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Article ; Online: Of Fields and Phantoms : The Importance of Virtual Humans in Optimizing Cancer Treatment with Tumor Treating Fields.

Bomzon, Ze'ev / Wenger, Cornelia

2017 Volume 8, Issue 4, Page(s) 46–49

Abstract: Cancer represents a compilation of diseases characterized by rapidly dividing, invasive cells. Worldwide data indicate that over 14 million new cancers were diagnosed in 2012, with a projected increase of more than 19 million diagnosed cases by 2025 [1]. ...

Abstract	Cancer represents a compilation of diseases characterized by rapidly dividing, invasive cells. Worldwide data indicate that over 14 million new cancers were diagnosed in 2012, with a projected increase of more than 19 million diagnosed cases by 2025 [1]. Survival rates for some cancers have increased dramatically, but there are still cancer types for which the prognosis is poor and few treatments exist. Thus, there is a growing need for new therapies targeting these difficult-to-treat cancers.
Language	English
Publishing date	2017-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2567191-1
ISSN	2154-2317 ; 2154-2287
ISSN (online)	2154-2317
ISSN	2154-2287
DOI	10.1109/MPUL.2017.2701238
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Conference proceedings: Influence of TTFields dose on tumour progression pattern in the EF-14 trial

Glas, Martin / Bomzon, Ze'ev / Ballo, Matthew T.

2020 , Page(s) V013

Title translation	Einfluss der TTFields-Dosis auf das Tumorprogressionsmuster in der EF-14 Studie
Event/congress	71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie; sine loco [digital]; Deutsche Gesellschaft für Neurochirurgie; 2020
Keywords	Medizin, Gesundheit
Publishing date	2020-06-26
Publisher	German Medical Science GMS Publishing House; Düsseldorf
Document type	Conference proceedings
DOI	10.3205/20dgnc013
Database	German Medical Science

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Article: Permeabilizing Cell Membranes with Electric Fields.

Aguilar, Alondra A / Ho, Michelle C / Chang, Edwin / Carlson, Kristen W / Natarajan, Arutselvan / Marciano, Tal / Bomzon, Ze'ev / Patel, Chirag B

Cancers

2021 Volume 13, Issue 9

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2021-05-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13092283
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Article ; Online: Enhancing Tumor Treating Fields Therapy with Skull-Remodeling Surgery. The Role of Finite Element Methods in Surgery Planning.

Korshoej, Anders R / Mikic, Nikola / Hansen, Frederik Lundgaard / Saturnino, Guilherme B / Thielscher, Axel / Bomzon, Ze'ev

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2019 Volume 2019, Page(s) 6995–6997

Abstract: Skull-remodeling surgery has been proposed to enhance the dose of tumor treating fields in glioblastoma treatment. This abstract describes the finite element methods used to plan the surgery and evaluate the treatment efficacy. ...

Abstract	Skull-remodeling surgery has been proposed to enhance the dose of tumor treating fields in glioblastoma treatment. This abstract describes the finite element methods used to plan the surgery and evaluate the treatment efficacy.
MeSH term(s)	Brain Neoplasms/surgery ; Finite Element Analysis ; Glioblastoma ; Humans ; Skull ; Treatment Outcome
Language	English
Publishing date	2019-12-30
Publishing country	United States
Document type	Journal Article
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC.2019.8856556
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Article ; Online: The dielectric properties of skin and their influence on the delivery of tumor treating fields to the torso: a study combining in vivo measurements with numerical simulations.

Hershkovich, Hadas Sara / Urman, Noa / Yesharim, Ofir / Naveh, Ariel / Bomzon, Ze'ev

Physics in medicine and biology

2019 Volume 64, Issue 18, Page(s) 185014

Abstract: The study of the dielectric properties of tissues plays a key role in understanding the interaction between electromagnetic energy and the human body, for safety assessments of human exposure to electromagnetic fields, as well as for numerous biomedical ... ...

Abstract	The study of the dielectric properties of tissues plays a key role in understanding the interaction between electromagnetic energy and the human body, for safety assessments of human exposure to electromagnetic fields, as well as for numerous biomedical applications such as tumor treating fields (TTFields). TTFields are low-intensity alternating electric fields in the 100-500 kHz frequency range, which have an antimitotic effect on cancerous cells. TTFields are delivered to the body through pairs of transducer arrays placed on a patient's skin in close proximity to the tumor. Therefore, it is essential to understand how the skin's dielectric properties affect TTFields delivery in clinical settings. In this paper, we present a study combining in vivo measurements with numerical simulations that elucidate how different layers of the skin influence TTFields distribution in the body. The dielectric properties of the skin were measured on volunteers using a setup that ensured skin conditions resembled those when TTFields are delivered to patients. The measured properties were incorporated into a realistic human computational phantom and delivery of TTFields to the phantom's abdomen was simulated. The total impedance of the simulated model was within the mid-range of impedance values measured in patients with pancreatic cancer treated with TTFields. A computational study investigating model sensitivity to the dielectric properties of the skin and subcutaneous adipose tissue (SAT) showed that when skin conductivity increased above a threshold value, the total impedance of the model was largely insensitive to changes in the conductivity of these tissues. Furthermore, for a given current, the field intensity within the internal organs was mostly unaffected by skin properties but was highly sensitive to the conductivity of the organ itself. This study provides a new insight into the role of skin in determining the distribution of TTFields within the body.
MeSH term(s)	Computer Simulation ; Electric Conductivity ; Electric Impedance ; Electric Stimulation Therapy ; Electromagnetic Fields ; Female ; Humans ; Male ; Models, Theoretical ; Neoplasms/therapy ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/therapy ; Phantoms, Imaging ; Skin/pathology ; Torso ; Transducers
Language	English
Publishing date	2019-09-19
Publishing country	England
Document type	Journal Article
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/ab33c6
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Article ; Online: Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma: A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial.

Ballo, Matthew T / Urman, Noa / Lavy-Shahaf, Gitit / Grewal, Jai / Bomzon, Ze'ev / Toms, Steven

International journal of radiation oncology, biology, physics

2019 Volume 104, Issue 5, Page(s) 1106–1113

Abstract: Introduction: Tumor Treating Fields (TTFields) are approved for glioblastoma based on improved overall survival (OS) and progression-free survival (PFS) in the phase 3 EF-14 trial of newly diagnosed glioblastoma. To test the hypothesis that increasing ... ...

Abstract	Introduction: Tumor Treating Fields (TTFields) are approved for glioblastoma based on improved overall survival (OS) and progression-free survival (PFS) in the phase 3 EF-14 trial of newly diagnosed glioblastoma. To test the hypothesis that increasing TTFields dose at the tumor site improves patient outcomes, we performed a simulation-based study investigating the association between TTFields dose and survival (OS and PFS) in patients treated with TTFields in EF-14. Methods and materials: EF-14 patient cases (N = 340) were included. Realistic head models were derived from T1-contrast images captured at baseline. The transducer array layout on each patient was obtained from EF-14 records; average compliance (fraction of time patient was on active treatment) and average electrical current delivered to the patient were derived from log files of the TTFields devices used by patients. TTFields intensity distributions and power densities were calculated using the finite element method. Local minimum dose density (LMiDD) was defined as the product of TTFields intensity, tissue-specific conductivities, and patient compliance. The average LMiDD within a tumor bed comprising the gross tumor volume and the 3-mm-wide peritumoral boundary zone was calculated. Results: The median OS and PFS were significantly longer when the average LMiDD in the tumor bed was ≥0.77 mW/cm Conclusions: In this study we present the first reported analysis demonstrating patient-level dose responses to TTFields. We provide a rigorous definition for TTFields dose and set a conceptual framework for future work on TTFields dosimetry and treatment planning.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/mortality ; Brain Neoplasms/pathology ; Brain Neoplasms/radiotherapy ; Electrophysiological Phenomena ; Female ; Glioblastoma/diagnostic imaging ; Glioblastoma/mortality ; Glioblastoma/pathology ; Glioblastoma/radiotherapy ; Humans ; Kaplan-Meier Estimate ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Progression-Free Survival ; Radiotherapy Dosage ; Radiotherapy Planning, Computer-Assisted ; Transducers ; Young Adult
Language	English
Publishing date	2019-04-23
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2019.04.008
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Conference proceedings: EF-14 Phase III post-hoc analysis – TTFields affect tumour growth rates

Kinzel, Adrian / Urman, Noa / Lavy-Shahaf, Gitit / Levi, Shay / Bomzon, Ze\'ev

2020 , Page(s) P012

Title translation	Post-Hoc Analyse der EF-14 Phase III Studie – TTFields beeinflussen die Tumorwachstumsraten
Event/congress	71. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 9. Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie; sine loco [digital]; Deutsche Gesellschaft für Neurochirurgie; 2020
Keywords	Medizin, Gesundheit
Publishing date	2020-06-26
Publisher	German Medical Science GMS Publishing House; Düsseldorf
Document type	Conference proceedings
DOI	10.3205/20dgnc439
Database	German Medical Science

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Article: Computational simulations establish a novel transducer array placement arrangement that extends delivery of therapeutic TTFields to the infratentorium of patients with brainstem gliomas.

Ramirez-Fort, Marigdalia K / Naveh, Ariel / McClelland, Shearwood / Gilman, Casey K / Fort, Migdalia / Mendez, Melissa / Matta, Jaime / Bomzon, Ze'ev / Lange, Christopher S

Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology

2021 Volume 26, Issue 6, Page(s) 1045–1050

Abstract: Background and purpose: Tumor treating fields (TTFields) are a non-invasive, efficacious treatment modality currently approved for supratentorial glioblastomas. Despite their ability to improve overall survival in supratentorial tumors, the current ... ...

Abstract	Background and purpose: Tumor treating fields (TTFields) are a non-invasive, efficacious treatment modality currently approved for supratentorial glioblastomas. Despite their ability to improve overall survival in supratentorial tumors, the current placement of arrays is limited to the supratentorial head, precluding its use in infratentorial tumors. Infratentorial malignancies are in need of new therapy modalities given their poor prognoses in both children and adults. The aim of this research is to determine whether rearrangement of TTFields may allow for management of infratentorial tumors. Materials and methods: Delivery of TTFields using Novocure's prototype Optune™ device human male head model was simulated based on brain MRIs from patients with brainstem gliomas to develop a novel array layout designed to extend adequate infratentorial coverage. Results: Array placement on the vertex, bilateral posterolateral occiput, and superior-posterior neck achieved intensities above 1.1 V/cm (average 1.7 V/cm; maximum 2.3 V/cm) in the vertical field direction and above 1 V/cm (average 2 V/cm; maximum 2.8 V/cm) in the horizontal field direction of the infratentorium. The calculated field intensity within the simulated tumors were in the therapeutic range and demonstrated the effective delivery of TTFields to the infratentorial brain. Conclusions: Our findings suggest that rearrangement of the TTFields standard array with placement of electrodes on the vertex, bilateral posterolateral occiput, and superior-posterior neck allows for adequate electric field distribution in the infratentorium that is within the therapeutic range.
Language	English
Publishing date	2021-12-30
Publishing country	Poland
Document type	Journal Article
ZDB-ID	2188087-6
ISSN	1507-1367
ISSN	1507-1367
DOI	10.5603/RPOR.a2021.0132
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Article ; Online: Modeling Tumor Treating Fields (TTFields) application in single cells during metaphase and telophase.

Wenger, Cornelia / Giladi, Moshe / Bomzon, Ze'ev / Salvador, Ricardo / Basser, Peter J / Miranda, Pedro C

Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual International Conference

2016 Volume 2015, Page(s) 6892–6895

Abstract: Effects of electric fields on biological cells have been extensively studied but primarily in the low and high frequency regimes. Low frequency AC fields have been investigated for applications to nerve and muscle stimulation or to examine possible ... ...

Abstract	Effects of electric fields on biological cells have been extensively studied but primarily in the low and high frequency regimes. Low frequency AC fields have been investigated for applications to nerve and muscle stimulation or to examine possible environmental effects of 60 Hz excitation. High frequency fields have been studied to understand tissue heating and tumor ablation. Biological effects at intermediate frequencies (in the 100-500 kHz regime) have only recently been discovered and are now being used clinically to disrupt cell division, primarily for the treatment of recurrent glioblastoma multiforme. In this study, we develop a computational framework to investigate the mechanisms of action of these Tumor Treating Fields (TTFields) and to understand in vitro findings observed in cell culture. Using Finite Element Method models of isolated cells we show that the intermediate frequency range is unique because it constitutes a transition region in which the intracellular electric field, shielded at low frequencies, increases significantly. We also show that the threshold at which this increase occurs depends on the dielectric properties of the cell membrane. Furthermore, our models of different stages of the cell cycle and of the morphological changes associated with cytokinesis show that peak dielectrophoretic forces develop within dividing cells exposed to TTFields. These findings are in agreement with in vitro observations, and enhance our understanding of how TTFields disrupt cellular function.
MeSH term(s)	Cell Line, Tumor ; Electric Stimulation Therapy/methods ; Electricity ; Humans ; Metaphase ; Models, Theoretical ; Neoplasms/pathology ; Neoplasms/therapy ; Spindle Apparatus/metabolism ; Telophase
Language	English
Publishing date	2016-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ISSN	2694-0604
ISSN (online)	2694-0604
DOI	10.1109/EMBC.2015.7319977
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Article ; Online: The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.

Glas, Martin / Ballo, Matthew T / Bomzon, Ze'ev / Urman, Noa / Levi, Shay / Lavy-Shahaf, Gitit / Jeyapalan, Suriya / Sio, Terence T / DeRose, Paul M / Misch, Martin / Taillibert, Sophie / Ram, Zvi / Hottinger, Andreas F / Easaw, Jacob / Kim, Chae-Yong / Mohan, Suyash / Stupp, Roger

International journal of radiation oncology, biology, physics

2021 Volume 112, Issue 5, Page(s) 1269–1278

Abstract: Purpose: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from ... ...

Abstract	Purpose: Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. Methods and materials: Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. Results: Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. Conclusions: There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.
MeSH term(s)	Antimitotic Agents/therapeutic use ; Brain/diagnostic imaging ; Brain/pathology ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/radiotherapy ; Electric Stimulation Therapy/methods ; Glioblastoma/diagnostic imaging ; Glioblastoma/radiotherapy ; Humans ; Magnetic Resonance Imaging
Chemical Substances	Antimitotic Agents
Language	English
Publishing date	2021-12-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2021.12.152
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