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Histological evidence of extravasated red blood cells in DC-ET-treated tumours: (a) control Sa-1 tumour; (b) control LPB tumour; (c) DC-ET-treated Sa-1 tumour; (d) DC-ETtreated LPB tumour.
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Anti-tumour effects of direct current electrotherapy are attributed to different mechanisms depending on the electrode configuration and on the parameters of electric current. The effects mostly arise from the electrochemical products of electrolysis. Direct toxicity of these products to tumour tissue is, however, not a plausible explanation for th...
Citations
... Despite being a preliminary investigation, carried out with a single stimulation session instead of repeated daily applications, this study supports the possible role of tDCS as a novel therapeutic approach for brain cancers, especially if combined with standard CHT regimens and applied for repeated sessions, as currently performed with electrochemotherapy in extracranial tumours where intratumoural perfusion reduction seems to prolong drug persistence in the tumour vessels, possibly boosting their actions [42] . Given the perfusion reduction observed following a single session of tDCS (20 minutes), it is reasonable to assume a greater -and clinically meaningful -decrease following repeated sessions of tDCS, as observed in extracranial tumours with electrochemotherapy that can even lead to necrosis [45] . However, potential negative effects need to be carefully taken into consideration before scaling up this type of investigation in brain tumours patients, such as the theoretical reduction of cancer sensitivity to radiotherapy treatment (due to the lower oxygen concentration consequent to the perfusion reduction [46] ), potential perfusion decrease in the healthy brain tissue surrounding the lesion, or the promotion of the recently discovered neuronto-glioma communications. ...
... GBM is characterised by vascular proliferation and necrosis, with the latter representing a consequence of the extreme hypoxia in the tumour core due to high proliferation and lack of adequate metabolic supply [39] . A possible solution to avoid the hypoxia induced mechanisms with NiBS intervention, could be represented by the application of repetitive and prolonged sessions of stimulations that do not allow the tumour to sufficiently activate the neoangiogenesis response and rapidly prompt its necrosis, as observed in extracranial tumours [45] . ...
Malignant brain tumours are among the most aggressive human cancers, and despite intensive efforts made over the last decades, patients' survival has scarcely improved. Recently, high-grade gliomas (HGG) have been found to be electrically integrated with healthy brain tissue, a communication that facilitates tumour mitosis and invasion. This link to neuronal activity has provided new insights into HGG pathophysiology and opened prospects for therapeutic interventions based on electrical modulation of neural and synaptic activity in the proximity of tumour cells, which could potentially slow tumour growth. Noninvasive brain stimulation (NiBS), a group of techniques used in research and clinical settings to safely modulate brain activity and plasticity via electromagnetic or electrical stimulation, represents an appealing class of interventions to characterise and target the electrical properties of tumour-neuron interactions. Beyond neuronal activity, NiBS may also modulate function of a range of substrates and dynamics that locally interacts with HGG (e.g., vascular architecture, perfusion and blood-brain barrier permeability). Here we discuss emerging applications of NiBS in patients with brain tumours, covering potential mechanisms of action at both cellular, regional, network and whole-brain levels, also offering a conceptual roadmap for future research to prolong survival or promote wellbeing via personalised NiBS interventions.
... Moreover, reduction of perfusion was followed by a decrease in tumor size 1 day after the intervention. The decrease in blood flow caused a decrease in tumoral partial oxygen pressure (pO 2 ), supposedly promoting tumor necrosis (6). Several, not mutually exclusive, mechanisms for ET effects on tumors have been proposed: (i) pH alterations near the electrodes due to electrolysis reaction, (ii) apoptosis, (iii) microembolism, (iv) immunomodulation, (v) toxic derivate of electrochemical reactions, and (vi) vasoconstriction (3,6). ...
... The decrease in blood flow caused a decrease in tumoral partial oxygen pressure (pO 2 ), supposedly promoting tumor necrosis (6). Several, not mutually exclusive, mechanisms for ET effects on tumors have been proposed: (i) pH alterations near the electrodes due to electrolysis reaction, (ii) apoptosis, (iii) microembolism, (iv) immunomodulation, (v) toxic derivate of electrochemical reactions, and (vi) vasoconstriction (3,6). ...
... Notably, these results are in line with the reported effects of ET on bodily tumors, where a strong reduction in tumor perfusion-followed by a decrease in volume and necrosis-has been shown (3,5,6). Given the safety profile of tDCS, the feasibility of its application in both hospital and home settings, its relatively low cost, and the possibility of its combination with other drug-based therapies, the present findings might lead to additional noninvasive therapeutic options for patients with brain tumors. ...
Malignant brain neoplasms have a poor prognosis despite aggressive treatments. Animal models and evidence from human bodily tumors reveal that sustained reduction in tumor perfusion via electrical stimulation promotes tumor necrosis, therefore possibly representing a therapeutic option for patients with brain tumors. Here, we demonstrate that transcranial electrical stimulation (tES) allows to safely and noninvasively reduce intratu-moral perfusion in humans. Selected patients with glioblastoma or metastasis underwent tES, while perfusion was assessed using magnetic resonance imaging. Multichannel tES was applied according to personalized bio-physical modeling, to maximize the induced electrical field over the solid tumor mass. All patients completed the study and tolerated the procedure without adverse effects, with tES selectively reducing the perfusion of the solid tumor. Results potentially open the door to noninvasive therapeutic interventions in brain tumors based on stand-alone tES or its combination with other available therapies.
... At time of maximal pO 2 , the tumor perfusion was unchanged indicating that the oxygen effect was not caused by an increase in tumor perfusion. In most tumor models, it has been demonstrated that high voltage pulse application causes a rapid but transient blockage of the tumor blood flow reduction that recovers in 24 h and a transient reduced tumor oxygenation [37]. The absence of change in TLT perfusion 24–72 h after pRDD electrotransfer was consistent with these data. ...
Background and purpose:
We hypothesized that electrotransfer of a plasmid encoding an antiangiogenic factor, the recombinant disintegrin domain of ADAM-15, (pRDD) could modify the tumor microenvironment and radiosensitize tumor.
Materials and methods:
pRDD was injected in the TLT tumor or FSaII fibrosarcomas before electroporation. pO2 in tumors and oxygen consumption in vitro were measured by electronic paramagnetic resonance (EPR) oximetry. Tumor perfusion was assessed by laser doppler imaging and patent blue assay.
Results:
pRDD electrotransfer caused a significant delay in TLT growth and an anti-angiogenic effect. It significantly increased tumor pO2 in TLT and FSaII for at least 4 days. pRDD electrotransfer and radiotherapy were more effective than either treatment alone. Modifications of tumor microenvironment were evaluated: tumor perfusion and interstitial fluid pressure were not modified. Oxygen consumption by the cells was decreased resulting both from a decrease in oxygen consumption rate and from a decrease in cell viability.
Conclusion:
The combination of localized antiangiogenic gene therapy and radiotherapy applied in the time of maximal oxygenation could be a promising alternative for cancer treatment.
... Several destruction mechanisms of electrochemical treatment have been proposed, the best supported of which are toxic species produced in the electrochemical reactions during electrolysis, 32 extreme local pH changes, 33 and perturbation of local blood flow. 34 It is likely that a combination of these complex processes plays a role in tumor death. An attempt to resolve the discrepancy between electrical stimulation enhancing healing of chronic wounds and retarding tumor growth suggests that currents may normalize cell proliferation. ...
Dysphagia is a potential consequence of treatment for head and neck cancer. Neuromuscular electrical stimulation (NMES) has evolved as a treatment option, with the goal of improved swallow function in patients with chronic dysphagia. However, the effects of NMES on tumorigenicity are unknown and often confound the initiation of this therapy, potentially limiting its efficacy in treating patients with head and neck cancer.
Squamous cell carcinoma was grown in the flank of athymic, nude mice. Mice were randomized into treatment and control groups; the experimental group received daily NMES directly to the flank for 8 days.
Tumor volumes, recorded on days 0, 3, 7, and 10, demonstrated no significant differences between groups on each day of measurement. Immunohistochemical analysis of apoptosis, proliferation, and vascularization also failed to demonstrate statistically significant differences between treated and untreated groups.
NMES does not promote the growth of underlying tumor in our model. These data may provide preliminary evidence that applying electrical stimulation over the muscles of the anterior neck does not increase the risk of tumorigenicity. Early initiation of NMES in this challenging population may be feasible from an oncologic standpoint. © 2011 Wiley Periodicals, Inc. Head Neck, 2011.
... Although increases of the local tissue temperature have been reported during electrolytic ablation, all authors report that the thermal effect is negligible (Gravante et al., 2011) and, therefore, may have potential advantages over more frequently used ablative procedures that employ extremes of temperatures to cause tumor death. Other characteristics of this method generally perceived as an advantage in treating malignant tumors are the occlusion of local arteries and veins (Jarm et al., 2003). EChT can be carried out on an out-patient basis. ...
Electrochemical therapy (EChT), also named low-level direct electric current therapy, has been suggested in the past as a therapeutic potential in local cancer treatment. It involves using destructive electrolysis induced by direct electric current passing through two or more electrodes inserted in or near the tumor. This creates a large pH change which leads to cell death. Additional contributory factors in tissue destruction have been reported, although their respective roles are not fully understood. Several studies on animal tumor models have been conducted to evaluate the effectiveness of EChT. Very few clinical trials have been published and EChT treatment is generally not established in the clinics. Nevertheless, EChT is currently available in some countries, mainly in China and Germany, but is almost exclusively being used for palliative treatment of advanced stages of tumors incurable by any other intervention. This review is meant as a general overview and first introduction to EChT.
... However, the complexity of changes occurring in the microenvironment suggests that other factors may well be involved. Apoptosis, modifications of ion channels [17] and changes in tumour perfusion and oxygenation [32,33] have all been suggested. Immune system modifications involve the activation of macrophages and the accumulation of leukocytes in the cathodic field by extravasation [17]. ...
Electrolytic ablation (EA) is a treatment that destroys tissues through electrochemical changes in the local microenvironment. This review examined studies using EA for the treatment of liver and pancreatic tumours, in order to define the characteristics that could endow the technique with specific advantages compared with other ablative modalities.
Literature search of all studies focusing on liver and pancreas EA.
A specific advantage of EA is its safety even when conducted close to major vessels, while a disadvantage is the longer ablation times compared to more frequently employed techniques. Bimodal electric tissue ablation modality combines radiofrequency with EA and produced significant larger ablation zones compared to EA or radiofrequency alone, reducing the time required for ablation. Pancreatic EA has been investigated in experimental studies that confirmed similar advantages to those found with liver ablation, but has never been evaluated on patients. Furthermore, few clinical studies examined the results of liver EA in the short-term but there is no appropriate follow-up to confirm any survival advantage.
EA is a safe technique with the potential to treat lesions close to major vessels. Specific clinical studies are required to confirm the technique's safety and eventually demonstrate a survival advantage.
The inclusion of a diffusion term in the modified Gompertz equation (Cabrales et al., 2018) allows to describe the spatiotemporal growth of direct current treated tumors. The aim of this study is to extend the previous model to the case of anisotropic tumors, simulating the spatiotemporal behaviour of direct current treated anisotropic tumors, also carrying out a theoretical analysis of the proposed model. Growths in the mass, volume and density of the solid tumors are shown for each response type after direct current application (disease progression, partial response, stationary partial response and complete remission). For this purpose, the Method of Lines and different diffusion tensors are used. The results show that the growth of the tumor treated with direct current is faster for the shorter duration of the net antitumor effect and the higher diffusion coefficient and anisotropy degree of the solid tumor. It is concluded that the greatest direct current antitumor effectiveness occurs for the highly heterogeneous, anisotropic, aggressive and hypodense malignant solid tumors.
Transcranial direct current stimulation (tDCS) is a re-emerging non-invasive brain stimulation technique that has been used in animal models and human trials aimed to elucidate neurophysiology and behavior interactions. It delivers subthreshold electrical currents to neuronal populations that shift resting membrane potential either toward depolarization or hyperpolarization, depending on stimulation parameters and neuronal orientation in relation to the induced electric field (EF). Although the resulting cerebral EFs are not strong enough to induce action potentials, spontaneous neuronal firing in response to inputs from other brain areas is influenced by tDCS. Additionally, tDCS induces plastic synaptic changes resembling long-term potentiation (LTP) or long-term depression (LTD) that outlast the period of stimulation. Such properties place tDCS as an appealing intervention for the treatment of diverse neuropsychiatric disorders. Although findings of clinical trials are preliminary for most studied conditions, there is already convincing evidence regarding its efficacy for unipolar depression. The main advantages of tDCS are the absence of serious or intolerable side effects and the portability of the devices, which might lead in the future to home-use applications and improved patient care. This chapter provides an up-to-date overview of a number tDCS relevant topics such as mechanisms of action, contemporary applications and safety. Furthermore, we propose ways to further develop tDCS research.
Possibilities and trends of adjuvant bioelectrochemical and bioelectromagnetic treatments of cancer on the cellular, animal, and patient levels are presented. Currently, DC electrotherapy, pulse electrochemotherapy, and pulse electrogenetherapy are used widely and successfully to treat tumors. However, needle electrodes have to be inserted into the tumor region for pulse applications (about E < 2 kV/cm). Only for skin carcinoma are caliper electrodes placed directly outside on the skin. Pulsating electromagnetic fields (PEMF) and sinusoidal electromagnetic fields (SEMF) (B > 5 mT) generated by Helmholtz coils or solenoids offer a novel noninvasive cancerostatic possibility. However, despite effective treatment of various cancer cells and cancerous animals the therapy of cancer patients, unfortunately, is still in the very beginning, partially because of impeding regulations. Nevertheless this adjuvant noninvasive therapy in synergistic combination with cancerostatic agents, hyperthermia, and photodynamics has great promise for the near future.
In recent years electrotherapy has become an accepted treatment option in several medical subfields such as defibrillation during cardiopulmonary resuscitation, electroconvulsive shock treatment (ECT) in conjunction with antidepressant therapy, pain management and physical therapy [transcutaneous electrical nerve stimulation (TENS), diathermia, Stanger bath therapy, etc.]. In recent years several groups, especially from Asia, have investigated the therapeutic effect of electricity in the treatment of malignant tumours. They determined basic principles of electrotherapy and developed different theories of tumour destruction. They postulated a multifactorial tissue effect of continuous current based on tumour cell necrosis due to pH shifting and alteration of membrane potential.
In clinical trials similar oncological results of electrotherapy in several malignant tumours compared to established therapeutic methods were observed, whereas clinical trial designs to some extent were not consistent with internationally accepted scientific standards. Regarding electrotherapy of localised prostate cancer only limited data with a few cases and controversial study designs were published. According to EAU guidelines electrotherapy of localised prostate cancer as an alternative treatment option is not recommended and is still an experimental method. For this procedure well-designed clinical trials and a longer follow-up are mandatory to assess the true role of electrotherapy in the management of prostate cancer.
