Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo.

Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor-related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. It does so by triggering α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV). How Dex specifically activates α5 integrin in these GBM lines is unknown. Several chaperone proteins are known to activate integrins, including calreticulin (CALR). We explore the role of CALR as a potential mediator of Dex-dependent induction of α5 integrin activity in primary human GBM cells. We use CALR knock-down and knock-in strategies to explore the effects on FNMA, aggregate compaction, and dispersal velocity in vitro, as well as dispersal ex vivo on extirpated mouse retina and brain slices. We show that Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated FNMA. Overexpression of CALR in GBM cells activates FNMA, increases compaction, and decreases DV in vitro and on explants of mouse retina and brain slices. Our results define a novel interaction between Dex, CALR, and FNMA as inhibitors of GBM dispersal.

Dexamethasone-mediated inhibition of Glioblastoma neurosphere dispersal in an ex vivo organotypic neural assay.

Glioblastoma is highly aggressive. Early dispersal of the primary tumor renders localized therapy ineffective. Recurrence always occurs and leads to patient death. Prior studies have shown that dispersal of Glioblastoma can be significantly reduced by Dexamethasone (Dex), a drug currently used to control brain tumor related edema. However, due to high doses and significant side effects, treatment is tapered and discontinued as soon as edema has resolved. Prior analyses of the dispersal inhibitory effects of Dex were performed on tissue culture plastic, or polystyrene filters seeded with normal human astrocytes, conditions which inherently differ from the parenchymal architecture of neuronal tissue. The aim of this study was to utilize an ex-vivo model to examine Dex-mediated inhibition of tumor cell migration from low-passage, human Glioblastoma neurospheres on multiple substrates including mouse retina, and slices of mouse, pig, and human brain. We also determined the lowest possible Dex dose that can inhibit dispersal. Analysis by Two-Factor ANOVA shows that for GBM-2 and GBM-3, Dex treatment significantly reduces dispersal on all tissue types. However, the magnitude of the effect appears to be tissue-type specific. Moreover, there does not appear to be a difference in Dex-mediated inhibition of dispersal between mouse retina, mouse brain and human brain. To estimate the lowest possible dose at which Dex can inhibit dispersal, LogEC50 values were compared by Extra Sum-of-Squares F-test. We show that it is possible to achieve 50% reduction in dispersal with Dex doses ranging from 3.8 x10-8M to 8.0x10-9M for GBM-2, and 4.3x10-8M to 1.8x10-9M for GBM-3, on mouse retina and brain slices, respectively. These doses are 3-30-fold lower than those used to control edema. This study extends our previous in vitro data and identifies the mouse retina as a potential substrate for in vivo studies of GBM dispersal.

Delayed Occipital Artery Pseudoaneurysm Following Blunt Force Trauma.

BACKGROUND: Occipital artery pseudoaneurysms are extremely rare pathologies that manifest after traumatic injury; only 11 cases have been reported in the literature. Because of their low incidence and vague symptoms, the initial diagnosis can be difficult. However, for correctly diagnosed occipital artery pseudoaneurysms, many successful treatment modalities exist. METHODS: We review the pathology of occipital pseudoaneurysms, elucidate the reasons for their rarity, discuss effective diagnostic measures, and discuss the currently available treatment options. We also present a case of a 16-year-old boy who sustained blunt force trauma in May 2014 and presented 6 months later with a painful, pulsatile mass in the occipital region. RESULTS: The patient underwent surgical resection to alleviate the pain and the potential risk of hemorrhage. He experienced complete resolution of pain and associated symptoms. CONCLUSIONS: Our case highlights the fact that occipital swelling, a significant initial sign of pseudoaneurysm development, can be delayed. Therefore, occipital artery pseudoaneurysms cannot be ruled out of the differential diagnosis based on time course alone. Surgical resection is a quick and effective method for relief of severe pain resulting from occipital artery pseudoaneurysms. Although they are rare entities, occipital artery pseudoaneurysms must be considered in the differential diagnosis of cases of pulsatile mass lesions in the posterior scalp.

Titanium mesh-assisted dural tenting for an expansile suboccipital cranioplasty in the treatment of Chiari 1 malformation.

Cerebellar ptosis and dural prolapse are known complications after posterior craniocervical decompression of Chiari 1 malformation (CM1), and are associated with larger craniectomies, epidural scarring and intradural adhesions. Although management of these complications has been well documented, little has been reported in regards to their prevention. We describe our variation of the posterior fossa decompression technique for CM1 using a titanium mesh-assisted dural tenting expansile cranioplasty to prevent both cerebellar ptosis and dural prolapse. A watertight dural augmentation patch is performed after posterior craniocervical decompression. A titanium mesh cranioplasty is performed to cover the superior aspect of the craniectomy. The duraplasty is then tented to the titanium mesh plate with several interrupted sutures. The titanium mesh plate was intended to prevent postoperative cerebellar ptosis or sag, while the dural tenting was performed to prevent delayed collapse and restenosis of the cistern magna. Four patients with CM1 underwent this technique without complication. Postoperative MRI did not demonstrate cerebellar ptosis, restenosis or collapse of the cisterna magna. The expansile suboccipital cranioplasty with titanium mesh-assisted dural tenting technique is a simple and efficient strategy that may be useful to prevent cerebellar ptosis and dural prolapse and maintain the patency of the surgically created neo-cisterna magna.