The Role of Mesenchymal Reprogramming in Malignant Clonal Evolution and Intra-Tumoral Heterogeneity in Glioblastoma.

Glioblastoma (GBM) is the most common yet uniformly fatal adult brain cancer. Intra-tumoral molecular and cellular heterogeneities are major contributory factors to therapeutic refractoriness and futility in GBM. Molecular heterogeneity is represented through molecular subtype clusters whereby the proneural (PN) subtype is associated with significantly increased long-term survival compared to the highly resistant mesenchymal (MES) subtype.

Epigenetic Activation of TUSC3 Sensitizes Glioblastoma to Temozolomide Independent of MGMT Promoter Methylation Status.

Temozolomide (TMZ) is an important first-line treatment for glioblastoma (GBM), but there are limitations to TMZ response in terms of durability and dependence on the promoter methylation status of the DNA repair gene O-methylguanine DNA methyltransferase (). MGMT-promoter-hypermethylated (MGMT-M) GBMs are more sensitive to TMZ than MGMT-promoter-hypomethylated (MGMT-UM) GBMs. Moreover, TMZ resistance is inevitable even in TMZ-sensitive MGMT-M GBMs.

A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma.

Stemness reprogramming remains a largely unaddressed principal cause of lethality in glioblastoma (GBM). It is therefore of utmost importance to identify and target mechanisms that are essential for GBM stemness and self-renewal. Previously, we implicated BIRC3 as an essential mediator of therapeutic resistance and survival adaptation in GBM.

Durable Progression-Free Survival With the Use of BRAF and MEK Inhibitors in Four Cases With V600E-Mutated Gliomas.

Introduction: V600 E mutations have been identified in a subset of patients with primary brain tumors. Combination therapy with BRAF and Mitogen-activated protein kinase (MEK) inhibitors (BRAF/MEKi) targeting sequential steps in the MAPK pathway has replaced BRAFi monotherapy as the standard of care in multiple tumors with V600 E mutations, and clinical evidence for this strategy continues to grow in primary brain tumors.

Case Series: We describe four patients with V600 E mutated gliomas, including a 21-year-old woman with a ganglioglioma WHO grade I, a 19-year-old man with a pleomorphic xanthoastrocytoma WHO grade III, and 21-year-old and 33-year-old women with epithelioid GBM WHO grade IV, who achieved durable progression-free survival with combination BRAF/MEKi.

Multiple myeloma presenting as an intramedullary spinal cord tumor: a case report and review of the literature.

Background: Extramedullary disease in multiple myeloma often portends a worse diagnosis. In approximately 1% of cases, multiple myeloma may metastasize to the central nervous system as either leptomeningeal involvement or an intracranial, intraparenchymal lesion. Spinal cord metastases, however, are exceedingly rare.

Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma.

Introduction: A patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors.

Paradoxical epigenetic regulation of XAF1 mediates plasticity towards adaptive resistance evolution in MGMT-methylated glioblastoma.

Epigenetic regulation of O-alkylguanine DNA alkyltransferase (MGMT) is surrogate of intrinsic resistance to temozolomide (TMZ). However, mechanisms associated with adaptive resistance evolution of glioblastoma (GBM) relative to MGMT methylation remain unclear. We hereby report a paradoxical yet translational epigenetic regulation of plasticity towards adaptive resistance in GBM.

BIRC3 is a biomarker of mesenchymal habitat of glioblastoma, and a mediator of survival adaptation in hypoxia-driven glioblastoma habitats.

Tumor hypoxia is an established facilitator of survival adaptation and mesenchymal transformation in glioblastoma (GBM). The underlying mechanisms that direct hypoxia-mediated survival in GBM habitats are unclear. We previously identified BIRC3 as a mediator of therapeutic resistance in GBM to standard temozolomide (TMZ) chemotherapy and radiotherapy (RT).

Impending Impact of Molecular Pathology on Classifying Adult Diffuse Gliomas.

Background: Progress in molecular oncology during the last decade has enabled investigators to more precisely define and group gliomas. The impacts of isocitrate dehydrogenase (IDH) mutation (mut) status and other molecular markers on the classification, prognostication, and management of diffuse gliomas are likely to be far-reaching.

Methods: Clinical experience and the medical literature were used to assess the current status of glioma categorization and the likely impact of the pending revision of the classification scheme of the World Health Organization (WHO).

Butyrylcholinesterase activity in multiple sclerosis neuropathology.

Butyrylcholinesterase (BuChE) is an enzyme capable of hydrolysing a wide variety of esters including acetylcholine, a molecule involved in neurotransmission and modulation of immune cell activity. In the brain, BuChE is expressed in white matter and certain populations of neurons and glia. Multiple sclerosis (MS) is an autoimmune disease affecting white matter characterized by neuroinflammation and neurodegeneration in the central nervous system.

Autosomal dominant sensory ataxia: a neuroaxonal dystrophy.

Autosomal dominant sensory ataxia (ADSA), a rare hereditary ataxia, is characterized by progressive dysfunction of central sensory pathways. Its pathological features have not been previously documented. We report a case of a 61-year-old man with ADSA who died of congestive heart failure.

Fourth ventricular neurocytoma: case report and review of the literature.

Objectives: Central neurocytoma is a tumour that typically occurs in young adults in close association with the lateral and third ventricles of the cerebrum.

Methods: We report the unusual case of a central neurocytoma that developed in the fourth ventricle of a 59-year-old woman and metastasized to the upper cervical canal. Subtotal excision and adjuvant radiotherapy were used to treat the lesion.

Cell-cycle gene expression in lovastatin-induced medulloblastoma apoptosis.

Background: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a key rate-limiting enzyme in the mevalonate pathway, which generates precursors both for cholesterol biosynthesis and for the production of nonsteroidal mevalonate derivatives that are involved in a number of growth-regulatory processes. We have reported that lovastatin, a competitive inhibitor of HMG-CoA reductase, not only inhibits medulloblastoma proliferation in vitro, but also induces near-complete cell death via apoptosis. The mechanism of this phenomenon is unclear.

Oligodendrogliomas with neurocytic differentiation. A report of 4 cases with diagnostic and histogenetic implications.

Oligodendroglioma represents a distinct type of diffuse glioma with a relatively favorable prognosis. Although an O2A-like glial progenitor cell of origin has been suggested, a neuronal-oligodendroglial progenitor cell is also of interest, particularly because variable degrees of neuronal marker expression have been reported in typical oligodendrogliomas. We present 2 female and 2 male patients (ages 34-54) with frontal lobe oligodendrogliomas containing a) morphologically distinct collections of small round cells with hyperchromatic nuclei, b) well-formed Homer Wright-like and perivascular rosettes, and c) demonstrable neuronal differentiation by immunohistochemistry and/or electron microscopy in the rosette-associated regions.