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Abstract

High grade astrocytomas remain incurable even though these tumors often appear localized on modern imaging studies, rarely metastasize to systemic sites, and can be aggressively treated with surgery and radiation therapy. Recent data suggest that the dissemination of astrocytoma cells along white matter tracts to distant regions of the brain may be responsible for the poor survival of these patients and the limited impact of local therapies. Movement of astrocytoma cells along these white matter tracts can be active or passive in nature. To study the potential for tumor dissemination by bulk flow of interstitial fluid resulting from peritumoral edema. 20 microL of tritiated inulin, Evans Blue, and rat albumin were injected stereotactically into the right frontal lobe and the left temporal lobe at the gray-white matter junction in Sprague-Dawley rats. Six hours later, the rats were sacrificed and the brains were removed, frozen and prepared for quantitative autoradiography and histologic analysis. Interstitial flow rates were calculated from the autoradiographs, and flow pathways were determined from the movement of Evans Blue, inulin and histologic data. In each animal injected in the frontal lobe, Evans Blue and inulin were primarily confined to large ipsilateral white matter tracts and extended from the frontal injection site to the occipital lobe. The average interstitial fluid flow rate in the association fibers of the external capsule was 0.86 mm/hr. In contrast, the animals receiving temporal lobe injections had Evans Blue and inulin confined to the temporal lobe. The average interstitial fluid flow rate in the white matter tracts of the temporal lobe was 0.61 mm/hr. The rapid and preferential flow of interstitial fluid along white matter tracts and the differences in the clearance of extracellular fluid observed between the frontal and temporal lobes may have important clinical implications. These data suggest that aggressive treatment of peritumoral edema, expansion of radiotherapy ports, and consideration of the location of the tumor in treatment planning may improve therapeutic outcomes for some patients. An improved understanding of the mechanisms of tumor dissemination is crucial to designing more effective therapeutic approaches for patients with this devastating malignancy.

Dynamic contrast-enhanced MRI of Gd-albumin delivery to the rat hippocampus in vivo by convection-enhanced delivery

“…Other imaging modalities, such as autoradiography (Geer and Grossman, 1997; Groothuis et al, 1999) and histology may provide higher resolution than what is available with MR; however, they can only be utilized to evaluate final distribution profiles in excised sliced tissue. As mentioned previously, the limited resolution of dynamic MR images (240 µm 2 in-plane) did not allow certain substructures in the hippocampus, such as the granule cell layer of the dentate gyrus or hippocampal fissure, to be identified.…”

The regulation of brain states by neuroactive substances distributed via the cerebrospinal fluid; a review

“…Diffusion in the ECF compartment may appear anisotropic, due to the hindrances imposed by local differences in tortuosity [155]. White matter tracts are guiding tracts for the interstitial fluid flow as well as for the dissemination of primary brain tumors [158]. Diffusion and exchange between cerebrospinal and extracellular fluid compartments may occur in both directions [37,77] through an uninterrupted single-layered lining of the ventricular system, consisting of several types of ciliated ependymal cells [95,159].…”

Primary CNS Tumors and Leptomeningeal, Disseminated and/or Multicentric Disease in Children Treated in Phase II Studies with Antineoplastons A10 and AS2-1

“…In addition, some controversy persists as to the differentiation of multifocal and multicentric disease, perhaps because the described pathophysiological basis for both is similar in some respects. In this report, disseminated disease refers to CSF dissemination, which can result in multicentric disease (Geer et al, 1997) and/or LM. Multicentric disease (and LM) can also occur because of the unique propensity of glioma cells to invade normal brain (or spinal cord) and migrate long distances (Claes et al, 2007).…”

“…By this definition, multifocal glioma consisted of tumors separated by white matter tracts within the same hemisphere, whereas multicentric glioma consisted of widespread tumors, such as those occurring in opposite hemispheres or separated by the tentorium. In contrast to this, Geer and Grossman, in 1997, suggested that interstitial fluid along white matter tracts could be a potentially important mechanism for the dissemination of glioma cells, explaining that glioma cells are inherently capable of migration along white matter tracts to distant areas of the brain (Geer et al, 1997). In 2007, Claes and colleagues (Claes et al, 2007) suggested that multicentric tumors are likely to develop because of the unique propensity of glioma cells to invade normal brain and migrate long distances.…”