Temperature and Impedance Variations During Tumor Treating Fields (TTFields) Treatment.

Tumor Treating Fields (TTFields) is an FDA-approved cancer treatment technique used for glioblastoma multiforme (GBM). It consists in the application of alternating (100-500 kHz) and low-intensity (1-3 V/cm) electric fields (EFs) to interfere with the mitotic process of tumoral cells. In patients, these fields are applied via transducer arrays strategically positioned on the scalp using the NovoTAL™ system. It is recommended that the patient stays under the application of these fields for as long as possible. Inevitably, the temperature of the scalp increases because of the Joule effect, and it will remain above basal values for most part of the day. Furthermore, it is also known that the impedance of the head changes throughout treatment and that it might also play a role in the temperature variations. The goals of this work were to investigate how to realistically account for these increases and to quantify their impact in the choice of optimal arrays positions using a realistic head model with arrays positions obtained through NovoTAL™. We also studied the impedance variations based on the log files of patients who participated in the EF-14 clinical trial. Our computational results indicated that the layouts in which the arrays were very close to each other led to the appearance of a temperature hotspot that limited how much current could be injected which could consequently reduce treatment efficacy. Based on these data, we suggest that the arrays should be placed at least 1 cm apart from each other. The analysis of the impedance showed that the variations seen during treatment could be explained by three main factors: slow and long-term variations, array placement, and circadian rhythm. Our work indicates that both the temperature and impedance variations should be accounted for to improve the accuracy of computational results when investigating TTFields.

A computational study of the relation between the power density in the tumor and the maximum temperature in the scalp during Tumor Treating Fields (TTFields) therapy.

In this work we investigated the relation between the power density in the tumor and the maximum temperature reached in the scalp during TTFields treatment for glioblastoma. We used a realistic head model to perform the simulations in COMSOL Multiphysics and we solved Pennes' equation to obtain the temperature distribution. Our results indicate that there might be a linear relation between these two quantities and that TTFields are safe from a thermal point of view.

In Vivo Safety of Tumor Treating Fields (TTFields) Applied to the Torso.

BACKGROUND: Tumor Treating Fields (TTFields) therapy is a non-invasive, loco-regional, anti-mitotic treatment modality that targets rapidly dividing cancerous cells, utilizing low intensity, alternating electric fields at cancer-cell-type specific frequencies. TTFields therapy is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in the US, Europe, Israel, Japan, and China. The favorable safety profile of TTFields in patients with GBM is partially attributed to the low rate of mitotic events in normal, quiescent brain cells. However, specific safety evaluations are warranted at locations with known high rates of cellular proliferation, such as the torso, which is a primary site of several of the most aggressive malignant tumors. METHODS: The safety of delivering TTFields to the torso of healthy rats at 150 or 200 kHz, which were previously identified as optimal frequencies for treating multiple torso cancers, was investigated. Throughout 2 weeks of TTFields application, animals underwent daily clinical examinations, and at treatment cessation blood samples and internal organs were examined. Computer simulations were performed to verify that the targeted internal organs of the torso were receiving TTFields at therapeutic intensities (≥ 1 V/cm root mean square, RMS). RESULTS: No treatment-related mortality was observed. Furthermore, no significant differences were observed between the TTFields-treated and control animals for all examined safety parameters: activity level, food and water intake, stools, motor neurological status, respiration, weight, complete blood count, blood biochemistry, and pathological findings of internal organs. TTFields intensities of 1 to 2.5 V/cm RMS were confirmed for internal organs within the target region. CONCLUSIONS: This research demonstrates the safety of therapeutic level TTFields at frequencies of 150 and 200 kHz when applied as monotherapy to the torso of healthy rats.

Permeabilizing Cell Membranes with Electric Fields.

The biological impact of exogenous, alternating electric fields (AEFs) and direct-current electric fields has a long history of study, ranging from effects on embryonic development to influences on wound healing. In this article, we focus on the application of electric fields for the treatment of cancers. In particular, we outline the clinical impact of tumor treating fields (TTFields), a form of AEFs, on the treatment of cancers such as glioblastoma and mesothelioma. We provide an overview of the standard mechanism of action of TTFields, namely, the capability for AEFs (e.g., TTFields) to disrupt the formation and segregation of the mitotic spindle in actively dividing cells. Though this standard mechanism explains a large part of TTFields' action, it is by no means complete. The standard theory does not account for exogenously applied AEFs' influence directly upon DNA nor upon their capacity to alter the functionality and permeability of cancer cell membranes. This review summarizes the current literature to provide a more comprehensive understanding of AEFs' actions on cell membranes. It gives an overview of three mechanistic models that may explain the more recent observations into AEFs' effects: the voltage-gated ion channel, bioelectrorheological, and electroporation models. Inconsistencies were noted in both effective frequency range and field strength between TTFields versus all three proposed models. We addressed these discrepancies through theoretical investigations into the inhomogeneities of electric fields on cellular membranes as a function of disease state, external microenvironment, and tissue or cellular organization. Lastly, future experimental strategies to validate these findings are outlined. Clinical benefits are inevitably forthcoming.

Real-time sensing of cell morphology by infrared waveguide spectroscopy.

We demonstrate that a live epithelial cell monolayer can act as a planar waveguide. Our infrared reflectivity measurements show that highly differentiated simple epithelial cells, which maintain tight intercellular connectivity, support efficient waveguiding of the infrared light in the spectral region of 1.4-2.5 µm and 3.5-4 µm. The wavelength and the magnitude of the waveguide mode resonances disclose quantitative dynamic information on cell height and cell-cell connectivity. To demonstrate this we show two experiments. In the first one we trace in real-time the kinetics of the disruption of cell-cell contacts induced by calcium depletion. In the second one we show that cell treatment with the PI3-kinase inhibitor LY294002 results in a progressive decrease in cell height without affecting intercellular connectivity. Our data suggest that infrared waveguide spectroscopy can be used as a novel bio-sensing approach for studying the morphology of epithelial cell sheets in real-time, label-free manner and with high spatial-temporal resolution.

Effect of incident light wavelength and corneal edema on light scattering and penetration: laboratory study of human corneas.

PURPOSE: The outcome of ultrashort pulse laser surgery of the cornea is strongly influenced by the light scattering properties of the tissue, for which little data are available. The purpose of the present study is to provide quantitative values for light scattering and its relation to the degree of edema. METHODS: An experimental optical measuring setup based on confocal geometry was used to measure the unscattered and scattered fractions of light transmitted by eye bank corneas presenting various degrees of edema. From these measurements, the effective light penetration depth in the cornea was calculated as a function of wavelength. RESULTS: Corneal transparency depends on the pathological state of the cornea and on wavelength. It may be predicted as a function of corneal thickness, ie, the degree of edema. In healthy and edematous cornea, the percentage of scattered light decreases with increasing wavelength. The total penetration depths at the wavelengths of ~1050 nm (which is used in typical clinical systems) and 1650 nm (which is recommended for future devices) are comparable; however, the former is limited by scattering, which degrades the laser beam quality, whereas the latter is only limited by optical absorption, which may be compensated for. CONCLUSIONS: The use of longer wavelengths should help improve the surgical outcome in ultrashort pulse laser surgery of the cornea when working on pathological tissue. A wavelength of approximately 1650 nm appears to be a good compromise, as it allows for reduced light scattering while keeping optical absorption reasonably low.