Mark H. Bilsky, Steven D. Chang, Peter C. Gerszten and Steven Kalkanis
Xin Hong, Kevin K. Nelson, Ana C. deCarvalho and Steven N. Kalkanis
Mammalian heparanase has been shown to function in tumor progression, invasion, and angiogenesis. However, heparanase expression in gliomas has not been well analyzed. To clarify its expression in gliomas, human glioma tissues and glioma animal models were investigated.
The expression of heparanase mRNA was determined in 33 resected human glioma tissues by semiquantitative real-time polymerase chain reaction. Heparanase expression was verified with a Western blot assay and immunohistochemistry (IHC) staining. Primary neurospheres from human glioblastoma multiforme (GBM) were developed in vitro. Heparanase expression in murine astrocytoma and human primary neurosphere animal models was examined using IHC.
The authors found that heparanase mRNA is greatly increased in gliomas including oligodendroglioma (9 samples), anaplastic astrocytoma (11 samples), and GBM (13 samples) as compared with healthy brain mRNA (3 samples). Note, however, that no significant difference was observed among the 3 tumor groups. Increased heparanase expression was also found in tumor tissues on Western blotting. Immunohistochemistry staining demonstrated that heparanase was expressed by neovessel endothelial cells, infiltrated neutrophils, and in some cases, by neoplastic cells. Heparanase-expressing cells, including GBM tumor cells and neovessel endothelial cells, exhibited decreased expression of CD44, a cell adhesion molecule on the cell membrane that is important for regulating tumor invasion. In addition, heparanase-expressing tumor cells showed an elevated density of the cell proliferation marker Ki 67, as compared with its density in non–heparanase-expressing tumor cells, suggesting that heparanase expression is correlated with enhanced tumor proliferation. Two animal glioma models were tested for heparanase expression. Both murine astrocytoma cells (Ast11.9-2) and cultured primary human GBM neurospheres expressed heparanase when grown in animal brain tissue.
Glioma tissues contain increased levels of heparanase. Multiple cell types contribute to the expression of heparanase, including neovessel endothelial cells, tumor cells, and infiltrated neutrophils. Heparanase plays an important role in the control of cell proliferation and invasion. Animal models using Ast11.9-2 and primary neurospheres are suitable for antitumor studies targeting heparanase.
Michael C. Dewan, Reid C. Thompson, Steven N. Kalkanis, Fred G. Barker II and Constantinos G. Hadjipanayis
Antiepileptic drugs (AEDs) are often administered prophylactically following brain tumor resection. With conflicting evidence and unestablished guidelines, however, the nature of this practice among tumor surgeons is unknown.
On November 24, 2015, a REDCap (Research Electronic Database Capture) survey was sent to members of the AANS/CNS Section on Tumors to query practice patterns.
Responses were received from 144 individuals, including 18.8% of board-certified neurosurgeons surveyed (across 86 institutions, 16 countries, and 5 continents). The majority reported practicing in an academic setting (85%) as a tumor specialist (71%). Sixty-three percent reported always or almost always prescribing AED prophylaxis postoperatively in patients with a supratentorial brain tumor without a prior seizure history. Meanwhile, 9% prescribed occasionally and 28% rarely prescribed AED prophylaxis. The most common agent was levetiracetam (85%). The duration of seizure prophylaxis varied widely: 25% of surgeons administered prophylaxis for 7 days, 16% for 2 weeks, 21% for 2 to 6 weeks, and 13% for longer than 6 weeks. Most surgeons (61%) believed that tumor pathology influences epileptogenicity, with high-grade glioma (39%), low-grade glioma (31%), and metastases (24%) carrying the greatest seizure risk. While the majority used prophylaxis, 62% did not believe or were unsure if prophylactic AEDs reduced seizures postoperatively. The vast majority (82%) stated that a well-designed randomized trial would help guide their future clinical decision making.
Wide knowledge and practice gaps exist regarding the frequency, duration, and setting of AED prophylaxis for seizure-naive patients undergoing brain tumor resection. Acceptance of universal practice guidelines on this topic is unlikely until higher-level evidence supporting or refuting the value of modern seizure prophylaxis is demonstrated.
Steven N. Kalkanis, Rona S. Carroll, Jianping Zhang, Amir A. Zamani and Peter McL. Black
✓ Intracranial meningiomas are often complicated by peritumoral vasogenic cerebral edema, which appears to result from increased microvascular permeability and extravasation of proteinaceous and plasma fluid into the adjacent peritumoral space. The source of such edema has long been mysterious. The contents of this paper support the concept that vascular endothelial growth factor (VEGF) production plays a significant role in edema formation.
Vascular endothelial growth factor messenger RNA expression has been found in a wide range of intracranial neoplasms, including malignant gliomas, metastatic melanomas, meningiomas, and other benign tumors. Several studies have confirmed the importance of VEGF in tumorigenesis, neovascularization, and edema production.
This study tests the hypothesis that the presence of peritumoral edema in meningiomas is positively correlated with increased expression of VEGF mRNA. To investigate this hypothesis, 31 meningioma specimens were subjected to Northern blot analysis, hybridization with a complementary DNA VEGF probe, and laser densitometry to determine the relative levels of VEGF mRNA expression. Magnetic resonance imaging was then used in a double-blind fashion to correlate the neuropathological tissue samples with the presence of preoperative peritumoral edema.
Of 31 patients studied, 14 exhibited no edema and 17 exhibited some level of peritumoral fluid accumulation. There was a marked increase in VEGF expression in patients with edema (p = 0.0004, Wilcoxon-Mann-Whitney rank-sum test). Meningiomas with peritumoral edema exhibited 3.4 times the level of VEGF mRNA as those without edema.
These data demonstrate a strong link between VEGF mRNA expression and peritumoral edema and indicate that VEGF expression is an important factor in the etiology of edema around meningiomas.