Alpha 1-antichymotrypsin contributes to stem cell characteristics and enhances tumorigenicity of glioblastoma.

BACKGROUND: Glioblastomas (GBMs) are the main primary brain tumors in adults with almost 100% recurrence rate. Patients with lateral ventricle proximal GBMs (LV-GBMs) exhibit worse survival compared to distal locations for unknown reasons. One hypothesis is the proximity of these tumors to the cerebrospinal fluid (CSF) and its chemical cues that can regulate cellular phenotype. We therefore investigated the role of CSF on GBM gene expression and the role of a CSF-induced gene, SERPINA3, in GBM malignancy in vitro and in vivo. METHODS: We utilized human CSF and GBM brain tumor-initiating cells (BTICs). We determined the impact of SERPINA3 expression in glioma patients using The Cancer Genome Atlas (TCGA) database. SERPINA3 expression changes were evaluated at mRNA and protein levels. The effects of knockdown (KD) and overexpression (OE) of SERPINA3 on cell migration, viability and cell proliferation were evaluated. Stem cell characteristics on KD cells were evaluated by differentiation and colony formation experiments. Tumor growth was studied by intracranial and flank injections. RESULTS: GBM-CSF increased BTIC migration accompanied by upregulation of the SERPINA3 gene. In patient samples and TCGA data, we observed SERPINA3 to correlate directly with brain tumor grade and indirectly with GBM patient survival. SERPINA3 KD induced a decrease in cell proliferation, migration, invasion, and stem cell characteristics, while SERPINA3 OE increased cell migration. In vivo, SERPINA3 KD BTICs showed increased survival in a murine model. CONCLUSIONS: SERPINA3 plays a key role in GBM malignancy and its inhibition results in a better outcome using GBM preclinical models.

Endoscope-assisted contralateral transmaxillary approach to the clivus and the hypoglossal canal: technical case report.

Clival lesions are still considered surgically complex due to their anatomical location. Critical structures, such as the internal carotid arteries (ICAs), cavernous sinuses, cranial nerves, and brainstem, may be encased within the lesion. Although advances in endoscopic endonasal approaches have provided new routes to these lesions, exposure and resection of clival tumors through the endonasal route remain a technical challenge. Here, the authors report a left-sided endoscopic transmaxillary approach to access the right aspect of the clivus and the hypoglossal canal.A 35-year-old woman presented with progressive right 6th cranial nerve palsy. MRI revealed a contrast-enhancing right petroclival chondrosarcoma that involved Meckel's cave and extended into the right hypoglossal canal. An endoscopic-contralateral-transmaxillary approach through a left sublabial incision was used to access the right petroclival region and right hypoglossal canal. A left maxillary osteoplastic flap was elevated to expose the left maxillary sinus. This was followed by a left medial maxillectomy, gaining access to the left posterior nasal cavity. The posterior third of the left inferior turbinate and nasal septum were removed to access the right side of the petroclival region. Near-total resection was achieved without any vascular or neurological complications. A thin shell of residual tumor was left behind due to involvement of vital structures, such as the ICA, and further treated with proton-beam radiotherapy.The endoscopic-contralateral-transmaxillary approach provides a direct surgical corridor and good lateral visualization of the skull base vasculature. This approach allows wide maneuverability around the ICA and hypoglossal canal, which, in this case, allowed maximal tumor resection with full preservation of neurological function.

Long-term hydrocephalus alters the cytoarchitecture of the adult subventricular zone.

Hydrocephalus can develop secondarily to a disturbance in production, flow and/or absorption of cerebrospinal fluid. Experimental models of hydrocephalus, especially subacute and chronic hydrocephalus, are few and limited, and the effects of hydrocephalus on the subventricular zone are unclear. The aim of this study was to analyze the effects of long-term obstructive hydrocephalus on the subventricular zone, which is the neurogenic niche lining the lateral ventricles. We developed a new method to induce hydrocephalus by obstructing the aqueduct of Sylvius in the mouse brain, thus simulating aqueductal stenosis in humans. In 120-day-old rodents (n=18 per group), the degree of ventricular dilatation and cellular composition of the subventricular zone were studied by immunofluorescence and transmission electron microscopy. In adult patients (age>18years), the sizes of the subventricular zone, corpus callosum, and internal capsule were analyzed by magnetic resonance images obtained from patients with and without aqueductal stenosis (n=25 per group). Mice with 60-day hydrocephalus had a reduced number of Ki67+ and doublecortin+cells on immunofluorescence, as well as decreased number of neural progenitors and neuroblasts in the subventricular zone on electron microscopy analysis as compared to non-hydrocephalic mice. Remarkably, a number of extracellular matrix structures (fractones) contacting the ventricular lumen and blood vessels were also observed around the subventricular zone in mice with hydrocephalus. In humans, the widths of the subventricular zone, corpus callosum, and internal capsule in patients with aqueductal stenosis were significantly smaller than age and gender-matched patients without aqueductal stenosis. In summary, supratentorial hydrocephalus reduces the proliferation rate of neural progenitors and modifies the cytoarchitecture and extracellular matrix compounds of the subventricular zone. In humans, this similar process reduces the subventricular niche as well as the width of corpus callosum and internal capsule.