Intraarterial administration of norcantharidin attenuates ischemic stroke damage in rodents when given at the time of reperfusion: novel uses of endovascular capabilities.

OBJECT Matrix metalloprotease-9 (MMP-9) plays a critical role in infarct progression, blood-brain barrier (BBB) disruption, and vasogenic edema. While systemic administration of MMP-9 inhibitors has shown neuroprotective promise in ischemic stroke, there has been little effort to incorporate these drugs into endovascular modalities. By modifying the rodent middle cerebral artery occlusion (MCAO) model to allow local intraarterial delivery of drugs, one has the ability to mimic endovascular delivery of therapeutics.

Emerging strategies for the treatment of tumor stem cells in central nervous system malignancies.

High-grade central nervous system (CNS) tumors are notorious for high rates of recurrence and poor outcomes. A small cohort of tumor cells, dubbed tumor stem cells (TSC), are now being recognized as an important subset of the tumor that is resistant to chemotherapy and radiotherapy and account for the high recurrence rates. Recent research is developing modalities to target TSCs specifically in a bid to improve the response of the tumor as a whole.

Laboratory models for central nervous system tumor stem cell research.

Central nervous system (CNS) tumors are complex organ systems comprising of a neoplastic component with associated vasculature, inflammatory cells, and reactive cellular and extracellular components. Research has identified a subset of cells in CNS tumors that portray defining properties of neural stem cells, namely, that of self-renewal and multi-potency. Growing evidence suggests that these tumor stem cells (TSC) play an important role in the maintenance and growth of the tumor.

Isolation and characterization of stem cells from human central nervous system malignancies.

Central Nervous System (CNS) tumors include some of the most invasive and lethal tumors in humans. The poor prognosis in patients with CNS tumors is ascribed to their invasive nature. After the description of a stem cell-like cohort in hematopoietic cancers, tumor stem cells (TSCs) have been isolated from a variety of solid tumors, including brain tumors.

Targeting glioblastoma cancer stem cells: the next great hope?

Glioblastoma multiforme (GBM) is the most common primary brain tumor and is notorious for its poor prognosis. The highly invasive nature of GBM and its inherent resistance to therapy lead to very high rates of recurrence. Recently, a small cohort of tumor cells, called cancer stem cells (CSCs), has been recognized as a subset of tumor cells with self-renewal ability and multilineage capacity.

Surgical management of large scalp infantile hemangiomas.

Background: Infantile Hemangiomas (IH) are the most common benign tumor of infancy, occurring in over 10% of newborns. While most IHs involute and never require intervention, some scalp IHs may cause severe cosmetic deformity and threaten tissue integrity that requires surgical excision.

Case Description: We present our experience with two infants who presented with large scalp IH.

Resolution of trigeminal neuralgia by coil embolization of a persistent primitive trigeminal artery aneurysm.

The persistent primitive trigeminal artery (PTA) is a rare anastomosis between the carotid artery and basilar artery. While most PTAs are asymptomatic, lateral variants can occasionally compress the trigeminal nerve and precipitate trigeminal neuralgia. Aneurysms of the PTA are exceptionally rare in the literature and have not previously been associated with trigeminal neuralgia.

Microsurgical localization of the cochlea in the extended middle fossa approach.

Objective In the extended middle fossa approach, a portion of the petrous bone known as Kawase's rhomboid can be drilled to expose the posterior fossa through a middle fossa corridor. During this bony resection, the cochlea is placed at risk. The objective of this study was to objectively detail the position of the cochlea in relation to reliable surgical landmarks.

Endovascular thrombolysis for pediatric cerebral sinus venous thrombosis with tissue plasminogen activator and abciximab.

Cerebral sinus venous thrombosis (CSVT) is a relatively rare but potentially devastating disease. Medical management of CSVT with systemic anticoagulation has been the mainstay treatment strategy with these patients. However, some patients may not respond to this treatment or may present with very severe symptoms indicating more aggressive management strategies.

Resolution of trigeminal neuralgia by coil embolization of a persistent primitive trigeminal artery aneurysm.

The persistent primitive trigeminal artery (PTA) is a rare anastomosis between the carotid artery and basilar artery. While most PTAs are asymptomatic, lateral variants can occasionally compress the trigeminal nerve and precipitate trigeminal neuralgia. Aneurysms of the PTA are exceptionally rare in the literature and have not previously been associated with trigeminal neuralgia.

The role of the CXCR4 cell surface chemokine receptor in glioma biology.

CXCR4, a cell surface chemokine receptor, mediates cellular dissemination, invasion, and proliferation in a wide range of cancers including gliomas. It is over-expressed in glioma progenitor cells, and its protein ligand, CXCL12, has been shown to mediate a specific proliferative response in these cells thereby implicating a role for CXCR4 in glioma initiation and renewal. Given the failure of currently employed therapies to meaningfully impact prognosis in patients with high-grade gliomas, the CXCR4-CXCL12 axis represents a novel biologically relevant mechanism that could be specifically targeted for therapy.

CXCR4-Expressing Glial Precursor Cells Demonstrate Enhanced Migratory Tropism for Glioma.

Malignant glioma remains one of the most intractable of human cancers principally due to the highly infiltrative nature of these neoplasms. The use of neural precursor cells (NPC) has received considerable attention based on their ability to selectively migrate towards disseminated areas of tumor in vivo and their described ability to deliver tumor-directed therapies specifically to infiltrating tumor cells. Fundamental to optimizing the use of these cells for potential clinical translation is the development of an understanding regarding the biologic cues that govern their ability to migrate towards infiltrative glioma foci.

Rat model of blood-brain barrier disruption to allow targeted neurovascular therapeutics.

Endothelial cells with tight junctions along with the basement membrane and astrocyte end feet surround cerebral blood vessels to form the blood-brain barrier(1). The barrier selectively excludes molecules from crossing between the blood and the brain based upon their size and charge. This function can impede the delivery of therapeutics for neurological disorders.

Preclinical molecular imaging of the translocator protein (TSPO) in a metastases model based on breast cancer xenografts propagated in the murine brain.

Previous studies have demonstrated the feasibility of translocator protein (TSPO) imaging to visualize and quantify human breast adenocarcinoma (MDA-MB-231) cells in vivo using a TSPO-targeted near-infrared (NIR) probe (NIR-conPK11195). This study aimed to extend the use of the TSPO-targeted probe to a more biologically relevant and clinically important tumor microenvironment as well as to assess our ability to longitudinally detect the presence and progression of breast cancer cells in the brain. The in vivo biodistribution and accumulation of NIR-conPK11195 and free (unconjugated) NIR dye were quantitatively evaluated in intracranial MDA-MB-231-bearing mice and non-tumor-bearing control mice longitudinally once a week from two to five weeks post-inoculation.

T2 detection of tumor invasion within segmented components of glioblastoma multiforme.

Purpose: To use T2-weighted images to detect tumor invasion when comparing normal individuals to groups of gliomablastoma multiforme (GBM) patients with varying levels of CXCR4, a chemokine receptor that promotes tumor migration.

Materials And Methods: T2-weighted images were acquired preoperatively in 22 treatment-naïve GBM patients. Two groups were formed based on the expression levels of CXCR4.

CXCR4 mediates the proliferation of glioblastoma progenitor cells.

Increasing evidence points to a fundamental role for cancer stem cells (CSC) in the initiation and propagation of many tumors. As such, in the context of glioblastoma multiforme (GBM), the development of treatment strategies specifically targeted towards CSC-like populations may hold significant therapeutic promise. To this end, we now report that the cell surface chemokine receptor, CXCR4, a known mediator of cancer cell proliferation and invasion, is overexpressed in primary glioblastoma progenitor cells versus corresponding differentiated tumor cells.

CXCR4 expression is elevated in glioblastoma multiforme and correlates with an increase in intensity and extent of peritumoral T2-weighted magnetic resonance imaging signal abnormalities.

Objective: With the objective of investigating the utility of CXCR4, a chemokine receptor known to mediate glioma cell invasiveness, as a molecular marker for peritumoral disease extent in high-grade gliomas, we sought to characterize the expression profile of CXCR4 in a large panel of tumor samples and determine whether CXCR4 expression levels within glioblastoma multiforme might correlate with radiological evidence of a more extensive disease process.

Methods: Freshly resected tumor tissue samples were processed for immunohistochemical and quantitative polymerase chain reaction analyses to identify and quantify expression levels of CXCR4 and its corresponding ligand CXCL12. T1 postcontrast and T2-weighted magnetic resonance imaging brain scans were used to generate voxel signal intensity histograms that were quantitatively analyzed to determine the extent and intensity of peritumoral signal abnormality as a marker of disseminated disease in the brain.

Integrating spatially resolved three-dimensional MALDI IMS with in vivo magnetic resonance imaging.

We have developed a method for integrating three dimensional-volume reconstructions of spatially resolved matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) ion images of whole mouse heads with high-resolution images from other modalities in an animal-specific manner. This approach enabled us to analyze proteomic profiles from MALDI IMS data with corresponding in vivo data provided by magnetic resonance imaging.

Stem cells as vehicles for the treatment of brain cancer.

Stem cell therapy represents a promising new therapeutic modality for infiltrative gliomas. The promise of this emerging technology centers on the potent migratory tropism exhibited by stem cells for disseminated foci of intracranial pathologic findings. This important characteristic, which has been validated in a wide set of preclinical studies, forms a foundation for the use of transplanted stem cell populations as vehicles for the delivery of tumor-toxic molecules to sites of intracranial tumor.

Stem cell therapies for malignant glioma.

The prognosis for patients with malignant glioma, which is the most common primary intracranial neoplasm, remains dismal despite significant progress in neurooncological therapies and technology. This is largely due to the inability of current treatment strategies to address the highly invasive nature of this disease. Malignant glial cells often disseminate throughout the brain, making it exceedingly difficult to target and treat all intracranial neoplastic foci, with the result that tumor recurrence is inevitable despite aggressive surgery and adjuvant radiotherapy and/or chemotherapy.

Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma.

PGE(2), synthesized by cyclooxygenase-2 (COX-2)-overexpressing tumor, is known to contribute to cellular immune suppression in cancer patients, but the mechanism remains unclear. We report the mechanism of a CD4(+) T regulatory type 1 (Tr1) induction by CD11c(+) mature dendritic cells (DCs) that phagocytose allogeneic and autologous COX-2-overexpressing glioma. A human glioma cell line, U-87MG, and primary cultured glioblastoma cells (MG-377) overexpressed COX-2.

Small interference RNA modulation of IL-10 in human monocyte-derived dendritic cells enhances the Th1 response.

RNA interference technology has been used to modulate dendritic cell (DC) function by targeting the expression of genes such as IL-12 and NF-kappa B. In this paper, we demonstrate that transfection of DC with IL-10-specific double strands of small interference RNA (siRNA) resulted in potent suppression of IL-10 gene expression without inducing DC apoptosis or blocking DC maturation. Inhibition of IL-10 by siRNA was accompanied by increased CD40 expression and IL-12 production after maturation, which endowed DC with the ability to significantly enhance allogeneic T cell proliferation.

Recent progress in immunotherapy for malignant glioma: treatment strategies and results from clinical trials.

Background: Despite advances in surgical and adjuvant radiation therapy and chemotherapy strategies, malignant gliomas continue to be associated with poor prognoses.

Methods: We review immune-mediated treatment approaches for malignant glioma and the relevance of recent clinical trials and their outcomes. We specifically address the increasing evidence implicating the role of cytotoxic T cells in ensuring adequate immune-mediated clearance of neoplastic cells and the need for the optimization of therapies that can elicit and support such antitumor T-cell activity.

Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4.

Malignant gliomas spawn disseminated microsatellites, which are largely refractory to currently employed therapies, resulting in eventual tumor recurrence and death. The use of tumor-tropic neural stem cells (NSCs) as delivery vehicles for therapeutic gene products represents an attractive strategy specifically focused at treating these residual neoplastic foci. We wished to elucidate the biological cues governing NSC tropism for glioma.