Co-evolution of breast-to-brain metastasis and neural progenitor cells.

Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi-directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-ß superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain metastatic) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling.

Pediatric neurosurgery outreach: sustainability appraisal of a targeted teaching model in Kiev, Ukraine.

PURPOSE: This study evaluates the efficacy of operative skill transfer in the context of targeted pediatric outreach missions completed in Kiev, Ukraine. In addition the ability to create sustainable surgical care improvement is investigated as an efficient method to improve global surgical care. METHODS: Three 1-week targeted neurosurgical missions were performed (2005-2007) to teach neuroendoscopy, which included donation of the necessary surgical equipment, so the host team can deliver newly acquired surgical skills to their citizens after the visiting mission team departs. The neuroendoscopy data for the 4 years after the final mission in 2007 was obtained. RESULTS: After performing pediatric neurosurgery missions in 2005-2007, with a focus on teaching neuroendoscopy, the host team demonstrated the sustainability of our educational efforts in the subsequent 4 years by performing cases independently for their citizens. Since the last targeted mission of 2007, neuroendoscopic procedures have continued to be performed by the trained host surgeons. In 2008, 33 cases were performed. In 2009 and 2010, 29 and 22 cases were completed, respectively. In 2011, local neurosurgeons accomplished 27 cases. To date, a total of 111 operations have been performed over the past 4 years independent of any visiting team, illustrating the sustainability of educational efforts of the missions in 2005-2007. CONCLUSIONS: Effective operative skill transfer to host neurosurgeons can be accomplished with limited international team visits using a targeted approach that minimizes expenditures on personnel and capital. With the priority being teaching of an operative technique, as opposed to perennially performing operations by a visiting mission team, sustainable surgical care was achieved and perpetuated after missions officially concluded.

Targeted neurosurgical outreach: 5-year follow-up of operative skill transfer and sustainable care in Lima, Peru.

PURPOSE: This study evaluates the efficacy of operative skill transfer in the context of targeted pediatric outreach missions. In addition, the ability to implement surgical care improvements that are sustainable is investigated. METHODS: Three 1-week targeted neurosurgical missions were performed (2004-2006) to teach neuroendoscopy, which included donation of the necessary equipment so newly acquired surgical skills could be performed by local neurosurgeons in between and after the departure of the mission team. After the targeted missions were completed, 5 years of neuroendoscopy case follow-up data were obtained. RESULTS: After performing pediatric neurosurgery missions in 2004-2006, with a focus on teaching neuroendoscopy, the host team demonstrated the sustainability of our didactic efforts in the subsequent 5 years by performing cases independently for their citizens. To date, a total of 196 operations have been performed in the past 5 years independent of any visiting team. CONCLUSIONS: Effective operative skill transfer to host neurosurgeons can be accomplished with limited international team visits utilizing a targeted approach that minimizes expenditures on personnel and capital. With the priority being teaching of an operative technique, as opposed to perennially performing operations by the mission team, sustainable surgical care was achieved after missions officially concluded.

Animal models of neurological disease.

The use of animal models to study human pathology has proved valuable in a number of fields. Animal models of neurological disease have successfully and accurately recreated many aspects of human illness allowing for in-depth study ofneuropathophysiology. These models have been the source of a plethora of information, such as the importance of certain molecular mechanisms and genetic contributions in neurological disease. Additionally, animal models have been utilized in the discovery and testing of possible therapeutic treatments. Although most neurological diseases are still not yet completely understood and reliable treatment is lacking, animal models provide a major step in the right direction.

Biological horizons for targeting brain malignancy.

Though currently available clinical treatments and therapies have clearly extended the survival of patients with brain tumors, many of these advances are short lived, particularly with respect to high grade gliomas such as glioblastoma multiforme. The missing link to an efficacious treatment of high grade gliomas is a more complete understanding of the basic molecular and cellular origin of brain tumors. However, new discoveries of stem cell and developmental neurobiology have now borne the cancer stem cell hypothesis, drawing off of intriguing similarities between benign and malignant cells within the central nervous system. Investigation of cancer stem cell hypothesis and brain tumor propagation is the current frontier of stem cell and cancer biology. Neurosurgery is also watching closely this promising new area of focus. "Molecular neurosurgery", glioma treatments involving biologics using neural stem cells to target the cancer at the level of individual migratory cell, is a rapidly evolving field. This coming progression of applied cancer stem cell research, coupled with current modalities, promises more comprehensive brain cancer interventions.