Background and aims: Electroporation demonstrated certain modulable actions on tumoral cell membrane permeability to increase the intracellular bioavailability of chemotherapeutic drugs. The current ...in vivo study aimed to investigate the synergic effect of concomitant electroporation application to the intratumoral administration of cisplatin on murine invasive ductal adenocarcinoma breast cancer. Methods: The fragments of the extracted tumor were implanted subcutaneously in healthy female Balb/C mice. Having reached the determined tumoral volume, the mice were randomly divided into five groups, including control, intratumoral cisplatin injection, tumoral electroporation application, electrochemotherapy (ECT), and double course ECT. The normalized tumoral volume and the inhibition ratios were calculated during a 30-day follow-up period. The data were tested by ANONA, and a statistically significant level was set at P<0.05. Results: The inhibition ratio was significantly different between the intra-tumoral cisplatin administration and tumoral electroporation application groups compared to the control group (P<0.05). ECT displayed superior results in comparison to the two later groups (P<0.05). The double-course ECT group even represented a significant difference compared to the ECT group (P<0.05). Conclusion: Concomitant ECT to the cisplatin intratumoral administration indicated contributive anti-tumoral impacts in an in vivo murine model of invasive ductal adenocarcinoma breast cancer. ECT promises further applications to overcome the occurrence of therapeutic resistance to chemotherapeutic drugs.
Standard electrochemotherapy (ECT) is effective in many tumour types but is confined to the treatment of small superficial lesions. Variable electrode-geometry ECT (VEG-ECT) may overcome these ...limitations by using long freely-placeable electrodes. Patients with bulky or deep-seated soft-tissue malignancies not amenable to resection participated in a single-arm phase-2 study (ISRCTN.11667954) and received a single course of VEG-ECT with intravenous bleomycin (15,000 IU/m
) and concomitant electric pulses applied through an adjustable electrode array. The primary outcome was radiologic complete response rate (CRR) per RECIST; secondary endpoints included feasibility, metabolic response, toxicity (CTCAE), local progression-free survival (LPFS) and patient perception (EQ-5D). During 2009-2014, we enrolled 30 patients with trunk/limb sarcomas, melanoma, Merkel-cell carcinoma, and colorectal/lung cancer. Median tumour size was 4.7 cm. Electrode probes were placed under US/TC guidance (28 and 2 patients, respectively). Median procedure duration was 80 minutes. Tumour coverage rate was 97% (29 of 30 patients). Perioperative side-effects were negligible; one patient experienced grade-3 ulceration and infection. One-month
F-FDG-SUV decreased by 86%; CRR was 63% (95% CI 44-79%). Local control was durable in 24 of 30 patients (two-year LPFS, 62%). Patients reported an improvement in "usual activities", "anxiety/depression", and "overall health" scores. VEG-ECT demonstrated encouraging antitumour activity in soft-tissue malignancies; a single course of treatment produced high and durable responses, with low complications.
Electroporation-based therapies are powerful biotechnological tools for enhancing the delivery of exogeneous agents or killing tissue with pulsed electric fields (PEFs). Electrochemotherapy (ECT) and ...gene therapy based on gene electrotransfer (EGT) both use reversible electroporation to deliver chemotherapeutics or plasmid DNA into cells, respectively. In both ECT and EGT, the goal is to permeabilize the cell membrane while maintaining high cell viability in order to facilitate drug or gene transport into the cell cytoplasm and induce a therapeutic response. Irreversible electroporation (IRE) results in cell kill due to exposure to PEFs without drugs and is under clinical evaluation for treating otherwise unresectable tumors. These PEF therapies rely mainly on the electric field distributions and do not require changes in tissue temperature for their effectiveness. However, in immediate vicinity of the electrodes the treatment may results in cell kill due to thermal damage because of the inhomogeneous electric field distribution and high current density during the electroporation-based therapies. Therefore, the main objective of this numerical study is to evaluate the influence of pulse number and electrical conductivity in the predicted cell kill zone due to irreversible electroporation and thermal damage. Specifically, we simulated a typical IRE protocol that employs ninety 100-µs PEFs. Our results confirm that it is possible to achieve predominant cell kill due to electroporation if the PEF parameters are chosen carefully. However, if either the pulse number and/or the tissue conductivity are too high, there is also potential to achieve cell kill due to thermal damage in the immediate vicinity of the electrodes. Therefore, it is critical for physicians to be mindful of placement of electrodes with respect to critical tissue structures and treatment parameters in order to maintain the non-thermal benefits of electroporation and prevent unnecessary damage to surrounding healthy tissue, critical vascular structures, and/or adjacent organs.
Abstract Chest wall breast cancer recurrence after mastectomy is a disease difficult to treat. Its incidence varies between 5% and 30% in different subset of patients. When possible, radical surgical ...therapy represents the main treatment approach, however when the disease progresses and/or treatments are not successful, ulceration, bleeding, lymphedema and psychological distress of progressive disease significantly decrease the quality of the remaining life of a patient. When surgical excision of chest wall recurrence is not possible, other local treatments such as radiotherapy, radiotherapy with hyperthermia, topical chemotherapy and electrochemotherapy might be taken into account. Electrochemotherapy provides safe, efficient and non-invasive locoregional treatment approach for chest wall breast cancer recurrence. Several clinical studies have demonstrated high efficacy and a good safety profile of electrochemotherapy applied in single or multiple consecutive sessions, till clinical response was reached. Electrochemotherapy can be performed either with cisplatin injected intratumorally or with bleomycin given intratumorally or intravenously. Furthermore, it can be effectively used in heavily pre-treated areas, after surgery, radiotherapy or systemic chemotherapy. These are the advantages that might demand its use especially in patients with pre-treated extensive disease and in frail elderly patients. With development of the technology electrochemotherapy could even be suggested as a primary local therapy in patients not suitable for surgical removal of the primary tumor.
Electrochemotherapy represents a strategy to enhance chemotherapeutic drug uptake by delivering electrical pulses which exceed the dielectric strength of the cell membrane, causing transient ...formation of structures that enhance permeabilization. Here we show that brain tumors in a rat model can be eliminated by electrochemotherapy with a novel electrode device developed for use in the brain. By using this method, the cytotoxicity of bleomycin can be augmented more than 300-fold because of increased permeabilization and more direct passage of drug to the cytosol, enabling highly efficient local tumor treatment. Bleomycin was injected intracranially into male rats inoculated with rat glia-derived tumor cells 2 weeks before the application of the electrical field (32 pulses, 100 V, 0.1 ms, and 1 Hz). In this model, where presence of tumor was confirmed by magnetic resonance imaging (MRI) before treatment, we found that 9 of 13 rats (69%) receiving electrochemotherapy displayed a complete elimination of tumor, in contrast to control rats treated with bleomycin only, pulses only, or untreated where tumor progression occurred in each case. Necrosis induced by electrochemotherapy was restricted to the treated area, which MRI and histology showed to contain a fluid-filled cavity. In a long-range survival study, treatment side effects seemed to be minimal, with normal rat behavior observed after electrochemotherapy. Our findings suggest that electrochemotherapy may offer a safe and effective new tool to treat primary brain tumors and brain metastases.
•Schiff base and its Co(II) and Ru(II) complexes were synthesized and characterized.•In vitro anticancer activities were evaluated on the human Caco-2 cancer cell line.•The effectiveness of ECT on ...cytotoxic activities in the Caco-2 cancer cell line were examined.•The complexes showed considerable anticancer properties in Caco-2 colon cancer cells.•The complexes can be developed as chemotherapeutic agents for colon cancer treatment.
In this study, a new Schiff base ligand and its two M(II) complexes CoCl·L(H2O)2·2H2O, RuCl(p-cymene)L were synthesized. The structural features were confirmed from their micro analytical, IR, UV–Vis., 1H–13C NMR, TGA, X-ray diffraction analysis, mass spectral data and magnetic susceptibility measurements. The Co(II) and Ru(II) complexes displayed an octahedral geometry. In vitro anticancer activities of the Schiff base, Co(II) and Ru(II) complexes were evaluated on the human colon cancer cell line (Caco-2) and biocompatibility characteristics were determined in the l-929 (normal fibroblast cells) cell line by using the MTT assay. Furthermore, we examined the effectiveness of electrochemotherapy (ECT) on cytotoxic activities of these compounds in Caco-2 cancer cell line. According to the findings of the study, Co(II) and Ru(II) complexes showed considerable anticancer properties in the Caco-2 colon cancer cells; however, the ligand did not show significant anticancer activity. It was determined that the combined application of electroporation (EP)+complexes were much more effective than the application of complexes alone in the treatment of Caco-2 colon cancer cells. In a conclusion, the Co(II) and Ru(II) complexes, which showed significant anticancer activity in Caco-2 colon cancer cells, increased cytotoxicity levels by 2.07 and 2.12, respectively in their combined applications with EP. These complexes can be developed as chemotherapeutic agents for colon cancer treatment and can yield promising results when used in ECT.
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Cutaneous angiosarcoma (cAS) is a highly aggressive malignancy that challenges the radicality of surgical treatment. Electrochemotherapy (ECT), a skin-directed treatment based on cytotoxic ...chemotherapy combined with local electric pulses, may be an intraoperative adjunct and a new opportunity in the therapeutic strategy. This cohort study reports the experience with ECT as an option.
Data on patients with locally-advanced/metastatic cAS who underwent ECT between October 2013 and October 2018 at eight European centres were prospectively submitted to the InspECT (International network for sharing practices of ECT) register. Patients received therapy according to the European Standard Operating Procedures of ECT (ESOPE). Treatment feasibility was assessed based on tumour coverage with electrodes and recorded tissue current; treatment toxicity and tumour response were graded according to CTCAE v5.0 and RECIST v1.1 criteria, respectively; patient-reported outcomes (PRO) were evaluated using a visual analogue score (VAS) for pain, acceptance of retreatment and the EQ-5D questionnaire.
We enrolled 20 patients with advanced cAS in the scalp/face (n = 7), breast/trunk (n = 10) or limbs (n = 3). Target tumours (n = 51) had a median size of 2.3 cm (range, 1–20). We administered 24 ECT courses using 1–4 cm treatment safety margin around tumours. In five patients, ECT was combined/sequenced with surgery. Median tissue current was 3 A (range, 1.5–10), tumour margins coverage rate was 75% (15/20 patients). The objective response rate (ORR) was 80% (complete, 40%). Grade-3 toxicity included skin ulceration (15%) and pain (10%), with no significant change of PRO scores. Bleeding control was achieved in 13/14 patients with ulcerated tumours. With a median overall survival of 12.5 months, the local progression-free survival (LPFS) was 10.9 months.
ECT produces sustained response rate with minimal side effects and should be considered an option for advanced cAS. Palliative benefits include patient tolerability, local haemostasis and durable local control. Definition of optimal timing, treatment safety margins and combination with surgery need further investigation.
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•Radical resection is a challenge in advanced cutaneous angiosarcoma.•Electrochemotherapy may be avaluable alternative or an adjunct to surgical strategy•Complete response was reported in 8/20 patients in the InspECT register.•The procedure was tolerable, with mild and reversible skin toxicity.•Benefits included durable control on local tumour growth and bleeding.
Electrochemotherapy provides non-thermal ablation of cutaneous as well as deep seated tumors. Based on positive results of the treatment of colorectal liver metastases, we conducted a prospective ...pilot study on hepatocellular carcinomas with the aim of testing the feasibility, safety and effectiveness of electrochemotherapy.
Electrochemotherapy with bleomycin was performed on 17 hepatocellular carcinomas in 10 patients using a previously established protocol. The procedure was performed during open surgery and the patients were followed for median 20.5 months.
Electrochemotherapy was feasible for all 17 lesions, and no treatment-related adverse events or major post-operative complications were observed. The median size of the treated lesions was 24 mm (range 8–41 mm), located either centrally, i.e., near the major hepatic vessels, or peripherally. The complete response rate at 3–6 months was 80% per patient and 88% per treated lesion.
Electrochemotherapy of hepatocellular carcinoma proved to be a feasible and safe treatment in all 10 patients included in this study. To evaluate the effectiveness of this method, longer observation period is needed; however the results at medium observation time of 20.5 months after treatment are encouraging, in 15 out of 17 lesions complete response was obtained. Electrochemotherapy is predominantly applicable in patients with impaired liver function due to liver cirrhosis and/or with lesions where a high-risk operation is needed to achieve curative intent, given the intra/perioperative risk for high morbidity and mortality.
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