Focused transhepatic electroporation mediated by hypersaline infusion through the portal vein in murine model : Preliminary results on differential conductivity and safety

INTRODUCCIÓN: Este estudio evalúa el aumento selectivo de la conductividad hepática mediante la infusión hipersalina en el sistema portomesentérico para tratar simultáneamente todos los tumores hepáticos mediante electroporación irreversible. MATERIAL Y MÉTODOS: La estandarización de la técnica fue con ratón. Se emplearon ratas Sprague Dawley(n=20) y ratas atímicas con tumor hepático(n=8). La infusión de NaCl (20%) fue por punción transesplénica. Se monitorizó la conductividad entre tejido sano y tumoral. Se realizó seguimiento analítico e histológico. RESULTADOS: La conductividad hepática máxima fue 1,4 veces mayor que el tejido tumoral durante 175±115,23 segundos. La natremia se normalizó a las 24h postinfusión. La acidosis y la hipertransaminasemia (24h) se asociaron con la mortalidad. La diferencia de necrosis hepática entre ratas sobrevivientes/no-sobrevivientes fue significativa.INTRODUCTION: This study evaluates the selective increase in liver conductivity by hypersaline infusion through the portomesenteric system in order to treat all the hepatic tumors simultaneously by irreversible electroporation. MATERIAL AND METHODS: The standardization of the technique was with mice. Sprague Dawley rats(n=20) and athymic rats with liver tumor(n=8) were used. The infusion of NaCl (20%) was by transesplenic puncture. The conductivity between healthy and tumor tissue was monitored. Analytical and histological follow-up was performed. RESULTS: The maximum hepatic conductivity was 1.4 times higher than the tumor tissue during 175±115.23 seconds. The natremia was normalized at 24h post-infusion. Acidosis and hypertransaminasemia (24h) were associated with mortality. The difference in liver necrosis among surviving/non-surviving rats was significant. CONCLUSION: Hypersaline infusion increases liver conductivity, which could let focus irreversible electroporation into hepatic tumors. However, side effects of such infusion should be considered

Focused transhepatic electroporation mediated by hypersaline infusion through the portal vein in murine model : Preliminary results on differential conductivity and safety

INTRODUCCIÓN: Este estudio evalúa el aumento selectivo de la conductividad hepática mediante la infusión hipersalina en el sistema portomesentérico para tratar simultáneamente todos los tumores hepáticos mediante electroporación irreversible. MATERIAL Y MÉTODOS: La estandarización de la técnica fue con ratón. Se emplearon ratas Sprague Dawley(n=20) y ratas atímicas con tumor hepático(n=8). La infusión de NaCl (20%) fue por punción transesplénica. Se monitorizó la conductividad entre tejido sano y tumoral. Se realizó seguimiento analítico e histológico. RESULTADOS: La conductividad hepática máxima fue 1,4 veces mayor que el tejido tumoral durante 175±115,23 segundos. La natremia se normalizó a las 24h postinfusión. La acidosis y la hipertransaminasemia (24h) se asociaron con la mortalidad. La diferencia de necrosis hepática entre ratas sobrevivientes/no-sobrevivientes fue significativa.INTRODUCTION: This study evaluates the selective increase in liver conductivity by hypersaline infusion through the portomesenteric system in order to treat all the hepatic tumors simultaneously by irreversible electroporation. MATERIAL AND METHODS: The standardization of the technique was with mice. Sprague Dawley rats(n=20) and athymic rats with liver tumor(n=8) were used. The infusion of NaCl (20%) was by transesplenic puncture. The conductivity between healthy and tumor tissue was monitored. Analytical and histological follow-up was performed. RESULTS: The maximum hepatic conductivity was 1.4 times higher than the tumor tissue during 175±115.23 seconds. The natremia was normalized at 24h post-infusion. Acidosis and hypertransaminasemia (24h) were associated with mortality. The difference in liver necrosis among surviving/non-surviving rats was significant. CONCLUSION: Hypersaline infusion increases liver conductivity, which could let focus irreversible electroporation into hepatic tumors. However, side effects of such infusion should be considered

Focused transhepatic electroporation mediated by hypersaline infusion through the portal vein in rat model. Preliminary results on differential conductivity

Background. Spread hepatic tumours are not suitable for treatment either by surgery or conventional ablation methods. The aim of this study was to evaluate feasibility and safety of selectively increasing the healthy hepatic conductivity by the hypersaline infusion (HI) through the portal vein. We hypothesize this will allow simultaneous safe treatment of all nodules by irreversible electroporation (IRE) when applied in a transhepatic fashion. Material and methods. Sprague Dawley (Group A, n = 10) and Athymic rats with implanted hepatic tumour (Group B, n = 8) were employed. HI was performed (NaCl 20%, 3.8 mL/Kg) by trans-splenic puncture. Deionized serum (40 mL/ Kg) and furosemide (2 mL/Kg) were simultaneously infused through the jugular vein to compensate hypernatremia. Changes in conductivity were monitored in the hepatic and tumour tissue. The period in which hepatic conductivity was higher than tumour conductivity was defined as the therapeutic window (TW). Animals were monitored during 1-month follow-up. The animals were sacrificed and selective samples were used for histological analysis. Results. The overall survival rate was 82.4% after the HI protocol. The mean maximum hepatic conductivity after HI was 2.7 and 3.5 times higher than the baseline value, in group A and B, respectively. The mean maximum hepatic conductivity after HI was 1.4 times higher than tumour tissue in group B creating a TW to implement selective IRE. Conclusions. HI through the portal vein is safe when the hypersaline overload is compensated with deionized serum and it may provide a TW for focused IRE treatment on tumour nodules.This work received financial support from the Spanish Government (Ministry of Economy and Competitiveness) under Grant TEC2014-52383-C3. The authors disclose no conflicts of interests

Focused transhepatic electroporation mediated by hypersaline infusion through the portal vein in rat model: Preliminary results on differential conductivity

Background. Spread hepatic tumours are not suitable for treatment either by surgery or conventional ablation methods. The aim of this study was to evaluate feasibility and safety of selectively increasing the healthy hepatic conductivity by the hypersaline infusion (HI) through the portal vein. We hypothesize this will allow simultaneous safe treatment of all nodules by irreversible electroporation (IRE) when applied in a transhepatic fashion. Material and methods. Sprague Dawley (Group A, n = 10) and Athymic rats with implanted hepatic tumour (Group B, n = 8) were employed. HI was performed (NaCl 20%, 3.8 mL/Kg) by trans-splenic puncture. Deionized serum (40 mL/Kg) and furosemide (2 mL/Kg) were simultaneously infused through the jugular vein to compensate hypernatremia. Changes in conductivity were monitored in the hepatic and tumour tissue. The period in which hepatic conductivity was higher than tumour conductivity was defined as the therapeutic window (TW). Animals were monitored during 1-month follow-up. The animals were sacrificed and selective samples were used for histological analysis. Results. The overall survival rate was 82.4% after the HI protocol. The mean maximum hepatic conductivity after HI was 2.7 and 3.5 times higher than the baseline value, in group A and B, respectively. The mean maximum hepatic conductivity after HI was 1.4 times higher than tumour tissue in group B creating a TW to implement selective IRE. Conclusions. HI through the portal vein is safe when the hypersaline overload is compensated with deionized serum and it may provide a TW for focused IRE treatment on tumour nodules.This work received financial support from the Spanish Government (Ministry of Economy and Competitiveness) under Grant TEC2014-52383-C3. The authors disclose no conflicts of interests

Long-term effectiveness of irreversible electroporation in a murine model of colorectal liver metastasis

Irreversible electroporation (IRE) has recently gained in popularity as an ablative technique, however little is known about its oncological long-term outcomes. To determine the long-time survival of animals treated with a high dose of IRE and which histological changes it induces in tumoral tissue, IRE ablation was performed in forty-six athymic-nude mice with KM12C tumors implanted in the liver by applying electric current with different voltages (2000 V/cm, 1000 V/cm). The tumors were allowed to continue to grow until the animals reached the end-point criteria. Histology was harvested and the extent of tumor necrosis was semi-quantitatively assessed. IRE treatment with the 2000 V/cm protocol significantly prolonged median mouse survival from 74.3 ± 6.9 days in the sham group to 112.5 ± 15.2 days in the 2000 V/cm group. No differences were observed between the mean survival of the 1000 V/cm and the sham group (83.2 ± 16.4 days, p = 0.62). Histology revealed 63.05% ± 23.12 of tumor necrosis in animals of the 2000 V/cm group as compared to 17.50% ± 2.50 in the 1000 V/cm group and 25.6% ± 22.1 in the Sham group (p = 0.001). IRE prolonged the survival of animals treated with the highest electric field (2000 V/cm). The animals in this group showed significantly higher rate of tumoral necrosis.This research was supported by the spanish government under grants TEC2011-27133-c02 and TEC2010-17285, and by the spanish “plan estatal de investigación, desarrollo e innovación orientada a los retos de la sociedad” under grant TEC2014–52383-c3-r (TEC2014–52383-c3-2-r and TEC2014–52383-c3-3-r)

Irreversible electroporation of the liver: is there a safe limit to the ablation volume?

Irreversible electroporation is a fast-growing liver ablation technique. Although safety has been well documented in small ablations, our aim is to assess its safety and feasibility when a large portion of liver is ablated. Eighty-seven mice were subjected to high voltage pulses directly delivered across parallel plate electrodes comprising around 40% of mouse liver. One group consisted in 55 athymic-nude, in which a tumor from the KM12C cell line was grown and the other thirty-two C57-Bl6 non-tumoral mice. Both groups were subsequently divided into subsets according to the delivered field /nstrength (1000V/cm, 2000V/cm) and whether or not they received anti-hyperkalemia therapy. Early mortality (less than 24hours post-IRE) in the 2000V/cm group was observed and revealed considerably higher mean potassium levels. In contrast, the animals subjected to a 2000V/cm field treated with the anti-hyperkalemia therapy had higher survival rates (OR=0.1, 95%CI=0.02–0.32, p<0.001). Early mortality also depended on the electric field magnitude of the IRE protocol, as mice given 1000V/cm survived longer than those given 2000V/cm (OR=4.7, 95%CI=1.8–11.8, p=0.001). Our findings suggest that ionic disturbances, mainly due to potassium alterations, should be warned and envisioned when large volume ablations are performed by IRE.This research was supported by the Spanish “Plan Estatal de Investigación, Desarrollo e Innovación Orientada/na los Retos de la Sociedad” under Grant TEC2014–52383-C3 (TEC2014-52383-C3-1-R, TEC2014-52383-C3-/n2-R, and TEC2014-52383-C3-3-R), and by the Spanish “Plan Nacional de I + D + i del Ministerio de Ciencia e/nInnovación” under Grants TEC2011-27133-C02 and TEC2010-17285