Notes

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The combined effects of MTX plus HDACIs were evaluated using a cell viability assay, mass spectroscopy imaging, and subcutaneous and intracranial xenograft models.

HDACIs upregulated the ratio of FPGS/GGH expression resulting in increased polyglutamylation of MTX, but also downregulated expression of the target molecule of MTX DHFR. The combination of MTX and vorinostat decreased cell viability in vitro (
< .05) and tumor volumes in a subcutaneous model (
< .0001), and prolonged survival in an intracranial model (
< .01), relative to controls.

HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression.
HDACIs enhanced the therapeutic effect of MTX through increased polyglutamylation of MTX and concomitant downregulation of DHFR expression.
Despite maximal therapy with surgery, chemotherapy, and radiotherapy, glioblastoma (GBM) patients have a median survival of only 15 months. Almost all patients inevitably experience symptomatic tumor recurrence. A hallmark of this tumor type is the large heterogeneity between patients and within tumors itself which relates to the failure of standardized tumor treatment. In this study, tissue samples of paired primary and recurrent GBM tumors were investigated to identify individual factors related to tumor progression.

Paired primary and recurrent GBM tumor tissues from 8 patients were investigated with a multiomics approach using transcriptomics, proteomics, and phosphoproteomics.

In the studied patient cohort, large variations between and within patients are observed for all omics analyses. A few pathways affected at the different omics levels partly overlapped if patients are analyzed at the individual level, such as synaptogenesis (containing the SNARE complex) and cholesterol metabolism. Phosphoproteomics revealed increased STMN1(S38) phosphorylation as part of ERBB4 signaling. A pathway tool has been developed to visualize and compare different omics datasets per patient and showed potential therapeutic drugs, such as abobotulinumtoxinA (synaptogenesis) and afatinib (ERBB4 signaling). Afatinib is currently in clinical trials for GBM.

A large variation on all omics levels exists between and within GBM patients. Therefore, it will be rather unlikely to find a drug treatment that would fit all patients. Instead, a multiomics approach offers the potential to identify affected pathways on the individual patient level and select treatment options.
A large variation on all omics levels exists between and within GBM patients. selleck chemical Therefore, it will be rather unlikely to find a drug treatment that would fit all patients. Instead, a multiomics approach offers the potential to identify affected pathways on the individual patient level and select treatment options.
Glioblastoma (GBM) is a highly aggressive incurable brain tumor. The main cause of mortality in GBM patients is the invasive rim of cells migrating away from the main tumor mass and invading healthy parts of the brain. Although the motion is driven by forces, our current understanding of the physical factors involved in glioma infiltration remains limited. This study aims to investigate the adhesion properties within and between patients' tumors on a cellular level and test whether these properties correlate with cell migration.

Six tissue samples were taken from spatially separated sections during 5-aminolevulinic acid (5-ALA) fluorescence-guided surgery. Navigated biopsy samples were collected from strongly fluorescent tumor cores, a weak fluorescent tumor rim, and nonfluorescent tumor margins. A microfluidics device was built to induce controlled shear forces to detach cells from monolayer cultures. Cells were cultured on low modulus polydimethylsiloxane representative of the stiffness of brain tissue. Cell migration and morphology were then obtained using time-lapse microscopy.

GBM cell populations from different tumor fractions of the same patient exhibited different migratory and adhesive behaviors. These differences were associated with sampling location and amount of 5-ALA fluorescence. Cells derived from weak- and nonfluorescent tumor tissue were smaller, adhered less well, and migrated quicker than cells derived from strongly fluorescent tumor mass.

GBM tumors are biomechanically heterogeneous. Selecting multiple populations and broad location sampling are therefore important to consider for drug testing.
GBM tumors are biomechanically heterogeneous. Selecting multiple populations and broad location sampling are therefore important to consider for drug testing.Brain metastases comprise the majority of central nervous tumors in adults and confer poorer survival for patients with primary cancer. Systemic disease control is improving with advances in treatment for primary tumors and the complexity of brain metastases management is increasing with multimodality approaches incorporating combinations of surgery, radiotherapy, chemotherapy, targeted therapies, and immunotherapy. Accordingly, the Society for Neuro-Oncology established an annual brain metastases conference to unite colleagues from multiple disciplines with content spanning a range of timely topics relevant to improving our understanding of brain metastases and how they are optimally treated. The inaugural meeting on August 16-17, 2019 was very successful with 163 impactful presentations being delivered to a large multidisciplinary audience on current research advances in the field of neuro-oncology. This review summarizes the major themes of the meeting and highlights the main findings presented.The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials.
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