Irreversible electroporation for metastatic pancreatic carcinoma with liver metastasis:What does the evidence say

Irreversible electroporation is a promising non-thermal ablation method that has been shown to increase overall survival in locally advanced pancreatic cancer in some studies.However,higher quality studies with proper controls and randomization are required to establish its superiority when added with neoadjuvant chemotherapy over the current management of choice,which is chemotherapy alone.Further studies are required before establishment of any survival benefit in metastatic pancreatic carcinoma,and such evidence is lacking at present.

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.

Experimental study on the irreversible displacement evolution and energy dissipation characteristics of disturbance instability of regular joints

To investigate the disturbance-induced shear instability mechanism of structural catastrophe in the deep rock mass,MTS 815 material testing machine was used to carry out quasi-static loading tests and disturbance shear tests on symmetrical regular dentate joints of two materials at three undulation angles under specific initial static stress,disturbance frequency,and peak value.The test results indicate that:(i)the total ultimate instability displacement is only related to the intrinsic properties of the joints but not to the initial static stress and disturbance parameters;(ii)the cumulative irreversible displacement required for the disturbance instability conforms to the logistic inverse function relationship with the number of disturbances,displaying the variation trend of“rapid increase in the front,stable in the middle,and sudden increase in the rear”;(iii)the accumulation of plastic deformation energy is consistent with the evolution law of irreversible displacement of joints and the overall proportion of hysteretic energy is not large;(iv)the dissipated energy required for the instability of each group of joints is basically the same under various disturbance conditions,and this energy is mainly controlled by the initial shear stress and has no connection with the disturbance parameters.The stability of the total disturbance deformation and the disturbance energy law of the joints revealed in the tests provide data support for reasonably determining the disturbance instability criterion of joints.

Irreversible electroporation of the pancreas-A decade on

Irreversible electroporation(IRE) employs the use of an electric field to cause irreversible permeability of the cell membrane, inducing apoptosis. The use of IRE for locally advanced pancreatic cancer(LAPC) was first described in 2012. The crucial advantage of IRE compared with other devices employing thermal ablation is the safety around vital structures such as vessels and ducts. This makes it an attractive option for use in the pancreas due to the close proximity of multiple major vascular structures, biliary ducts, and adjacent gastrointestinal organs. Over the past decade, IRE has established itself as a useful treatment adjunct and may soon become the standard of care, particularly for LAPC. This article will explore the current evidence and provide a concise summary of pertinent issues, including patient selection, preoperative management, clinical outcomes, radiological response and future prospects of IRE in pancreatic cancer.

The effects of irreversible electroporation triggering anti-tumor immunity and the value of its combination with immunotherapy

Recently,interventional ablation techniques have gained prominence in tumor treatment guidelines and complement traditional approaches,such as surgery,chemotherapy,and radiotherapy.Conventional ablation techniques,such as microwave,radiofrequency,and cryoablation,have been used;however,they have certain limitations,including the risk of damaging surrounding normal tissues and the heat sink effect caused by tumor blood flow.1 Irreversible electroporation(IRE),an ablation technology independent of thermal energy,is a promising alternative.2 Clinical studies have demonstrated IRE's efficacy in treating tumors,such as pancreatic and liver tumors.3 Recent research has shown that IRE can elicit specific anti-tumor immune responses in the body.5 IRE also plays a crucial role in eliminating residual tumor cells postoperatively and preventing tumor recurrence.

The Application of Thermomechanical Dynamics (TMD) to the Analysis of Nonequilibrium Irreversible Motion and a Low-Temperature Stirling Engine

We applied the method of Thermomechanical Dynamics (TMD) to a low-temperature Stirling engine, and the dissipative equation of motion and time-evolving physical quantities are self-consistently calculated for the first time in this field. The thermomechanical states of the heat engine are in Nonequilibrium Irreversible States (NISs), and time-dependent thermodynamic work W(t), internal energy E(t), energy dissipation or entropy Qd(t), and temperature T(t), are precisely studied and computed in TMD. We also introduced the new formalism, Q(t)-picture of thermodynamic heat-energy flows, for consistent analyses of NISs. Thermal flows in a long-time uniform heat flow and in a short-time heat flow are numerically studied as examples. In addition to the analysis of time-dependent physical quantities, the TMD analysis suggests that the concept of force and acceleration in Newtonian mechanics should be modified. The acceleration is defined as a continuously differentiable function of Class C2 in Newtonian mechanics, but the thermomechanical dynamics demands piecewise continuity for acceleration and thermal force, required from physical reasons caused by frictional variations and thermal fluctuations. The acceleration has no direct physical meaning associated with force in TMD. The physical implications are fundamental for the concept of the macroscopic phenomena in NISs composed of systems in thermal and mechanical motion.

Reversible and irreversible heat generation of NCA/Si–C pouch cell during electrochemical energy-storage process

To meet the requirements of electronic vehicles(EVs) and hybrid electric vehicles(HEVs),the high energy density Li Ni_(0.8) Co_(0.15) Al_(0.05) O_2(NCA) cathode and Si–C anode have attracted more attention.Here we report the thermal behaviors of NCA/Si–C pouch cell during the charge/discharge processes at different current densities.The total heat generations are derived from the surface temperature change during electrochemical Li+insertion/extraction in adiabatic surrounding.The reversible heat is determined by the entropic coefficients,which are related with open-circuit voltage at different temperatures; while the irreversible heat is determined by the internal resistance,which can be obtained via V–I characteristic,electrochemical impedance spectroscopy and hybrid pulse power characterization(HPPC).During the electrochemical process,the reversible heat contributes less than 10% to total heat generation; and the heat generated in charge process is less than that in discharge process.The results of thermal behaviors analyses are conducive to understanding the safety management and paving the way for building a reliable thermal model of high energy density lithium ion battery.

Entransy analyses of heat–work conversion systems with inner irreversible thermodynamic cycles

In this paper, we try to use the entransy theory to analyze the heat–work conversion systems with inner irreversible thermodynamic cycles. First, the inner irreversible thermodynamic cycles are analyzed. The influences of different inner irreversible factors on entransy loss are discussed. We find that the concept of entransy loss can be used to analyze the inner irreversible thermodynamic cycles. Then, we analyze the common heat–work conversion systems with inner irreversible thermodynamic cycles. As an example, the heat–work conversion system in which the working fluid of the thermodynamic cycles is heated and cooled by streams is analyzed. Our analyses show that larger entransy loss leads to larger output work when the total heat flow from the high temperature heat source and the corresponding equivalent temperature are fixed.Some numerical cases are presented, and the results verify the theoretical analyses. On the other hand, it is also found that larger entransy loss does not always lead to larger output work when the preconditions are not satisfied.

Is irreversible electroporation safe and effective in the treatment of hepatobiliary and pancreatic cancers?

Background: Irreversible electroporation(IRE) is a novel ablative technique for hepatobiliary and pancreatic cancers. This review summarizes the data regarding the safety and efficacy of IRE in the treatment of hepatobiliary and pancreatic cancers. Data sources: Studies were identified by searching Pub Med and Embase for articles published in English from database inception through July 31, 2017. For inclusion, each clinical study had to report morbidity and survival data on hepatobiliary and pancreatic cancers treated with IRE and contain at least 10 patients. Studies that met these criteria were included for analysis. Two authors assessed each clinical study for data extraction. The controversial parts were resolved through discussion with seniors. Results: A total of 24 clinical studies were included. Fourteen focused on hepatic ablation with IRE comprising 437 patients with 666 lesions of different tumor types. Two patients(0.5%) died after the IRE procedure. Morbidity of hepatic ablation with IRE ranged from 7% to 35%. Most complications were mild. Complete response for hepatic tumors was reported as 57%–97%. Ten studies with 455 patients focused on pancreatic IRE. The overall mortality of IRE in pancreatic cancer was 2%. Overall severe morbidity of IRE in pancreatic cancer ranged from 0 to 20%. The median overall survival after IRE ranged from 7 to 23 months. Patients treated with IRE combined with surgical resection showed a longer overall survival. Conclusions: IRE significantly improves the prognosis of advanced hepatobiliary and pancreatic malignances, and companied with less complications. Hence, IRE is a relatively safe and effective non-thermal ablation strategy and potentially recommended as an option for therapy of patients with hepatobiliary and pancreatic malignances.

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.

Predictors of irreversible intestinal resection in patients with acute mesenteric venous thrombosis

BACKGROUND Acute mesenteric venous thrombosis(AMVT)can cause a poor prognosis.Prompt transcatheter thrombolysis(TT)can achieve early mesenteric revascularization.However,irreversible intestinal ischemia still occurs and the mechanism is still unclear.AIM To evaluate the clinical outcomes of and to identify predictive factors for irreversible intestinal ischemia requiring surgical resection in AMVT patients treated by TT.METHODS The records of consecutive patients with AMVT treated by TT from January 2010 to October 2017 were retrospectively analyzed.We compared patients who required resection of irreversible intestinal ischemia to patients who did not require.RESULTS Among 58 patients,prompt TT was carried out 28.5 h after admission.A total of 42(72.4%)patients underwent arteriovenous combined thrombolysis,and 16(27.6%)underwent arterial thrombolysis alone.The overall 30-d mortality rate was 8.6%.Irreversible intestinal ischemia was indicated in 32(55.2%)patients,who had a higher 30-d mortality and a longer in-hospital stay than patients without resection.The significant independent predictors of irreversible intestinal ischemia were Acute Physiology and Chronic Health Evaluation(APACHE)II score(odds ratio=2.368,95% confidence interval:1.047-5.357,P=0.038)and leukocytosis(odds ratio=2.058,95% confidence interval:1.085-3.903,P=0.027).Using the receiver operating characteristic curve,the cutoff values of the APACHE II score and leukocytosis for predicting the onset of irreversible intestinal ischemia were calculated to be 8.5 and 12×10^9/L,respectively.CONCLUSION Prompt TT could achieve a favorable outcome in AMVT patients.High APACHE II score and leukocytosis can significantly predict the occurrence of irreversible intestinal ischemia.Therefore,close monitoring of these factors may help with the early identification of patients with irreversible intestinal ischemia,in whom ultimately surgical resection is required,before the initiation of TT.

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.

The Determination of Iodide Based on a Flow-injection Coupling Irreversible Biamperometry

A novel flow-injection irreversible biamperometric method is described for the direct determination of iodide. The method is based on electrochemical oxidation of iodide at the gold electrode and the reduction of permanganate at the platinum electrode to form an irreversible biamperometric detection system. Under the applied potential difference of 0 V, in the 0.05 mol/L sulfuric acid, iodidecan be determined over the range 4.00×10^-7-1.00×10^-5 mol/L with a sampling frequency of 120 samples per hour. The detection limit for I- is 3.0×10^-7 mol/L and the RSD for 40 replicate determinations of 4.0×10^-5 mol/L potassium iodide is 1.68%. The new method was applied to the analysis of iodide in table salt with satisfactory results.

Determination of chlorogenic acid by flow injection irreversible biamperometry

A flow injection irreversible biamperometric method for the determination of chlorogenic acid is described. The proposed method is based on the electrochemical oxidation of chlorogenic acid at pretreated platinum electrode and the reduction of permanganate at another electrode to form an irreversible biamperometric detection system. Under the external potential difference （z^v） of 0 V, in the 0.05 mol/L sulfuric acid, chlorogenic acid can be determined over the range 0.8-120 mg/L with a sample measurement frequency of 80 samples/h. The detection limit is 0.18 mg/L. The proposed method exhibits the satisfactory reproducibility with a relative standard derivation （R.S.D.） of 2.21% for 19 successive determinations of 40 mg/L.

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.

The role of degenerative pathways in the development of irreversible consequences after brain ischemia

Ischemic stroke and irreversible consequences:Ischemic stroke in humans is the second most common cause of death in the world(Mozaffarian et al.,2016).The outcomes after a stroke are often dependent on complications,including motor disorders,depression and dementia(Pluta et al.,2018a),which causes a high risk of re-hospitalization and/or palliative care.This is also the main reason for long-term disability in people after stroke,with up to half of those who survived the stroke will not regain their independence until the end of their lives(Mozaffarian et al.,2016).According to epidemiological forecasts,human ischemic stroke will soon become the dominant cause of death worldwide(Bejot et al.,2016)as well as dementia with the phenotype of Alzheimer’s disease(AD;Kim and Lee 2018).It is suggested that human ischemic stroke and experimental brain ischemia in animals are associated with the possible development of AD neuropathology(Pluta et al.,2018a).

Irreversible electroporation and the pancreas:What we know and where we are going?

Pancreatic adenocarcinoma continues to have a poor prognosis with 1 and 5 years survival rates of 27% and 6% respectively. The gold standard of treatment is resection, however, only approximately 10% of patients present with resectable disease. Approximately 40% of patients present with disease that is too locally advancedto resect. There is great interest in improving outcomes in this patient population and ablation techniques have been investigated as a potential solution. Unfortunately early investigations into thermal ablation techniques, particularly radiofrequency ablation, resulted in unacceptably high morbidity rates. Irreversible electroporation(IRE) has been introduced and is promising as it does not rely on thermal energy and has shown an ability to leave structural cells such as blood vessels and bile ducts intact during animal studies. IRE also does not suffer from heat sink effect, a concern given the large number of blood vessels surrounding the pancreas. IRE showed significant promise during preclinical animal trials and as such has moved on to clinical testing. There are as of yet only a few studies which look at the applications of IRE within humans in the setting of pancreatic adenocarcinoma. This paper reviews the basic principles, techniques, and current clinical data available on IRE.

Thymoquinone and Poloxin are slow-irreversible inhibitors to human Polo-like kinase 1 Polo-box domain

Objective： To provide a kinetic model（s） and reveal the mechanism of thymoquinone and Poloxin blocking an emerging anti-cancer target, human Polo-like kinase 1 （hPlkl） Polo-box domain （PBD）. Methods： The binding kinetics was determined by using a fluorescence polarization based assay. The putative mechanism was examined with a competition test. Results： Thymoquinone follows a one-step binding with an association rate constant （k1） of 6.635× 10^3 L.mol^-1 min^-1.Poloxin fit a two-step binding with a dissociation constant （Ki） of 118 μmol/L for the intermediate complex and its isomerization rate （k4） of 0.131 5 minJ to form an irreversible adduct. No significant dissociation was observed for either ligand up to 13 h. The inhibitors responded insignificantly to the presence of Michael donors as hPIkl-PBD competitors. Conclusion： Thymoquinone and Poloxin are slow-tight ligands to the hPlkl-PBD with kinetic models distinct from each other. Michael addition as the mechanism is excluded.

Determination of levodopa in pharmaceutical preparations by irreversible biamperometry

Based on the electrocatalytic oxidation of levodopa at gold electrode and the reduction of permanganate at platinum electrode, a novel flow injection irreversible biamperometric method is developed for the determination of levodopa under the potential difference of 0 V imposed between two electrodes. In H2SO4 solution, the linear relationships between currents and the concentrations of levodopa are obtained in the range from 0.04 mg/L to 20 mg/L with the detection limit of 0.012 mg/L. The proposed method is applied to the determination of levodopa in pharmaceutical preparations.

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.