Optimization of multi-electrode implant configurations and programming for the delivery of non-ablative electric fields in intratumoral modulation therapy.

PURPOSE: Application of low intensity electric fields to interfere with tumor growth is being increasingly recognized as a promising new cancer treatment modality. Intratumoral modulation therapy (IMT) is a developing technology that uses multiple electrodes implanted within or adjacent tumor regions to deliver electric fields to treat cancer. In this study, the determination of optimal IMT parameters was cast as a mathematical optimization problem, and electrode configurations, programming, optimization, and maximum treatable tumor size were evaluated in the simplest and easiest to understand spherical tumor model. The establishment of electrode placement and programming rules to maximize electric field tumor coverage designed specifically for IMT is the first step in developing an effective IMT treatment planning system. METHODS: Finite element method electric field computer simulations for tumor models with 2 to 7 implanted electrodes were performed to quantify the electric field over time with various parameters, including number of electrodes (2 to 7), number of contacts per electrode (1 to 3), location within tumor volume, and input waveform with relative phase shift between 0 and 2π radians. Homogeneous tissue specific conductivity and dielectric values were assigned to the spherical tumor and surrounding tissue volume. In order to achieve the goal of covering the tumor volume with a uniform threshold of 1 V/cm electric field, a custom least square objective function was used to maximize the tumor volume covered by 1 V/cm time averaged field, while maximizing the electric field in voxels receiving less than this threshold. An additional term in the objective function was investigated with a weighted tissue sparing term, to minimize the field to surrounding tissues. The positions of the electrodes were also optimized to maximize target coverage with the fewest number of electrodes. The complexity of this optimization problem including its non-convexity, the presence of many local minima, and the computational load associated with these stochastic based optimizations led to the use of a custom pattern search algorithm. Optimization parameters were bounded between 0 and 2π radians for phase shift, and anywhere within the tumor volume for location. The robustness of the pattern search method was then evaluated with 50 random initial parameter values. RESULTS: The optimization algorithm was successfully implemented, and for 2 to 4 electrodes, equally spaced relative phase shifts and electrodes placed equidistant from each other was optimal. For 5 electrodes, up to 2.5 cm diameter tumors with 2.0 V, and 4.1 cm with 4.0 V could be treated with the optimal configuration of a centrally placed electrode and 4 surrounding electrodes. The use of 7 electrodes allow for 3.4 cm diameter coverage at 2.0 V and 5.5 cm at 4.0 V. The evaluation of the optimization method using 50 random initial parameter values found the method to be robust in finding the optimal solution. CONCLUSIONS: This study has established a robust optimization method for temporally optimizing electric field tumor coverage for IMT, with the adaptability to optimize a variety of parameters including geometrical and relative phase shift configurations

Spatiotemporally dynamic electric fields for brain cancer treatment: an in vitro investigation

Objective. The treatment of glioblastoma (GBM) using low intensity electric fields (∼1 V cm-1) is being investigated using multiple implanted bioelectrodes, which was termed intratumoral modulation therapy (IMT). Previous IMT studies theoretically optimized treatment parameters to maximize coverage with rotating fields, which required experimental investigation. In this study, we employed computer simulations to generate spatiotemporally dynamic electric fields, designed and purpose-built an IMT device for in vitro experiments, and evaluated the human GBM cellular responses to these fields. Approach. After measuring the electrical conductivity of the in vitro culturing medium, we designed experiments to evaluate the efficacy of various spatiotemporally dynamic fields: (a) different rotating field magnitudes, (b) rotating versus non-rotating fields, (c) 200 kHz versus 10 kHz stimulation, and (d) constructive versus destructive interference. A custom printed circuit board (PCB) was fabricated to enable four-electrode IMT in a 24-well plate. Patient derived GBM cells were treated and analyzed for viability using bioluminescence imaging. Main results. The optimal PCB design had electrodes placed 6.3 mm from the center. Spatiotemporally dynamic IMT fields at magnitudes of 1, 1.5, and 2 V cm-1reduced GBM cell viability to 58%, 37% and 2% of sham controls respectively. Rotating versus non-rotating, and 200 kHz versus 10 kHz fields showed no statistical difference. The rotating configuration yielded a significant reduction (p\u3c 0.01) in cell viability (47 ± 4%) compared to the voltage matched (99 ± 2%) and power matched (66 ± 3%) destructive interference cases. Significance. We found the most important factors in GBM cell susceptibility to IMT are electric field strength and homogeneity. Spatiotemporally dynamic electric fields have been evaluated in this study, where improvements to electric field coverage with lower power consumption and minimal field cancellations has been demonstrated. The impact of this optimized paradigm on cell susceptibility justifies its future use in preclinical and clinical trial investigations

Planning system for the optimization of electric field delivery using implanted electrodes for brain tumor control

BACKGROUND: The use of non-ionizing electric fields from low-intensity voltage sources (\u3c 10 V) to control malignant tumor growth is showing increasing potential as a cancer treatment modality. A method of applying these low-intensity electric fields using multiple implanted electrodes within or adjacent to tumor volumes has been termed as intratumoral modulation therapy (IMT). PURPOSE: This study explores advancements in the previously established IMT optimization algorithm, and the development of a custom treatment planning system for patient-specific IMT. The practicality of the treatment planning system is demonstrated by implementing the full optimization pipeline on a brain phantom with robotic electrode implantation, postoperative imaging, and treatment stimulation. METHODS: The integrated planning pipeline in 3D Slicer begins with importing and segmenting patient magnetic resonance images (MRI) or computed tomography (CT) images. The segmentation process is manual, followed by a semi-automatic smoothing step that allows the segmented brain and tumor mesh volumes to be smoothed and simplified by applying selected filters. Electrode trajectories are planned manually on the patient MRI or CT by selecting insertion and tip coordinates for a chosen number of electrodes. The electrode tip positions and stimulation parameters (phase shift and voltage) can then be optimized with the custom semi-automatic IMT optimization algorithm where users can select the prescription electric field, voltage amplitude limit, tissue electrical properties, nearby organs at risk, optimization parameters (electrode tip location, individual contact phase shift and voltage), desired field coverage percent, and field conformity optimization. Tables of optimization results are displayed, and the resulting electric field is visualized as a field-map superimposed on the MR or CT image, with 3D renderings of the brain, tumor, and electrodes. Optimized electrode coordinates are transferred to robotic electrode implantation software to enable planning and subsequent implantation of the electrodes at the desired trajectories. RESULTS: An IMT treatment planning system was developed that incorporates patient-specific MRI or CT, segmentation, volume smoothing, electrode trajectory planning, electrode tip location and stimulation parameter optimization, and results visualization. All previous manual pipeline steps operating on diverse software platforms were coalesced into a single semi-automated 3D Slicer-based user interface. Brain phantom validation of the full system implementation was successful in preoperative planning, robotic electrode implantation, and postoperative treatment planning to adjust stimulation parameters based on actual implant locations. Voltage measurements were obtained in the brain phantom to determine the electrical parameters of the phantom and validate the simulated electric field distribution. CONCLUSIONS: A custom treatment planning and implantation system for IMT has been developed in this study and validated on a phantom brain model, providing an essential step in advancing IMT technology toward future clinical safety and efficacy investigations

Echoes of time. The mobility of Brazilian researchers and students in Portugal

A investigação que apresentamos, de caráter exploratório, recaiu sobre histórias biográficas de brasileiros que escolhem Portugal para prosseguir formação e ou investigação. Procura-se encontrar na sua experiência elos de ligação explicativos sobre as motivações e os processos que os trazem para Portugal, assim como as expetativas e os projetos que comportam para os seus futuros e que incluem, ou não, este país. Temos em conta, especialmente, a forma como essa narrativa transporta sentidos identitários decorrentes das formas de relacionamento intercultural e político entre Portugal e Brasil e formas de cooperação implícitas, assim como mapas representacionais acerca dos lugares de eleição para desenvolvimento de carreiras científicas e académicas. A nossa pesquisa incide sobre as informações recolhidas através de um inquérito por questionário e entrevistas realizadas junto de estudantes e bolseiros brasileiros em Portugal.We present an exploratory study that investigated biographical stories of Brazilians who choose to continue their education or develop research in Portugal. We sought to find in their experiences explanatory links connecting the motivations and processes that bring them to Portugal, as well as the expectations and projects that they hold for the future, which may include, or not, this country. We take into account, particularly, the way this narrative carries senses of identity arising from the forms of intercultural and political relationship between Portugal and Brazil, as well as implicit forms of cooperation and representations about the places chosen for the development of scientific and academic careers. Our research draws on information collected through a survey based on questionnaires and interviews with Brazilian students and scholarship holders in Portugal.(undefined

Reversibility of liver fibrosis

Liver fibrosis, and its end stage cirrhosis are a major cause of morbidity and mortality and therapeutic options are limited. However, the traditional view of liver disease as an irreversible process is obsolete and it is now evident that the development of liver fibrosis is a dynamic and potentially bidirectional process. Spontaneous resolution of scarring is seen in animal models of liver fibrosis and in human trials in which the stimuli responsible for chronic or repeated hepatic inflammation is successfully removed. Key players in the process are hepatic stellate cells, macrophages, MMPs and their inhibitors Timps. It is also evident that in advanced fibrotic liver disease, specific histological features define what is currently described as "irreversible" fibrosis. This includes the development of paucicellular scars enriched in extensively cross-linked matrix components, such as fibrillar collagen and elastin. Our recent work has focused on the role of macrophage metalloelastase (MMP-12) in the turnover of elastin in reversible and irreversible models of fibrosis. We have shown that elastin turnover in liver injury and fibrosis is regulated by macrophages via Mmp-12 expression, activity and ratio to its inhibitor Timp-1. Failure of elastin degradation, together with increased deposition leads to accumulation of elastin in the fibrotic scars

A prospective cohort study assessing clinical referral management & workforce allocation within a UK regional medical genetics service

Abstract Ensuring patient access to genomic information in the face of increasing demand requires clinicians to develop innovative ways of working. This paper presents the first empirical prospective observational cohort study of UK multi-disciplinary genetic service delivery. It describes and explores collaborative working practices including the utilisation and role of clinical geneticists and non-medical genetic counsellors. Six hundred and fifty new patients referred to a regional genetics service were tracked through 850 clinical contacts until discharge. Referral decisions regarding allocation of lead health professional assigned to the case were monitored, including the use of initial clinical contact guidelines. Significant differences were found in the cases led by genetic counsellors and those led by clinical geneticists. Around a sixth, 16.8% (109/650) of referrals were dealt with by a letter back to the referrer or re-directed to another service provider and 14.8% (80/541) of the remaining patients chose not to schedule an appointment. Of the remaining 461 patients, genetic counsellors were allocated as lead health professional for 46.2% (213/461). A further 61 patients did not attend. Of those who did, 86% (345/400) were discharged after one or two appointments. Genetic counsellors contributed to 95% (784/825) of total patient contacts. They provided 93.7% (395/432) of initial contacts and 26.8% (106/395) of patients were discharged at that point. The information from this study informed a planned service re-design. More research is needed to assess the effectiveness and efficiency of different models of collaborative multi-disciplinary working within genetics services. Keywords (MeSH terms) Genetic Services, Genetic Counseling, Interdisciplinary Communication, Cohort Studies, Delivery of Healthcare, Referral and Consultation

A Complete Expression Profile of Matrix-Degrading Metalloproteinases in Dupuytren’s Disease

Dupuytren’s disease (DD) is a common fibrotic condition of the palmar fascia, leading to deposition of collagen-rich cords and finger contractions. The metzincin superfamily contains key enzymes in the turnover of collagen and other extracellular matrix macromolecules. A number of broad-spectrum matrix metalloproteinase inhibitors, used in cancer clinical trials, caused side effects of DD-like contractures. We tested the hypothesis that changes in the expression of specific metalloproteinases underlie or contribute to the fibrosis and contracture seen in DD. We collected tissue from patients with DD and used normal palmar fascia as a control. We profiled the expression of the entire matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinases (TIMP), and a disintegrin and metalloproteinase domain with thrombospondin motif (ADAMTS) gene families in these tissues using real-time reverse-transcription polymerase chain reaction. A number of metalloproteinases and inhibitors are regulated in DD. The expression of 3 key collagenases, MMP1, MMP13, and MMP14 is increased significantly in the DD nodule, as is the expression of the collagen biosynthetic enzyme ADAMTS14. The expression of MMP7, an enzyme with broad substrate specificity, is increased in the DD nodule and remains equally expressed in the DD cord. TIMP1 expression is increased significantly in DD nodule compared with normal palmar fascia. This study measured the expression of all MMP, ADAMTS, and TIMP genes in DD. Contraction and fibrosis may result from: (1) increased collagen biosynthesis mediated by increased ADAMTS-14; (2) an increased level of TIMP-1 blocking MMP-1– and MMP-13–mediated collagenolysis; and (3) contraction enabled by MMP-14–mediated pericellular collagenolysis (and potentially MMP-7), which may escape inhibition by TIMP-1. The complete expression profile will provide a knowledge-based approach to novel therapeutics targeting these genes

Multiphase modelling of tumour growth and extracellular matrix interaction: mathematical tools and applications

Resorting to a multiphase modelling framework, tumours are described here as a mixture of tumour and host cells within a porous structure constituted by a remodelling extracellular matrix (ECM), which is wet by a physiological extracellular fluid. The model presented in this article focuses mainly on the description of mechanical interactions of the growing tumour with the host tissue, their influence on tumour growth, and the attachment/detachment mechanisms between cells and ECM. Starting from some recent experimental evidences, we propose to describe the interaction forces involving the extracellular matrix via some concepts coming from viscoplasticity. We then apply the model to the description of the growth of tumour cords and the formation of fibrosis