New therapeutic target for pediatric anaplastic ependymoma control: study of anti-tumor activity by a Kunitz-type molecule, Amblyomin-X.

EPNs comprise a heterogeneous group of neuroepithelial tumors, accounting for about 10% of all intracranial tumors in children and up to 30% of brain tumors in those younger than 3 years. Actually, the pattern therapy for low-grade EPNs includes complete surgical resection followed by radiation therapy. Total surgical excision is often not possible due to tumor location. The aim of this study was to evaluate, for the first time, the anti-tumor activity of Amblyomin-X in 4 primary cultures derived from pediatric anaplastic posterior fossa EPN, Group A (anaplastic, WHO grade III) and one primary culture of a high grade neuroepithelial tumor with MN1 alteration, which was initially misdiagnosed as EPN: i) by in vitro assays: comparisons of temozolomide and cisplatin; ii) by intracranial xenograft model. Amblyomin-X was able to induce cell death in EPN cells in a more significant percentage compared to cisplatin. The cytotoxic effects of Amblyomin-X were not detected on hFSCs used as control, as opposed to cisplatin-treatment, which promoted a substantial effect in the hAFSCs viability. TEM analysis showed ultrastructural alterations related to the process of cell death: mitochondrial degeneration, autophagosomes and aggregate-like structures. MRI and histopathological analyzes demonstrated significant tumor mass regression. Our results suggest that Amblyomin-X has a selective effect on tumor cells by inducing apoptotic cell death and may be a therapeutic option for Group AEPNs.

Tropism of mesenchymal stem cell toward CD133+ stem cell of glioblastoma in vitro and promote tumor proliferation in vivo.

BACKGROUND: Previous studies have demonstrated remarkable tropism of mesenchymal stem cells (MSCs) toward malignant gliomas, making these cells a potential vehicle for delivery of therapeutic agents to disseminated glioblastoma (GBM) cells. However, the potential contribution of MSCs to tumor progression is a matter of concern. It has been suggested that CD133+ GBM stem cells secrete a variety of chemokines, including monocytes chemoattractant protein-1 (MCP-1/CCL2) and stromal cell-derived factor-1(SDF-1/CXCL12), which could act in this tropism. However, the role in the modulation of this tropism of the subpopulation of CD133+ cells, which initiate GBM and the mechanisms underlying the tropism of MSCs to CD133+ GBM cells and their effects on tumor development, remains poorly defined. METHODS/RESULTS: We found that isolated and cultured MSCs (human umbilical cord blood MSCs) express CCR2 and CXCR4, the respective receptors for MCP-1/CCL2 and SDF-1/CXCL12, and demonstrated, in vitro, that MCP-1/CCL2 and SDF-1/CXC12, secreted by CD133+ GBM cells from primary cell cultures, induce the migration of MSCs. In addition, we confirmed that after in vivo GBM tumor establishment, by stereotaxic implantation of the CD133+ GBM cells labeled with Qdots (705 nm), MSCs labeled with multimodal iron oxide nanoparticles (MION) conjugated to rhodamine-B (Rh-B) (MION-Rh), infused by caudal vein, were able to cross the blood-brain barrier of the animal and migrate to the tumor region. Evaluation GBM tumors histology showed that groups that received MSC demonstrated tumor development, glial invasiveness, and detection of a high number of cycling cells. CONCLUSIONS: Therefore, in this study, we validated the chemotactic effect of MCP-1/CCL2 and SDF-1/CXCL12 in mediating the migration of MSCs toward CD133+ GBM cells. However, we observed that, after infiltrating the tumor, MSCs promote tumor growth in vivo probably by release of exosomes. Thus, the use of these cells as a therapeutic carrier strategy to target GBM cells must be approached with caution.

Establishment of primary cell culture and an intracranial xenograft model of pediatric ependymoma: a prospect for therapy development and understanding of tumor biology.

BACKGROUND: Ependymoma (EPN), the third most common pediatric brain tumor, is a central nervous system (CNS) malignancy originating from the walls of the ventricular system. Surgical resection followed by radiation therapy has been the primary treatment for most pediatric intracranial EPNs. Despite numerous studies into the prognostic value of histological classification, the extent of surgical resection and adjuvant radiotherapy, there have been relatively few studies into the molecular and cellular biology of EPNs. RESULTS: We elucidated the ultrastructure of the cultured EPN cells and characterized their profile of immunophenotypic pluripotency markers (CD133, CD90, SSEA-3, CXCR4). We established an experimental EPN model by the intracerebroventricular infusion of EPN cells labeled with multimodal iron oxide nanoparticles (MION), thereby generating a tumor and providing a clinically relevant animal model. MRI analysis was shown to be a valuable tool when combined with effective MION labeling techniques to accompany EPN growth. CONCLUSIONS: We demonstrated that GFAP/CD133+CD90+/CD44+ EPN cells maintained key histopathological and growth characteristics of the original patient tumor. The characterization of EPN cells and the experimental model could facilitate biological studies and preclinical drug screening for pediatric EPNs. METHODS: In this work, we established notoriously challenging primary cell culture of anaplastic EPNs (WHO grade III) localized in the posterior fossa (PF), using EPNs obtained from 1 to 10-year-old patients (n = 07), and then characterized their immunophenotype and ultrastructure to finally develop a xenograft model.

Fusiform superior cerebellar artery aneurysm treated with STA-SCA bypass and trapping.

BACKGROUND: Fusiform aneurysms of cerebellar arteries are rare. Different surgical techniques to address these challenging lesions have been described, and their application depends on whether the goal is to maintain the flow in the parent vessel or to occlude it. CASE DESCRIPTION: The authors reported a case of a fusiform aneurysm located in the lateral pontomesencephalic segment of the superior cerebellar artery (SCA) in a 32-year-old man who presented with subarachnoid hemorrhage. The patient was subjected to aneurysm trapping followed by a bypass between the superficial temporal artery (STA) and SCA and had an uneventful recovery. CONCLUSIONS: Although only a few cases of fusiform aneurysms in the supracerebellar artery have been reported in the literature, the treatment strategies adopted were diverse. In selected cases of patients in good neurological condition with ruptured fusiform aneurysms at the proximal segments of SCA and who have poor evidence of collateral supply, the possibility of a STA-SCA bypass with aneurysm trapping must be considered. A review of the current treatment modalities of this pathology is also presented.

Endonasal versus supraorbital keyhole removal of craniopharyngiomas and tuberculum sellae meningiomas.

OBJECTIVE: Endonasal and supraorbital "eyebrow" craniotomies are increasingly being used to remove craniopharyngiomas and tuberculum sellae meningiomas. Herein, we assess the relative advantages, disadvantages, and selection criteria of these 2 keyhole approaches. METHODS: All consecutive patients who had endonasal or supraorbital removal of a craniopharyngioma or tuberculum sellae meningioma were analyzed. RESULTS: Of 43 patients, 22 had a craniopharyngioma (18 endonasal, 4 supraorbital), and 21 had a meningioma (12 endonasal, 7 supraorbital, 2 both routes); 33% had prior surgery. Craniopharyngiomas were primarily retrochiasmal in location in 78% of endonasal cases versus 25% of supraorbital cases (P = 0.08). Meningiomas were larger when approached by the supraorbital route versus the endonasal route (33 +/- 10 versus 25 +/- 8 mm, respectively; P = 0.008). Endoscopy was used in 84% of endonasal approaches and in 31% of supraorbital approaches (P = 0.001). Of patients having first-time surgery for a craniopharyngioma (n = 14) or meningioma (n = 15), total/near total removal was achieved in 83% and 80% of patients by the endonasal route and in 50% and 80% of patients by the supraorbital route, respectively. Vision improved in 87% and 70% of patients who had surgery by an endonasal versus supraorbital route, respectively (P = 0.3). Visual deterioration occurred in 2 patients with meningiomas, 1 by endonasal (7%), and 1 by supraorbital (11%) removal. The endonasal approach was associated with a higher rate of postoperative cerebrospinal fluid leaks (16 versus 0%; P = 0.3), 4 of 5 of which occurred in patients with meningioma. CONCLUSION: The endonasal route is preferred for removal of most retrochiasmal craniopharyngiomas, whereas the supraorbital route is recommended for meningiomas larger than 30 to 35 mm or with growth beyond the supraclinoid carotid arteries. For smaller midline tumors, either approach can be used, depending on surgeon experience and tumor anatomy. Compared with traditional craniotomies, the major limitation of both approaches is a narrow surgical corridor. The endonasal approach has the added challenges of restricted lateral suprasellar access, a greater need for endoscopy, and a more demanding cranial base repair.

The endonasal microscopic approach for pituitary adenomas and other parasellar tumors: a 10-year experience.

THE DIRECT ENDONASAL transsphenoidal approach to the sella with the operating microscope was initially described more than 20 years ago. Herein, we describe the technique, its evolution, and lessons learned over a 10-year period for treating pituitary adenomas and other parasellar pathology. From July 1998 to January 2008, 812 patients underwent a total of 881 operations for a pituitary adenoma (n = 605), Rathke's cleft cyst (n = 59), craniopharyngioma (n = 26), parasellar meningioma (n = 23), chordoma (n = 18), or other pathological condition (n = 81). Of these, 118 operations (13%) included an extended approach to the suprasellar, infrasellar/clival, or cavernous sinus regions. Endoscopic assistance was used in 163 cases (19%) overall, including 36% of the last 200 cases in the series and 18 (72%) of the last 25 extended endonasal cases. Surgical complications included 19 postoperative cerebrospinal fluid leaks (2%), 6 postoperative hematomas (0.7%), 4 carotid artery injuries (0.4%), 4 new permanent neurological deficits (0.4%), 3 cases of bacterial meningitis (0.3%), and 2 deaths (0.2%). The overall complication rate was higher in the first 500 cases in the series and in extended approach cases. Major technical modifications over the 10-year period included increased use of shorter (60-70 mm) endonasal speculums for greater instrument maneuverability and visualization, the micro-Doppler probe for cavernous carotid artery localization, endoscopy for more panoramic visualization, and a graded cerebrospinal fluid leak repair protocol. These changes appear to have collectively and incrementally made the approach safer and more effective. In summary, the endonasal approach provides a minimally invasive route for removal of pituitary adenomas and other parasellar tumors.