An assessment of vascular normalization in 9L gliosarcoma brain tumor: Using dynamic susceptibility contrast (DSC) imaging and dynamic contrast enhancement (DCE) imaging

Moses M Darpolor, Marquette University


Emerging concepts and evidence have purported that certain antiangiogenic drugs can transiently "normalize" the abnormal morphology and function of tumor vasculature. It is suggested that this transitory period of vascular "normalization" is suitable for drug delivery to tumor microenvironment, and may improve the efficiency of chemotherapy or radiotherapy. From another perspective, this view seems rather counterintuitive since the normalization of tumor vasculature could potentially augment the growth rate of tumor. Understanding this process has significant implications for improving therapeutic outcomes. For if normalization provides the best time during which treatment should be administered, we want to know when the normalization occurs, and how to optimize timing, dosing and possibly the combinations of drugs administered. If normalization results in advanced tumor growth, rather than a window of opportunity, we want to make sure treatment strategies avoid normalization as an endpoint. We hypothesize that advanced physiologic imaging methods can provide the information necessary to detect and characterize "normalization" and subsequently optimize treatment strategies. DSC can provide parametric measurements such as relative cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) which can be use to estimate the vascular morphology (i.e. micro/macro vessels) and vascular function of tumors. Rat brain was implanted with tumor and examined on a 3 Tesla MR system by implementing DSC and DCE techniques. Cerebral perfusion (CBF/MTT) in brain tumor is quite inefficient as demonstrated by DSC. This inefficient perfusion is attributed to the density of irregularly shaped vessels in rat brain tumors as elucidate by micro-computed tomography of intact vessel tree. It is shown that the density of tortuous vessels is the prime suspect of abnormal perfusion. DSC parameters were validated by use of microscopy on brain tissues. Immunohistochemistry, anti-CD31, showed some regression in vessel size after dexamethasone therapy as possible indication of vascular "normalization". Dexamethasone treatment also reduced vascular permeability in terms of Ktrans as computed from DCE. Cerebral blood volume measure from DSC is a potential surrogate marker to characterize the "normalization" of tumor vasculatures during antiangiogenic therapy. And Temozolomide treatment in this window produced a synergistic effect. Therefore, it is suggested here that DSC-MRI measurements could play an important role for assessing vascular "normalization" of tumor and the efficacy of combining drug treatment.

Recommended Citation

Darpolor, Moses M, "An assessment of vascular normalization in 9L gliosarcoma brain tumor: Using dynamic susceptibility contrast (DSC) imaging and dynamic contrast enhancement (DCE) imaging" (2006). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI3244562.