Predictive therapeutic planning for irreversible electroporation treatment of spontaneous malignant glioma.

PURPOSE: Irreversible electroporation (IRE) has been developed as a promising minimally invasive treatment to ablate spontaneous brain tumors with pulsed electric fields in canine patients. The purpose of the study is to determine the Peleg-Fermi parameters needed to incorporate pulse number and pulse duration into the therapeutic planning of IRE. METHODS: Seven canine patients were treated with IRE for spontaneous malignant glioma with MRI-based treatment planning. The treatment planning method consists of building patient-specific finite element models and using them to compute electric fields used in the IRE treatment. We evaluate the predictive power of tumor coverage with electric field alone vs. cell kill probability using radiographically confirmed clinical outcomes. RESULTS: Results of post-treatment diagnostic imaging, tumor biopsies, and neurological examinations indicated successful tumor ablation without significant direct neurotoxicity in six of the seven dogs. Objective tumor responses were seen in four (80%) of five dogs with quantifiable target lesions according to RANO criteria. Two dogs experienced survivals in excess of 1 yr, including one dog that resulted in complete response to IRE treatment for 5+ years to date. Tumor fraction exposed to electric field over 600 V/cm was between 0.08 and 0.73, while tumor fraction exposed to electric field over 300 V/cm was between 0.17 and 0.95. Probability of cell kill of ≥ 90% was found in tumor volume fractions between 0.21 and 0.99. CONCLUSIONS: We conclude that IRE is a safe and effective minimally invasive treatment for malignant glioma and can be predicted with the Peleg-Fermi cell kill probability function. A tumor coverage of ≥ 0.9 at a cell kill probability ≥ 90% can be used to guide IRE treatments of spontaneous malignant glioma based on the radiographically confirmed clinical outcomes achieved.

Web-based tool for visualization of electric field distribution in deep-seated body structures and planning of electroporation-based treatments.

BACKGROUND: Treatments based on electroporation are a new and promising approach to treating tumors, especially non-resectable ones. The success of the treatment is, however, heavily dependent on coverage of the entire tumor volume with a sufficiently high electric field. Ensuring complete coverage in the case of deep-seated tumors is not trivial and can in best way be ensured by patient-specific treatment planning. The basis of the treatment planning process consists of two complex tasks: medical image segmentation, and numerical modeling and optimization. METHODS: In addition to previously developed segmentation algorithms for several tissues (human liver, hepatic vessels, bone tissue and canine brain) and the algorithms for numerical modeling and optimization of treatment parameters, we developed a web-based tool to facilitate the translation of the algorithms and their application in the clinic. The developed web-based tool automatically builds a 3D model of the target tissue from the medical images uploaded by the user and then uses this 3D model to optimize treatment parameters. The tool enables the user to validate the results of the automatic segmentation and make corrections if necessary before delivering the final treatment plan. RESULTS: Evaluation of the tool was performed by five independent experts from four different institutions. During the evaluation, we gathered data concerning user experience and measured performance times for different components of the tool. Both user reports and performance times show significant reduction in treatment-planning complexity and time-consumption from 1-2 days to a few hours. CONCLUSIONS: The presented web-based tool is intended to facilitate the treatment planning process and reduce the time needed for it. It is crucial for facilitating expansion of electroporation-based treatments in the clinic and ensuring reliable treatment for the patients. The additional value of the tool is the possibility of easy upgrade and integration of modules with new functionalities as they are developed.

Segmentation of hepatic vessels from MRI images for planning of electroporation-based treatments in the liver.

INTRODUCTION: Electroporation-based treatments rely on increasing the permeability of the cell membrane by high voltage electric pulses delivered to tissue via electrodes. To ensure that the whole tumor is covered by the sufficiently high electric field, accurate numerical models are built based on individual patient geometry. For the purpose of reconstruction of hepatic vessels from MRI images we searched for an optimal segmentation method that would meet the following initial criteria: identify major hepatic vessels, be robust and work with minimal user input. MATERIALS AND METHODS: We tested the approaches based on vessel enhancement filtering, thresholding, and their combination in local thresholding. The methods were evaluated on a phantom and clinical data. RESULTS: Results show that thresholding based on variance minimization provides less error than the one based on entropy maximization. Best results were achieved by performing local thresholding of the original de-biased image in the regions of interest which were determined through previous vessel-enhancement filtering. In evaluation on clinical cases the proposed method scored in average sensitivity of 93.68%, average symmetric surface distance of 0.89 mm and Hausdorff distance of 4.04 mm. CONCLUSIONS: The proposed method to segment hepatic vessels from MRI images based on local thresholding meets all the initial criteria set at the beginning of the study and necessary to be used in treatment planning of electroporation-based treatments: it identifies the major vessels, provides results with consistent accuracy and works completely automatically. Whether the achieved accuracy is acceptable or not for treatment planning models remains to be verified through numerical modeling of effects of the segmentation error on the distribution of the electric field.

Intraoperative electrochemotherapy of colorectal liver metastases.

BACKGROUND AND OBJECTIVES: Electrochemotherapy is effective in treatment of various cutaneous tumors and could be translated into treatment of deep-seated tumors. With this aim a prospective pilot study was conducted to evaluate feasibility, safety, and efficacy of intraoperative electrochemotherapy in the treatment of colorectal liver metastases. METHODS: Electrochemotherapy with bleomycin was performed during open surgery, by insertion of long needle electrodes into and around the tumor according to the individualized pretreatment plan. RESULTS: A 29 metastases in 16 patients were treated in 16 electrochemotherapy sessions. No immediate (intraoperative) and/or postoperative serious adverse events related to electrochemotherapy were observed. Radiological evaluation of all the treated metastases showed 85% complete responses and 15% partial responses. In a group of seven patients that underwent a second operation at 6-12 weeks after the first one, during which electrochemotherapy was performed, the histology of resected metastases treated by electrochemotherapy showed less viable tissue (P = 0.001) compared to non-treated ones. CONCLUSIONS: Electrochemotherapy of colorectal liver metastases proved to be feasible, safe, and efficient treatment modality, providing its specific place in difficult to treat metastases, located in the vicinity of major hepatic vessels, not amenable to surgery or radiofrequency ablation.

Electroporation-based treatment planning for deep-seated tumors based on automatic liver segmentation of MRI images.

Electroporation is the phenomenon that occurs when a cell is exposed to a high electric field, which causes transient cell membrane permeabilization. A paramount electroporation-based application is electrochemotherapy, which is performed by delivering high-voltage electric pulses that enable the chemotherapeutic drug to more effectively destroy the tumor cells. Electrochemotherapy can be used for treating deep-seated metastases (e.g. in the liver, bone, brain, soft tissue) using variable-geometry long-needle electrodes. To treat deep-seated tumors, patient-specific treatment planning of the electroporation-based treatment is required. Treatment planning is based on generating a 3D model of the organ and target tissue subject to electroporation (i.e. tumor nodules). The generation of the 3D model is done by segmentation algorithms. We implemented and evaluated three automatic liver segmentation algorithms: region growing, adaptive threshold, and active contours (snakes). The algorithms were optimized using a seven-case dataset manually segmented by the radiologist as a training set, and finally validated using an additional four-case dataset that was previously not included in the optimization dataset. The presented results demonstrate that patient's medical images that were not included in the training set can be successfully segmented using our three algorithms. Besides electroporation-based treatments, these algorithms can be used in applications where automatic liver segmentation is required.

Planning of electroporation-based treatments using Web-based treatment-planning software.

Electroporation-based treatment combining high-voltage electric pulses and poorly permanent cytotoxic drugs, i.e., electrochemotherapy (ECT), is currently used for treating superficial tumor nodules by following standard operating procedures. Besides ECT, another electroporation-based treatment, nonthermal irreversible electroporation (N-TIRE), is also efficient at ablating deep-seated tumors. To perform ECT or N-TIRE of deep-seated tumors, following standard operating procedures is not sufficient and patient-specific treatment planning is required for successful treatment. Treatment planning is required because of the use of individual long-needle electrodes and the diverse shape, size and location of deep-seated tumors. Many institutions that already perform ECT of superficial metastases could benefit from treatment-planning software that would enable the preparation of patient-specific treatment plans. To this end, we have developed a Web-based treatment-planning software for planning electroporation-based treatments that does not require prior engineering knowledge from the user (e.g., the clinician). The software includes algorithms for automatic tissue segmentation and, after segmentation, generation of a 3D model of the tissue. The procedure allows the user to define how the electrodes will be inserted. Finally, electric field distribution is computed, the position of electrodes and the voltage to be applied are optimized using the 3D model and a downloadable treatment plan is made available to the user.

Patient-specific treatment planning of electrochemotherapy: procedure design and possible pitfalls.

Electrochemotherapy uses electroporation for enhancing chemotherapy. Electrochemotherapy can be performed using standard operating procedures with predefined electrode geometries, or using patient-specific treatment planning to predict electroporation. The latter relies on realistic computer models to provide optimal results (i.e. electric field distribution as well as electrodes' position and number) and is suitable for treatment of deep-seated tumors. Since treatment planning for deep-seated tumors has been used in radiotherapy, we expose parallelisms with radiotherapy in order to establish the procedure for electrochemotherapy of deep-seated tumors. We partitioned electrochemotherapy in the following phases: the mathematical model of electroporation, treatment planning, set-up verification, treatment delivery and monitoring, and response assessment. We developed a conceptual treatment planning software that incorporates mathematical models of electroporation. Preprocessing and segmentation of the patient's medical images are performed, and a 3D model is constructed which allows placement of electrodes and implementation of the mathematical model of electroporation. We demonstrated the feasibility of electrochemotherapy of deep-seated tumors treatment planning within a clinical study where treatment planning contributed to the effective electrochemotherapy treatment of deep-seated colorectal metastases in the liver. The described procedure can provide medical practitioners with information on using electrochemotherapy in the clinical setting. The main aims of this paper are: 1) to present the procedure for treating deep-seated tumors by electrochemotherapy based on patient-specific treatment planning, and 2) to identify gaps in knowledge and possible pitfalls of such procedure.

Blumlein configuration for high-repetition-rate pulse generation of variable duration and polarity using synchronized switch control.

Blumlein generators are used in different applications such as radars, lasers, and also recently in various biomedical studies, where the effects of high-voltage nanosecond pulses on biological cells are evaluated. In these studies, it was demonstrated that by applying high-voltage nanosecond pulses to cells, plasma membrane and cell organelles are permeabilized. As suggested in a recent publication, the repetition rate and polarity of nanosecond high-voltage pulses could have an important effect on the electropermeabilization process, and consequently, on the observed phenomena. Therefore, we designed a new Blumlein configuration that enables a higher repetition rate of variable duration of either bipolar or unipolar high-voltage pulses. We achieved a maximal pulse repetition rate of 1.1 MHz. However, theoretically, this rate could be even higher. We labeled endocytotic vesicles with lucifer yellow and added propidium iodide to a cell suspension for testing the cell plasma membrane integrity, so we were able to observe the permeabilization of endocytotic vesicles and the cell plasma membrane at the same time. The new design of pulse generator was built, verified, and also tested in experiments. The resulting flexibility and variability allow further in vitro experiments to determine the importance of the pulse repetition rate and pulse polarity on membrane permeabilization -- both of the cell plasma membrane as well as of cell organelle membranes.