This study introduces a new method for minimally invasive treatment of cancer-the ablation of undesirable tissue through the use of irreversible electroporation. Electroporation is the ...permeabilization of the cell membrane due to an applied electric field. As a function of the field amplitude and duration, the permeabilization can be reversible or irreversible. Over the last decade, reversible electroporation has been intensively pursued as a very promising technique for the treatment of cancer. It is used in combination with cytotoxic drugs, such as bleomycin, in a technique known as electrochemotherapy. However, irreversible electroporation was completely ignored in cancer therapy. We show through mathematical analysis that irreversible electroporation can ablate substantial volumes of tissue, comparable to those achieved with other ablation techniques, without causing any detrimental thermal effects and without the need of adjuvant drugs. This study suggests that irreversible electroporation may become an important and innovative tool in the armamentarium of surgeons treating cancer.
About 25 years after the publication of the first report on gene transfer in vitro in cultured cells by the means of electric pulses delivery, reversible cell electroporation for gene transfer and ...gene therapy (DNA electrotransfer) is at a cross in its development. Present knowledge on the effects of cell exposure to appropriate electric field pulses, particularly at the level of the cell membrane, is reported here. The importance of the models of electric field distribution in tissues and of the correct choice of electrodes and applied voltages is highlighted. The mechanisms involved in DNA electrotransfer, which include cell electropermeabilization and DNA electrophoresis, are also surveyed. This knowledge has allowed developing new nucleic acids electrotransfer conditions using combinations of permeabilizing pulses of high voltage and short duration, and of electrophoretic pulses of low voltage and long duration, which are very efficient and safer. Feasibility of electric pulses delivery for gene transfer in humans is discussed taking into account that electric pulses delivery is already regularly used for localized drug delivery in the treatment of cutaneous and subcutaneous solid tumors by electrochemotherapy. Because recent technological developments made DNA electrotransfer more and more efficient and safer, this non-viral gene therapy approach is now ready to reach the clinical stage. A good understanding of DNA electrotransfer principles and the respect of safe procedures will be key elements for a successful future transfer DNA electrotransfer into the clinics.
The aim of this paper is to present a new model of in vitro cell electropermeabilization, which describes separately the conducting state and the permeable state of the membrane submitted to high ...voltage pulses. We first derive the model based on the experimental observations and we present the numerical methods to solve the non-linear partial differential equations. We then present numerical simulations that corroborate qualitatively the experimental data dealing with the uptake of propidium iodide (PI) after millipulses. This tends to justify the validity of our modeling. Forthcoming work will be to calibrate the parameters of the model for quantitative description of the uptake.
•We differentiate conductive and permeable states of a cell membrane.•We follow concentrations of markers uptaken by permeabilized cells.•Numerical methods and a 3D code have been specifically written to provide results.•in vitro experimental results validate qualitatively our model.
Abstract The role and timing of percutaneous mechanical circulatory support (MCS) devices in the treatment of acute myocardial infarction complicated by cardiogenic shock (AMICS) is not well ...understood. We sought to evaluate patient characteristics and predictors of outcomes in patients presenting with AMICS supported with an axial flow percutaneous MCS device. 287 consecutive unselected patients enrolled in the cVAD Registry presenting with AMICS who underwent percutaneous coronary intervention (PCI) were included in this analysis. All patients were supported with either the Impella 2.5 or Impella CP. Mean patient age was 66±12.5 years, 76% were male, mean left ventricular ejection fraction was 25 ±12 %. Prior to receiving MCS, 80% of patients required inotropes or vasopressors and 40% were supported with intra-aortic balloon pump. 9% of patients were under active cardiopulmonary resuscitation at the time of MCS implantation. Survival to discharge was 44%. In a multivariate analysis early implantation of a MCS device prior to PCI (p=0.04) and prior to requiring inotropes and vasopressors (p=0.05) was associated with increased survival. Survival was 66% when MCS was initiated <1.25 hours from shock onset, 37% when initiated within 1.25-4.25 hours, and 26% when initiated after 4.25 hours (p=0.017). Survival was 68%, 46%, 35%, 35%, 26% for patients requiring 0, 1, 2, 3, ≥4 inotropes prior to MCS support respectively (P<0.001). In conclusion, MCS implantation early after shock onset, before initiation of inotropes or vasopressors and prior to PCI, is independently associated with improved survival in patients presenting with AMICS.
Over the last decade a new cancer treatment modality,
electrochemotherapy, has emerged. By using short, intense electric pulses that surpass the capacitance of the cell membrane, permeabilization can ...occur (electroporation). Thus, molecules that are otherwise non-permeant can gain direct access to the cytosol of cells in the treated area.
A highly toxic molecule that does not usually pass the membrane barrier is the hydrophilic drug bleomycin. Once inside the cell, bleomycin acts as an enzyme creating single- and double-strand DMA-breaks. The cytotoxicity of bleomycin can be augmented several 100-fold by electroporation. Drug delivery by electroporation has been in experimental use for cancer treatment since 1991.
This article reviews 11 studies of electrochemotherapy of malignant cutaneous or subcutaneous lesions, e.g., metastases from melanoma, breast or head- and neck cancer. These studies encompass 96 patients with altogether 411 malignant tumours. Electroporation was performed using plate or needle electrodes under local or general anaesthesia. Bleomycin was administered intratumourally or intravenously prior to delivery of electric pulses. The rates of complete response (CR) after once-only treatments were between 9 and 100% depending on the technique used. The treatment was well tolerated and could be performed on an out-patient basis.
Cell electropermeabilization (also termed cell electroporation) is nowadays a routine technique used in biochemical and pharmacological studies for the in vitro introduction of nonpermeant molecules ...into living cells. But electric pulses can be used as well in vivo for the delivery of drugs or DNA into cells of tissues. This review then gives an updated overview of the therapeutic perspectives of cell electropermeabilization in vivo, in particular of the antitumour electrochemotherapy (i.e., the combination of a cytotoxic nonpermeant drug with permeabilizing electric pulses delivered to the tumours) and of in vivo DNA electrotransfer for gene therapy. After a short summary of the present knowledge on cell electropermeabilization (particularly in vivo), the basis, the present achievements, and the challenges of electrochemotherapy are described and discussed, which includes an overview of still open questions and an update on recent clinical trials. DNA electrotransfer for gene therapy is an emerging field in which results are rapidly accumulating. Present knowledge on DNA electrotransfer mechanisms, as wel as the potentialities of DNA electrotransfer to become an efficient non-viral approach for gene therapy, are reviewed.
The use of electric pulses to transfect all types of cells is well known and regularly used in vitro for bacteria and eukaryotic cells transformation. Electric pulses can also be delivered in vivo ...either transcutaneously or with electrodes in direct contact with the tissues. After injection of naked DNA in a tissue, appropriate local electric pulses can result in a very high expression of the transferred genes. This manuscript describes the evolution in the concepts and the various optimization steps that have led to the use of combinations of pulses that fit with the known roles of the electric pulses in DNA electrotransfer, namely cell electropermeabilization and DNA electrophoresis. A summary of the main applications published until now is also reported, restricted to the in vivo preclinical trials using therapeutic genes.
To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to ...establish predictors of efficacy and adverse events.
Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators.
Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P=0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P=0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P<0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed.
Treatment with CyA showed a lower rate of SAE and a similar efficacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefit of sequential CyA-IFX for CyA non-responders is acceptable.
Applications of cell electropermeabilization are rapidly growing but basic concepts are still unclear. In particular, the impact of electric pulse repetition rate in the efficiency of ...permeabilization has not yet been understood.
The impact of electric pulse repetition rate in the efficiency of permeabilization was analyzed in experiments performed on potato tissue and partially transposed on mice liver. On potato tissue, pulses with durations of 100μs or 10ns are applied. The intensity of permeabilization was quantified by means of bioimpedance changes and electric current measurements and a new index was defined.
For the two pulse durations tested, very low repetition rates (below 0.1Hz) are much more efficient to achieve cell permeabilization in potato tissue. In mice liver, using 100μs pulses, the influence of the repetition rate is more complex. Indeed, repetition rates of 1Hz and 10Hz are more efficient than 100Hz or 1kHz, but not the repetition rate of 0.1Hz for which there is an impact of the living mice organism response.
We propose that the effects reported here might be caused by an electroporation-induced cell membrane ‘electro-desensitization’ which requires seconds to dissipate due to membrane resealing.
This study not only reinforces previous observations, but moreover it sustains a new concept of ‘electro-desensitization’ which is the first unifying mechanism enabling to explain all the results obtained until now both in vitro and in vivo, with long and short pulses.
•We expose vegetal and animal tissues to 10ns and 100μs electric pulses.•We assess permeabilization by impedance measurements.•Low repetition rate permeabilizes more efficiently potato tissue for all pulse lengths.•We show similar efficiency of low repetition rate on mice liver for 100μs pulses.•We propose a new concept of cell membrane ‘electro-desensitization’.
The role of subthreshold depression (subD) in Parkinson's Disease (PD) is not clear. The present study aimed to compare the quality of life (QoL) in PD patients with subD vs patients with no ...depressive disorder (nonD). Factors related to subD were identified.
PD patients and controls recruited from the COPPADIS cohort were included. SubD was defined as Judd criteria. The 39-item Parkinson's disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8) were used to assess QoL.
The frequency of depressive symptoms was higher in PD patients (n = 694) than in controls (n = 207) (p < 0.0001): major depression, 16.1% vs 7.8%; minor depression, 16.7% vs 7.3%; subD, 17.4% vs 5.8%. Both health-related QoL (PDQ-39; 18.1 ± 12.8 vs 11.6 ± 10; p < 0.0001) and global QoL (EUROHIS-QOL8; 3.7 ± 0.5 vs 4 ± 0.5; p < 0.0001) were significantly worse in subD (n = 120) than nonD (n = 348) PD patients. Non-motor Symptoms Scale (NMSS) total score was higher in subD patients (45.9 ± 32 vs 29.1 ± 25.8;p < 0.0001). Non-motor symptoms burden (NMSS;OR = 1.019;95%CI 1.011–1.028; p < 0.0001), neuropsychiatric symptoms (NPI; OR = 1.091; 95%CI 1.045–1.139; p < 0.0001), impulse control behaviors (QUIP-RS; OR = 1.035; 95%CI 1.007–1063; p = 0.013), quality of sleep (PDSS; OR = 0.991; 95%CI 0.983–0.999; p = 0.042), and fatigue (VAFS-physical; OR = 1.185; 95%CI 1.086–1.293; p < 0.0001; VAFS-mental; OR = 1.164; 95%CI 1.058–1.280; p = 0.0001) were related to subD after adjustment to age, disease duration, daily equivalent levodopa dose, motor status (UPDRS-III), and living alone.
SubD is a frequent problem in patients with PD and is more prevalent in these patients than in controls. QoL is worse and non-motor symptoms burden is greater in subD PD patients.
•Subthreshold depression (SubD) is a frequent problem in patients with PD and is near to triple prevalent than in controls.•Health-related and global perceived quality of life (QoL) are worse in subD than in non-depressed (nonD) PD patients.•A greater non-motor symptoms burden is associated with subthreshold depression in PD.•Specifically, fatigue, sleep problems, and neuropsychiatric symptoms seems to be related to subD in PD.•All this suggests that detection of subD in PD could be an important factor in clinical practice.
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