Abstract
BackgroundMalignant gliomas are highly invasive, difficult to treat, and account for 2% of cancer deaths worldwide. Glioblastoma Multiforme (GBM) comprises the most common and aggressive intracranial tumor. The study hypothesis is to investigate the modification of Photodynamic Therapy (PDT) efficacy by mild hypothermia leads to increased glioma cell kill while protecting normal neuronal structures.MethodsPhotosensitizer accumulation and PDT efficacy in vitro were quantified in various glioma cell lines, primary rat neurons, and astrocytes. In vivo studies were carried out in healthy brain and RG2 glioma of naïve Fischer rats. Hypothermia was induced at 1 hour pre- to 2 hours post-PDT, with ALA-PpIX accumulation and PDT treatments effects on tumor and normal brain PDT quantified using optical spectroscopy, histology, immunohistochemistry, MRI, and survival studies, respectively.FindingsIn vitro studies demonstrated significantly improved post-PDT survival in primary rat neuronal cells. Rat in vivo studies confirmed a neuroprotective effect to hypothermia following PpIX mediated PDT by T2 mapping at day 10, reflecting edema/inflammation volume reduction. Mild hypothermia increased PpIX fluorescence in tumors five-fold, and the median post-PDT rat survival time (8.5 days normothermia; 14 days hypothermia). Histology and immunohistochemistry show close to complete cellular protection in normal brain structures under hypothermia.ConclusionsThe benefits of hypothermia on both normal neuronal tissue as well as increased PpIX fluorescence and RG2 induced rat survival strongly suggest a role for hypothermia in photonics-based surgical techniques, and that a hypothermic intervention could lead to considerable patient outcome improvements.
Highlights
Glioblastoma Multiforme (GBM), comprising the most common and aggressive adult intracranial malignancy, has presented with a constant increasing incidence rate at over 2% per year between 1970 and 2000 [1]
The study hypothesis is to investigate the modification of Photodynamic Therapy (PDT) efficacy by mild hypothermia leads to increased glioma cell kill while protecting normal neuronal structures
The benefits of hypothermia on both normal neuronal tissue as well as increased PpIX fluorescence and RG2 induced rat survival strongly suggest a role for hypothermia in photonicsbased surgical techniques, and that a hypothermic intervention could lead to considerable patient outcome improvements
Summary
Glioblastoma Multiforme (GBM), comprising the most common and aggressive adult intracranial malignancy, has presented with a constant increasing incidence rate at over 2% per year between 1970 and 2000 [1]. Current therapeutic options are limited for non-surgically accessible GBM and those tumors which are proximal to eloquent areas of the brain, as most lengthy surgical interventions are not recommended For these cases, photonics-based assistive tools including Photodynamic Therapy (PDT) and Fluorescence-Guided Resection (FGR) with the pro-drug Aminolevulinic Acid (ALA) are being investigated [11, 12]. One advantage of exogenous ALA-induced PpIX is that tumors show a preferential uptake of ALA, increasing synthesis of PpIX and retention thereof within the tumor mitochondria, versus normal intracranial tissues [13, 14] This difference in PpIX concentration provides contrast between normal brain and tumor, enabling FGR and an increased therapeutic index for PDT. The study hypothesis is to investigate the modification of Photodynamic Therapy (PDT) efficacy by mild hypothermia leads to increased glioma cell kill while protecting normal neuronal structures
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