Clinical implications of in silico mathematical modeling for glioblastoma: a critical review.

Glioblastoma remains a clinical challenge in spite of years of extensive research. Novel approaches are needed in order to integrate the existing knowledge. This is the potential role of mathematical oncology. This paper reviews mathematical models on glioblastoma from the clinical doctor's point of view, with focus on 3D modeling approaches of radiation response of in vivo glioblastomas based on contemporary imaging techniques. As these models aim to provide a clinically useful tool in the era of personalized medicine, the integration of the latest advances in molecular and imaging science and in clinical practice by the in silico models is crucial for their clinical relevance. Our aim is to indicate areas of GBM research that have not yet been addressed by in silico models and to point out evidence that has come up from in silico experiments, which may be worth considering in the clinic. This review examines how close these models have come in predicting the outcome of treatment protocols and in shaping the future of radiotherapy treatments.

Analysis of Two Electrocution Accidents in Greece that Occurred due to Unexpected Re-energization of Power Lines.

Investigation and analysis of accidents are critical elements of safety management. The over-riding purpose of an organization in carrying out an accident investigation is to prevent similar accidents, as well as seek a general improvement in the management of health and safety. Hundreds of workers have suffered injuries while installing, maintaining, or servicing machinery and equipment due to sudden re-energization of power lines. This study presents and analyzes two electrical accidents (1 fatal injury and 1 serious injury) that occurred because the power supply was reconnected inadvertently or by mistake.

Motive related positivity: decision-making during a prisoners' dilemma task.

The neural mechanisms underlying decision-making to cooperate or defect were investigated using event-related potentials during an iterated computer Prisoner's Dilemma task, adapted to induce working memory operation. Event-related potentials from 64 leads of 22 participants were recorded during 90 trials and averaged depending on the condition of cooperation and defect. The P200 component of the event-related potentials provided evidence for activation differences between cooperation and defect. Cooperation elicited significantly increased P200 activation at parieto-occipital leads, while defect activated primarily the prefrontal electrodes. Functional mapping using Low Resolution Electromagnetic Tomography indicated that in the 150-180 ms time window Brodmann areas 19 (precuneus) and 17 (lingual gyrus), exhibited increased activation during cooperation, while Brodmann area 6 (precentral gyrus) exhibited increased activation when participants defected. In conclusion, the current study provides evidence that cooperation and defect elicit different brain activation at specific loci and within specific time windows.

Temporal processing dysfunction in schizophrenia as measured by time interval discrimination and tempo reproduction tasks.

OBJECTIVE: Time perception deficiency has been implicated in schizophrenia; however the exact nature of this remains unclear. The present study was designed with the aim to delineate timing deficits in schizophrenia by examining performance of patients with schizophrenia and healthy volunteers in an interval discrimination test and their accuracy and precision in a pacing reproduction­replication test. METHODS: The first task involved temporal discrimination of intervals, in which participants (60 patients with schizophrenia and 35 healthy controls) had to judge whether intervals were longer, shorter or equal than a standard interval. The second task required repetitive self-paced tapping to test accuracy and precision in the reproduction and replication of tempos. RESULTS: Patients were found to differ significantly from the controls in the psychoticism scale of EPQ, the proportion of correct responses in the interval discrimination test and the overall accuracy and precision in the reproduction and replication of sound sequences (p < 0.01). Within the patient group bad responders concerning the ability to discriminate time intervals were associated with increased scores in the Positive and Negative Syndrome Scale (PANSS) and in the Brief Psychiatric Rating Scale (BPRS) in comparison to good responders (p < 0.01). There were no gender effects and there were no differences between subgroups of patients taking different kinds or combinations of drugs. CONCLUSIONS: Analysis has shown that performance on timing tasks decreased with increasing psychopathology and therefore that timing dysfunctions are directly linked to the severity of the illness. Different temporal dysfunctions can be traced to different psychophysiological origins that can be explained using the Scalar Expectancy Theory (SET).

Experimental study of a hybrid microwave radiometry-hyperthermia apparatus with the use of an anatomical head phantom.

This paper presents the latest progress made concerning a hybrid diagnostic and therapeutic system able to provide focused microwave radiometric temperature and/or conductivity variation measurements and hyperthermia treatment. Previous experimental studies of our group have demonstrated the system performance and focusing properties in phantom as well as human experiments. The system is able to detect temperature and conductivity variations with frequency-dependent detection depth and spatial sensitivity. Numerous studies have also demonstrated the improvement of the system focusing properties attributed to the use of dielectric and left handed matching layers. In this study, similar experimental procedures are performed but this time using an anatomical head model as phantom aiming to achieve a more accurate modeling of the system's future real function. This way, another step is made toward the deeper understanding of the system's capabilities, with the view to further use it in experimental procedures with laboratory animals and human volunteers.

Effect of frequency deviance direction on performance and mismatch negativity.

The mismatch negativity (MMN) component of the auditory event-related potential is associated with automatic perceptual inference concerning changes in auditory stimulation. Recent studies have addressed the question whether performance and MMN is affected by the direction of frequency deviance. In the present study, the frequency MMN and performance is investigated during an auditory identification task. Specifically, we examined the effect of positive and negative differences between the present stimulus and the previous response frequencies on performance as well as on the characteristics of stimulus-locked ERPs and brain activation maps. The results show that frequency deviants creating mismatch conditions increase the likelihood of error commission. The decrease in performance achieves statistical significance in the case of positive frequency deviants. In the latter case, ERP amplitude values of the Fz electrode at 164 ms after stimulus onset are statistically larger for mismatch as opposed to no-mismatch condition. This corresponds to significance differences in the activation maps at Brodmann area 11, superior frontal gyrus, and the frontal lobe. The present findings revealed dissociations in behavioral and ERP responses in the processing of positive and negative frequency deviance, lending support to the notion that MMN is more sensitive to increments than to decrements in frequency.

Noninvasive focused monitoring and irradiation of head tissue phantoms at microwave frequencies.

In this study, new aspects of our research regarding a novel hybrid system able to provide focused microwave radiometric temperature and/or conductivity measurements and hyperthermia treatment via microwave irradiation are presented. On one hand, it is examined whether the system is capable of sensing real-time progressive local variations of temperature and/or conductivity in customized phantom setups; on the other hand, the focusing attributes of the system are explored for different positions and types of phantoms used for hyperthermia in conjunction with dielectric matching layers surrounding the areas of interest. The main module of the system is an ellipsoidal cavity, which provides the appropriate focusing of the electromagnetic energy on the area of interest. The system has been used for the past few years in experiments with different configuration setups including phantom, animal, and human volunteer measurements yielding promising outcome. The present results show that the system is able to detect local concentrated gradual temperature and conductivity variations expressed as an increase of the output radiometric voltage. Moreover, when contactless focused hyperthermia is performed, the results show significant temperature increase at specific phantom areas. In this case, the effect of the dielectric matching layers placed around the phantoms is critical, thus resulting in the enhancement of the energy penetration depth.

Contactless passive diagnosis for brain intracranial applications: A study using dielectric matching materials.

A prototype system for passive intracranial monitoring using microwave radiometry is proposed. It comprises an ellipsoidal conductive wall cavity to achieve beamforming and focusing, in conjunction with sensitive multiband receivers for detection. The system has already shown the capability to provide temperature and/or conductivity variations in phantoms and biological tissue. In this article, a variant of the initially constructed modality is theoretically and experimentally investigated. Specifically, dielectric matching materials are used in an effort to improve the system's focusing attributes. The theoretical study investigates the effect of dielectric matching materials on the system's detection depth, whereas measurements with phantoms focus on the investigation of the system's detection level and spatial resolution. The combined results suggest that the dielectric matching layers lead to the improvement of the system's detection depth and temperature detection level. Also, the system's spatial resolution is explored at various experimental setups. Theoretical and experimental results conclude that with the appropriate combination of operation frequencies and dielectric layers, it is possible to monitor areas of interest inside human head models with a variety of detection depths and spatial resolutions.

Mismatch task conditions and error related ERPs.

BACKGROUND: The N200 component of event related potentials (ERPs) is considered an index of monitoring error related responses. The aim of the present work was to study the effect of mismatch conditions on the subjects' responses in an auditory identification task and their relation to the N200 of stimulus-locked ERPs. METHODS: An auditory identification task required to correctly map a horizontal slider onto an active frequency range by selecting a slider position that matched the stimulus tone in each trial. Fourteen healthy volunteers participated in the study and ERPs were recorded by 32 leads. RESULTS: Results showed that the subjects' erroneous responses were equally distributed within trials, but were dependent on mismatch conditions, generated by large differences between the frequencies of the tones of consecutive trials. Erroneous trials showed a significantly greater negativity within the time window of 164-191 ms after stimulus, located mainly at the Cz and Fz electrodes. The LORETA solution showed that maximum activations, as well as maximum differences, were localized mainly at the frontal lobe. CONCLUSIONS: These findings suggest that the fronto-central N200 component, conceived an index of "reorientation of attention", represents a correlate of an error signal, being produced when representation of the actual response and the required response are compared. Furthermore the magnitude of the amplitude of the N200 rests on the relation between the present and the previous stimulus.

Classification of event-related potentials associated with response errors in actors and observers based on autoregressive modeling.

Event-Related Potentials (ERPs) provide non-invasive measurements of the electrical activity on the scalp related to the processing of stimuli and preparation of responses by the brain. In this paper an ERP-signal classification method is proposed for discriminating between ERPs of correct and incorrect responses of actors and of observers seeing an actor making such responses. The classification method targeted signals containing error-related negativity (ERN) and error positivity (Pe) components, which are typically associated with error processing in the human brain. Feature extraction consisted of Multivariate Autoregressive modeling combined with the Simulated Annealing technique. The resulting information was subsequently classified by means of an Artificial Neural Network (ANN) using back-propagation algorithm under the "leave-one-out cross-validation" scenario and the Fuzzy C-Means (FCM) algorithm. The ANN consisted of a multi-layer perceptron (MLP). The approach yielded classification rates of up to 85%, both for the actors' correct and incorrect responses and the corresponding ERPs of the observers. The electrodes needed for such classifications were situated mainly at central and frontal areas. Results provide indications that the classification of the ERN is achievable. Furthermore, the availability of the Pe signals, in addition to the ERN, improves the classification, and this is more pronounced for observers' signals. The proposed ERP-signal classification method provides a promising tool to study error detection and observational-learning mechanisms in performance monitoring and joint-action research, in both healthy and patient populations.

Behavioral and brain pattern differences between acting and observing in an auditory task.

BACKGROUND: Recent research has shown that errors seem to influence the patterns of brain activity. Additionally current notions support the idea that similar brain mechanisms are activated during acting and observing. The aim of the present study was to examine the patterns of brain activity of actors and observers elicited upon receiving feedback information of the actor's response. METHODS: The task used in the present research was an auditory identification task that included both acting and observing settings, ensuring concurrent ERP measurements of both participants. The performance of the participants was investigated in conditions of varying complexity. ERP data were analyzed with regards to the conditions of acting and observing in conjunction to correct and erroneous responses. RESULTS: The obtained results showed that the complexity induced by cue dissimilarity between trials was a demodulating factor leading to poorer performance. The electrophysiological results suggest that feedback information results in different intensities of the ERP patterns of observers and actors depending on whether the actor had made an error or not. The LORETA source localization method yielded significantly larger electrical activity in the supplementary motor area (Brodmann area 6), the posterior cingulate gyrus (Brodmann area 31/23) and the parietal lobe (Precuneus/Brodmann area 7/5). CONCLUSION: These findings suggest that feedback information has a different effect on the intensities of the ERP patterns of actors and observers depending on whether the actor committed an error. Certain neural systems, including medial frontal area, posterior cingulate gyrus and precuneus may mediate these modulating effects. Further research is needed to elucidate in more detail the neuroanatomical and neuropsychological substrates of these systems.

The "Oncosimulator": a multilevel, clinically oriented simulation system of tumor growth and organism response to therapeutic schemes. Towards the clinical evaluation of in silico oncology.

The "Oncosimulator" is at the same time a concept of multilevel integrative cancer and (treatment affected) normal tissue biology, an algorithmic construct and a software tool which aims at supporting the clinician in the process of optimizing cancer treatment on the patient individualized basis. Additionally it is a platform for better understanding and exploring the natural phenomenon of cancer as well as training doctors and interested patients alike. In order to achieve all of these goals it has to undergo a thorough clinical optimization and validation process. This is one of the goals of the European Commission funded integrated project "ACGT: Advancing Clinicogenomic Trials on Cancer". Nephroblastoma (Wilms' tumor) and breast cancer have been selected to serve as two paradigms to clinically specify and evaluate the "Oncosimulator" as well as the emerging domain of in silico oncology.

Enhancing the focusing properties of a prototype non-invasive brain hyperthermia system: a simulation study.

Aim of this study is the improvement of the focusing properties of a prototype system for deep brain hyperthermia able to provide also passive measurements of temperature distributions inside the human body and especially the brain. One of the main modules of the system which ensures the necessary beamforming and focusing on the body and brain cortex areas of interest is the symmetrical axis ellipsoidal conductive wall cavity. The proposed system operates in a total non-invasive contactless passive manner and is designed to provide hyperthermia treatment and temperature monitoring. Extensive simulations to compute electric field distributions and SAR values at several frequencies inside the human head model and inside the whole ellipsoidal reflector were carried out. One of the main problems that have to be tackled in order to achieve the desired depth and focusing resolution is to reduce back scattering while improving penetration. With this view, the FEM simulations using a commercial tool aimed at improving the system's focusing properties following various approaches. In order to enhance the matching conditions on the air-head interface, layers made of metamaterials (left handed materials) and dielectric materials were placed around the human head model. The results show that the use of a metamaterial layer in conjunction with a layer of lossless dielectric material generates the largest improvement. Measurements using phantoms with the proposed focusing improvement techniques in future studies will complement the present research and reveal the potential practical value of the system.

FDTD study of the focusing properties of a hybrid hyperthermia and radiometry imaging system using a realistic human head model.

Aim of this study is twofold; on one hand, the investigation of the focusing attributes of a microwave radiometry tomography system with the use of a realistic human head model and on the other hand, the system's ability to perform a hyperthermia treatment. The operation principle of the device is based on an ellipsoidal conductive wall cavity, which provides the required beamforming and focusing. The biological tissue under treatment and/or measurement is placed on one of the two focal points whereas on the other one, a radiating or receiving antenna, which measures the black body type radiation emitted from the head's tissue, is placed. In previous studies simple spherical head models were used, comprising one or two layers for simulating the head tissues, along with a commercial FEM tool. In this work, a realistic adult head model developed from MRI scans of a human head is used. The realistic model with detailed structural and electromagnetic tissue characteristics enables more in depth theoretical investigation of the system capabilities. Extensive simulations using a commercial FDTD tool are performed in a wide range of operating frequencies. In order to explore the feasibility of heating and monitoring specific brain areas, the capability of focusing the electric field in specific areas inside the human head is investigated and further discussed. The results show that simple spherical head models, used in previous studies, provide similar results with the realistic one used herein for the given geometry; that is, the electric field focuses on the head's center, assuming the head as a homogeneous sphere. However, the deposition of the electromagnetic energy on the head tissues depends on the operating frequency and position of the head in the given geometry, so in therefore calculated, revealing the ability of the system to operate as a hyperthermia clinical tool, not as a stand alone device but in conjunction with other already validated devices/methods.

Electromagnetic analysis of coupling and guiding phenomena in elliptical cross-section parallel waveguides with rotated symmetry planes.

Rigorous electromagnetic analysis methods, based on the Green's function method along with the method of moments, are utilized to analyze coupling, guiding, and polarization phenomena in elliptic cross-section parallel waveguides. The analysis is carried out for the general case of closely spaced elliptic fibers of arbitrary orientation of the ellipses' axes. Numerical results are presented for the cases of 0 degrees and 45 degrees angles between axes, as well as for the single elliptical fiber and closely spaced circular dielectric waveguides. The possibility of using this type of coupling structure in quantum signal processing applications is examined.

Analysis of scattering by a linear chain of spherical inclusions in an optical fiber.

The scattering by a linear chain of spherical dielectric inclusions, embedded along the axis of an optical fiber, is analyzed using a rigorous integral equation formulation, based on the dyadic Green's function theory. The coupled electric field integral equations are solved by applying the Galerkin technique with Mie-type expansion of the field inside the spheres in terms of spherical waves. The analysis extends the previously studied case of a single spherical inhomogeneity inside a fiber to the multisphere-scattering case, by utilizing the classic translational addition theorems for spherical waves in order to analytically extract the direct-intersphere-coupling coefficients. Results for the transmitted and reflected power, on incidence of the fundamental HE(11) mode, are presented for several cases.

Transmission medium and full fiber-optic setup for quantum key distribution applications.

A fiber-optic-based coupled waveguide transmission medium is proposed to distribute secret keys in a single-photon polarization-based quantum cryptography setup. Polarization maintenance properties and coupling phenomena of the transmission medium are exploited to achieve accuracy and security of the transferred key. Elliptic fibers and fiber couplers are used to prepare the transmitted photons at the sender as well as analyze them at the receiver. The uniqueness of the setup stands on the exclusive use of fiber-optic components, enabling its construction on a single fiber line.

Rigorous integral equation analysis of nonsymmetric coupled grating slab waveguides.

A rigorous integral equation formulation in conjunction with Green's function theory is used to analyze the waveguiding and coupling phenomena in nonsymmetric (composed of dissimilar slabs) optical couplers with gratings etched on both slabs. The resulting integral equation is solved by applying an entire-domain Galerkin technique based on a Fourier series expansion of the unknown electric field on the grating regions. The proposed analysis actually constitutes a special type of the method of moments and provides high numerical stability and controllable accuracy. The singular points of the system's matrix accurately determine the complex propagation constants of the guided waves. The results obtained improve on those derived by coupled-mode methods in the cases of large grating perturbations and highly dissimilar slabs. Numerical results referring to the evolution of the propagation constants as a function of the grating's characteristics are presented. Optimal grating parameters with respect to minimum coupling length and maximum coupling efficiency are reported. The coupler's efficient operation as an optical bandpass filter is thoroughly investigated.

A spatiotemporal, patient individualized simulation model of solid tumor response to chemotherapy in vivo: the paradigm of glioblastoma multiforme treated by temozolomide.

A novel four-dimensional, patient-specific Monte Carlo simulation model of solid tumor response to chemotherapeutic treatment in vivo is presented. The special case of glioblastoma multiforme treated by temozolomide is addressed as a simulation paradigm. Nevertheless, a considerable number of the involved algorithms are generally applicable. The model is based on the patient's imaging, histopathologic and genetic data. For a given drug administration schedule lying within acceptable toxicity boundaries, the concentration of the prodrug and its metabolites within the tumor is calculated as a function of time based on the drug pharamacokinetics. A discretization mesh is superimposed upon the anatomical region of interest and within each geometrical cell of the mesh the most prominent biological "laws" (cell cycling, necrosis, apoptosis, mechanical restictions, etc.) are applied. The biological cell fates are predicted based on the drug pharmacodynamics. The outcome of the simulation is a prediction of the spatiotemporal activity of the entire tumor and is virtual reality visualized. A good qualitative agreement of the model's predictions with clinical experience supports the applicability of the approach. The proposed model primarily aims at providing a platform for performing patient individualized in silico experiments as a means of chemotherapeutic treatment optimization.

Transformation of radially traveling cylindrical waves between two skew cylindrical coordinate systems.

The transformation of radially traveling cylindrical waves between two cylindrical coordinate systems with skew (nonparallel) axes is derived for the first time to our knowledge. The analytical procedure is based on the complex integral representation of the Hankel function and appropriate contour deformation and change of variables to obtain a final Fourier transform expression of the cylindrical wave in the new system. Scalar and vector waves are considered. This new result is a powerful tool for the rigorous analysis of scattering and coupling in nonparallel optical fiber configurations.