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Abstract
Non‐thermal, intermediate frequency (100–500 kHz) electrotherapies present a unique therapeutic strategy to treat malignant neoplasms. Here, pulsed electric fields (PEFs) which induce reversible or irreversible electroporation (IRE) and tumour‐treating fields (TTFs) are reviewed highlighting the foundations, advances, and considerations of each method when applied to glioblastoma (GBM). Several biological aspects of GBM that contribute to treatment complexity (heterogeneity, recurrence, resistance, and blood‐brain barrier(BBB)) and electrophysiological traits which are suggested to promote glioma progression are described. Particularly, the biological responses at the cellular and molecular level to specific parameters of the electrical stimuli are discussed offering ways to compare these parameters despite the lack of a universally adopted physical description. Reviewing the literature, a disconnect is found between electrotherapy techniques and how they target the biological complexities of GBM that make treatment difficult in the first place. An attempt is made to bridge the interdisciplinary gap by mapping biological characteristics to different methods of electrotherapy, suggesting important future research topics and directions in both understanding and treating GBM. To the authors' knowledge, this is the first paper that attempts an in‐tandem assessment of the biological effects of different aspects of intermediate frequency electrotherapy methods, thus offering possible strategies toward GBM treatment.
Highlights
Given the biophysical understanding of the cell membrane potential and electrophysiology, it seems intuitive that electrotherapy techniques could exploit the electrical characteristics of glioma. While this may be the case, it appears there is an interdisciplinary disconnect at the interface of neuroscience, biology, and applied physics/engineering that is limiting the pace of progression in this field, we propose research questions that require urgent consideration
Ion channel modulation studies by nsPEF are ongoing in the field of neurostimulation and cancer treatment. These results suggest that nsPEF protocols below electroporation thresholds present opportunities that may be therapeutically beneficial for cancer treatment and should be considered in future studies
The main observations were that lethal thresholds for NK-irreversible electroporation (IRE) were consistent across the temperature range (2–37 °C) and that the ablation zone increased by 7% across the ranging temperatures
Summary
As implied by the moniker “multiforme,” GBM is characterized by a widespread inter (different between tumors) and intratumoral (within the same tumour) heterogeneity.[18,19] Heterogeneity can present in multiple different ways within the same tumour including molecular, metabolic, microenvironmental, and vascular heterogeneity. These factors can vary within the same tumour leading to regional variations in therapy response and cellular behaviors. There is extensive intra-tumoral heterogeneity displayed by GBM and that this occurs at the genetic, metabolic, and microenviron-
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