Figure - available from: Frontiers in Veterinary Science
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Photographic images of a perineal region melanoma before H-FIRE treatment (A), immediately following a series of 2 treatments with H-FIRE (B), immediately following a series of 4 treatments (C), and 2 weeks following 4 treatments (D). In (D), notice the loss of melanin pigmentation in the treated area.
Source publication
Irreversible electroporation is a proven ablation modality for local ablation of soft tissue tumors in animals and humans. However, the strong muscle contractions associated with the electrical impulses (duration, 50–100 μs) requires the use of general anesthesia and, in most situations, application of neuromuscular blockade. As such, this technolo...
Citations
... In pigs, the acceleration transducer can be placed between the third and fourth digits, the cathode placed 10-12 cm from the elbow joint and the anode 4-6 cm proxomedially [21]. In ponies, the peroneus superficialis is reported in association with the ventral buccal branch of the facial nerve, and also the radial nerve was identified on the non-dependent thoracic limb by palpation of the groove between the lateral extensor digitorum and the lateral ulnaris muscles 4 cm distal to the lateral tuberosity of the radius [22]. For cats, the monitoring site reported in a recent study is the peroneal nerve with electrodes placed 1 cm apart in the lateral tibial area [23]. ...
There is a global trend of new guidelines highly recommending quantitative neuromuscular monitoring in the operating room. In fact, it is almost certain that quantitatively monitoring the depth of intraoperative muscle paralysis may permit the rational use of muscle relaxants and avoid some of the major related complications, namely postoperative pulmonary complications. A specific culture related to this issue is necessary to integrate quantitative monitoring of muscle relaxants as part of a major monitoring entity in anesthetized patients. For this purpose, it is necessary to fully understand the physiology, pharmacology and concept of monitoring as well as the choice of pharmacological reversal, including the introduction of sugammadex a decade ago.
... Local tissue heating is low (<5 • C) which allows treatment close to sensible structures such as nerves and vessels. Byron et al. [70] revealed tumor reduction of 52% and 99% after this treatment in two horses with dermal melanomas. ...
Adult grey horses have a high incidence of melanocytic tumors. This article narratively reviews the role of some genetic features related to melanoma formation in horses, such as STX17 mutation, ASIP or MITF alterations, and the link between the graying process and the development of these tumors. A clear system of clinical and pathological classification of melanocytic tumors in naevus, dermal melanoma, dermal melanomatosis and anaplastic malignant melanoma is provided. Clinical and laboratorial methods of diagnosing are listed, with fine needle aspiration and histopathology being the most relevant. Relevance is given to immunohistochemistry, describing potentially important diagnostic biomarkers such as RACK1 and PNL2. Different therapeutical options available for equine practitioners are mentioned, with surgery, chemotherapy and electroporation being the most common. This article also elucidatesnew fields of research, perspectives, and new therapeutic targets, such as CD47, PD-1 and COX-2 biomarkers.
... Treatment using high-frequency irreversible electroporation is less restricted by the environment and monitoring equipment without the need for general anesthesia (Byron et al. 2019). Muscle contractions and transient discomfort may occur during electrotherapy (Scacco et al. 2013). ...
... High-frequency irreversible electroporation uses electrical pulses to generate an electric field that can destroy tumor cells. Both horses with multifocal melanoma treated with 3-4 sessions of irreversible electroporation (at 2-week intervals) achieved partial responses (Byron et al. 2019). Electrochemotherapy is a combination of electrical pulse direct delivery and local chemotherapeutic delivery to achieve increased cytotoxicity while using lower doses of chemotherapeutic drugs. ...
Several therapies have been developed to treat equine cutaneous melanoma, but formal comparisons among different treatment options are currently unavailable. It was our intent to assess the efficacy of different treatment protocols and the quality of the studies based on the original published data, and summarize the knowledge concerning the outcome after equine cutaneous melanoma management. This structured review followed PRISMA procedure to search for treatment protocols on equine cutaneous melanoma published from 1960 until June 2021. Studies were assessed for the risk of bias. A descriptive analysis was performed, considering the disease control rate, the recurrence rate of the tumor, comorbidities, need for anesthesia, and horses’ welfare. Twenty-three studies were included, from which the treatment outcomes of 173 horses were assessed. The homogeneity of the included trials was low. The percentages of each treatment arm achieving a partial response and curative effects accounted for 93.1% (surgical intervention), 90% (medication), and 39.4% (immunotherapies), respectively. A variable efficacy of different therapies of equine cutaneous melanoma was observed. Surgical intervention performed the best from the perspective of local antitumor effects alone. This literature review and descriptive analysis can serve as a source to assist in designing quality therapy research and can potentially aid in providing a clinical treatment reference for equine cutaneous melanoma.
... Recently, an online platform was developed to further streamline treatment planning for use with IRE treatments (Perera-Bel et al. 2020). Treatment plans provide users with information regarding probe location and spacing, electrode exposure, and delivered voltage required to achieve optimal tumor ablation while sparing adjacent normal tissue (Byron et al. 2019). ...
... Thus, additional research into safety and efficacy for treatment of non-resectable soft tissue tumors is warranted. IRE and H-FIRE have been used to safely and effectively treat infiltrative superficial tumors in awake, standing horses (Byron et al. 2019). Cutaneous tumors are extremely common in horses, with sarcoids, squamous cell carcinoma (Fig. 3), and melanoma representing the predominant histologic subtypes. ...
... Cutaneous tumors are extremely common in horses, with sarcoids, squamous cell carcinoma (Fig. 3), and melanoma representing the predominant histologic subtypes. As with soft tissue sarcomas, tumors may become locally aggressive and infiltrate around critical structures, making complete surgical removal difficult (Byron et al. 2019). The current standard of care involves a combination of surgery, cryoablation, and/or intralesional chemotherapy with 5-fluoruracil or cisplatin. ...
In veterinary medicine, irreversible electroporation (IRE) applications have been evaluated in several early phase clinical trials evaluating the safety and feasibility of treatment of solid tumors located within different organ systems. These clinical trials support the use of IRE as a safe and effective alternative treatment option for tumors that are otherwise not amenable to current standard of care therapy. The recent development of high-frequency irreversible electroporation (H-FIRE) has made treatment delivery even more feasible for veterinary clinical patients. Here, we provide an overview of treatment planning and techniques while acknowledging current limitations associated with treatment delivery, followed by a review of IRE applications in veterinary clinical trials of spontaneous cancers. Lastly, we review the application of IRE in preclinical normal animal models or experimentally induced tumors as results of these studies may help facilitate translation of IRE into standard clinical practice.
... Moreover, H-FIRE does not cause muscle contraction. Prospectively, it might exclude intraoperative paralytics or cardiac synchronization, reducing the procedure time [90,91]. However, it was proved that H-FIRE pulses require a higher electric field to achieve the same level of cell permeabilization compared to standard monopolar pulses [91]. ...
The observation that an application of a pulsed electric field (PEF) resulted in an increased permeability of the cell membrane has led to the discovery of the phenomenon called electroporation (EP). Depending on the parameters of the electric current and cell features, electroporation can be either reversible or irreversible. The irreversible electroporation (IRE) found its use in urology as a non-thermal ablative method of prostate and renal cancer. As its mechanism is based on the permeabilization of cell membrane phospholipids, IRE (as well as other treatments based on EP) provides selectivity sparing extracellular proteins and matrix. Reversible EP enables the transfer of genes, drugs, and small exogenous proteins. In clinical practice, reversible EP can locally increase the uptake of cytotoxic drugs such as cisplatin and bleomycin. This approach is known as electrochemotherapy (ECT). Few in vivo and in vitro trials of ECT have been performed on urological cancers. EP provides the possibility of transmission of genes across the cell membrane. As the protocols of gene electrotransfer (GET) over the last few years have improved, EP has become a well-known technique for non-viral cell transfection. GET involves DNA transfection directly to the cancer or the host skin and muscle tissue. Among urological cancers, the GET of several plasmids encoding prostate cancer antigens has been investigated in clinical trials. This review brings into discussion the underlying mechanism of EP and an overview of the latest progress and development perspectives of EP-based treatments in urology.
... Note that general anesthesia is required with paralytic agents to prevent undesired muscular contractions, as well as careful synchronization with the electrical activity of the heart to avoid arrhythmias that could arise if the administered pulses stray outside of the refractory period of the cardiac cycle. Recently, high-frequency irreversible electroporation (H-FIRE) technology has been developed to enable electroporation of tumors without stimulation of the nearby skeletal muscle; this would avoid the need for general anesthesia [292]. Treatment efficacy decreases with increasing tumor size, and the procedure becomes more challenging with a large number of electrodes. ...
The therapeutic application of heat is very effective in cancer treatment. Both hyperthermia, i.e., heating to 39–45 °C to induce sensitization to radiotherapy and chemotherapy, and thermal ablation, where temperatures beyond 50 °C destroy tumor cells directly are frequently applied in the clinic. Achievement of an effective treatment requires high quality heating equipment, precise thermal dosimetry, and adequate quality assurance. Several types of devices, antennas and heating or power delivery systems have been proposed and developed in recent decades. These vary considerably in technique, heating depth, ability to focus, and in the size of the heating focus. Clinically used heating techniques involve electromagnetic and ultrasonic heating, hyperthermic perfusion and conductive heating. Depending on clinical objectives and available technology, thermal therapies can be subdivided into three broad categories: local, locoregional, or whole body heating. Clinically used local heating techniques include interstitial hyperthermia and ablation, high intensity focused ultrasound (HIFU), scanned focused ultrasound (SFUS), electroporation, nanoparticle heating, intraluminal heating and superficial heating. Locoregional heating techniques include phased array systems, capacitive systems and isolated perfusion. Whole body techniques focus on prevention of heat loss supplemented with energy deposition in the body, e.g., by infrared radiation. This review presents an overview of clinical hyperthermia and ablation devices used for local, locoregional, and whole body therapy. Proven and experimental clinical applications of thermal ablation and hyperthermia are listed. Methods for temperature measurement and the role of treatment planning to control treatments are discussed briefly, as well as future perspectives for heating technology for the treatment of tumors.
Introduction
Integrated time nanosecond pulse irreversible electroporation (INSPIRE) is a novel tumor ablation modality that employs high voltage, alternating polarity waveforms to induce cell death in a well-defined volume while sparing the underlying tissue. This study aimed to demonstrate the in vivo efficacy of INSPIRE against spontaneous melanoma in standing, awake horses.
Methods
A custom applicator and a pulse generation system were utilized in a pilot study to treat horses presenting with spontaneous melanoma. INSPIRE treatments were administered to 32 tumors across 6 horses and an additional 13 tumors were followed to act as untreated controls. Tumors were tracked over a 43–85 day period following a single INSPIRE treatment. Pulse widths of 500ns and 2000ns with voltages between 1000 V and 2000 V were investigated to determine the effect of these variables on treatment outcomes.
Results
Treatments administered at the lowest voltage (1000 V) reduced tumor volumes by 11 to 15%. Higher voltage (2000 V) treatments reduced tumor volumes by 84 to 88% and eliminated 33% and 80% of tumors when 500 ns and 2000 ns pulses were administered, respectively.
Discussion
Promising results were achieved without the use of chemotherapeutics, the use of general anesthesia, or the need for surgical resection in regions which are challenging to keep sterile. This novel therapeutic approach has the potential to expand the role of pulsed electric fields in veterinary patients, especially when general anesthesia is contraindicated, and warrants future studies to demonstrate the efficacy of INSPIRE as a solid tumor treatment.
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.
