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Electrochemotherapy is a novel, locoregional therapy that is used to treat cutaneous and deep-seated tumors. The electric pulses used in electrochemotherapy increase the permeability of the cell membranes of the target lesion and thus enhance the delivery of low-permeant cytotoxic drugs to the cells, leading to their death. It has also been postulated that electrochemotherapy acts as an in situ vaccination by inducing immunogenic cell death. This in turn leads to an enhanced systemic antitumor response, which could be further exploited by immunotherapy. However, only a few clinical studies have investigated the role of combined treatment in patients with melanoma, breast cancer, hepatocellular carcinoma, and cutaneous squamous cell carcinoma. In this review, we therefore aim to review the published preclinical evidence on combined treatment and to review clinical studies that have investigated the combined role of electrochemotherapy and immunotherapy. [ABSTRACT FROM AUTHOR]

Bipolar cancellation is the phenomenon in which the permeability of cell membranes subjected to high intensity short pulsed electric field (ns-μs range) is reduced or eliminated when the system is subjected to bipolar instead of monopolar pulses. Although several studies have tried to explain bipolar cancellation, the underlying mechanisms remain unclear. Very few articles study bipolar cancellation by means of molecular dynamics (MD) simulation. In this paper, we investigated the molecular mechanisms underlying the difference in electroporation induced by bipolar and monopolar picosecond electric pulses (EPs) using MD simulation. The electric field gradients and electric forces on water molecules of the two pulses were analyzed in detail for the first time. For a certain pulse width, when the field intensity is relatively small, the direction of bipolar electric force on the interfacial water molecule reverses as the bipolar EPs reverse, while the electric force on interfacial water molecules of the cathode side remains in the same direction as that of applied monopolar EPs. The bipolar electric force reversal delays the water protrusion and increases the pore formation time. Therefore, this phenomenon could correspond to bipolar cancellation. When the field intensity is relatively large, although the bipolar electric force direction still reverses, half of the total time of the monopolar EPs has no electric fields. The electric forces of monopolar no-field half-cycles are much smaller than those of the bipolar EPs. Therefore, the pore formation time of bipolar EPs reduces, and this phenomenon is called bipolar enhancement. The occurrence of bipolar cancellation or bipolar enhancement depends on conditions such as the width and intensity of the pulse. [Display omitted] • Hypotheses about the molecular mechanism involved in bipolar cancellation • Hypotheses about the molecular mechanism involved in bipolar enhancement • Molecular mechanisms of electroporation induced by bipolar and monopolar pulse trains [ABSTRACT FROM AUTHOR]

[Display omitted] The formation of transient pores in their membranes is a well-known mechanism of permeabilization of cells exposed to high-intensity electric pulses. However, the formation of such pores is not able to explain all aspects of the so-called electroporation phenomenon. In particular, the reasons for sustained permeability of cell membranes, persisting long after the pulses' application, remain elusive. The complete resealing of cell membranes takes indeed orders of magnitude longer than the time for electropore closure as reported from molecular dynamics (MD) investigations. Lipid peroxidation has been suggested as a possible mechanism to explain the sustainable permeability of cell membranes. However, theoretical investigations of membrane lesions containing excess amounts of hydroperoxides have shown that the conductivities of such lesions were not high enough to account for the experimental measurements. Here, expanding on these studies, we investigate quantitatively the permeability of cell membrane lesions that underwent secondary oxidation. MD simulations and free energy calculations of lipid bilayers show that such lesions provide a better model of post-pulse permeable and conductive electropermeabilized cells. These results are further discussed in the context of sonoporation and ferroptosis, respectively a procedure and a phenomenon, among others, in which, alike electroporation, substantial lipid oxidation might be triggered. [ABSTRACT FROM AUTHOR]