Impact of tumor position, conductivity distribution and tissue homogeneity on the distribution of tumor treating fields in a human brain:A computer modeling study

Tumor treating fields (TTFields) are increasingly used in the treatment of glioblastoma. TTFields inhibit cancer growth through induction of alternating electrical fields. To optimize TTFields efficacy, it is necessary to understand the factors determining the strength and distribution of TTFields. In this study, we provide simple guiding principles for clinicians to assess the distribution and the local efficacy of TTFields in various clinical scenarios.We calculated the TTFields distribution using finite element methods applied to a realistic head model. Dielectric property estimates were taken from the literature. Twentyfour tumors were virtually introduced at locations systematically varied relative to the applied field. In addition, we investigated the impact of central tumor necrosis on the induced field.Local field "hot spots" occurred at the sulcal fundi and in deep tumors embedded in white matter. The field strength was not higher for tumors close to the active electrode. Left/right field directions were generally superior to anterior/posterior directions. Central necrosis focally enhanced the field near tumor boundaries perpendicular to the applied field and introduced significant field non-uniformity within the tumor.The TTFields distribution is largely determined by local conductivity differences. The well conducting tumor tissue creates a preferred pathway for current flow, which increases the field intensity in the tumor boundaries and surrounding regions perpendicular to the applied field. The cerebrospinal fluid plays a significant role in shaping the current pathways and funnels currents through the ventricles and sulci towards deeper regions, which thereby experience higher fields. Clinicians may apply these principles to better understand how TTFields will affect individual patients and possibly predict where local recurrence may occur. Accurate predictions should, however, be based on patient specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity

Enhancing predicted efficacy of tumor treating fields therapy of glioblastoma using targeted surgical craniectomy: A computer modeling study

OBJECTIVE:The present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer. METHODS:We used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios. RESULTS:For the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60-70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30-50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50-70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect. CONCLUSIONS:Our results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in healthy tissues. A clinical trial is being planned to validate safety and efficacy

Importance of electrode position for the distribution of tumor treating fields (TTFields) in a human brain. Identification of effective layouts through systematic analysis of array positions for multiple tumor locations

<div><p>Tumor treating fields (TTFields) is a new modality used for the treatment of glioblastoma. It is based on antineoplastic low-intensity electric fields induced by two pairs of electrode arrays placed on the patient’s scalp. The layout of the arrays greatly impacts the intensity (dose) of TTFields in the pathology. The present study systematically characterizes the impact of array position on the TTFields distribution calculated in a realistic human head model using finite element methods. We investigate systematic rotations of arrays around a central craniocaudal axis of the head and identify optimal layouts for a large range of (nineteen) different frontoparietal tumor positions. In addition, we present comprehensive graphical representations and animations to support the users’ understanding of TTFields. For most tumors, we identified two optimal array positions. These positions varied with the translation of the tumor in the anterior-posterior direction but not in the left-right direction. The two optimal directions were oriented approximately orthogonally and when combining two pairs of orthogonal arrays, equivalent to clinical TTFields therapy, we correspondingly found a single optimum position. In most cases, an oblique layout with the fields oriented at forty-five degrees to the sagittal plane was superior to the commonly used anterior-posterior and left-right combinations of arrays. The oblique configuration may be used as an effective and viable configuration for most frontoparietal tumors. Our results may be applied to assist clinical decision-making in various challenging situations associated with TTFields. This includes situations in which circumstances, such as therapy-induced skin rash, scar tissue or shunt therapy, etc., require layouts alternative to the prescribed. More accurate distributions should, however, be based on patient-specific models. Future work is needed to assess the robustness of the presented results towards variations in conductivity.</p></div

Guidelines for Burr Hole Surgery in Combination With Tumor Treating Fields for Glioblastoma:A Computational Study on Dose Optimization and Array Layout Planning

Tumor treating fields (TTFields) is an anti-cancer technology increasingly used for the treatment of glioblastoma. Recently, cranial burr holes have been used experimentally to enhance the intensity (dose) of TTFields in the underlying tumor region. In the present study, we used computational finite element methods to systematically characterize the impact of the burr hole position and the TTFields transducer array layout on the TTFields distribution calculated in a realistic human head model. We investigated a multitude of burr hole positions and layouts to illustrate the basic principles of optimal treatment planning. The goal of the paper was to provide simple rules of thumb for physicians to use when planning the TTFields in combination with skull remodeling surgery. Our study suggests a number of key findings, namely that (1) burr holes should be placed directly above the region of interest, (2) field enhancement occurs mainly underneath the holes, (3) the ipsilateral array should directly overlap the holes and the contralateral array should be placed directly opposite, (4) arrays in a pair should be placed at far distance and not close to each other to avoid current shunting, and finally (5) rotation arrays around their central normal axis can be done without diminishing the enhancing effect of the burr holes. Minor deviations and adjustments (<3 cm) of arrays reduces the enhancement to some extent although the procedure is still effective in these settings. In conclusion, our study provides simple guiding principles for implementation of dose-enhanced TTFields in combination with burr-holes. Future studies are required to validate our findings in additional models at the patient specific level

Effect of gene dosage on single-cell hippocampal electrophysiology in a murine model of SSADH deficiency (γ-hydroxybutyric aciduria)

Human and murine succinic semialdehyde dehydrogenase (SSADH; gamma-hydroxybutyric (GHB) aciduria) deficiency represents an epileptic disorder associated with hyperGABA- and hyperGHB-ergic states. Despite significant neurotransmitters alterations, well-defined single-cell electrophysiological studies, aimed to provide insight into regional neuropathology, have been lacking. In this study, we characterized the effect of residual SSADH enzyme function/increased GABA levels on single-cell hippocampal electrophysiology in SSADH+/+ (wild-type; WT), SSADH+/- (heterozygous; HET), and SSADH-/- (knock-out; KO) mice. Tonic extrasynaptic GABAA receptor (GABAAR)-mediated currents were elevated in HET and KO mice, whereas phasic synaptic GABAAR currents were unaltered in dentate gyrus granule cells. Similarly, tonic GABAAR-mediated currents were increased in dentate gyrus interneurons of KO animals, while phasic GABAergic neurotransmission was unaffected in the same cells. Our results indicate global disruption of cortical networks in SSADH KO mice, affecting both excitatory and inhibitory neurons. Our findings provide new clues concerning seizure evolution in the murine model (absence→tonic-clonic→status epilepticus), and extend pathophysiological insight into human SSADH deficiency. © 2010 Elsevier B.V

Effect of 5-Aminolevulinic Acid and Sodium Fluorescein on the Extent of Resection in High-Grade Gliomas and Brain Metastasis

Surgery is essential in the treatment of high-grade gliomas (HGG) and gross total resection (GTR) is known to increase the overall survival and progression-free survival. Several studies have shown that fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) increases GTR considerably compared to white light surgery (65% vs. 36%). In recent years, sodium fluorescein (SF) has become an increasingly popular agent for fluorescence-guided surgery due to numerous utility benefits compared to 5-ALA, including lower cost, non-toxicity, easy administration during surgery and a wide indication range covering all contrast-enhancing lesions with disruption of the blood&ndash;brain barrier in the CNS. However, currently, SF is an off-label agent and the level of evidence for use in HGG surgery is inferior compared to 5-ALA. Here, we give an update and review the latest literature on fluorescence-guided surgery with 5-ALA and SF for brain tumors with emphasis on fluorescence-guided surgery in HGG and brain metastases. Further, we assess the advantages and disadvantages of both fluorophores and discuss their future perspectives