Critical parameters determining standard radiotherapy treatment outcome for glioblastoma multiforme: a computer simulation.

The aim of this paper is to investigate the most critical parameters determining radiotherapy treatment outcome in terms of tumor cell kill for glioblastoma multiforme tumors by using an already developed simulation model of in vivo tumor response to radiotherapy.

Application of the Kohonen network for automatic point correspondence in retinal images.

In this paper, an algorithm for automatic point correspondence is proposed towards retinal image registration. Given a pair of corresponding retinal images and a set of bifurcations or other salient points in one of the images, the algorithm detects effectively the set of corresponding points in the second image, by exploiting the properties of Kohonen's Self Organizing Maps and embedding them in a stochastic optimization procedure. The proposed algorithm was tested on 20 unimodal retinal pairs and the obtained results show an enhanced performance in terms of accuracy and robustness compared to the existing algorithm, on which it is based.

Preliminary study on the association of vessel diameter variation and glaucoma.

In this paper, the relation between retinal vessel diameters and glaucoma by means of advanced image processing techniques is examined. Eighteen (18) patients with ocular hypertension who converted to early glaucoma (converters) and nineteen (19) patients with ocular hypertension who remain stable (non-converters) were imaged with a fundus camera at regular intervals. The first acquired image serves as the reference image, which is compared to each follow-up image. The proposed methodology involves the extraction of vessel centerlines by means of differential calculus, the geometrical alignment (registration) of the images using the chamfer matching algorithm, the estimation of vessel diameters by fitting a Gaussian function to intensity profiles. The statistical analysis of the variations of the vessels diameters revealed a significant difference between the two populations. This difference indicates a probable association between glaucoma and variations of the vessel diameter.

A four-dimensional computer simulation model of the in vivo response to radiotherapy of glioblastoma multiforme: studies on the effect of clonogenic cell density.

Tumours behave as complex, self-organizing, opportunistic dynamic systems. In an attempt to better understand and describe the highly complicated tumour behaviour, a novel four-dimensional simulation model of in vivo tumour growth and response to radiotherapy has been developed. This paper presents the latest improvements to the model as well as a parametric validation of it. Improvements include an advanced algorithm leading to conformal tumour shrinkage, a quantitative consideration of the influence of oxygenation on radiosensitivity and a more realistic, imaging based description of the neovasculature distribution. The tumours selected for the validation of the model are a wild type and a mutated p53 gene glioblastomas multiforme. According to the model predictions, a whole tumour with larger cell cycle duration tends to repopulate more slowly. A lower oxygen enhancement ratio value leads to a more radiosensitive whole tumour. Higher clonogenic cell density (CCD) produces a higher number of proliferating tumour cells and, therefore, a more difficult tumour to treat. Simulation predictions agree at least semi-quantitatively with clinical experience, and particularly with the outcome of the Radiation Therapy Oncology Group (RTOG) Study 83-02. It is stressed that the model allows a quantitative study of the interrelationship between the competing influences in a complex, dynamic tumour environment. Therefore, the model can already be useful as an educational tool with which to study, understand and demonstrate the role of various parameters in tumour growth and response to irradiation. A long term quantitative clinical adaptation and validation of the model aiming at its integration into the treatment planning procedure is in progress.

Glioblastoma multiforme treated by the chemotherapeutic agent temozolomide in vivo: a 4D simulation model of the tumor response.

A novel four dimensional, patient specific 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. The model is based on the patient's imaging, histopathologic and genetic data. For a given drug administration schedule Iying 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 phramacokinetics. A discretization mesh is superimposed upon the anatomical region of interest and within each geometrical cell of the mesh the most prominent biological "laws" 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 has strengthened the applicability of the approach. Long term clinical and quantitative adaptation and validation as well as modeling the normal tissue reactions are in progress. The proposed model primarily aims at providing a reliable platform for performing patient individualized in silico experiments as a means of chemotherapeutic treatment optimization.

The inverse problem of a passive multiband microwave intracranial imaging method.

A novel Microwave Radiometry Imaging System (MiRaIS) has been developed and experimentally tested for feasible brain activation "remote" imaging via contactless measurements. The technique implemented, is focused microwave radiometry with the use of an ellipsoidal conductive wall cavity for focusing and a sensitive radiometric receiver for the detection of the brain conductivity and temperature variation. All system attributes in terms of spatial resolution and detection depth have been theoretically calculated. Phantom experimentation as well as human tests using single frequency receivers, have shown promising outcome concerning the potential clinical value of the proposed system, which seems to be able to pick-up brain activation, possibly caused by cortex conductivity changes. Following this research, a four-frequency radiometric receiver with a broadband antenna operating within the range 1.3-3.1GHz has been recently developed. In the present paper, a method for retrieving the conductivity variation profile detected in the above mentioned frequencies is discussed. The inverse problem solution is in detail addressed and indicative measurements are used for the validation of the solution in question. The latter represents the estimation of the conductivity variation of cortical areas, corresponding to the detection depth and spatial resolution predicted by the forward problem solution.

Limitations of quantitative bone-mass measurements using assessments of first-order statistics of grey-level histograms in plain radiographs.

PURPOSE: To evaluate the quality assurance of image-processing techniques in plain radiographs of skeletal structures. MATERIAL AND METHODS: Twenty-two patients were studied, each with one osteolytic metastasis. Accuracy and precision of tube voltage and timer were confirmed. The mean value of grey-level histograms in plain radiographs (MVGLHs) was assessed. The deviation was monitored after five sets of sequential X-rays retaining the same settings for each radiograph. RESULTS: Deviation was significantly higher in anatomical areas of thorax (21.2%) and abdomen (42.4%), while the consistency of MVGLH for weight-bearing bones was satisfactory with a maximum deviation of 2.9% (P<0.001, Kruskal-Wallis test). CONCLUSION: Assessment of MVGLH in plain radiographs is a reliable method for the extremities and generally for regions without superimposed movable tissues.

The genetic profile of a tumor as a determinant of its response to radiotherapy: a computer simulation of two different radiotherapeutic schemes.

The aim of this paper is to present comparative results of a tumor response to radiotherapy model, concerning two different fractionation schemes and the insulin-like growth factor I receptor expression. A clinical case of glioblastoma multiforme is selected. The model parameters are appropriately adjusted according to the literature. The results of the simulation procedure are three-dimensionally visualized and compared with clinical experience.

Stochastic modeling and validation of growth saturation and radiotherapeutic response of multicellular tumor spheroids.

An advanced three-dimensional (3D) Monte Carlo simulation model of both the avascular development of multicellular tumor 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. Predicted histological structure and tumor growth rates evaluated for the case of EMT6/Ro spheroids have been shown to be in agreement with published experimental data. Furthermore, the underlying structure of the tumor spheroid as well as its response to irradiation satisfactorily agrees with laboratory experience.

Independent component analysis applied to the P600 component of event-related potentials.

The analysis of the P600 component of Event-related Potentials (ERPs) has attracted attention due to its relation to covert cognitive mechanisms, in connection to memory processes. The component may often be low-amplitude, compared to other components such as the P300. Independent component analysis (ICA) techniques have been successfully applied in ERP processing, in the framework of blind source separation (BSS) for unmixing recorded potentials into a sum of temporally independent and spatially fixed components. In the present work ICA was used for reconstructing averaged ERPs in the time window of the P600 component, selecting a subset of independent components' projections to the original electrode recording positions. The selection is based on two empirical criteria, selecting the projection that reconstructs a P600 nearest temporally to the original P600, or selecting the projection combination - up to a preselected maximum number of combined projections providing maximum reconstructed P600 amplitude. The techniques are tested on ERPs recorded from healthy subjects and psychiatric patients, notably improving the differentiation of the two groups, based on either the amplitude or the latency of the reconstructed P600 component, in comparison to results achieved using the original ERPs.

A three dimensional inverse scattering algorithm in the time-domain based on nonlinear optimization.

A new algorithm for solving the three-dimensional inverse scattering problem using time-domain data is presented. The algorithm is intended for application in cases where linearization using the Born or Rytov approximations is not possible. A functional is defined accounting for the error of the object and data equations and the unknown coefficients of the internal field and the object function are sought in order to minimize it. The algorithm projects the unknown internal field into a space of Gaussian basis functions aiming to decrease the number of the unknown coefficients. Time-windowing is utilized in order to reduce the size of the optimization problem.

Experimental study of 3D contactless conductivity detection using microwave radiometry: a possible method for investigation of brain conductivity fluctuations.

The capability of detecting electrical conductivity variations using focused microwave radiometry, a method used in clinical applications for temperature distribution imaging of subcutaneous tissues, is discussed in the present study. A novel microwave radiometric system operating at 3.5 GHz, including an ellipsoidal conductive wall cavity, which provides the required beamforming and focusing, is developed. The system is capable of providing distribution measurements of the product of conductivity and temperature of any object being at a temperature above the absolute zero. The implemented experimental procedure is based on the results of an electromagnetic numerical analysis using a semianalytical method which was developed in order to compute the focusing properties of the ellipsoidal reflector. Each measurement is realized by placing the region of interest in the area of the first focus of the cavity and collecting the radiation converged at the second by an almost isotropic dipole antenna connected to a sensitive radiometer. Experimental data from cylindrical shaped saline or de-ionized water filled tank phantoms in which saline solutions of different concentrations were infused, provide promising results concerning the system's ability of detecting conductivity variations. Future research is needed in order to elucidate the potential of the proposed methodology to be used for brain conductivity measurements.

Working memory deficits in multiple sclerosis: a controlled study with auditory P600 correlates.

BACKGROUND: Recently, the P600 component of event related potentials, a waveform that is conceived to be generated and/or modulated by basal ganglia and cingulate area has been considered an index of the completion of any synchronised operation after target detection, having much in common with working memory operation. Moreover, dysfunction of these brain structures as well as working memory deficits have been implicated in the pathophysiology of multiple sclerosis. The aim of this study was to investigate the patterns of P600 elicited during a working memory test in multiple sclerosis patients compared with healthy controls. METHODS: Twenty two definite, chronic progressive multiple sclerosis patients, with recent exacerbation of their illness, and 20 normal subjects matched for age, sex, and educational level, were studied with a computerised version of the digit span test of Wechsler batteries. Auditory P600 were measured during the anticipatory period of this test. RESULTS: The patient group, as compared with healthy controls, showed significantly reduced latencies of P600 at left frontal areas and reduced P600 amplitudes at left temporoparietal region. Moreover, memory performance of patients was significantly more impaired when compared with healthy controls. CONCLUSIONS: These findings may indicate that multiple sclerosis is associated with abnormal features of the completion of synchronised operation after target detection, as they are reflected by P600 amplitudes and latencies. Dysfunction of this mechanism may contribute to the identification of basic cognitive processes that could account for the cognitive deficits in multiple sclerosis.

A 3D high-resolution gamma camera for radiopharmaceutical studies with small animals.

The results of studies conducted with a small field of view tomographic gamma camera based on a Position Sensitive Photomultiplier Tube are reported. The system has been used for the evaluation of radiopharmaceuticals in small animals. Phantom studies have shown a spatial resolution of 2mm in planar and 2-3mm in tomographic imaging. Imaging studies in mice have been carried out both in 2D and 3D. Conventional radiopharmaceuticals have been used and the results have been compared with images from a clinically used system.

Improving spatial resolution in SPECT with the combination of PSPMT based detector and iterative reconstruction algorithms.

This paper investigates the possibility of developing a SPECT system that combines the high spatial resolution of position sensitive photomultiplier tubes (PSPMTs) with the excellent performance of iterative reconstruction algorithms. A small field of view (FOV) camera based on a PSPMT and a pixelized scintillation crystal made of CsI(Tl) have been used for the acquisition of the projections. With the use of maximum likelihood expectation maximization (ML-EM) and ordered subsets expectation maximization (OSEM) slices of the object are obtained while three-dimensional (3D) reconstruction of the object is carried out using a modified marching cubes (MMC) algorithm. The spatial resolution of tomographic images obtained with the system was 2-3mm. The spatial resolution of a conventional system that uses filtered backprojection (FBP) for slices reconstruction was more than 9 mm.

Intraoperative hyperthermia and chemoradiotherapy for inoperable pancreatic carcinoma.

The aim of this study was to evaluate the tolerability and the possible clinical benefit of intraoperative hyperthermia combined with multischedule chemotherapy and bypass surgery for the palliative treatment of inoperable pancreatic cancer. Ten patients with unresectable adenocarcinoma of the pancreas received preoperative chemotherapy [5-fluorouracil (5-FU)], bypass surgery and postoperative chemotherapy (5-FU, doxorubicin and cisplatin) plus sandostatin and radiotherapy (45 Gy, 25 fractions, 5 days a week). A single session of intraoperative hyperthermia was performed, by using a waveguide-type applicator (433 MHz). The tumour region was heated to 43-45 degrees C for up to 60 min, while 500 mg 5-FU was infused simultaneously through the gastroduodenal into the splenic artery. Postoperative recovery was uneventful for all patients. A brief instrument was developed for evaluating patients' quality of life. Chemotherapy-related toxicity included myelosuppression, vomiting, alopecia and increase in blood urea nitrogen (BUN), creatinine, SGOT and SGPT. Glucose and amylase determinations remained within normal limits throughout the whole treatment. There was a significant improvement before and 1 month after combined treatment in Eastern Cooperative Oncology Group (ECOG) status (1.8 +/- 0.4), Scott-Huskinsson pain scale (3.2 +/- 0.8) and quality of life score (30.5 +/- 6.7). No progressive disease was noticed and the median overall survival was 11 (SE = 2.4) months. There was also a significant (P = 0.002, Wilcoxon test) decrease in values of both serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), from 7.6 +/- 1.3 ng/mL and 875.7 +/- 104.8 U/mL to 3.5 +/- 0.7 ng/mL and 65.3 +/- 14.1 U/mL respectively. The first clinical results suggest a potential advantage of using combined intraoperative hyperthermia, chemotherapy and postoperative radiotherapy in the palliative treatment of the adenocarcinoma of the pancreas. The whole procedure seems to be free of perioperative morbidity, while the chemotherapy toxicity was rather moderate. However, the preliminary nature limits the general applicability of our results.

Intraoperative hyperthermia in conjunction with multi-schedule chemotherapy (pre-, intra- and post-operative), by-pass surgery, and post-operative radiotherapy for the management of unresectable pancreatic adenocarcinoma.

The aim of this study was to evaluate the potential role of intraoperative hyperthermia (IOHT) in the management of stage IV pancreatic adenocarcinoma. Twenty-seven patients (group A) received pre-operative chemotherapy (5-FU), by-pass surgery with intraoperative bolus infusion of 5-FU and post-operatively multi-agent chemotherapy plus sandostatin and external beam irradiation (45Gy, 25 fractions, 5 days a week). In a non-randomized way, 10 patients (group B) received an additional single session of IOHT (43-45 degrees C, 1h) performed directly on the tumour using a waveguide applicator (433MHz) with interstitial measurements of temperature measured. A brief instrument was developed for evaluating patients' quality of life. No progressive disease (PD) was noticed in group B vs 11% (3/27) of PD in group A. There was also a significant increase of overall survival (OS) in group B vs A patients (p = 0.029, log-rank test). Moreover, there was a significant improvement for group B vs A patients regarding Karnofsky performance status (p < 0.001, Mann-Whitney test), pain score (p < 0.001, Mann-Whitney test) and quality of life score (p = 0.031, Mann-Whitney test). A significant correlation was noticed between OS and thermal parameters such as average T(min) (p = 0.043), average T(max) (p = 0.027) and cumulative minutes T(90) >or= 44 degrees C (p < 0.001). Combined IOHT with chemotherapy (pre-, intra- and post-operative) and external beam post-operative radiotherapy seem to have a potential benefit in the management of unresectable adenocarcinoma of the pancreas, concerning local response, OS and quality of life. Further clinical studies to evaluate the benefit of IOHT suggested in this study are warranted.

Impaired P600 in neuroleptic naive patients with first-episode schizophrenia.

Deficits of working memory (WM) are recognized as an important pathological feature in schizophrenia. Since the P600 component of event related potentials has been hypothesized that represents aspects of second-pass parsing processes of information processing, and is related to WM, the present study focuses on P600 elicited during a WM test in drug-naive first-episode schizophrenics (FES) compared to healthy controls. We examined 16 drug-naive first-episode schizophrenic patients and 23 healthy controls matched for age and sex. Compared with controls schizophrenic patients showed reduced P600 amplitude on left temporoparietal region and increased P600 amplitude on left occipital region. With regard to the latency, the patients exhibited significantly prolongation on right temporoparietal region. The obtained pattern of differences classified correctly 89.20% of patients. Memory performance of patients was also significantly impaired relative to controls. Our results suggest that second-pass parsing process of information processing, as indexed by P600, elicited during a WM test, is impaired in FES. Moreover, these findings lend support to the view that the auditory WM in schizophrenia involves or affects a circuitry including temporoparietal and occipital brain areas.

Abnormal P600 in heroin addicts with prolonged abstinence elicited during a working memory test.

The P600 component of event-related potentials, believed to be generated by anterior cingulate gyrus and basal ganglia, is considered as an index of aspects of second-pass parsing processes of information processing, having much in common with working memory (WM) systems. Moreover, dysfunction of these brain structures as well as WM deficits have been implicated in the pathophysiology of opioid addicts. The present study is focused on P600 elicited during a WM test in twenty heroin addicts with prolonged abstinence compared with an equal number of healthy controls. The results showed significantly prolonged latencies at right hemisphere, specifically at Fp2 abduction. Moreover, memory performance of patients did not differ from that of normal controls. These findings may indicate that abstinent heroin addicts manifest abnormal aspects of second-pass parsing processes as are reflected by the P600 latencies, elicited during a WM test. Additionally, the P600 might serve as a valuable investigative tool for a more comprehensive understanding of the neurobiological substrate of drug abuse.

Modeling tumor growth and irradiation response in vitro--a combination of high-performance computing and web-based technologies including VRML visualization.

A simplified three-dimensional Monte Carlo simulation model of in vitro tumor growth and response to fractionated radiotherapeutic schemes is presented in this paper. The paper aims at both the optimization of radiotherapy and the provision of insight into the biological mechanisms involved in tumor development. The basics of the modeling philosophy of Duechting have been adopted and substantially extended. The main processes taken into account by the model are the transitions between the cell cycle phases, the diffusion of oxygen and glucose, and the cell survival probabilities following irradiation. Specific algorithms satisfactorily describing tumor expansion and shrinkage have been applied, whereas a novel approach to the modeling of the tumor response to irradiation has been proposed and implemented. High-performance computing systems in conjunction with Web technologies have coped with the particularly high computer memory and processing demands. A visualization system based on the MATLAB software package and the virtual-reality modeling language has been employed. Its utilization has led to a spectacular representation of both the external surface and the internal structure of the developing tumor. The simulation model has been applied to the special case of small cell lung carcinoma in vitro irradiated according to both the standard and accelerated fractionation schemes. A good qualitative agreement with laboratory experience has been observed in all cases. Accordingly, the hypothesis that advanced simulation models for the in silico testing of tumor irradiation schemes could substantially enhance the radiotherapy optimization process is further strengthened. Currently, our group is investigating extensions of the presented algorithms so that efficient descriptions of the corresponding clinical (in vivo) cases are achieved.