Bipolar radiofrequency ablation with 2 × 2 electrodes as a building block for matrix radiofrequency ablation: Ex vivo liver experiments and finite element method modelling.

PURPOSE: Size and geometry of the ablation zone obtained by currently available radiofrequency (RF) electrodes is highly variable. Reliability might be improved by matrix radiofrequency ablation (MRFA), in which the whole tumour volume is contained within a cage of x × y parallel electrodes. The aim of this study was to optimise the smallest building block for matrix radiofrequency ablation: a recently developed bipolar 2 × 2 electrode system. MATERIALS AND METHODS: In ex vivo bovine liver, the parameters of the experimental set-up were changed one by one. In a second step, a finite element method (FEM) modelling of the experiment was performed to better understand the experimental findings. RESULTS: The optimal power to obtain complete ablation in the shortest time was 50-60 W. Performing an ablation until impedance rise was superior to ablation for a fixed duration. Increasing electrode diameter improved completeness of ablation due to lower temperature along the electrodes. A chessboard pattern of electrode polarity was inferior to a row pattern due to an electric field void in between the electrodes. Variability of ablation size was limited. The FEM correctly simulated and explained the findings in ex vivo liver. CONCLUSIONS: These experiments and FEM modelling allowed a better insight in the factors influencing the ablation zone in a bipolar 2 × 2 electrode RF system. With optimal parameters, complete ablation was obtained quickly and with limited variability. This knowledge will be useful to build a larger system with x × y electrodes for MRFA.

Bipolar radiofrequency ablation with four electrodes: ex vivo liver experiments and finite element method analysis. Influence of inter-electrode distance on coagulation size and geometry.

PURPOSE: The aim of this study was to develop an electrode system with simple needle electrodes which would allow a reliable and predictable ablation zone with radiofrequency ablation (RFA). MATERIALS AND METHODS: In the first step, four parallel electrodes (active length 3 cm, diameter 1.8 mm) were inserted in ex vivo bovine liver. A power of 50 W was applied between two pairs of electrodes for 10 min or until current shut-off due to impedance rise. In the second step, the influence of changing inter-electrode distance on coagulation size and geometry was measured. In the third step, a finite element method (FEM) analysis of the experiment was performed to better understand the experimental findings. RESULTS: A bipolar four-electrode system with templates adjusting the inter-electrode distance was successfully developed for ex vivo experiments. A complete and reliable coagulation zone of a 3 × 2 × 2-cm block was obtained most efficiently with an inter-electrode distance of 2 cm in 5.12 ± 0.71 min. Above 2 cm, coagulation was incomplete due to a too low electric field, as demonstrated by the FEM analysis. CONCLUSIONS: The optimal inter-electrode distance of the present bipolar four-electrode system was 2 cm, allowing a reliable and predictable ablation zone in ex vivo liver. The FEM analysis correctly simulated and explained the findings in ex vivo liver. The experimental set-up may serve as a platform to gain more insight and to optimise the application of RFA by means of four or more simple needle electrodes.

Hypothesis: What is the Best We Can Do with Hydroxychloroquine for COVID-19?

There are widespread anecdotal reports of seemingly successful treatment among the early (three to seven days from symptoms) stage coronavirus disease 2019 (COVID-19) patients with the drug hydroxychloroquine (HCQ), and randomized placebo-controlled trials of HCQ in outpatient settings are underway. In this note, we (1) report observational evidence and present scientific reasoning as to why early treatment with HCQ may succeed while treatment later in the disease progression is likely to fail and (2) hypothesize a public health regime under which HCQ may be used to mitigate the impact of the current pandemic.

Radiofrequency ablation with four electrodes as a building block for matrix radiofrequency ablation: Ex vivo liver experiments and finite element method modelling. Influence of electric and activation mode on coagulation size and geometry.

PURPOSE: Radiofrequency ablation (RFA) is increasingly being used to treat unresectable liver tumors. Complete ablation of the tumor and a safety margin is necessary to prevent local recurrence. With current electrodes, size and shape of the ablation zone are highly variable leading to unsatisfactory local recurrence rates, especially for tumors >3 cm. In order to improve predictability, we recently developed a system with four simple electrodes with complete ablation in between the electrodes. This rather small but reliable ablation zone is considered as a building block for matrix radiofrequency ablation (MRFA). In the current study we explored the influence of the electric mode (monopolar or bipolar) and the activation mode (consecutive, simultaneous or switching) on the size and geometry of the ablation zone. MATERIALS AND METHODS: The four electrode system was applied in ex vivo bovine liver. The electric and the activation mode were changed one by one, using constant power of 50 W in all experiments. Size and geometry of the ablation zone were measured. Finite element method (FEM) modelling of the experiment was performed. RESULTS: In ex vivo liver, a complete and predictable coagulation zone of a 3 × 2 × 2 cm block was obtained most efficiently in the bipolar simultaneous mode due to the combination of the higher heating efficacy of the bipolar mode and the lower impedance by the simultaneous activation of four electrodes, as supported by the FEM simulation. CONCLUSIONS: In ex vivo liver, the four electrode system used in a bipolar simultaneous mode offers the best perspectives as building block for MRFA. These results should be confirmed by in vivo experiments.

Radiofrequency ablation versus resection for resectable colorectal liver metastases: time for a randomized trial?

BACKGROUND: Surgical resection is the gold standard in the treatment of resectable colorectal liver metastases (CRLM). In several centers, resection is being replaced by radiofrequency ablation (RFA), even though there is no evidence yet from randomized trials to support this. The aim of this study was to critically review the oncological evidence for and against the use of RFA for resectable CRLM. METHODS: An exhaustive review of RFA of colorectal metastases was carried out. RESULTS: Five-year survival data after RFA for resectable CRLM are not available. Percutaneous RFA is associated with worse local control, worse staging, and a small risk of electrode track seeding when compared with resection (level V evidence). For tumors

Influence of approach on outcome in radiofrequency ablation of liver tumors.

In this article some recent data concerning the approach on radiofrequency ablation (RFA) of liver tumors are reviewed. Specifically, several critical statements between surgical and percutaneous approach are raised and discussed: (1) Open approach may lead to a higher complication rate; (2) Temporary occlusion of hepatic inflow during surgical approach may lead to a higher rate of ablation of the liver tumors; (3) Surgical approach may permit better targeting of the tumor to be ablated. (4) Surgical approach may discover additional liver tumors. Finally, several conclusions and recommendations are also addressed.

Radiofrequency ablation versus resection for resectable colorectal liver metastases: time for a randomized trial? An update.

BACKGROUND: A recent proposal of a randomized trial comparing resection and radiofrequency ablation (RFA) in a selected subgroup of patients with small resectable colorectal liver metastases (CRLM) has initiated a debate on this issue. Meanwhile, new data have been published. The aim of the study was to update and critically review the oncological evidence in favor of and against the use of RFA for resectable CRLM in general and in favor of and against conducting a randomized trial in a selected subgroup of patients. METHODS: An exhaustive review was carried out of papers and abstracts on RFA of colorectal metastases published before July 15, 2008. RESULTS: Local recurrence rate after resection of CRLM is 1.2-10.4%. Local recurrence rate after RFA of CRLM is between 1.7 and 66.7%. For tumors <3 cm, local control after open RFA is equivalent to resection. Local recurrence rates, however, are higher for larger tumors and for the percutaneous and laparoscopic route. Accumulating evidence suggests that RFA and resection induce profoundly different biological effects, which may influence survival. CONCLUSIONS: Local recurrence rate after open RFA for CRLM <3 cm seems to be equivalent to resection. A randomized trial under strict conditions would be justified in this subgroup of patients. A randomized trial is currently not justified for larger tumors or for percutaneous or laparoscopic RFA, since local recurrence rates in these groups are too high to be acceptable for resectable tumors.

A piecewise function of resistivity of liver: determining parameters with finite element analysis of radiofrequency ablation.

Radiofrequency ablation (RFA) is a widely used thermal treatment for liver tumors. Knowledge about the resistivity of liver is a prerequisite for the predictability of producible thermo-necrosis with RFA. Most research to date has focused on performing specific experiments to determine the resistivity of a given liver. This work aims to determine the resistivity from the time course of impedance obtained in RFA. We assume that the liver resistivity obeys a piecewise function of temperature. We determine in this work the means and standard derivations of parameters in the resistivity function with finite element analysis of ex vivo bipolar RFA. We experimentally found the temperature at the electrode equal to 125.2 °C. This finding validates a parameter in the function relating to the temperature at which the resistivity starts to rise exponentially. We conclude that it is feasible and reliable to characterize the resistivity function of liver in using the time course of impedance from RFA. This work opens a pathway for the automatic determination of the patient specific resistivity of in vivo liver.

A methodology for constraining power in finite element modeling of radiofrequency ablation.

Radiofrequency ablation (RFA) is a minimally invasive thermal therapy for the treatment of cancer, hyperopia, and cardiac tachyarrhythmia. In RFA, the power delivered to the tissue is a key parameter. The objective of this study was to establish a methodology for the finite element modeling of RFA with constant power. Because of changes in the electric conductivity of tissue with temperature, a nonconventional boundary value problem arises in the mathematic modeling of RFA: neither the voltage (Dirichlet condition) nor the current (Neumann condition), but the power, that is, the product of voltage and current was prescribed on part of boundary. We solved the problem using Lagrange multiplier: the product of the voltage and current on the electrode surface is constrained to be equal to the Joule heating. We theoretically proved the equality between the product of the voltage and current on the surface of the electrode and the Joule heating in the domain. We also proved the well-posedness of the problem of solving the Laplace equation for the electric potential under a constant power constraint prescribed on the electrode surface. The Pennes bioheat transfer equation and the Laplace equation for electric potential augmented with the constraint of constant power were solved simultaneously using the Newton-Raphson algorithm. Three problems for validation were solved. Numerical results were compared either with an analytical solution deduced in this study or with results obtained by ANSYS or experiments. This work provides the finite element modeling of constant power RFA with a firm mathematical basis and opens pathway for achieving the optimal RFA power.

Electrodes and multiple electrode systems for radio frequency ablation: a proposal for updated terminology.

OBJECTIVE: Research on technology for soft tissue radio frequency (RF) ablation is ever advancing. A recent proposal to standardize terminology of RF electrodes only deals with the most frequently used commercial electrodes. The aim of this study was to develop a logical, versatile, and unequivocal terminology to describe present and future RF electrodes and multiple electrode systems. MATERIALS AND METHODS: We have carried out a PubMed search for the period from January 1st 1990 to July 1st 2004 in seven languages and contacted the six major companies that produce commercial RF electrodes for use in the liver. In a first step, names have been defined for the five existing basic designs of single-shaft electrode. These names had to be unequivocal, descriptive of the electrode's main working principle and as short as possible. In a second step, these basic names have been used as building blocks to describe the single-shaft electrodes in combination designs. In a third step, using the same principles, a logical terminology has been developed for multiple electrode systems, defined as the combined use of more than one single-shaft RF electrode. RESULTS: Five basic electrode designs were identified and defined: plain, cooled, expandable, wet, and bipolar electrodes. Combination designs included cooled-wet, expandable-wet, bipolar-wet, bipolar-cooled, bipolar-expandable, and bipolar-cooled-wet electrodes. Multiple electrode systems could be characterized by describing several features: the number of electrodes that were used (dual, triple, etc.), the electric mode (monopolar or bipolar), the activation mode (consecutive, simultaneous or switching), the site of the inserted electrodes (monofocal or multifocal), and the type of single-shaft electrodes that were used. CONCLUSION: In this terminology, the naming ofthe basic electrode designs has been based on objective criteria. The short and unequivocal names of the basic designs can easily be combined to describe current and future combination electrodes. This terminology provides an exact and complete description of the versatile novel multiple electrode systems.

Rat model of cholelithiasis with human gallstones implanted in cholestasis-induced virtual gallbladder.

AIM: To facilitate translational research on cholelithiasis, we have developed a rat model of human gallstones by exploiting the unique biliopancreatic features of this species. METHODS: Under anesthesia, 16 adult rats of equal genders underwent two times of abdominal surgery. First, their common bile duct (CBD) was ligated to cause cholestasis by total biliary obstruction (TBO). On day 0, 1, 3, 7, 14, 21 and 28 after TBO, magnetic resonance imaging (MRI) was conducted to monitor the dilatation of the CBD, and blood was sampled to analyze total serum bilirubin (TSB). Secondly, on day 30, the abdomen was re-opened and gallstone(s) collected from human patients were implanted in the dilated CBD as a virtual gallbladder (VGB), which was closed by suture ligation. This rat cholelithiasis model was examined by MRI, clinical observation, microcholangiography and histology. RESULTS: All rats survived two laparotomies. After ligation, the CBD was dilated to a stable size of 4 to 30 mm in diameter on day 21-28, which became a VGB. The rats initially showed signs of jaundice that diminished over time, which paralleled with the evolving TSB levels from 0.6 ± 0.3 mg/dL before ligation, through a peak of 10.9 ± 1.9 mg/dL on day 14, until a nearly normalized value after day 28. The dilated CBD with thickened wall allowed an incision for implantation of human gallstones of 1-10 mm in diameter. The rat cholelithiasis was proven by in vivo MRI and postmortem microcholangiography and histomorphology. CONCLUSION: A rat model cholelithiasis with human gallstones has been established, which proves feasible, safe, reliable, nontoxic and cost-effective. Given the gallstones of human origin, applications of this model may be of help in translational research such as optical detection and lysis of gallstones by systemic drug administration.

Differential diagnosis of gallstones by using hypericin as a fluorescent optical imaging agent.

AIM: To explore the feasibility of using hypericin as an optical imaging probe with affinity for cholesterol for differential fluorescent detection of human gallstones. METHODS: Cholesterol, mixed and pigment stones from cholecystectomy patients were incubated with hypericin or solvent. After 72 h, the stones were analysed for fluorescence (365 nm) and treated with 2-propanol/dimethyl sulfoxide for high performance liquid chromatography (HPLC) analysis. Rats with virtual gallbladder containing human cholesterol, mixed or pigment gallstones (VGHG) received 5 mg/kg hypericin or solvent and VGHG rats with cholesterol stones were given different hypericin doses (5-15 mg/kg). Twelve hours later, the stones were analysed at 365 nm. Biliary excretion and metabolites of hypericin were assessed in common bile duct (CBD) cannulated rats for 9 h using fluorospectrometry, HPLC and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: Homogeneous high fluorescence was seen on cholesterol stones either pre-incubated with hypericin or extracted from VGHG rats receiving hypericin. Mixed stones showed a dotted fluorescent pattern, whereas pigment and solvent-treated ones lacked fluorescence. HPLC showed 7.68, 6.65 and 0.08 × 10(-3) M of cholesterol in extracts from cholesterol, mixed, and pigment gallstones, respectively. Hypericin accounted for 2.0, 0.5 and 0.2 × 10(-6) M in that order. On cholesterol stones from VGHG rats receiving different hypericin doses, a positive correlation was observed between dose and fluorescence. In the bile from CBD-cannulated rats, fluorescence represented 20% of the injected dose with two peaks in 9 h. HPLC analysis revealed that hypericin conjugates reached 60% of the peak area. By MALDI-TOF MS, hypericin-glucuronide was detected. CONCLUSION: This study proves the potential use of hypericin for differential fluorescent detection of human gallstones regarding their chemical composition.

Survival benefit of adding Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) at the different time-points of treatment of ovarian cancer: review of evidence.

The standard treatment for advanced ovarian cancer consists in complete cytoreductive surgery (CRS) and intravenous combination chemotherapy with a platinum compound and a taxane. Although response rates to initial therapy are high, many patients will recur and die of peritoneal carcinomatosis. The addition of Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) to the standard therapy aims at increasing survival by reducing peritoneal recurrence. This review describes the survival results of HIPEC at the different time-points of the treatment of ovarian cancer: at upfront CRS, at interval CRS, at consolidation CRS after complete response to initial therapy, at secondary CRS after incomplete response, at salvage CRS for recurrence and as palliative treatment without CRS for unresectable ovarian cancer with chemotherapy resistant ascites. The available evidence suggests that a potential survival benefit of adding HIPEC may be largest in the settings of secondary CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer, two time-points representing failure of initial standard therapy. There is much less evidence for a potential benefit of HIPEC for less advanced stages (I-II) and for earlier time-points in the treatment of ovarian cancer (upfront, interval and consolidation). Postoperative mortality is not higher after CRS and HIPEC (0.7%) than after CRS only (1.4%). Four randomised trials are ongoing and their results are eagerly awaited. Palliative HIPEC without CRS might be used more in patients with incapacitating ascites due to recurrent ovarian cancer which has become resistant to systemic chemotherapy.

Experimental and clinical radiofrequency ablation: proposal for standardized description of coagulation size and geometry.

BACKGROUND: Radiofrequency (RF) ablation is used to obtain local control of unresectable tumors in liver, kidney, prostate, and other organs. Accurate data on expected size and geometry of coagulation zones are essential for physicians to prevent collateral damage and local tumor recurrence. The aim of this study was to develop a standardized terminology to describe the size and geometry of these zones for experimental and clinical RF. METHODS: In a first step, the essential geometric parameters to accurately describe the coagulation zones and the spatial relationship between the coagulation zones and the electrodes were defined. In a second step, standard terms were assigned to each parameter. RESULTS: The proposed terms for single-electrode RF ablation include axial diameter, front margin, coagulation center, maximal and minimal radius, maximal and minimal transverse diameter, ellipticity index, and regularity index. In addition a subjective description of the general shape and regularity is recommended. CONCLUSIONS: Adoption of the proposed standardized description method may help to fill in the many gaps in our current knowledge of the size and geometry of RF coagulation zones.

Magnetic resonance imaging after radiofrequency ablation in a rodent model of liver tumor: tissue characterization using a novel necrosis-avid contrast agent.

We exploited a necrosis-avid contrast agent ECIV-7 for magnetic resonance imaging (MRI) in rodent liver tumors after radiofrequency ablation (RFA). Rats bearing liver rhabdomyosarcoma (R1) were randomly allocated to three groups: group I, complete RFA, group II, incomplete RFA, and group III, sham ablation. Within 24 h after RFA, T1-weighted (T1-w) MRI was performed before and after injection of ECIV-7 at 0.05 mmol/kg and followed up from 6-24 h. Signal intensities (SIs) were measured with relative enhancement (RE) and contrast ratio (CR) calculated. The MRI findings were verified histomorphologically. On plain T1-w MRI the contrasts between normal liver, RFA lesion, residual and/or intact tumor were vague. Early after administration of ECIV-7, the liver SI was strongly enhanced (RE=40-50%), leaving the RFA lesion as a hypointense region in groups I and II. At delayed phase, two striking peri-ablational enhancement patterns appeared (RE=90% and CR=1.89%), i.e., "O" type of hyperintense rim in group I and "C" type of incomplete rim in group II. These MRI manifestations could be proven histologically. In this study, tissue components after RFA could be characterized with discernable contrasts by necrosis-avid contrast agent (NACA)-enhanced MRI, especially at delayed phase. This approach may prove useful for defining the ablated area and identifying residual tumor after RFA.

Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of contributing factors.

OBJECTIVE: The purpose of this study was to analyze the factors that influence local recurrence after radiofrequency coagulation of liver tumors. SUMMARY BACKGROUND DATA: Local recurrence rate varies widely between 2% and 60%. Apart from tumor size as an important risk factor for local recurrence, little is known about the impact of other factors. METHODS: An exhaustive literature search was carried out for the period from January 1, 1990 to January 1, 2004. Only series with a minimal follow-up of 6 months and/or mean follow-up of 12 months were included. Univariate and multivariate meta-analyses were carried out. RESULTS: Ninety-five independent series were included, allowing the analysis of the local recurrence rate of 5224 treated liver tumors. In a univariate analysis, tumor-dependent factors with significantly less local recurrences were: smaller size, neuroendocrine metastases, nonsubcapsular location, and location away from large vessels. Physician-dependent favorable factors were: surgical (open or laparoscopic) approach, vascular occlusion, general anesthesia, a 1-cm intentional margin, and a greater physician experience. In a multivariate analysis, significantly less local recurrences were observed for small size (P < 0.001) and a surgical (versus percutaneous) approach (P < 0.001). CONCLUSIONS: Radiofrequency coagulation by laparoscopy or laparotomy results in superior local control, independent of tumor size. The percutaneous route should mainly be reserved for patients who cannot tolerate a laparoscopy or laparotomy. The short-term benefits of less invasiveness for the percutaneous route do not outweigh the longer-term higher risk of local recurrence.

Electrodes and multiple electrode systems for radiofrequency ablation: a proposal for updated terminology.

Research on technology for soft tissue radiofrequency (RF) ablation is ever advancing. A recent proposal to standardise terminology of RF electrodes only deals with the most frequently used commercial electrodes. The aim of this study was to develop a logical, versatile and unequivocal terminology to describe present and future RF electrodes and multiple electrode systems. We have carried out a PubMed search for the period from January 1 1990 to July 1 2004 in seven languages and contacted the six major companies that produce commercial RF electrodes for use in clinic. In a first step, names have been defined for the five existing basic designs of single-shaft electrode. These names had to be unequivocal, descriptive of the electrode's main working principle and as short as possible. In a second step, these basic names have been used as building blocks to describe the single-shaft electrodes in combination designs. In a third step, using the same principles, a logical terminology has been developed for multiple electrode systems, defined as the combined use of more than one single-shaft RF electrode. Five basic electrode designs were identified and defined: plain, cooled, expandable, wet and bipolar electrodes. Combination designs included cooled-wet, expandable-wet, bipolar-wet, bipolar-cooled, bipolar-expandable and bipolar-cooled-wet electrodes. Multiple electrode systems could be characterised by describing several features: the number of electrodes that were used (dual, triple, ...), the electric mode (monopolar or bipolar), the activation mode (consecutive, simultaneous or switching), the site of the inserted electrodes (monofocal or multifocal), and the type of single shaft electrodes that were used. In this terminology, the naming of the basic electrode designs has been based on objective criteria. The short and unequivocal names of the basic designs can easily be combined to describe current and future combination electrodes. This terminology provides an exact and complete description of the versatile novel multiple electrode systems.

Factors affecting mortality in generalized postoperative peritonitis: multivariate analysis in 96 patients.

Mortality of generalized postoperative peritonitis remains high at 22% to 55%. The aim of the present study was to identify prognostic factors by means of univariate and multivariate analysis in a consecutive series of 96 patients. Mortality was 30%. Inability to clear the abdominal infection or to control the septic source, older age, and unconsciousness were significant factors related to mortality in the multivariate analysis. Failure to control the peritoneal infection (15%) was always fatal and correlated with failed septic source control, high Acute Physiology and Chronic Health Evaluation (APACHE) II score, and male gender. Failure to control the septic source (8%) also was always fatal and correlated with high APACHE II score and therapeutic delay. In patients with immediate source control, residual peritonitis occurred in 9% after purulent or biliary peritonitis and in 41% after fecal peritonitis ( p = 0.002). In patients without immediate control of the septic source, delayed control was still achieved in 100% after a planned relaparotomy (PR) strategy versus 43% after an on-demand relaparotomy (ODR) strategy ( p = 0.018). In the same patients, mortality was 0% in the PR group versus 64% in the ODR group ( p = 0.007). Early relaparotomy is related to improved septic source control. After relaparotomy for generalized postoperative peritonitis, a PR strategy is indicated whenever source control is uncertain. It also might decrease mortality in fecal peritonitis. An ODR approach is adequate for purulent and biliary peritonitis with safe septic source control.