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Cellular MRI in Glioma and Radiation Necrosis (1R01CA122031-01A2) Differentiation of Glioma from Radiation Injury Using Cellular MRI (1R21NS058589-01A1) Grant Number: 1R01CA122031-01A2 Principal Investigator(s): SYED ARBAB ALI, MD Project Title: Cellular MRI in Glioma and Radiation Necrosis Project Period: 09/07/2007 – 07/31/2011 Abstract: Recently, using two FDA-approved agents, we formed ferumoxides-protamine sulfate complex and labeled any kind of mammalian cells. To examine whether labeled cells can be used as probes to detect and differentiate physiological and/or pathological conditions, we have selected glioma and radiation necrosis models. It is hypothesized that in vivo MR tracking of magnetically labeled cells will enable us to identify different patterns of accumulation and incorporation of labeled injected cells, thus allowing for differentiation between recurrent glioma and radiation necrosis. Glioma is a central nervous system neoplasm that typically shows hypervascularity. Unlike the surrounding normal regions of cerebral vasculature, areas of hypervascularity are typically permeable to contrast agents, and can thus be detected by contrast-enhanced MRI or CT. However, areas of radiation necrosis can also show enhancement due to active inflammatory reactions and increasing vascular permeability. Thus, distinguishing recurrent glioma from radiation necrosis becomes problematic if only changes in vascular permeability and/or volume are considered. One distinguishing characteristic, however, is that there is little active angiogenesis at the site of radiation necrosis. By determining the differential migration and incorporation patterns of labeled endothelial progenitor cells (EPCs) at the site of glioma, it should be possible to differentiate between radiation necrosis and recurrent glioma. If this proves feasible, a translation into clinical trials can quickly follow, employing autologous labeled EPCs. These labeled cells, once incorporated into the tumors or areas of necrosis, can be detected as low signal intensity areas on in vivo and ex vivo MRI because of the susceptibility effects of iron oxides inside the cells. These objectives will be achieved by obtaining serial MRI of tumors and radiation necrotic areas after injecting labeled cells at different time points. The findings on MRI will be correlated with histology and different markers of endothelial cells. Angiogenic factors will also be assessed by immunohistochemistry at the site of accumulated EPCs in tumors or radaition necrosis. Early detection of recurrent or metastatic glioma as well as early differentiation of glioma from radiation necrosis will help clinician to tackle the devastating neurological disease. Grant Number: 1R21NS058589-01A1 Principal Investigator(s): SYED ARBAB ALI, MD Project Title: Differentiation of Glioma from Radiation Injury Using Cellular MRI Project Period: 09/15/2007 – 02/28/2009 Abstract: Despite extensive treatment strategies and investigations, the prognosis of glioblastomamultiforme is still poor. The main reason is the inability to delineate the margin of the tumor during routine investigations or during surgery. Moreover, current imaging modalities fail to differentiate, conclusively, the recurrent or left over tumor from radiation necrosis or necroitic tissues. For proper management and follow up it is utmost important to detect recurrent tumor as early as possible. Recently dendritic cell based vaccination and cytotoxic T-lymphocytes (CTL) are being considered for the treatment of recurrent glioma. In the animal models as well as in the early pahses of clinical trials, CTL has been shown to accumulate in the glioma. By tracking the migration and homing of CTL it may be possible to differentiate recurrent glioma from radaition necrosis Recently, using two FDA-approved agents, we formed ferumoxides-protamine sulfate complex and labeled any kind of mammalian cells. To examine whether labeled cells can be used as cellular probes to detect and differentiate physiological and/or pathological conditions, we have selected glioma and radiation injury models. It is hypothesized that in vivo magnetic resonance imaging (MRI) tracking of magnetically labeled CTLs will enable us to identify different patterns of accumulation and incorporation of labeled injected CTLs, thus allowing for differentiation between recurrent glioma and radiation injury. The goals of this study will be achieved by making glioma as well as radiation injury models in tumor bearing or control nude rats. Nude rats will be used to implant human U-251 glioma cell lines. In these rats we will test whether CTLs produced in vitro by U-251 cell lysate-pulsed dendritic cells can recognize the implanted human glioma and differentiate it from radaition injury. CTLs prouced in vitro will be magnetically labeled using feridex-protamine sulfate complexes and the labeled cells will be injected into tail vein of the rats at different stages of their disease processes. These labeled cells, once incorporated into the tumors or areas of injury, can be detected as low signal intensity areas on in vivo and ex vivo MRI because of the susceptibility effects of iron oxides inside the cells. Serial MRI of tumors and radiation injured areas after injecting labeled cells at different time points will be obtained by a 7 tesla MRI system. The findings of MRI will be correlated with histology, and immuonohistochemical detection of CTLs. The results will also be compared among the animals of all groups. Early detection of recurrent or metastatic glioma as well as early differentiation of glioma from radiation necrosis will help clinician to tackle this devastating neurological malignant tumor. |
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