Abstract 3931: Determining extracellular fluid velocity along white matter tracts with injections of increasing concentrations of intracranial albumin using both histological and radiological techniques.
Authors: Carmen Kut, Vadappuram Chacko, Betty Tyler, Arvind P. Pathak, Zaver Bhujwalla, Elliot R. McVeigh, Xingde Li, Daniel A. Herzka, Stuart A. Grossman
Journal: Cancer Research (2013)

Abstract INTRODUCTION: Tumor cells are passively carried by extracellular fluid flow to regional lymph nodes in most systemic cancers including breast cancer, melanoma and colorectal cancer. Although the brain does not contain lymphatics, cancer spread within the brain may be a function of extracellular fluid velocity. As malignant brain tumors are characterized by a disrupted blood-brain-barrier that leaks albumin from blood vessels into brain parenchyma, we hypothesize that this albumin influx will pull water in osmotically and increase flow rates and glioma cell dissemination down adjacent white matter tracts. High flow rates may increase tumor dissemination via the WMT. This study sought to determine if increasing intracranial albumin concentrations affect WMT flow rates. If true, restricting albumin extravasation (through steroids or VEGF inhibitors) has the potential to reduce glioma dissemination and may have implications for future radiation planning and steroid/VEGF inhibitor dosing. METHODS: Our study examines flow rates in white matter tracts after intracranial administration of albumin. 0.12-6 mg bovine albumin were mixed with 20 μL of 2% Evans Blue and injected stereotactically into the right frontal lobe at the gray-white matter junction over 80 minutes in 15 anesthetized Sprague-Dawley female rats. Seven hours later, the rats were sacrificed and the brains sectioned into 0.5mm coronal slices, and imaged to determine interstitial flow rates. RESULTS: Average anterior-posterior (AP) velocity for rats receiving 0.12 mg and 6.0 mg of albumin were 0.43 and 1.02 mm/hour respectively (p = 0.029). Correlation was observed between administered albumin dose and interstitial fluid velocity (R = 0.57). In vivo MRI results were consistent with ex vivo Evans blue results and demonstrate markedly increased edema (T2) in the hemisphere where albumin was injected. CONCLUSIONS: This study demonstrates higher interstitial fluid flow rates in adjacent white matter tracts in response to albumin-induced-edema. These observations provide insight into expected pathways for glioma dissemination which could be used to tailor radiation plans for individual patients. Furthermore, these findings provide a rationale for interventions to reduce glioma dissemination by limiting the extravasation of albumin through the blood-brain-barrier while local radiation is being administered. Citation Format: Carmen Kut, Vadappuram Chacko, Betty Tyler, Arvind P. Pathak, Zaver Bhujwalla, Elliot R. McVeigh, Xingde Li, Daniel A. Herzka, Stuart A. Grossman. Determining extracellular fluid velocity along white matter tracts with injections of increasing concentrations of intracranial albumin using both histological and radiological techniques. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3931. doi:10.1158/1538-7445.AM2013-3931