scholarly journals P11.25 Assessing electrical properties of cells as predictive marker for patient-specific TTFields response and optimal frequency

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii48-iii48
Author(s):  
A Kinzel ◽  
E Zeevi ◽  
K Gotlib ◽  
C Wenger ◽  
A Naveh ◽  
...  
Keyword(s):  
Electrical Properties ◽  
Cell Lines ◽  
Electric Fields ◽  
Predictive Marker ◽  
Membrane Capacitance ◽  
Patient Specific ◽  
Optimal Frequency ◽  
Tumor Treating Fields ◽  
Mitotic Frequency ◽  
Tumor Types

Abstract BACKGROUND Tumor treating fields (TTFields) are currently approved for the treatment of glioblastoma multiforme (GBM, using 200 kHz), and being tested in other tumor types such as non-small cell lung cancer and brain metastases occurring in this indication (LUNAR and METIS trials, using 150 kHz). Response to TTFields in cancer cells was empirically shown to be frequency-dependent specific for cell type; however, there are no markers available predicting optimal frequency or response in different cancer types or individual patients to date. There is evidence indicating electrical properties determine the optimal anti-mitotic frequency. This study analyzed the correlation of electrical properties of cells with their optimal TTFields frequency and sensitivity using the 3DEP reader (LabTech) to determine the electrical properties with the help of Dielectrophoresis (DEP) force. With this technique, cell movements within electric fields of different frequencies can by analyzed based on the physical effect of DEP, exercising a force on polarizable particles inside a non-homogeneous electric field. MATERIAL AND METHODS We used the 3DEP reader to obtain baseline properties (permittivity and conductivity) of 17 different cell lines of several tumor types. The resulting curves were analyzed by a 2-way ANOVA. Additionally, we determined the optimal frequency for maximum cytotoxic effect for each cell line using the inovitroTM system and eventually compared with the detected electrical properties. RESULTS We found cell lines with an optimal TTFields frequency of 150 kHz (corresponding to cells with a membrane capacitance in the lower range of the observed 3DEP curves, n=9) to possess significantly different (p<0.001) electrical properties from cells with an optimal TTFields frequency of 200 kHz (n=8). According to the curve differences in the lower frequency range, the measure of membrane capacitance served as a good predictor for TTFields response. CONCLUSION This study showed a correlation of cell membrane capacitance and optimal TTFields frequency and response. Our results provide a substantial rationale for further studies investigating the predictive potential of electrical properties of tumor cells as a measure for the optimal frequency and sensitivity to TTFields in individual patients.

scholarly journals CBMT-13. 3DEP SYSTEM TO TEST THE ELECTRICAL PROPERTIES OF DIFFERENT CELL LINES AS PREDICTIVE MARKERS OF OPTIMAL TUMOR TREATING FIELDS (TTFIELDS) FREQUENCY AND SENSITIVITY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi35-vi35
Author(s):  
Moshe Giladi ◽  
Einav Zeevi ◽  
Karnit Gotlib ◽  
Cornelia Wenger ◽  
Ariel Naveh ◽  
...  
Keyword(s):  
Electrical Properties ◽  
Cell Line ◽  
Cell Lines ◽  
Electric Fields ◽  
Intermediate Frequency ◽  
Predictive Markers ◽  
Membrane Capacitance ◽  
Frequency Range ◽  
Optimal Frequency ◽  
Tumor Treating Fields

Abstract BACKGROUND Tumor Treating Fields (TTFields; approved anti-neoplastic treatment modality) are delivered via application of low intensity, intermediate frequency, alternating electrical fields. The electrical properties of cells (eg, permittivity and conductivity) determine the optimal TTFields frequency that would elicit the greatest cell count reduction. Currently, no predictive markers exist to determine TTFields response and optimal frequency for individual patient application. The study goal was to evaluate the correlation between electrical properties of cells and TTFields’s optimal frequency and sensitivity. The 3DEPTM reader (LabTech) determines cellular electrical properties, including permittivity and conductivity, by using dielectrophoresis (DEP) force. DEP is a physical effect that generates a force on polarizable particles, such as cells, subjected to non-uniform electric fields. METHODS Utilizing the 3DEP reader, baseline electrical properties (permittivity and conductivity) of 17 cell lines from different tumor-types were determined. Curves were analyzed using 2-way ANOVA. The optimal TTFields frequency of each cell line was determined by evaluating TTFields cytotoxicity at various frequencies using the inovitroTM system. Electrical properties of each cell line were compared with the optimal TTFields frequency and sensitivity. RESULTS Significant differences (P< 0.001) were demonstrated between the lower frequency range of the 3DEP curves that correspond to cellular membrane capacitance at TTFields optimal frequencies of 150 kHz (9 cell lines) and 200 kHz (8 cell lines). Also, membrane capacitance was a good predictor of TTFields sensitivity based on curve differences within the low-frequency range. CONCLUSIONS These results demonstrate that cell membrane capacitance correlates with TTFields optimal frequency and sensitivity. Based on these data, there is a strong rational to further explore the potential of measuring the electrical properties of cells as predictive markers to help determine the optimal TTFields frequency for individual patient application and to identify ideal treatment-responders to TTFields.

scholarly journals EXTH-69. INCREASED CANCER CELL PERMEABILITY FOLLOWING TUMOR TREATING FIELDS (TTFIELDS) APPLICATION IN VITRO

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii102-ii102
Author(s):  
Tali Voloshin ◽  
Yaara Porat ◽  
Noa Kaynan ◽  
Anat Klein-Goldberg ◽  
Rom Paz ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Cell Permeability ◽  
Intracellular Accumulation ◽  
Optimal Frequency ◽  
Tumor Treating Fields ◽  
Cell Counts ◽  
Cellular Permeability ◽  
Resistant Cells

Abstract INTRODUCTION Tumor Treating Fields (TTFields), encompassing alternating electric fields within the intermediate frequency range, is an anticancer treatment delivered to the tumor region through transducer arrays placed non-invasively on the skin. This novel loco-regional treatment has demonstrated efficacy and safety and is FDA-approved in patients with glioblastoma (GBM) and malignant pleural mesothelioma. TTFields are currently being investigated in other solid tumors in ongoing trials. Recently, TTFields were reported to alter the cellular membrane structure of GBM cells, rendering them more permeable. The objective of this study was to characterize TTFields-induced cellular permeability in cancerous cell lines. METHODS TTFields were applied to uterine sarcoma, glioblastoma, and breast adenocarcinoma cell lines across a range of frequencies (50–500 kHz). Cellular permeability was assessed by quantifying the percentages of cells with accumulated 7-aminoactinomycin D (7-AAD) using flow cytometry and cytotoxicity was assessed based on cell counts. Kinetics were determined using different 7-AAD exposure times relative to TTFields treatment end. Changes in intracellular accumulation of anthracycline chemotherapeutics were evaluated in chemotherapy-sensitive and chemotherapy-resistant cells. RESULTS TTFields induced cellular permeability to 7-AAD in all 4 cancer cell lines tested. The optimal frequency for TTFields-induced cellular permeability was different from the optimal cytotoxic frequency. Kinetics measurements demonstrated that TTFields-induced permeability is transient and is effective only during application of TTFields. In combination experiments, TTFields improved intracellular accumulation of chemotherapeutic agents. Furthermore, combining chemotherapy with TTFields treatment facilitated accumulation of chemotherapeutics in chemotherapy-resistant cells to levels comparable with accumulation in chemotherapy-sensitive cancer cells. CONCLUSIONS This study demonstrates that TTFields can transiently increase cancer cell permeability in vitro with an optimal frequency that is variable from the frequency that is used to induce cancer cell cytotoxicity. Moreover, this effect is reversible and cellular permeability is restored to a normal state upon TTFields treatment cessation.

scholarly journals EPCO-22. IDENTIFYING NEOANTIGENS FOR A PERSONALIZED MUTATION-DERIVED GENOMIC VACCINE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii73-ii74
Author(s):  
Julia Kodysh ◽  
Alex Rubinsteyn ◽  
Ana Blazquez ◽  
John Mandeli ◽  
Nina Bhardwaj ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Hla Typing ◽  
Class I ◽  
Patient Specific ◽  
Computational Pipeline ◽  
Tumor Treating Fields ◽  
Mutational Burden ◽  
Newly Diagnosed Glioblastoma ◽  
Tumor Types ◽  
Coding Variants

Abstract BACKGROUND Glioblastomas (GBM) are known for having a lower mutational burden than many other tumor types. Nevertheless, somatic variants that occur in GBM mutational processes may give rise to neoantigens, which can be targeted in a personalized genomic vaccine to elicit a patient-specific anti-tumor response. METHODS Normal and tumor DNA and tumor RNA are extracted from tumor specimens and PBMCs. Exome and RNA sequencing and HLA typing is performed for each patient. Neoantigens are identified using the OpenVax computational pipeline, which calls somatic variants in the DNA and prioritizes corresponding candidate neoantigens for vaccination based on tumor RNA expression and predicted MHC class I binding affinity for each of the patient’s HLA alleles. This work is the base for a phase I trial of personalized neoantigen vaccines in combination with Tumor Treating Fields for GBM (NCT03223103). RESULTS For each of the 9 patients enrolled in the trial, an average of 1005 somatic mutations were identified (range 299–2441), of which 118 were coding variants (range 52–198), 20 were coding and expressed in the tumor RNA (range 9–45), and 16 were coding, expressed and resulted in predicted MHC class I ligands (range 7–33). An average of 2.3% of all somatic variants identified in each tumor gave rise to predicted neoantigens. Sufficient numbers of neoantigens were identified in all tumor samples of the patients enrolled in the study. The overall somatic mutation landscape for the tumors revealed 4/9 PIK3R1 deletions, 2/9 IDH1 substitutions, as well as disruptions in PTEN, TP53, and ATRX, among others. CONCLUSIONS Identifying sufficient neoantigens for inclusion in the personalized genomic vaccine is computationally feasible despite a typically low GBM mutational burden. Driver and passenger mutations can be identified through the same computational pipeline utilized for other tumor types.

scholarly journals EXTH-31. INCREASING TUMOR TREATING FIELDS (TTFIELDS) EFFICACY BY TARGETING THE G2 CELL CYCLE CHECKPOINT WITH WEE1 OR CHK1 INHIBITORS IN GLIOBLASTOMA CELL LINES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii93-ii93
Author(s):  
Paul L G Slangen ◽  
Mark C de Gooijer ◽  
Mariska van Geldorp ◽  
Olaf van Tellingen ◽  
Gerben R Borst
Keyword(s):  
Cell Cycle ◽  
Cell Fate ◽  
Cell Lines ◽  
Electric Fields ◽  
Colony Formation ◽  
Cell Cycle Checkpoint ◽  
Cell Cycle Distribution ◽  
Tumor Treating Fields

Abstract Tumor Treating Fields (TTFields) are a novel, noninvasive FDA-approved treatment modality for glioblastoma (GBM) that utilizes alternating electric fields. While the mechanism of action was at first exclusively attributed to the effects of TTFields on cells during mitosis, additional effects during interphase have recently come to light. The aim of our research is to elucidate the effect of TTFields on the cell cycle to advance the understanding of TTFields and to find novel targets for increasing its efficacy. We studied the effect of TTFields on cell cycle distribution by (propidium iodide and phospho-Histone H3 labeling) flow cytometry using double-thymidine block (DTB) synchronized cell populations. Following the release of the DTB, TTFields treatment caused GBM cells to accumulate in G2, which was prevented by concomitant exposure to a Wee1 inhibitor. Next, we compared the efficacy of TTFields with or without Wee1 or Chk1 inhibitors in multiple GBM cell lines (A172, SNB-19, and U251) by colony formation assays and observed a strong and synergistic decrease in colony formation potential in all cell lines. To investigate the underlying mechanism of G2 arrest, we quantified the amount of DNA damage, but found no difference in either γH2AX foci or comet tail moments between control and TTFields treated cells. To follow up on this surprising observation, we are using live cell imaging (inovitro Live™) of PIP-FUCCI-transduced cells. This tool will allow us to track individual cells, to evaluate the time spent in each phase of the cell cycle and to determine the ultimate cell fate in control and treatment conditions. Our finding that Wee1 or Chk1 inhibition dramatically boosts the efficacy of TTFields may have great implications for treatment of patients with TTFields. The in vivo validation of our in vitro findings will be performed in tumor-bearing mice by using the inovivo™ system.

Surface confinement induces the formation of solid-like insulating ionic liquid nanostructures

2017 ◽  
Author(s):  
Massimiliano Galluzzi ◽  
Simone Bovio ◽  
Paolo Milani ◽  
Alessandro Podestà
Keyword(s):  
Ionic Liquid ◽  
Electrical Properties ◽  
Electric Fields ◽  
Relative Dielectric Constant ◽  
Ionic Mobility ◽  
Electric Properties ◽  
Bulk Liquid ◽  
Structural Reorganization ◽  
Surface Confinement ◽  
Insulator Layers

We report on the modification of the electric properties of the imidazolium-based [BMIM][NTf2] ionic liquid upon surface confinement in the sub-monolayer regime. Solid-like insulating nanostructures of [BMIM][NTf2] spontaneously form on a variety of insulating substrates, at odd with the liquid and conductive nature of the same substances in the bulk phase. A systematic spatially resolved investigation by atomic force microscopy of the morphological, mechanical and electrical properties of [BMIM][NTf2] nanostructures showed that this liquid substance rearranges into lamellar nanostructures with a high degree of vertical order and enhanced resistance to mechanical compressive stresses and very intense electric fields, denoting a solid-like character. The morphological and structural reorganization has a profound impact on the electric properties of supported [BMIM][NTf2] islands, which behave like insulator layers with a relative dielectric constant between 3 and 5, comparable to those of conventional ionic solids, and significantly smaller than those measured in the bulk ionic liquid. These results suggest that in the solid-like ordered domains confined either at surfaces or inside the pores of the nanoporous electrodes of photo-electrochemical devices, the ionic mobility and the overall electrical properties can be significantly perturbed with respect to the bulk liquid phase, which would likely influence the<br>performance of the devices.<br>

scholarly journals In Vitro Systematic Drug Testing Reveals Carboplatin, Paclitaxel, and Alpelisib as a Potential Novel Combination Treatment for Adult Granulosa Cell Tumors

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 368
Author(s):  
Joline Roze ◽  
Elena Sendino Garví ◽  
Ellen Stelloo ◽  
Christina Stangl ◽  
Ferdinando Sereno ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Cell Lines ◽  
Combination Treatment ◽  
Drug Testing ◽  
Drug Application ◽  
Hormonal Treatment ◽  
Patient Specific ◽  
Granulosa Cell Tumors ◽  
Potential Synergy

Adult granulosa cell tumors (AGCTs) arise from the estrogen-producing granulosa cells. Treatment of recurrence remains a clinical challenge, as systemic anti-hormonal treatment or chemotherapy is only effective in selected patients. We established a method to rapidly screen for drug responses in vitro using direct patient-derived cell lines in order to optimize treatment selection. The response to 11 monotherapies and 12 combination therapies, including chemotherapeutic, anti-hormonal, and targeted agents, were tested in 12 AGCT-patient-derived cell lines and an AGCT cell line (KGN). Drug screens were performed within 3 weeks after tissue collection by measurement of cell viability 72 h after drug application. The potential synergy of drug combinations was assessed. The human maximum drug plasma concentration (Cmax) and steady state (Css) thresholds obtained from available phase I/II clinical trials were used to predict potential toxicity in patients. Patient-derived AGCT cell lines demonstrated resistance to all monotherapies. All cell lines showed synergistic growth inhibition by combination treatment with carboplatin, paclitaxel, and alpelisib at a concentration needed to obtain 50% cell death (IC50) that are below the maximum achievable concentration in patients (IC50 < Cmax). We show that AGCT cell lines can be rapidly established and used for patient-specific in vitro drug testing, which may guide treatment decisions. Combination treatment with carboplatin, paclitaxel, and alpelisib was consistently effective in AGCT cell lines and should be further studied as a potential effective combination for AGCT treatment in patients.

scholarly journals Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3776
Author(s):  
Edouard Auclin ◽  
Perrine Vuagnat ◽  
Cristina Smolenschi ◽  
Julien Taieb ◽  
Jorge Adeva ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Prognostic Index ◽  
Predictive Marker ◽  
Risk Groups ◽  
Two Factors ◽  
One Year ◽  
Metastatic Sites ◽  
Tumor Types

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p <0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46–8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.

Electrical Properties of Flames. BurnerFlames in Longitudinal Electric Fields.

1951 ◽  
Vol 43 (12) ◽  
pp. 2726-2731 ◽  
Author(s):  
Hartwell F. Calcote ◽  
Robert N. Pease
Keyword(s):  
Electrical Properties ◽  
Electric Fields

scholarly journals Baseline local hemodynamics as predictor of lumen remodeling at 1-year follow-up in stented superficial femoral arteries

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Monika Colombo ◽  
Yong He ◽  
Anna Corti ◽  
Diego Gallo ◽  
Stefano Casarin ◽  
...  
Keyword(s):  
Predictive Marker ◽  
Patient Specific ◽  
Lumen Area ◽  
Major Drawback ◽  
Area Change ◽  
Stent Restenosis ◽  
Computed Tomography Images ◽  
Relative Residence Time ◽  
The Impact

AbstractIn-stent restenosis (ISR) is the major drawback of superficial femoral artery (SFA) stenting. Abnormal hemodynamics after stent implantation seems to promote the development of ISR. Accordingly, this study aims to investigate the impact of local hemodynamics on lumen remodeling in human stented SFA lesions. Ten SFA models were reconstructed at 1-week and 1-year follow-up from computed tomography images. Patient-specific computational fluid dynamics simulations were performed to relate the local hemodynamics at 1-week, expressed in terms of time-averaged wall shear stress (TAWSS), oscillatory shear index and relative residence time, with the lumen remodeling at 1-year, quantified as the change of lumen area between 1-week and 1-year. The TAWSS was negatively associated with the lumen area change (ρ = − 0.75, p = 0.013). The surface area exposed to low TAWSS was positively correlated with the lumen area change (ρ = 0.69, p = 0.026). No significant correlations were present between the other hemodynamic descriptors and lumen area change. The low TAWSS was the best predictive marker of lumen remodeling (positive predictive value of 44.8%). Moreover, stent length and overlapping were predictor of ISR at follow-up. Despite the limited number of analyzed lesions, the overall findings suggest an association between abnormal patterns of WSS after stenting and lumen remodeling.

Sign in / Sign up

Export Citation Format

Share Document