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Weijun Peng, Zhihua Xing, Jingjing Yang, Yang Wang, Weihao Wang and Wei Huang

Object

Erythropoietin (EPO) shows promise as a neuroprotective agent in animal models of traumatic brain injury (TBI). However, clinical trials of the efficacy of EPO treatment in patients with TBI yield conflicting results. The authors conducted a systematic review and meta-analysis to assess the effect of EPO in experimental animal models of TBI, the goal being to inform the design of future clinical trials.

Methods

The authors identified eligible studies by searching PubMed, Web of Science, MEDLINE, Embase, and Google Scholar in October 2013. Data were pooled using the random-effects model, and results were reported in terms of standardized mean difference. Statistical heterogeneity was examined using both I2 and chi-square tests, and the presence of small study effects was investigated with funnel plots and Egger tests. In-depth analyses were performed for lesion volume and neurobehavioral outcome, and the studies' methodological quality was also evaluated.

Results

Of a total of 290 studies, 13 found an effect of EPO on lesion volume and neurobehavioral outcome. Overall, the methodological quality of the studies was poor, and there was evidence of statistical heterogeneity among the publications as well as small-study effects. However, in-depth analyses showed statistically significant findings in favor of a beneficial effect of EPO after TBI.

Conclusions

Despite limitations of this systematic review that may have influenced the findings, the authors conclude that EPO might be beneficial in treating experimental TBI in terms of reducing lesion volume and improving neurobehavioral outcome. However, this review also indicates that more well-designed and well-reported animal studies are needed.

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Zhuo-Ying Du, Xiang Gao, Xiao-Luo Zhang, Zhi-Qiu Wang and Wei-Jun Tang

Object

In this paper the authors' goal was to evaluate the feasibility and efficacy of a virtual reality (VR) system in preoperative planning for microvascular decompression (MVD) procedures treating idiopathic trigeminal neuralgia and hemifacial spasm. The system's role in surgical simulation and training was also assessed.

Methods

Between May 2008 and April 2009, the authors used the Dextroscope system to visualize the neurovascular complex and simulate MVD in the cerebellopontine angle in a VR environment in 16 patients (6 patients had trigeminal neuralgia and 10 had hemifacial spasm). Reconstructions were carried out 2–3 days before MVD. Images were printed in a red-blue stereoscopic format for teaching and discussion and were brought into the operating room to be compared with real-time intraoperative findings.

Results

The VR environment was a powerful aid for spatial understanding of the neurovascular relationship in MVD for operating surgeons and trainees. Through an initial series of comparison/confirmation experiences, the senior neurosurgeon became accustomed to the system. He could predict intraoperative problems and simulate surgical maneuvering, which increased his confidence in performing the procedure.

Conclusions

The Dextroscope system is an easy and rapid method to create a stereoscopic neurovascular model for MVD that is highly concordant with intraoperative findings. It effectively shortens the learning curve and adds to the surgeon's confidence.

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Weijun Wang, Adel Kardosh, Yuzhuang S. Su, Axel H. Schonthal and Thomas C. Chen

Object

The incidence of primary central nervous system lymphomas (PCNSLs) has increased over the past several decades. Unfortunately, even with the most effective therapeutic regimen (that is, methotrexate with whole-brain radiation therapy), PCNSL recurs within a few years in more than half of the treated patients and is eventually fatal. Because PCNSL usually occurs in older patients and in those with acquired immunodeficiency syndrome, combination treatments in which both chemo- and radiation therapy are used is often poorly tolerated and results in a significant reduction in the quality of life. Recently, it has been demonstrated that the selective cyclooxygenase-2 inhibitor celecoxib (Celebrex), can block the growth of lymphoma cells in vitro.

Methods

To create an experimental animal model in vivo for the PCNSL study, the authors intracranially injected a human B-cell lymphoma cell line into nude mice. Their data demonstrate that this experimental model is an excellent one for human PCNSL with brain and leptomeningeal involvement. They also evaluated the feasibility of using celecoxib as a therapeutic agent in the treatment of PCNSL. Nude mice with intracranial lymphomas were treated with celecoxib contained in the animal chow. The treated animals demonstrated significantly prolonged survival times compared with the untreated animals.

Conclusions

Based on the authors' data, celecoxib may be a promising therapeutic agent for the treatment of PCNSL.

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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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Weijun Wang, Alex Ghandi, Leonard Liebes, Stan G. Louie, Florence M. Hofman, Axel H. Schönthal and Thomas C. Chen

Object

Irinotecan (CPT-11), a topoisomerase I inhibitor, is a cytotoxic agent with activity against malignant gliomas and other tumors. After systemic delivery, CPT-11 is converted to its active metabolite, SN-38, which displays significantly higher cytotoxic potency. However, the achievement of therapeutically effective plasma levels of CPT-11 and SN-38 is seriously complicated by variables that affect drug metabolism in the liver. Thus the capacity of CPT-11 to be converted to the active SN38 intratumorally in gliomas was addressed.

Methods

For in vitro studies, 2 glioma cell lines, U87 and U251, were tested to determine the cytotoxic effects of CPT-11 and SN-38 in a dose-dependent manner. In vivo studies were performed by implanting U87 intracranially into athymic/nude mice. For a period of 2 weeks, SN-38, CPT-11, or vehicle was administered intratumorally by means of an osmotic minipump. One series of experiments measured the presence of SN-38 or CPT-11 in the tumor and surrounding brain tissues after 2 weeks' exposure to the drug. In a second series of experiments, after 2 weeks' exposure to the drug, the animals were maintained, in the absence of drug, until death. The survival curves were then calculated.

Results

The results show that the animals that had CPT-11 delivered intratumorally by the minipump expressed SN-38 in vivo. Furthermore, both CPT-11 and SN-38 accumulated at higher levels in tumor tissues compared with uninvolved brain. Intratumoral delivery of CPT-11 or SN-38 extended the average survival time of tumor-bearing animals from 22 days to 46 and 65 days, respectively.

Conclusions

These results demonstrate that intratumorally administered CPT-11 can be effectively converted to SN-38 and this method of drug delivery is effective in extending the survival time of animals bearing malignant gliomas.

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Weijun Wang, Nian-Ling Zhu, Jason Chua, Steve Swenson, Fritz K. Costa, Stephanie Schmitmeier, Barbara A. Sosnowski, Toshiaki Shichinohe, Noriyuki Kasahara and Thomas C. Chen

Object. Adenovirus vector (AdV)—mediated gene delivery has been recently demonstrated in clinical trials as a novel potential treatment for malignant gliomas. Combined coxsackievirus B and adenovirus receptor (CAR) has been shown to function as an attachment receptor for multiple adenovirus serotypes, whereas the vitronectin integrins (αvβ3 and αvβ5) are involved in AdV internalization. In resected glioma specimens, the authors demonstrated that malignant gliomas have varying levels of CAR, αvβ3, and αvβ5 expression.

Methods. A correlation between CAR expression and the transduction efficiency of AdV carrying the green fluorescent protein in various human glioblastoma multiforme (GBM) cell lines and GBM primary cell lines was observed. To increase transgene activity in in vitro glioma cells with low or deficient levels of CAR, the authors used basic fibroblast growth factor (FGF2) as a targeting ligand to redirect adenoviral infection through its cognate receptor, FGF receptor 1 (FGFR1), which was expressed at high levels by all glioma cells. These findings were confirmed by in vivo study data demonstrating enhanced transduction efficiency of FGF2-retargeted AdV in CAR-negative intracranial gliomas compared with AdV alone, without evidence of increased angiogenesis.

Conclusions. Altogether, the results demonstrated that AdV-mediated gene transfer using the FGF2/FGFR system is effective in gliomas with low or deficient levels of CAR and suggested that FGF2-retargeting of AdV may be a promising approach in glioma gene therapy.

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Weijun Wang, Hee-Yeon Cho, Rachel Rosenstein-Sisson, Nagore I. Marín Ramos, Ryan Price, Kyle Hurth, Axel H. Schönthal, Florence M. Hofman and Thomas C. Chen

OBJECTIVE

Glioblastoma (GBM) is the most prevalent and the most aggressive of primary brain tumors. There is currently no effective treatment for this tumor. The proteasome inhibitor bortezomib is effective for a variety of tumors, but not for GBM. The authors' goal was to demonstrate that bortezomib can be effective in the orthotopic GBM murine model if the appropriate method of drug delivery is used. In this study the Alzet mini-osmotic pump was used to bring the drug directly to the tumor in the brain, circumventing the blood-brain barrier; thus making bortezomib an effective treatment for GBM.

METHODS

The 2 human glioma cell lines, U87 and U251, were labeled with luciferase and used in the subcutaneous and intracranial in vivo tumor models. Glioma cells were implanted subcutaneously into the right flank, or intracranially into the frontal cortex of athymic nude mice. Mice bearing intracranial glioma tumors were implanted with an Alzet mini-osmotic pump containing different doses of bortezomib. The Alzet pumps were introduced directly into the tumor bed in the brain. Survival was documented for mice with intracranial tumors.

RESULTS

Glioma cells were sensitive to bortezomib at nanomolar quantities in vitro. In the subcutaneous in vivo xenograft tumor model, bortezomib given intravenously was effective in reducing tumor progression. However, in the intracranial glioma model, bortezomib given systemically did not affect survival. By sharp contrast, animals treated with bortezomib intracranially at the tumor site exhibited significantly increased survival.

CONCLUSIONS

Bypassing the blood-brain barrier by using the osmotic pump resulted in an increase in the efficacy of bortezomib for the treatment of intracranial tumors. Thus, the intratumoral administration of bortezomib into the cranial cavity is an effective approach for glioma therapy.

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Weijun Wang, Steve Swenson, Hee-Yeon Cho, Florence M. Hofman, Axel H. Schönthal and Thomas C. Chen

OBJECTIVE

Many pharmaceutical agents are highly potent but are unable to exert therapeutic activity against disorders of the central nervous system (CNS), because the blood-brain barrier (BBB) impedes their brain entry. One such agent is bortezomib (BZM), a proteasome inhibitor that is approved for the treatment of multiple myeloma. Preclinical studies established that BZM can be effective against glioblastoma (GBM), but only when the drug is delivered via catheter directly into the brain lesion, not after intravenous systemic delivery. The authors therefore explored alternative options of BZM delivery to the brain that would avoid invasive procedures and minimize systemic exposure.

METHODS

Using mouse and rat GBM models, the authors applied intranasal drug delivery, where they co-administered BZM together with NEO100, a highly purified, GMP-manufactured version of perillyl alcohol that is used in clinical trials for intranasal therapy of GBM patients.

RESULTS

The authors found that intranasal delivery of BZM combined with NEO100 significantly prolonged survival of tumor-bearing animals over those that received vehicle alone and also over those that received BZM alone or NEO100 alone. Moreover, BZM concentrations in the brain were higher after intranasal co-delivery with NEO100 as compared to delivery in the absence of NEO100.

CONCLUSIONS

This study demonstrates that intranasal delivery with a NEO100-based formulation enables noninvasive, therapeutically effective brain delivery of a pharmaceutical agent that otherwise does not efficiently cross the BBB.

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Vinay Gupta, Yuzhuang S. Su, Weijun Wang, Adel Kardosh, Leonard F. Liebes, Florence M. Hofman, Axel H. Schönthal and Thomas C. Chen

Object

The chemotherapeutic agent temozolomide has demonstrated antitumor activity in patients with recurrent malignant glioma. Because responses are not enduring and recurrence is nearly universal, further improvements are urgently needed.

Methods

In an effort to increase the clinical activity of temozolomide, the authors investigated whether its antitumor activity could be enhanced by adding tamoxifen or hypericin, two drugs that are known to inhibit the activity of protein kinase C. Human glioblastoma multiforme cell lines A172 and LA567 were treated with combinations of temozolomide and tamoxifen or hypericin in vitro, and cell survival was analyzed using various methods. Tamoxifen and hypericin were able to greatly increase the growth-inhibitory and apoptosis-stimulatory potency of temozolomide via the downregulation of critical cell cycle–regulatory and prosurvival components. Furthermore, with the use of an in vivo xenograft mouse model, the authors demonstrated that hypericin was able to enhance the antiglioma effects of temozolomide in the in vivo setting as well.

Conclusions

Taken together, analysis of the results indicated that combination therapy involving temozolomide and tamoxifen or hypericin potently inhibited tumor growth by inducing apoptosis and provided an effective means of treating malignant glioma.

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Weijun Wang, Walavan Sivakumar, Shering Torres, Niyati Jhaveri, Vijaya Pooja Vaikari, Alex Gong, Adam Howard, Encouse B. Golden, Stan G. Louie, Axel H. Schönthal, Florence M. Hofman and Thomas C. Chen

OBJECT

Bevacizumab (Avastin), an antibody to vascular endothelial growth factor (VEGF), alone or in combination with irinotecan (Camptosar [CPT-11]), is a promising treatment for recurrent glioblastoma. However, the intravenous (IV) administration of bevacizumab produces a number of systemic side effects, and the increase in survival it provides for patients with recurrent glioblastoma is still only a few months. Because bevacizumab is an antibody against VEGF, which is secreted into the extracellular milieu by glioma cells, the authors hypothesized that direct chronic intratumoral delivery techniques (i.e., convection-enhanced delivery [CED]) can be more effective than IV administration. To test this hypothesis, the authors compared outcomes for these routes of bevacizumab application with respect to animal survival, microvessel density (MVD), and inflammatory cell distribution.

METHODS

Two human glioma cell lines, U87 and U251, were used as sources of intracranial tumor cells. The glioma cell lines were implanted into the brains of mice in an orthotopic xenograft mouse tumor model. After 7 days, the mice were treated with one of the following: 1) vehicle, 2) CED bevacizumab, 3) IV bevacizumab, 4) intraperitoneal (IP) irinotecan, 5) CED bevacizumab plus IP irinotecan, or 6) IV bevacizumab plus IP irinotecan. Alzet micro-osmotic pumps were used to introduce bevacizumab directly into the tumor. Survival was monitored. Excised tumor tissue samples were immunostained to measure MVD and inflammatory cell and growth factor levels.

RESULTS

The results demonstrate that mice treated with CED of bevacizumab alone or in combination with irinotecan survived longer than those treated systemically; CED-treated animals survived 30% longer than IV-treated animals. In combination studies, CED bevacizumab plus CPT-11 increased survival by more than 90%, whereas IV bevacizumab plus CPT-11 increased survival by 40%. Furthermore, CED bevacizumab-treated tissues exhibited decreased MVD compared with that of IV-treated tissues. In additional studies, the infiltration of macrophages and dendritic cells into CED-treated animals were increased compared with those in IV-treated animals, suggesting a highly active inflammatory response taking place in CED-treated mice.

CONCLUSIONS

The administration of bevacizumab via CED increases survival over that of treatment with IV bevacizumab. Thus, CED of bevacizumab alone or in combination with chemotherapy can be an effective protocol for treating gliomas.