Blood-Brain Barrier Disruption for the Treatment of Primary Brain Tumors: Advances in the Past Half-Decade.

PURPOSE OF REVIEW: To review relevant advances in the past half-decade in the treatment of primary brain tumors via modification of blood-brain barrier (BBB) permeability. RECENT FINDINGS: BBB disruption is becoming increasingly common in the treatment of primary brain tumors. Use of mannitol in BBB disruption for targeted delivery of chemotherapeutics via superselective intra-arterial cerebral infusion (SIACI) is the most utilized strategy to modify the BBB. Mannitol is used in conjunction with chemotherapeutics, oligonucleotides, and other active agents. Convection-enhanced delivery has become an attractive option for therapeutic delivery while bypassing the BBB. Other technologic innovations include laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) which have emerged as prime modalities to directly target tumors and cause significant local BBB disruption. In the past 5 years, interest has significantly increased in studying modalities to disrupt the BBB in primary brain tumors to enhance treatment responses and improve clinical outcomes.

Trends in glioblastoma: outcomes over time and type of intervention: a systematic evidence based analysis.

INTRODUCTION: Despite aggressive treatment with chemoradiotherapy and maximum surgical resection, survival in patients with glioblastoma (GBM) remains poor. Ongoing efforts are aiming to prolong the lifespan of these patients; however, disparities exist in reported survival values with lack of clear evidence that objectively examines GBM survival trends. We aim to describe the current status and advances in the survival of patients with GBM, by analyzing median overall survival through time and between treatment modalities. METHODS: A systematic review was conducted according to PRISMA guidelines to identify articles of newly diagnosed glioblastoma from 1978 to 2018. Full-text glioblastoma papers with human subjects, ≥ 18 years old, and n ≥ 25, were included for evaluation. RESULTS: The central tendency of median overall survival (MOS) was 13.5 months (2.3-29.6) and cumulative 5-year survival was 5.8% (0.01%-29.1%), with a significant difference in survival between studies that predate versus postdate the implementation of temozolomide and radiation, [12.5 (2.3-28) vs 15.6 (3.8-29.6) months, P < 0.001]. In clinical trials, bevacizumab [18.2 (10.6-23.0) months], tumor treating fields (TTF) [20.7 (20.5-20.9) months], and vaccines [19.2 (15.3-26.0) months] reported the highest central measure of median survival. CONCLUSION: Coadministration with radiotherapy and temozolomide provided a statistically significant increase in survival for patients suffering from glioblastoma. However, the natural history for GBM remains poor. Therapies including TTF pooled values of MOS and provide means of prolonging the survival of GBM patients.

Microglial Cytokines Induce Invasiveness and Proliferation of Human Glioblastoma through Pyk2 and FAK Activation.

Glioblastoma is the most aggressive brain tumor in adults. Multiple lines of evidence suggest that microglia create a microenvironment favoring glioma invasion and proliferation. Our previous studies and literature reports indicated the involvement of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in glioma cell proliferation and invasion, stimulated by tumor-infiltrating microglia. However, the specific microglia-released factors that modulate Pyk2 and FAK signaling in glioma cells are unknown. In this study, 20 human glioblastoma specimens were evaluated with the use of RT-PCR and western blotting. A Pierson correlation test demonstrated a correlation (0.6-1.0) between the gene expression levels for platelet-derived growth factor ß(PDGFß), stromal-derived factor 1α (SDF-1α), IL-6, IL-8, and epidermal growth factor (EGF) in tumor-purified microglia and levels of p-Pyk2 (Y579/Y580) and p-FAK(Y925) in glioma cells. siRNA knockdown against Pyk2 or FAK in three primary glioblastoma cell lines, developed from the investigated specimens, in combination with the cytokine receptor inhibitors gefitinib (1 µM), DMPQ (200 nM), and burixafor (1 µM) identified EGF, PDGFß, and SDF-1α as key extracellular factors in the Pyk2- and FAK-dependent activation of invadopodia formation and the migration of glioma cells. EGF and IL-6 were identified as regulators of the Pyk2- and FAK-dependent activation of cell viability and mitosis.

Intraoperative Direct Stimulation Identification and Preservation of Critical White Matter Tracts During Brain Surgery.

The study of brain connectomics has led to a rapid evolution in the understanding of human brain function. Traditional localizationist theories are being replaced by more accurate network, or hodologic, approaches that model brain function as widespread processes dependent on cortical and subcortical structures, as well as the white matter tracts (WMTs) that link these areas. Recent surgical literature suggests that WMTs may be more critical to preserve than cortical structures because of the comparably lower capacity of recovery of the former when damaged. Given the relevance of eloquent WMTs to neurologic function and thus quality of life, neurosurgical interventions must be tailored to maximize their preservation. Direct electric stimulation remains a vital tool for identification and avoidance of these critical tracts. Neurosurgeons therefore require proper understanding of the anatomy and function of WMTs, as well as the reported contemporary tasks used during intraoperative stimulation. We review the relevant tracts involved in language, visuospatial, and motor networks and the updated direct electric stimulation-based mapping tasks that aid in their preservation. The dominant-hemisphere language WMTs have been mapped using picture naming, semantic association, word repetition, reading, and writing tasks. For monitoring of vision and spatial functions, the modified picture naming and line bisection tasks, as well as the recording of visual evoked potentials, have been used. Repetitive movements and monitoring of motor evoked potentials and involuntary movements have been applied for preservation of the motor networks.