Irreversible electroporation for the management of pancreatic cancer: Current data and future directions

Pancreatic cancer is currently the seventh leading cause of cancer death(4.5%of all cancer deaths)while 80%-90%of the patients suffer from unresectable disease at the time of diagnosis.Prognosis remains poor,with a mean survival up to 15 mo following systemic chemotherapy.Loco-regional thermal ablative techniques are rarely implemented due to the increased risk of thermal injury to the adjacent structures,which can lead to severe adverse events.Irreversible electroporation,a promising novel non-thermal ablative modality,has been recently introduced in clinical practice for the management of inoperable pancreatic cancer as a safer and more effective loco-regional treatment option.Experimental and initial clinical data are optimistic.This review will focus on the basic principles of IRE technology,currently available data,and future directions.

Gemcitabine plus concurrent irreversible electroporation vs gemcitabine alone for locally advanced pancreatic cancer

BACKGROUND Locally advanced pancreatic cancer(LAPC)is a common malignant digestive system tumor that ranks as the fourth leading cause of cancer-related death in the world.The prognosis of LAPC is poor even after standard treatment.Irreversible electroporation(IRE)is a novel ablative strategy for LAPC.Several studies have confirmed the safety of IRE.To date,no prospective studies have been performed to investigate the therapeutic efficacy of conventional gemcitabine(GEM)plus concurrent IRE.AIM To compare the therapeutic efficacy between conventional GEM plus concurrent IRE and GEM alone for LAPC.METHODS From February 2016 to September 2017,a total of 68 LAPC patients were treated with GEM plus concurrent IRE(n=33)or GEM alone(n=35).Overall survival(OS),progression free survival(PFS),and procedure-related complications were compared between the two groups.Multivariate analyses were performed to identify any prognostic factors.RESULTS There were no treatment-related deaths.The technical success rate of IRE ablation was 100%.The GEM+IRE group had a significantly longer OS from the time of diagnosis of LAPC(19.8 mo vs 9.3 mo,P<0.0001)than the GEM alone group.The GEM+IRE group had a significantly longer PFS(8.3 mo vs 4.7 mo,P<0.0001)than the GEM alone group.Tumor volume less than 37 cm3 and GEM plus concurrent IRE were identified as significant favorable factors for both the OS and PFS.CONCLUSION Gemcitabine plus concurrent IRE is an effective treatment for patients with LAPC.

Arterial complication of irreversible electroporation procedure for locally advanced pancreatic cancer

Irreversible electroporation(IRE) is a non-thermal ablation technique used especially in locally advanced pancreatic carcinomas that are considered surgically unresectable.We present the first case of acute superior mesenteric artery(SMA) occlusion secondary to pancreatic IRE procedure that has not been reported before in the literature.A 66-year-old man underwent neoadjuvant chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma.IRE procedure was applied to the patient during laparotomy under general anesthesia.After finishing the procedure,an acute intestinal ischemia was detected.A conventional vascular angiography was performed and a metallic stent was successfully placed to the SMA and blood flow was maintained.It is important to be careful in such cases of tumor involvement of SMA when evaluating for IRE procedure of pancreatic tumor.

Postoperative inflammation as a possible cause of portal vein thrombosis after irreversible electroporation for locally advanced pancreatic cancer

Portal vein thrombosis(PVT) is a rare but serious postoperative complication associated with irreversible electroporation(IRE). We report a case of postoperative PVT in a 54-year-old woman who underwent IRE for locally advanced pancreatic cancer. Drain removal and discharge of the patient from the hospital were scheduled on postoperative day(POD) 7; however, a magnetic resonance imaging scan revealed the presence of PVT. We suspected postoperative inflammation in the pancreas as the main cause of PVT. However, the patient did not undergo any medical treatment because she did not have any clinical symptoms, and she was discharged on POD 8.

Safety and feasibility of irreversible electroporation for the pancreatic head in a porcine model

BACKGROUND Irreversible electroporation(IRE)is a local non-thermal ablative technique which has been suggested as a potential cancer therapy.However,the specific anatomic characteristics of the pancreatic head make it challenging to perform any local ablation in this region.Therefore,the safety and feasibility of IRE in the pancreatic head region should be further explored.AIM To evaluate the safety of IRE in pancreatic head region including its effects on pancreatic ducts,vessels,and adjacent gastrointestinal organs.METHODS Eight landrace miniature pigs underwent IRE of pancreatic head tissue successfully,with a total of 16 lesions created.Laboratory testing including white blood cell(WBC)count and serum amylase before IRE with follow-up laboratory analysis and pathological examination at 1,7,14,and 28 d postablation were performed.RESULTS All pigs tolerated the ablation procedure without serious perioperative complications.Transiently elevated WBC count and amylase were observed at 24 h post-IRE,suggesting an acute pancreatic tissue damage which was confirmed by pathological observations.Vascular endothelial cells and pancreatic duct epithelial cells in ablation zone were also positive in terminal deoxynucleotidyl transferase dUTP nick end labeling staining.There was extensive duodenum mucosa damage with local hemorrhage 24 h after ablation,while regeneration of new villous structures were observed at 7 and 28 d post-IRE.Masson’s trichromatic staining showed that the extracellular matrix was still intact in vessels and pancreatic ducts,and even in the duodenum.CONCLUSION IRE ablation to the pancreatic head may be safe and feasible without long-term damage to the surrounding vital structures.However,risks of stress injuries in acute phase should be taken into consideration to prevent severe perioperative complications.

Effectiveness and safety of irreversible electroporation for recurrent hepatocellular carcinoma ineligible for thermal ablation after surgery

Objectives:To preliminarily evaluate the clinical effectiveness and safety of computed tomography(CT)imageguided irreversible electroporation(IRE)for the treatment of recurrent hepatocellular carcinoma(HCC)after surgical resection.Methods:From January 2016 to February 2018,18 patients diagnosed with recurrent HCC after surgical resection received IRE under CT image guidance for 22 tumors.Patients were enrolled for IRE when ineligible for thermal ablation due to tumor location.Clinical records and imaging data were reviewed to assess complete ablation rate,local tumor progression free rate(LTPFR),local tumor progression free survival(LTPFS)and complications after a median follow-up time of 14 months.Results:Successful complete ablations were achieved in 20/22(90.1%)tumors.Mean LTPFS was 10.5?9.4 months.Overall 3-,6-and 12-months LTPFR in 22 tumors following IRE were 68.2%(95%confidence interval[CI]:45%–83%),59.1%(95%CI:33%–76%)and 36.4%(95%CI:17%–56%),respectively.Complications included pneumothorax(2/18,11.1%),localized pain(3/18,16.7%),bile duct dilation(1/18,5.6%)and transient hypertension(1/18,5.6%).No major complications or treatment-related deaths were observed.The alphafetoprotein levels of two patients decreased to the normal range at 3 and 4 months,respectively.Conclusions:This study showed that percutaneous CT image-guided IRE can serve as a safe and effective treatment for recurrent HCC not suitable for thermal ablation.

Irreversible electroporation for liver metastasis from pancreatic cancer: A case report

BACKGROUND Pancreatic cancer has a poor prognosis;40%–50% of patients have liver metastases at the time of initial diagnosis and only 15%–20% undergo surgical resection. Irreversible electroporation(IRE) is a new, non-thermal local ablation method for solid tumors, which can induce cell membrane permeabilization,resulting in unrecoverable nanoscale perforation and apoptotic cell death without damaging the structural components of tissues.CASE SUMMARY We report the case of a 66-year-old female patient with liver metastasis from pancreatic cancer with a pathological diagnosis of poorly differentiated adenocarcinoma. Carbohydrate antigen 19-9 was elevated to 420.3 U/m L.Computed tomography showed a pancreas mass of 2.7 cm × 2.5 cm and single liver metastasis of 1.4 cm × 1.1 cm in the S6 area. The patient underwent IRE and arterial infusion chemotherapy and received tegafur. The therapeutic effect of the combination treatment has been evaluated as complete response. To date, the patient has survived for > 12 mo and is receiving tegafur as maintenance therapy(at the time this case report was written).CONCLUSION IRE plus arterial infusion chemotherapy and tegafur may be synergistic,providing a reference for treating liver metastasis from pancreatic cancer.

Irreversible electroporation versus radiofrequency ablation for malignant hepatic tumor:A prospective single-center double-arm trial

Objective:Irreversible electroporation(IRE)is a nonthermal ablation technique for the treatment of malignant liver tumors.IRE has demonstrated efficacy and safety in the treatment of malignant liver tumors and its unique advantages in the treatment of nearby vascular lesions.This study aimed to compare the efficacy,safety,and intermediate-term outcomes of IRE and radiofrequency(RF)therapy in malignant liver tumors.Methods:Twenty-four patients with primary or secondary liver malignancies were included in this prospective,double-arm clinical trial.Patients were randomly divided into the IRE and RF groups.The primary outcome was the efficacy(local ablation control evaluation at 90 days).The secondary outcomes were safety(procedure-related complications at≤90 days)and intermediate-term survival(at 24 months).Results:The ablation assessment at 90 days after surgery with m RECIST for IRE versus RF were 70%,20%,0%,and 10%versus 92.9%,7.1%,0%,and 0%(CR,PR,SD,and PD,respectively).The complication rates of IRE versus RF with Clavien-Dindo classification were 16.7%,25%,0%,8.3%,and 8.3%versus 8.3%,50%,0%,0%,and 0%(Grade I,II,Ⅲ,IV,and V,respectively).The average overall survival(OS)was 17.55 months in the IRE group(95%CI 15.13-22.37)and 18.75 months in the RF group(95%CI 12.48-22.61).There was no statistical difference between the IRE and RF groups in terms of efficacy(p=0.48),safety(p=0.887),or 24-month OS(p=0.959).Conclusions:IRE ablation revealed similar efficacy and safety in a short-term follow-up,and similar OS in midterm survival as RF ablation in treating malignant hepatic tumors.

Comparison between high-frequency irreversible electroporation and irreversible electroporation ablation of small swine liver:follow-up of DCE-MRI and pathological observations

Background:High-frequency irreversible electroporation(H-FIRE)is a novel,next-generation nanoknife technology with the advantage of relieving irreversible electroporation(IRE)-induced muscle contractions.However,the difference between IRE and H-FIRE with distinct ablation parameters was not clearly defined.This study aimed to compare the efficacy of the two treatments in vivo.Methods:Ten Bamaminiature swinewere divided into two group:five in the 1-day group and five in the 7-day group.The efficacy of IRE and H-FIRE ablation was compared by volume transfer constant(Krans),rate constant(Kep)and extravascular extracellular volume fraction(Ve)value of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI),size of the ablation zone,and histologic analysis.Each animal underwent the IRE andH-FIRE.Temperatures of the electrodesweremeasured during ablation.DCE-MRI images were obtained 1,4,and 7 days after ablation in the 7-day group.All animals in the two groups were euthanized 1 day or 7 days after ablation,and subsequently,IRE and H-FIRE treated liver tissues were collected for histological examination.Student’s t test or Mann-Whitney U test was applied for comparing any two groups.One-way analysis of variance(ANOVA)test and Welch’s ANOVA test followed byHolm-Sidak’smultiple comparisons test,one-wayANOVAwith repeatedmeasures followed by Bonferroni test,or Kruskal-Wallis H test followed by Dunn’s multiple comparison test was used for multiple group comparisons and post hoc analyses.Pearson correlation coefficient test was conducted to analyze the relationship between two variables.Results:Higher Ve was seen in IRE zone than in H-FIRE zone(0.14±0.02 vs.0.08±0.05,t=2.408,P=0.043)on day 4,but no significant difference was seen in Ktrans or Kep between IRE and H-FIRE zones at all time points(all P>0.05).For IRE zone,the greatest Ktrans was seen on day 7,which was significantly higher than that on day 1(P=0.033).The ablation zone size of H-FIRE was significantly larger than IRE 1 day(4.74±0.88 cm^(2)vs.3.20±0.77 cm^(2),t=3.241,P=0.009)and 4 days(2.22±0.83 cm^(2)vs.1.30±0.50 cm^(2),t=2.343,P=0.041)after treatment.Apoptotic index(0.05±0.02 vs.0.73±0.06 vs.0.68±0.07,F=241.300,P<0.001)and heat shock protein 70(HSP70)(0.03±0.01 vs.0.46±0.09 vs.and 0.42±0.07,F=64.490,P<0.001)were significantly different between the untreated,IRE and H-FIRE zones,but no significant difference was seen in apoptotic index or HSP70 between IRE and H-FIRE zone(both P>0.05).Electrode temperature variations were not significantly different between the two zones(18.00±3.77℃ vs.16.20±7.45℃,t=0.682,P=0.504).The Ktrans value(r=0.940,P=0.017)and the Kep value(r=0.895,P=0.040)of the H-FIRE zone were positively correlated with the number of hepatocytes in the ablation zone.Conclusions:H-FIRE showed a comparable ablation effect to IRE.DCE-MRI has the potential to monitor the changes of H-FIRE ablation zone.

A Single-institution Experience with Open Irreversible Electroporation for Locally Advanced Pancreatic Carcinoma

Background： Locally advanced pancreatic carcinoma （LAPC） is characterized by poor prognosis despite recommended concurrent chemoradiotherapy. Irreversible electroporation （IRE） has emerged as a potential option for the management of unresectable pancreatic cancer. This study was conducted to evaluate the safety and short-term efficacy of open IRE for the treatment of LAPC. Methods： Retrospective data of 25 consecutive patients receiving IRE for T3 lesions from July 2015 to June 2016 at a single center were analyzed. The perioperative and long-term IRE-related complications were reviewed to evaluate the safety of the procedure. The tumor reduction and biological response were analyzed through computed tomography/magnetic resonance imaging; the serum level of CA19-9 was measured as a secondary endpoint to evaluate the short-term efficacy of IRE. Results： All patients were successfully treated; the median tumor size was 4.2 cm and the median IRE time was 36 min. Four intraoperative procedure-related complications were observed （16%）： two transient hypertensive episodes, one hypotension case, and one transient supraventricular tachycardia case. Nine postoperative complications were described, including three Grade A pancreatic fistulas, three delayed gastric emptying, one acute pancreatitis, one upper gastrointestinal hemorrhage, and one portal vein thrombosis. The overall rate of stable disease was 28%, 36% achieved partial response, and lower serum CA19-9 levels were recorded in all patients at discharge. Conclusions： IRE is feasible for the treatment of LAPC and is a reasonable intervention strategy owing to its combined attributes of safety and efficacy.

Irreversible Electroporation for Hepatocellular Carcinoma Abutting the Diaphragm:A Prospective Single-center Study

Background and Aims:Irreversible electroporation(IRE)is an emerging local ablation therapy which may be effective for unresectable tumors.This study aimed to evaluate the safety and efficacy of percutaneous IRE in the treatment of hepatocellular carcinoma(HCC)abutting the diaphragm.Methods:A total of 26 participants with 39 tumors abutting the diaphragm were prospectively evaluated between July 2015 and September 2018.Complications associated with IRE were recorded,and the survival benefit of IRE was analyzed.The factors associated with time to local tumor progression(LTP)were analyzed using univariate and multivariate Cox regression models.Results:No major complications or treatmentrelated deaths occurred.The technical success rate was 96.2%(25/26)and complete ablation rate was 92.3%(36/39).The median followup period was 16.7 months(range:3.0-43.0 months),the LTP occurred in 15.2%of tumors and median time to LTP was 20.4 months.Overall,tumor size(hazard ratio:1.24[95%confidence interval:0.38,3.81],p=0.03)was the only factor associated with time to LTP.Conclusions:This study shows for the first time that percutaneous IRE is a safe and effective ablation technology for HCC abutting the diaphragm.

Irreversible Electroporation Ablation for Atrial Fibrillation: Status and Challenges

Pulsed electric field(PEF)is a novel energy source by which high-voltage electric pulses are used to create irreversible electroporation.PEF is non-thermal and highly tissue-dependent in which specific targeting of the atrial myocardium is achieved and sparing of adjacent tissues is feasible,theoretically increasing the safety of the procedure,which could potentially break the trade-off between effective lesions and collateral damage and substantially improve risk-benefit ratios in atrial fibrillation(AF)ablation.Although recently published trials have shown a clear effect of AF ablation,large-scale clinical trials are lacking.Current clinical evidence has demonstrated significant efficacy in achieving durable pulmonary vein isolation without ablation-related adverse events.However,their putative benefits regarding efficacy,efficiency,and safety remain to be proven in randomized controlled trials.

Reduction of muscle contraction and pain in electroporation-based treatments:An overview

BACKGROUND In the first studies of electrochemotherapy(ECT),small cutaneous metastases were treated and only mild or moderate pain was observed;therefore,pain was not considered a significant issue.As the procedure began to be applied to larger cutaneous metastases,pain was reported more frequently.For that reason,reduction of both muscle contractions and pain have been investigated over the years.AIM To present an overview of different protocols described in literature that aim to reduce muscle contractions and pain caused by the electroporation(EP)effect in both ECT and irreversible EP treatments.METHODS Thirty-three studies published between January 1999 and November 2020 were included.Different protocol designs and electrode geometries that reduce patient pain and the number of muscle contractions and their intensity were analysed.RESULTS The analysis showed that both high frequency and bipolar/biphasic pulses can be used to reduce pain and muscle contractions in patients who undergo EP treatments.Moreover,adequate electrode design can decrease EP-related morbidity.Particularly,needle length,diameter and configuration of the distance between the needles can be optimised so that the muscle volume crossed by the current is reduced as much as possible.Bipolar/biphasic pulses with an inadequate pulse length seem to have a less evident effect on the membrane permeability compared with the standard pulse protocol.For that reason,the number of pulses and the voltage amplitude,as well as the pulse duration and frequency,must be chosen so that the dose of delivered energy guarantees EP efficacy.CONCLUSION Pain reduction in EP-based treatments can be achieved by appropriately defining the protocol parameters and electrode design.Most results can be achieved with high frequency and/or bipolar/biphasic pulses.However,the efficacy of these alternative protocols remains a crucial point to be assessed further.

Percutaneous ablation of pancreatic cancer

Pancreatic ductal adenocarcinoma is a highly aggressive tumor with an overall 5-year survival rate of less than 5%. Prognosis and treatment depend on whether the tumor is resectable or not, which mostly depends on how quickly the diagnosis is made. Chemotherapy and radiotherapy can be both used in cases of nonresectable pancreatic cancer. In cases of pancreatic neoplasm that is locally advanced, non-resectable, but non-metastatic, it is possible to apply percutaneous treatments that are able to induce tumor cytoreduction. The aim of this article will be to describe the multiple currently available treatment techniques(radiofrequency ablation, microwave ablation, cryoablation, and irreversible electroporation), their results, and their possible complications, with the aid of a literature review.

Recent progress in pulsed electric field ablation for liver cancer

The number of liver cancer patients is likely to continue to increase in the coming decades due to the aging of the population and changing risk factors.Traditional treatments cannot meet the needs of all patients.New treatment methods evolved from pulsed electric field ablation are expected to lead to breakthroughs in the treatment of liver cancer.This paper reviews the safety and efficacy of irreversible electroporation in clinical studies,the methods to detect and evaluate its ablation effect,the improvements in equipment and its antitumor effect,and animal and clinical trials on electrochemotherapy.We also summarize studies on the most novel nanosecond pulsed electric field ablation techniques in vitro and in vivo.These research results are certain to promote the progress of pulsed electric field in the treatment of liver cancer.

Laser Machined Fiber‑Based Microprobe: Application in Microscale Electroporation

Microscale electroporation devices are mostly restricted to in vitro experiments(i.e.,microchannel and microcapillary).Novel fiber-based microprobes enable in vivo microscale electroporation and arbitrarily select the cell groups of interest to electroporate.We developed a flexible,fiber-based microscale electroporation device through a thermal drawing process and femtosecond laser micromachining techniques.The fiber consists of four copper electrodes(80μm),one microfluidic channel(30μm),and has an overall diameter of 400μm.The dimensions of the exposed electrodes and channel were customizable through a delicate femtosecond laser setup.The feasibility of the fiber probe was validated through numerical simulations and in vitro experiments.Successful reversible and irreversible microscale electroporation was observed in a 3D collagen scaffold(seeded with U251 human glioma cells)using fluorescent staining.The ablation regions were estimated by performing the covariance error ellipse method and compared with the numerical simulations.The computational and experimental results of the working fiber-based microprobe suggest the feasibility of in vivo microscale electroporation in space-sensitive areas,such as the deep brain.

Advances in managing hepatocellular carcinoma

Multiple modalities for treatment of hepatocellular carcinoma are available, depending on tumor size and number. Surgical resection remains the gold standard, so long as the residual liver function reserve is sufficient. In patients with advanced cirrhosis, liver transplantation is the preferred option, as these patients may not have adequate hepatic reserve after resection. Salvage liver transplantation has also become an option for a select few patients who recur after surgical resection. Ablative techniques have been used for palliation as well as to either completely destroy the tumor, act as an adjunct to resection, or downstage the tumor to meet Milan criteria such that a patient may be a candidate for liver transplantation. Radiofrequency ablation, microwave ablation, chemoembolization, radioembolization, and irreversible electroporation have all been used in this capacity. Currently, sorafenib is the only US Food and Drug Administration-approved chemotherapeutic for hepatocellular carcinoma. The efficacy of sorafenib, in combination with other agents, transarterial chemoembolization, and surgical resection is currently being investigated. Sunitinib and brivanib, tyrosine kinase inhibitors, have failed as potential first- or second-line options for chemotherapy. Bevacizumab in combination with erlotinib is also currently being studied. Final analysis for ramucirumab and axitinib are pending. Tivantinib, a selective mesenchymai-epithelial transition factor （MET） inhibitor, is also undergoing clinical trials for efficacy in MET- high tumors. This review serves to emphasize the current and new technologies emerging in the treatment of hepatoeellular carcinoma.

Hepatocellular carcinoma clinical update: Current standards and therapeutic strategies

Hepatocellular carcinoma(HCC)accounts for the vast majority of primary hepatic malignancies.The overall incidence of this disease has always been significant,but in recent years it has continued to rise,now making HCC one of the leading causes of cancer deaths worldwide.Fortunately,research into the mechanisms of carcinogenesis and treatment options for this disease has also been progressing rapidly.Although the future for new insights and therapies appears more promising than ever,it also remains important to understand both the nature of HCC and the current state-of-the-art for treating affected patients.Although surgery is often considered to be a first choice,many patients present with extensive disease and are therefore not operative candidates.Fortunately,significant clinical advances over the last decade have contributed a number of new or improved treatment options.Many of these treatments require expertise from a variety of different clinical subspecialties.Indeed,managing patients with HCC has rapidly become a multi-modality,multi-disciplinary endeavor in which the details of each in-dividual’s circumstance can greatly impact outcomes,and strategies can be quite nuanced.The purpose of this review is to provide a perspective on the disease itself,the patients who become afflicted,the spectrum of currently available treatment options,and the strategies for their optimal implementation.Such knowledge can be critically important as new data become available on the research front.