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.

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.

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.

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.

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.

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.

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.

Simulating chemotherapeutic schemes in the individualized treatment context: the paradigm of glioblastoma multiforme treated by temozolomide in vivo.

A novel patient individualized, spatiotemporal Monte Carlo simulation model of tumor response to chemotherapeutic schemes in vivo is presented. Treatment of glioblastoma multiforme by temozolomide is considered as a paradigm. The model is based on the patient's imaging, histopathologic and genetic data. 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, apoptosis, etc.) in conjunction with pharmacokinetics and pharmacodynamics information are applied. A good qualitative agreement of the model's predictions with clinical experience supports the applicability of the approach to chemotherapy optimization.

A computer simulation of in vivo tumour growth and response to radiotherapy: new algorithms and parametric results.

The aim of this paper is to present the newest algorithms and simulation results of a computer model of in vivo tumour growth and response to radiotherapy. The new algorithms are analytically presented. A set of parametric simulations has been performed with special emphasis on the influence of the genetic profile of a tumour on its radiosensitivity. The results of the simulation procedure are three-dimensionally visualized and critically surveyed. The long-term goal of this work is twofold: the development of a computational tool for getting insight into cancer biology and the development of a patient-specific decision support system.

Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial.

PURPOSE: This is the first study to evaluate the tolerability and activity of liposomal doxorubicin (Caelyx; Schering-Plough Pharmaceuticals) < or =60 mg/km(2) in patients with locally recurrent breast cancer, when administered in conjunction with reirradiation and local hyperthermia treatment. EXPERIMENTAL DESIGN: Fifteen female patients, who had undergone a radical mastectomy and conventional radiotherapy (60 Gy) in the front chest wall, were entered on a multimodal protocol consisting of initial treatment with radiotherapy and a monthly infusion of liposomal doxorubicin < or =60 mg/m(2) in conjunction with local hyperthermia treatment. All patients received reirradiation up to a total dose of 30.6 Gy (1.8 Gy/fraction, 5 days a week). To evaluate the drug's safety, the first 5 patients initially received a dose of 40 mg/m(2) liposomal doxorubicin, which was then escalated to 60 mg/m(2). The other 10 patients received 60 mg/m(2) for all six cycles of chemotherapy. Hyperthermia (HT) was produced in the region of interest (ROI) using waveguides at a frequency of 433 MHz. The RSS was obtained from the curves representing the change in the ROI's surface with time for each patient, as fitted by linear regression. Linear regression analysis was used to study the relationship between the time interval from liposomal doxorubicin infusion to HT and the RSS. RESULTS: At doses of < or =60 mg/m(2), liposomal doxorubicin was well tolerated, with only mild hematological and nonhematological toxicity. All patients showed an objective measurable response, with 3 patients (20%) demonstrating a clinically complete response. There was a significant correlation between the duration of response and Avg Min T(90) > 44 degrees C (r(s) = 0.917, P < 0.0001) and the Mean[Tmin] (r(s) = 0.909, P < 0.0001). The RSS was significantly correlated with the interval between liposomal doxorubicin infusion and HT, as the smaller the time interval, the greater the clinical benefit (r = 0.76, P = 0.001). CONCLUSIONS: The multimodal treatment was effective and well tolerated, producing an objective measurable response in all patients. Local HT had a significant effect on patients' response to the drug. The relationship between thermal dose and liposomal action requires further investigation.

Long-term abstinence syndrome in heroin addicts: indices of P300 alterations associated with a short memory task.

Attentional deficits have been implicated in the pathophysiology of opioid addicts. The P300 component of event-related potentials (ERPs) is considered as a manifestation of attentional operations. The authors' goal was the comparison of P300 elicited during a short memory test between subjects with prolonged heroin abstinence and current heroin users as well as healthy controls. The P300 component was evaluated during the anticipatory period of a short memory task in 20 patients characterized by a past history of opioid dependence (6 months abstinence), in 18 current heroin users and in 20 healthy comparison subjects, matched for age, sex and educational level. Abstinent heroin addicts exhibited significant reduction of P300 amplitude at central frontal region, relative to the other two groups. The findings are discussed in connection to the aim of identifying psychophysiological indices, addressing issues in opioid use disorders, and suggest that knowledge about cognitive operations, such as those reflected by P300 component, could provide further insight into psychophysiological mechanisms underlying the long-term abstinence state of heroin addicts.

A spatio-temporal simulation model of the response of solid tumours to radiotherapy in vivo: parametric validation concerning oxygen enhancement ratio and cell cycle duration.

Advanced bio-simulation methods are expected to substantially improve radiotherapy treatment planning. To this end a novel spatio-temporal patient-specific simulation model of the in vivo response of malignant tumours to radiotherapy schemes has been recently developed by our group. This paper discusses recent improvements to the model: an optimized algorithm leading to conformal shrinkage of the tumour as a response to radiotherapy, the introduction of the oxygen enhancement ratio (OER), a realistic initial cell phase distribution and finally an advanced imaging-based algorithm simulating the neovascularization field. A parametric study of the influence of the cell cycle duration Tc, OER, OERbeta for the beta LQ parameter on tumour growth. shrinkage and response to irradiation under two different fractionation schemes has been made. The model has been applied to two glioblastoma multiforme (GBM) cases, one with wild type (wt) and another one with mutated (mt) p53 gene. Furthermore, the model has been applied to a hypothetical GBM tumour with alpha and beta values corresponding to those of generic radiosensitive tumours. According to the model predictions, a whole tumour with shorter Tc tends to repopulate faster, as is to be expected. Furthermore, a higher OER value for the dormant cells leads to a more radioresistant whole tumour. A small variation of the OERbeta value does not seem to play a major role in the tumour response. Accelerated fractionation proved to be superior to the standard scheme for the whole range of the OER values considered. Finally, the tumour with mt p53 was shown to be more radioresistant compared to the tumour with wt p53. Although all simulation predictions agree at least qualitatively with the clinical experience and literature, a long-term clinical adaptation and quantitative validation procedure is in progress.

Simulating growth dynamics and radiation response of avascular tumour spheroids-model validation in the case of an EMT6/Ro multicellular spheroid.

The goal of this paper is to provide both the basic scientist and the clinician with an advanced computational tool for performing in silico experiments aiming at supporting the process of biological optimisation of radiation therapy. Improved understanding and description of malignant tumour dynamics is an additional intermediate objective. To this end an advanced three-dimensional (3D) Monte-Carlo simulation model of both the avascular development of multicellular tumour spheroids and their response to radiation therapy is presented. The model is based upon a number of fundamental biological principles such as the transition between the cell cycle phases, the diffusion of oxygen and nutrients and the cell survival probabilities following irradiation. Efficient algorithms describing tumour expansion and shrinkage are proposed and applied. The output of the biosimulation model is introduced into the (3D) visualisation package AVS-Express, which performs the visualisation of both the external surface and the internal structure of the dynamically evolving tumour based on volume or surface rendering techniques. Both the numerical stability and the statistical behaviour of the simulation model have been studied and evaluated for the case of EMT6/Ro spheroids. Predicted histological structure and tumour growth rates have been shown to be in agreement with published experimental data. Furthermore, the underlying structure of the tumour spheroid as well as its response to irradiation satisfactorily agrees with laboratory experience.

CT-MRI automatic surface-based registration schemes combining global and local optimization techniques.

Medical image registration is commonly required in order to combine the complementary information provided by different medical imaging modalities. In this paper, a new automatic registration scheme is proposed to register 3-D CT-MR head images and is currently tested on a clinical environment. The proposed scheme, after the preprocessing and the outer surface extraction of the data, is based on the use the rigid transformation method, in conjunction with a combination of global and local optimization techniques. Analytically, the paper exploits the optimization efficiency of three widely used optimization techniques, in obtaining the parameters of the rigid transformation model: the Downhill Simplex Method, the Genetic Algorithms and the Simulated Annealing. These optimization techniques are further combined by the sequential application of the Powell optimization method in order to refine the registration and increase its accuracy. A comparative study involving these optimization techniques in conjunction with the rigid transformation, and two other methods, the ICP and the manual methods, is also presented, for a sufficient number of clinical CT-MR brain images. Finally, quantitative and qualitative results are also presented to validate the performance of these automatic surface-based registration schemes, in terms of consistency and accuracy. Throughout of this study, the automatic registration scheme comprising of the rigid transformation in conjunction with the Simulated Annealing method sequentially combined with the Powell method has been performed superior regarding all the other compared registration schemes.

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.

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.

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.

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.

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.