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Peter Pyrko, Weijun Wang, Francis S. Markland, Steve D. Swenson, Stephanie Schmitmeier, Axel H. Schönthal and Thomas C. Chen

Object

Malignant gliomas are not curable because of diffuse brain invasion. The tumor cells invade the surrounding brain tissue without a clear tumor—brain demarcation line, making complete resection impossible. Therapy aimed at inhibition of invasion is crucial not only for prevention of tumor spread, but also for selectively blocking migrating cells that may be more resistant to chemotherapy and radiation. Recently, investigations have shown that the snake venom disintegrin contortrostatin specifically binds to certain integrins on the surface of glioma cells and thereby inhibits their interaction with the extracellular matrix (ECM), resulting in a blockage of cell motility and invasiveness. To translate these in vitro findings into clinical settings, the authors examined the effect of contortrostatin on glioma progression in a rodent model.

Methods

Athymic mice were intracranially or subcutaneously injected with U87 glioma cells, and the effect of intratumorally administered contortrostatin on tumor progression and animal survival was then studied. In addition, the authors evaluated the pharmacological safety of contortrostatin use in the brains of tumor-free animals.

Conclusions

The results demonstrate that contortrostatin is able to inhibit tumor growth and angiogenesis and to prolong survival in a rodent glioma model. Moreover, contortrostatin appears to be well tolerated by the animal and lacks obvious neurotoxic side effects. Thus, contortrostatin may have potential as a novel therapeutic agent for the treatment of malignant gliomas.

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Peter C. Gerszten, Stephanie Chen, Mubina Quader, Yuanguang Xu, Josef Novotny Jr. and John C. Flickinger

Object

There is a growing body of evidence to support the safe and effective use of spine radiosurgery. However, there is much less experience regarding the use of radiosurgery for the treatment of benign as opposed to malignant spine tumors. This study represents an evaluation of, and reporting on, the technical aspects of using a dedicated radiosurgery system for the treatment of benign spine tumors.

Methods

Forty-five consecutive benign spine tumors were treated using the Elekta Synergy S 6-MV linear accelerator with a beam modulator and cone-beam computed tomography (CBCT) image guidance technology for target localization. The study cohort included 16 men and 29 women, ranging in age from 23 to 88 years (mean age 52 years). There were 14 cervical, 12 thoracic, 14 lumbar, and 5 sacral tumors. Forty-one lesions (91%) were intradural. The most common histological types of tumor were schwannoma, neurofibroma, and meningioma. Indications for radiosurgery included primary treatment in 24 cases (53%) and treatment of recurrent or residual tumor after open resection in 21 cases (47%).

Results

No subacute or long-term spinal cord or cauda equina toxicity occurred during the follow-up period (median 32 months). The mean maximum dose received by the gross tumor volume (GTV) was 16 Gy (range 12–24 Gy) delivered in a single fraction in 39 cases. The mean lowest dose received to the GTV was 12 Gy (range 8–16 Gy). The GTV ranged from 0.37 to 94.5 cm3 (mean 13.7 cm3, median 5.9 cm3). In the majority of cases, a planning target volume expansion of 2 mm was employed (38 cases; 84%). The mean maximum point dose delivered to the spinal cord was 8.7 Gy (range 4–11.5 Gy); the mean volume of the spinal cord that received greater than 8 Gy was 0.9 cm3 (range 0.0–5.1 cm3); and the mean dose delivered to 0.1 cm3 of the spinal cord was 7.5 Gy (range 3–10.5 Gy). The mean maximum point dose delivered to the cauda equina was 10 Gy (range 0–13 Gy); the mean volume of the cauda equina that received greater than 8 Gy was 1.45 cm3 (range 0.0–10.6 cm3); and the mean dose delivered to 0.1 cm3 of the cauda equina was 8 Gy (range 0.5–11 Gy).

Conclusions

In this study the authors describe the contouring and prescribed dose techniques used in the treatment planning and delivery of radiosurgery for benign neoplasms of the spine using CBCT image guidance. This technique may serve as an important reference for the performance of radiosurgery when one believes it is clinically indicated as a treatment modality for a benign spine tumor that is associated with both a high safety profile and a strong positive clinical outcome.

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Dallas L. Sheinberg, David J. McCarthy, Omar Elwardany, Jean-Paul Bryant, Evan Luther, Stephanie H. Chen, John W. Thompson and Robert M. Starke

Endothelial cell (EC) dysfunction is known to contribute to cerebral aneurysm (CA) pathogenesis. Evidence shows that damage or injury to the EC layer is the first event in CA formation. The mechanisms behind EC dysfunction in CA disease are interrelated and include hemodynamic stress, hazardous nitric oxide synthase (NOS) activity, oxidative stress, estrogen imbalance, and endothelial cell-to-cell junction compromise. Abnormal variations in hemodynamic stress incite pathological EC transformation and inflammatory zone formation, ultimately leading to destruction of the vascular wall and aneurysm dilation. Hemodynamic stress activates key molecular pathways that result in the upregulation of chemotactic cytokines and adhesion molecules, leading to inflammatory cell recruitment and infiltration. Concurrently, oxidative stress damages EC-to-EC junction proteins, resulting in interendothelial gap formation. This further promotes leukocyte traffic into the vessel wall and the release of matrix metalloproteinases, which propagates vascular remodeling and breakdown. Abnormal hemodynamic stress and inflammation also trigger adverse changes in NOS activity, altering proper EC mediation of vascular tone and the local inflammatory environment. Additionally, the vasoprotective hormone estrogen modulates gene expression that often suppresses these harmful processes. Crosstalk between these sophisticated pathways contributes to CA initiation, progression, and rupture. This review aims to outline the complex mechanisms of EC dysfunction in CA pathogenesis.

Free access

John W. Thompson, Omar Elwardany, David J. McCarthy, Dallas L. Sheinberg, Carlos M. Alvarez, Ahmed Nada, Brian M. Snelling, Stephanie H. Chen, Samir Sur and Robert M. Starke

Cerebral aneurysm rupture is a devastating event resulting in subarachnoid hemorrhage and is associated with significant morbidity and death. Up to 50% of individuals do not survive aneurysm rupture, with the majority of survivors suffering some degree of neurological deficit. Therefore, prior to aneurysm rupture, a large number of diagnosed patients are treated either microsurgically via clipping or endovascularly to prevent aneurysm filling. With the advancement of endovascular surgical techniques and devices, endovascular treatment of cerebral aneurysms is becoming the first-line therapy at many hospitals. Despite this fact, a large number of endovascularly treated patients will have aneurysm recanalization and progression and will require retreatment. The lack of approved pharmacological interventions for cerebral aneurysms and the need for retreatment have led to a growing interest in understanding the molecular, cellular, and physiological determinants of cerebral aneurysm pathogenesis, maturation, and rupture. To this end, the use of animal cerebral aneurysm models has contributed significantly to our current understanding of cerebral aneurysm biology and to the development of and training in endovascular devices. This review summarizes the small and large animal models of cerebral aneurysm that are being used to explore the pathophysiology of cerebral aneurysms, as well as the development of novel endovascular devices for aneurysm treatment.