Large Liver Blood Vessels and Bile Ducts Are Not Damaged by Electrochemotherapy with Bleomycin in Pigs

Žmuc, Jan; Gašljević, Gorana; Serša, Gregor; Edhemović, Ibrahim; Boc, Nina; Seliškar, Alenka; Plavec, Tanja; Brložnik, Maja; Milevoj, Nina; Brecelj, Erik; Kos, Bor; Izlakar, Jani; Jarm, Tomaž; Snoj, Marko; Štukelj, Marina; Miklavčič, Damijan; Čemažar, Maja

doi:10.1038/s41598-019-40395-y

Cited by 44 publications

(46 citation statements)

References 45 publications

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“…How can that be, if correlation between membrane permeabilization and released DAMPs is weak or does not even exist? Modeling 87 and in vivo experiments 88 show that application of nominally reversible electroporation pulses such as those used for ECT of tumors still causes some cell death by means of irreversible electroporation in tissue close to the electrodes, due to inhomogeneous electric field distribution, which can thus lead to the release of DAMPs and activation of the immune system.…”

Section: Discussionmentioning

confidence: 99%

Analysis of damage-associated molecular pattern molecules due to electroporation of cells in vitro

Polajžer

Jarm

Miklavčič

2020

Radiology and Oncology

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BackgroundTumor cells can die via immunogenic cell death pathway, in which damage-associated molecular pattern molecules (DAMPs) are released from the cells. These molecules activate cells involved in the immune response. Both innate and adaptive immune response can be activated, causing a destruction of the remaining infected cells. Activation of immune response is also an important component of tumor treatment with electrochemotherapy (ECT) and irreversible electroporation (IRE). We thus explored, if and when specific DAMPs are released as a consequence of electroporation in vitro.Materials and methodsIn this in vitro study, 100 μs long electric pulses were applied to a suspension of Chinese hamster ovary cells. The release of DAMPs – specifically: adenosine triphosphate (ATP), calreticulin, nucleic acids and uric acid was investigated at different time points after exposing the cells to electric pulses of different amplitudes. The release of DAMPs was statistically correlated with cell permeabilization and cell survival, e.g. reversible and irreversible electroporation.ResultsIn general, the release of DAMPs increases with increasing pulse amplitude. Concentration of DAMPs depend on the time interval between exposure of the cells to pulses and the analysis. Concentrations of most DAMPs correlate strongly with cell death. However, we detected no uric acid in the investigated samples.ConclusionsRelease of DAMPs can serve as a marker for prediction of cell death. Since the stability of certain DAMPs is time dependent, this should be considered when designing protocols for detecting DAMPs after electric pulse treatment.

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Section: Discussionmentioning

confidence: 99%

Analysis of damage-associated molecular pattern molecules due to electroporation of cells in vitro

Polajžer

Jarm

Miklavčič

2020

Radiology and Oncology

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“…In this prospective animal model study with regulatory approval issued by the National Ethics Committee at The Administration of the Republic of Slovenia for Food Safety, Veterinary, and Plant Protection (Approval number: U34401-1/2017/4, Approval date: 17.03.2017), nine female grower pigs, purchased from an authorized swine breeder (Globocnik, Sencur, Slovenia) 3–17 days before experiment, were included 28. Experimental animals were reared according to the European Council directive for minimum standards for the protection of pigs (2008/120/EC).…”

Section: Methodsmentioning

confidence: 99%

“…The animals were euthanized at two or seven days after ECT/EP using 3 ml/10 kg i.v. T61 euthanasia solution (Intervet, Boxmeer, Netherlands); the liver was explanted for histologic analyses, which were reported in a separate paper 28…”

Section: Methodsmentioning

confidence: 99%

Radiological findings of porcine liver after electrochemotherapy with bleomycin

Brložnik

Boc

Serša

et al. 2019

Radiology and Oncology

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BackgroundRadiologic findings after electrochemotherapy of large hepatic blood vessels and healthy hepatic parenchyma have not yet been described.Materials and methodsWe performed a prospective animal model study with regulatory approval, including nine grower pigs. In each animal, four ultrasound-guided electroporated regions were created; in three regions, electrodes were inserted into the lumen of large hepatic vessels. Two types of electrodes were tested; variable linear- and fixed hexagonal-geometry electrodes. Ultrasonographic examinations were performed immediately and up to 20 minutes after the procedure. Dynamic computed tomography was performed before and at 60 to 90 minutes and one week after the procedure.ResultsRadiologic examinations of the treated areas showed intact vessel walls and patency; no hemorrhage or thrombi were noted. Ultrasonographic findings were dynamic and evolved from hyperechogenic microbubbles along electrode tracks to hypoechogenicity of treated parenchyma, diffusion of hyperechogenic microbubbles, and hypoechogenicity fading. Contrast-enhanced ultrasound showed decreased perfusion of the treated area. Dynamic computed tomography at 60 to 90 minutes after the procedure showed hypoenhancing areas. The total hypoenhancing area was smaller after treatment with fixed hexagonal electrodes than after treatment with variable linear geometry electrodes.ConclusionsRadiologic findings of porcine liver after electrochemotherapy with bleomycin did not show clinically significant damage to the liver, even if a hazardous treatment strategy, such as large vessel intraluminal electrode insertion, was employed, and thus further support safety and clinical use of electrochemotherapy for treatment of hepatic neoplasia.

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“…Being a non-thermal ablative modality, it relies on reversible electroporation and a selective cytotoxic effect on replicating cells. Its safety in bone and liver tissue is documented in animal models and human studies 13,16,34,35 . A second advantage includes the coverage of large target volumes.…”

Section: Discussionmentioning

confidence: 99%

Ablation of soft tissue tumours by long needle variable electrode-geometry electrochemotherapy: final report from a single-arm, single-centre phase-2 study

Simioni

Valpione

Granziera

et al. 2020

Sci Rep

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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 2) 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 18 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. Soft tissue metastases are a frequent event in patients with metastatic melanoma or soft tissue sarcomas (STS) but can also arise in those with breast, lung, and colon cancer 1,2. Although surgical resection remains the first therapeutic option, locoregional therapies are increasingly being considered by the oncology team with either curative or palliative intent 3-5. Moreover, the introduction of new active systemic agents has revamped the interest in locoregional therapies and their possible integration into synergistic therapeutic strategies 6,7. Over the last decade, electrochemotherapy (ECT) has demonstrated efficacy across a great variety of superficial malignancies, including melanoma, breast, head and neck and gynecologic cancers 8. In ECT, targeted electric pulses are administered employing small, fixed-geometry electrodes to attain reversible cell membrane

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Large Liver Blood Vessels and Bile Ducts Are Not Damaged by Electrochemotherapy with Bleomycin in Pigs

Cited by 44 publications

References 45 publications

Analysis of damage-associated molecular pattern molecules due to electroporation of cells in vitro

Analysis of damage-associated molecular pattern molecules due to electroporation of cells in vitro

Radiological findings of porcine liver after electrochemotherapy with bleomycin

Ablation of soft tissue tumours by long needle variable electrode-geometry electrochemotherapy: final report from a single-arm, single-centre phase-2 study

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