Abstract
Δ24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Δ24-RGD may be effective, ...intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSC) could be harnessed as intravascular delivery vehicles of Δ24-RGD to human gliomas. To assess cellular events, green fluorescent protein–labeled hMSCs carrying Δ24-RGD (hMSC-Δ24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (E1A and hexon) at increasing times. hMSC-Δ24 selectively localized to glioma xenografts and released Δ24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase- labeled glioma xenografts, treated with hMSC-Δ24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-Δ24-treated animals compared with controls (P < 0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Δ24-treated animals (P < 0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSC-Δ24 selectively localize to human gliomas and are capable of delivering and releasing Δ24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice. Cancer Res 2009;69(23):8932–40
The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone ...marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.
Brain metastases from cervical cancer are extremely rare yet local recurrence and systemic spread is fairly common. The role of surgical resection and CNS screening for this pathology was ...interrogated from a review of the literature.
We present a case of a single brain metastasis that originated from the cervix and describe chronologically the spread of the disease with pathological confirmations.
Following an extensive English literature search, which only yielded 59 reported cases (n = 60 including the present case), we extrapolated basic trends regarding the demographics, pathophysiology, and treatment that portended a longer survival. Despite treatment, the majority of patients do not survive past 1 year from diagnosis of intracranial metastasis. A trend towards prolonged survival was observed among patients who received surgical resection of the brain metastasis.
Cervical carcinoma has been documented to metastasize to the brain, and this may occur via initial seeding of the lungs. Surgical resection and CNS screening may have beneficial roles in the management of metastatic cervical carcinoma.
Adenoviruses have been critical in the development of the molecular approaches to brain tumors. They have been engineered to function as vectors for delivering therapeutic genes in gene therapy ...strategies, and as direct cytotoxic agents in oncolytic viral therapies. This review outlines the uses of adenoviruses in brain tumor therapy by examining clinical trials of adenovirus-mediated p53 gene therapy and by reviewing the application of two conditionally replicative adenoviruses (CRAds) ONYX-015 and Delta 24 in brain tumors. The potential clinical use of CRAds that deliver trangenes, particularly p53, is also discussed.
Intramedullary neurenteric cysts (NEC) without associated malformations are extremely rare and, to our knowledge, have never been reported in association with calcification. We report a unique ...imaging presentation as a partially calcified mass of an isolated intramedullary neuroenteric cyst of the lower thoracic spinal cord with pathologic correlation. The literature for isolated forms of intramedullary NEC since the advent of magnetic resonance imaging is also reviewed.
To date, no report has been published on outcomes of patients undergoing resection for brain metastases who were previously treated with stereotactic radiosurgery (SRS). Consequently, the authors ...reviewed their institutional experience with this clinical scenario to assess the efficacy of surgical intervention.
Sixty-one patients (each harboring three or fewer brain lesions), who were treated at a single institution between June 1993 and August 2002 were identified. Patient charts and their neuroimaging and pathological reports were retrospectively reviewed to determine overall survival rates, surgical complications, and recurrence rates. A univariate analysis revealed that patient preoperative recursive partitioning analysis (RPA) classification, primary disease status, preoperative Karnofsky Performance Scale score, type of focal treatment undergone for nonindex lesions, and major postoperative surgical complications were factors that significantly affected survival (p < or = 0.05). In contrast, only the RPA class and focal (conventional surgery or SRS) treatment of nonindex lesions significantly (or nearly significantly) affected survival in the multivariate analysis. Major neurological complications occurred in only 2% of patients. The median time to distant recurrence after resection was 8.4 months; that to local recurrence was not reached. The overall median survival time was 11.1 months, with 25% of patients surviving 2 or more years. Conventional surgery facilitated tapering of steroid administration. Conclusions. The complication, morbidity, survival, and recurrence rates are consistent with those seen after conventional surgery for recurrent brain metastases. Our results indicate that in selected patients with a favorable RPA class in whom nonindex lesions are treated with focal modalities, surgery can provide long-term control of SRS-treated lesions and positively affect overall survival.
Background
Resection of giant thoracic schwannomas is challenging and usually requires a staged approach. The resection of the intraspinal component, usually via laminectomy, is done in one sitting ...and the intrathoracic component, via thoracotomy, follows at another. We describe the complete resection of a massive multi-compartmental thoracic schwannoma by an extended lateral parascapular approach.
Method and findings
The tumor, which presented with local pain and scapular displacement, had intrathoracic paraspinal (10 × 5 × 4 cm), posterolateral upper thoracic paramuscular (19 × 7 × 4 cm), foraminal, and epidural components. It was removed at a single sitting, via a posterior extended lateral parascapular approach that did not require staged procedures, multiple incisions, or repositioning of the patient. This operation included resection of the thoracic, foraminal, and intraspinal components and posterior stabilization with pedicle screws and rods. There were no postoperative neurological complications.
Conclusions
The extended lateral parascapular approach allows complete resection of giant multi-compartment schwannomas of the thoracic spine that extend from the canal into the thoracic cavity. It also permits posterior stabilization through the same incision used for tumor removal.
Delta-24-RGD is an infectivity-augmented, conditionally-replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta-24-RGD may be effective, ...intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSCs) could be harnessed as intravascular delivery vehicles of Delta-24-RGD to human gliomas. To assess cellular events, GFP-labeled hMSCs carrying Delta-24-RGD (hMSCs-Delta24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for GFP and viral proteins (E1A and hexon) at increasing times. hMSCs-Delta24 selectively localized to glioma xenografts and released Delta-24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase-labeled glioma xenografts, treated with hMSCs-Delta24 or controls and imaged weekly by bioluminescence imaging (BLI). Analysis of tumor size by BLI demonstrated inhibition of glioma growth and eradication of tumors in hMSCs-Delta24-treated animals compared with controls (
P
<0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Delta-24-treated animals (
P
<0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSCs-Delta24 selectively localize to human gliomas, and are capable of delivering and releasing Delta-24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice.
The ventricle is a rare site of brain metastases. Renal cell carcinoma has a higher propensity to metastasize to the ventricle compared with more common metastatic tumors (e.g., lung cancer). The ...trigone is the predominant location for intraventricular metastases, presumably because of the high concentration of choroid plexus in this region. Surgical resection is an important component of the management of these lesions, particularly if there is only a single intraventricular lesion. Despite the deep location of these tumors within the ventricle, survival in patients undergoing surgery for them is comparable to that in patients receiving surgery for intraparenchymal metastases.
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