Umbilical cord blood (UCB) is a rich source of hematopoetic stem cells (HSCs). We have isolated a novel cell line population of stem cells from human UCB that exhibit properties of self-renewal, but do not have cell-surface markers that are typically found on HSCs. Analysis of transcripts revealed that these cells express transcription factors Oct-4, Rex-1, and Sox-2 that are typically expressed by stem cells. We refer to these novel cells as nonhematopoietic umbilical cord blood stem cells (nh-UCBSCs). Previous studies have shown that the intravenous infusion of UCBCs can ameliorate neurological deficits arising from ischemic brain injury. The identity of the cells that mediate this restorative effect, however, has yet to be determined. We postulate that nh-UCBSCs may be a source of the UCB cells that can mediate these effects. To test this hypothesis, we intravenously injected one million human nh-UCBSCs into rats 48 h after transient unilateral middle cerebral artery occlusion. Animals in other experimental groups received either saline injections or injections of RN33b neural stem cells. Animals were tested for neurological function before the infusion of nh-UCBSCs and at various time periods afterwards using a battery of behavioral tests. In limb placement tests, animals treated with nh-UCBSCs exhibited mean scores that were significantly better than animals treated with RN33b neural stem cells or saline. Similarly, in stepping tests, nh-UCBSC-treated animals again exhibited significantly better performance than the other experimental groups of animals. Analysis of infarct volume revealed that ischemic animals treated with nh-UCBSCs exhibited a 50% reduction in lesion volume in comparison to saline-treated controls. Histological analysis of brain tissue further revealed the presence of cells that stained for human nuclei. Some human nuclei-positive cells were also co-labeled for NeuN, indicating that the transplanted cells expressed markers of a neuronal phenotype. Cells expressing the human nuclei marker within the brain, however, were rather scant, suggesting that the restorative effects of nh-UCBSCs may be mediated by mechanisms other than cell replacement. To test this hypothesis, nh-UCBSCs were directly transplanted into the brain parenchyma after ischemic brain injury. Sprouting of nerve fibers from the nondamaged hemisphere into the ischemically damaged side of the brain was assessed by anterograde tracing using biotinylated dextran amine (BDA). Animals with nh-UCBSC transplants exhibited significantly greater densities of BDA-positive cells in the damaged side of the brain compared to animals with intraparenchymal saline injections. These results suggest that restorative effects observed with nh-UCBSC treatment following ischemic brain injury may be mediated by trophic actions that result in the reorganization of host nerve fiber connections within the injured brain.

Glioblastoma is a fatal brain tumor that becomes highly vascularized by secreting proangiogenic factors and depends on continued angiogenesis to increase in size. Consequently, a successful antiangiogenic therapy should provide long-term inhibition of tumor-induced angiogenesis, suggesting long-term gene transfer as a therapeutic strategy. In this study a soluble vascular endothelial growth factor receptor (sFlt-1) and an angiostatin-endostatin fusion gene (statin-AE) were codelivered to human glioblastoma xenografts by nonviral gene transfer using the Sleeping Beauty (SB) transposon. In subcutaneously implanted xenografts, co-injection of both transgenes showed marked anti-tumor activity as demonstrated by reduction of tumor vessel density, inhibition or abolition of glioma growth, and increase in animal survival (P = 0.003). Using luciferase-stable engrafted intracranial gliomas, the anti-tumor effect of convection-enhanced delivery of plasmid DNA into the tumor was assessed by luciferase in vivo imaging. Sustained tumor regression of intracranial gliomas was achieved only when statin-AE and sFlt-1 transposons were coadministered with SB-transposase-encoding DNA to facilitate long-term expression. We show that SB can be used to increase animal survival significantly (P = 0.008) by combinatorial antiangiogenic gene transfer in an intracranial glioma model.

Object The management of chordomas involving the skull base continues to present a number of treatment-related problems. Recently, both radical resection and charged-particle irradiation or stereotactic radiosurgery have reportedly been found effective for tumor control and for promoting a better quality of life in patients. In this article the authors analyzed the outcomes in 17 patients with skull base chordomas who were surgically treated at Kobe University Hospital between 1972 and 2000. Methods Preoperative radiological examinations included magnetic resonance imaging, computerized tomography, angiography, and balloon occlusion test of the internal carotid artery. Among the various surgical approaches used to remove the tumor were the frontoorbitozygomatic, transmaxillary, transcondylar, transsphenoidal, and the transbasal. Total removal was achieved in two (12%), near-total removal in three (18%), subtotal removal in nine (52%), and partial removal in three patients (18%). Since 1990, chordomas have been radically resected via various skull base approaches; the combined total or near-total removal rate has been 80% in this period. Radical removal of the tumors has not led to an increased risk. At the final follow-up review (mean 59.5 month), 75% of the patients were still alive, and 25% had died of chordoma recurrence. The overall recurrence-free survival rate was 82% at 3 years and 51% at 5 years. The 5-year recurrence-free survival rate in the five patients who underwent the operation during the past decade was 77% (mean follow up of 5.2 years). In two patients with recurrent tumors who underwent radiosurgery, no evidence of tumor regrowth was demonstrated at 3 years posttreatment. Conclusions The authors suggest that for the treatment of skull base chordomas radical resection is a key factor for longer survival and improved quality of life. Patients with sufficiently small tumors, which show a favorable configuration and location, can be suitable candidates for stereotactic radiosurgery.

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