.

Repurposing autophagy regulators in brain tumors.

Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood-brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB-permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)-approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.

Combination of tucatinib and neural stem cells secreting anti-HER2 antibody prolongs survival of mice with metastatic brain cancer.

Brain metastases are a leading cause of death in patients with breast cancer. The lack of clinical trials and the presence of the blood-brain barrier limit therapeutic options. Furthermore, overexpression of the human epidermal growth factor receptor 2 (HER2) increases the incidence of breast cancer brain metastases (BCBM). HER2-targeting agents, such as the monoclonal antibodies trastuzumab and pertuzumab, improved outcomes in patients with breast cancer and extracranial metastases. However, continued BCBM progression in breast cancer patients highlighted the need for novel and effective targeted therapies against intracranial metastases. In this study, we engineered the highly migratory and brain tumor tropic human neural stem cells (NSCs) LM008 to continuously secrete high amounts of functional, stable, full-length antibodies against HER2 (anti-HER2Ab) without compromising the stemness of LM008 cells. The secreted anti-HER2Ab impaired tumor cell proliferation in vitro in HER2+ BCBM cells by inhibiting the PI3K-Akt signaling pathway and resulted in a significant benefit when injected in intracranial xenograft models. In addition, dual HER2 blockade using anti-HER2Ab LM008 NSCs and the tyrosine kinase inhibitor tucatinib significantly improved the survival of mice in a clinically relevant model of multiple HER2+ BCBM. These findings provide compelling evidence for the use of HER2Ab-secreting LM008 NSCs in combination with tucatinib as a promising therapeutic regimen for patients with HER2+ BCBM.

The Eclectic Nature of Glioma-Infiltrating Macrophages and Microglia.

Glioblastomas (GBMs) are complex ecosystems composed of highly multifaceted tumor and myeloid cells capable of responding to different environmental pressures, including therapies. Recent studies have uncovered the diverse phenotypical identities of brain-populating myeloid cells. Differences in the immune proportions and phenotypes within tumors seem to be dictated by molecular features of glioma cells. Furthermore, increasing evidence underscores the significance of interactions between myeloid cells and glioma cells that allow them to evolve in a synergistic fashion to sustain tumor growth. In this review, we revisit the current understanding of glioma-infiltrating myeloid cells and their dialogue with tumor cells in consideration of their increasing recognition in response and resistance to immunotherapies as well as the immune impact of the current chemoradiotherapy used to treat gliomas.