BACKGROUND: Contemporary biological observations have revealed a large variety of mechanisms acting during the expansion of a tumor. However, there are still many qualitative and quantitative aspects of the phenomenon that remain largely unknown. In this context, mathematical and computational modeling appears as an invaluable tool providing the means for conducting in silico experiments, which are cheaper and less tedious than real laboratory experiments. RESULTS: This paper aims at developing an extensible and computationally efficient framework for in silico modeling of tumor growth in a 3-dimensional, inhomogeneous and time-varying chemical environment. The resulting model consists of a set of mathematically derived and algorithmically defined operators, each one addressing the effects of a particular biological mechanism on the state of the system. These operators may be extended or re-adjusted, in case a different set of starting assumptions or a different simulation scenario needs to be considered. CONCLUSION: In silico modeling provides an alternative means for testing hypotheses and simulating scenarios for which exact biological knowledge remains elusive. However, finer tuning of pertinent methods presupposes qualitative and quantitative enrichment of available biological evidence. Validation in a strict sense would further require comprehensive, case-specific simulations and detailed comparisons with biomedical observations.

Following publication of the original article [1], the authors noticed that the following errors were introduced by pdf/html formatting issues.

The 5-year survival of non-small cell lung cancer patients can be as low as 1% in advanced stages. For patients with resectable disease, the successful choice of preoperative chemotherapy is critical to eliminate micrometastasis and improve operability. In silico experimentations can suggest the optimal treatment protocol for each patient based on their own multiscale data. A determinant for reliable predictions is the a priori estimation of the drugs' cytotoxic efficacy on cancer cells for a given treatment. In the present work a mechanistic model of cancer response to treatment is applied for the estimation of a plausible value range of the cell killing efficacy of various cisplatin-based doublet regimens. Among others, the model incorporates the cancer related mechanism of uncontrolled proliferation, population heterogeneity, hypoxia and treatment resistance. The methodology is based on the provision of tumor volumetric data at two time points, before and after or during treatment. It takes into account the effect of tumor microenvironment and cell repopulation on treatment outcome. A thorough sensitivity analysis based on one-factor-at-a-time and latin hypercube sampling/partial rank correlation coefficient approaches has established the volume growth rate and the growth fraction at diagnosis as key features for more accurate estimates. The methodology is applied on the retrospective data of thirteen patients with non-small cell lung cancer who received cisplatin in combination with gemcitabine, vinorelbine or docetaxel in the neoadjuvant context. The selection of model input values has been guided by a comprehensive literature survey on cancer-specific proliferation kinetics. The latin hypercube sampling has been recruited to compensate for patient-specific uncertainties. Concluding, the present work provides a quantitative framework for the estimation of the in-vivo cell-killing ability of various chemotherapies. Correlation studies of such estimates with the molecular profile of patients could serve as a basis for reliable personalized predictions.

Significant Virtual Physiological Human efforts and projects have been concerned with cancer modeling, especially in the European Commission Seventh Framework research program, with the ambitious goal to approach personalized cancer simulation based on patient-specific data and thereby optimize therapy decisions in the clinical setting. However, building realistic in silico predictive models targeting the clinical practice requires interactive, synergetic approaches to integrate the currently fragmented efforts emanating from the systems biology and computational oncology communities all around the globe. To further this goal, we propose an intelligent graphical workflow planning system that exploits the multiscale and modular nature of cancer and allows building complex cancer models by intuitively linking/interchanging highly specialized models. The system adopts and extends current standardization efforts, key tools, and infrastructure in view of building a pool of reliable and reproducible models capable of improving current therapies and demonstrating the potential for clinical translation of these technologies.

This paper outlines the major components and function of the technologically integrated oncosimulator developed primarily within the Advancing Clinico Genomic Trials on Cancer (ACGT) project. The Oncosimulator is defined as an information technology system simulating in vivo tumor response to therapeutic modalities within the clinical trial context. Chemotherapy in the neoadjuvant setting, according to two real clinical trials concerning nephroblastoma and breast cancer, has been considered. The spatiotemporal simulation module embedded in the Oncosimulator is based on the multiscale, predominantly top-down, discrete entity-discrete event cancer simulation technique developed by the In Silico Oncology Group, National Technical University of Athens. The technology modules include multiscale data handling, image processing, invocation of code execution via a spreadsheet-inspired environment portal, execution of the code on the grid, and the visualization of the predictions. A refining scenario for the eventual coupling of the oncosimulator with immunological models is also presented. Parameter values have been adapted to multiscale clinical trial data in a consistent way, thus supporting the predictive potential of the oncosimulator. Indicative results demonstrating various aspects of the clinical adaptation and validation process are presented. Completion of these processes is expected to pave the way for the clinical translation of the system.

Improving the initial diagnosis and the assessment of response to treatment in malignant gliomas, while avoiding invasive methods as much as justifiable, is one major aspect actual research is focusing on. Imaging studies are used to calculate tumor volume and define vital, necrotic and cystic areas within a tumor. Though the visual interpretation of magnetic resonance (MR) images is based on qualitative observation of variation in signal intensity, a correlation of signal intensities with histological features of a tumor is not possible. Better methods are needed for a reliable interpretation of follow-up studies in single patients. Histograms of signal intensities might serve as a method adding quantitative data to the description of a tumor. Using DoctorEye software, tumors can be easily rendered and histograms of the signal intensities within a tumor as well as mean and median signal intensities are possible to calculate. Our results in glioblastoma suggest that these histograms are an innovative method of gaining new tumor-specific information without performing additional investigations in a patient. It can be an additional diagnostic tool in differentiating various intracranial lesions from each other, as well as in assessing response to treatment or progression of malignant glioma.

Simulators of tumour growth can estimate the evolution of tumour volume and the quantity of various categories of cells as functions of time. However, the execution time of each simulation often takes several dozens of minutes (depending upon the dataset resolution), which clearly prevents easy interaction. The modern graphics processing unit (GPU) is not only a powerful graphics engine but also a highly parallel programmable processor featuring peak arithmetic performance and memory bandwidth that substantially outpaces its CPU counterpart. However, despite this, the GPU is little used in the context of the Virtual Physiological Human (VPH). This paper provides a case study to demonstrate the performance advantages that can be gained by using the GPU appropriately in the context of a VPH project in which the study of tumour growth is a central activity. We also analyse the algorithm performance on different modern parallel processing architectures, including multicore CPU and many-core GPU.

The ACGT Oncosimulator is an integrated Grid-based system, under development within a 25-partner European-Japanese project, for patient-specific simulation of the response of a tumour and surrounding tissue to various forms of therapy. The validation of the simulation code is an activity requiring extensive human-driven visual investigation of the influence of each of the dozens of parameters to the code, and comparison of the simulation results against the known outcomes of past patient treatments. This activity therefore calls for a visualisation environment that supports users in working with an extremely large potential result space, and in rapidly setting up visualisations that highlight the differences between chosen subsets of available results. We describe the innovative features of the OncoRecipeSheet, an environment designed to meet these requirements.

Mathematical and computational tumor dynamics models can provide considerable insight into the relative importance and interdependence of related biological mechanisms. They may also suggest the existence of optimal treatment windows in the generic setting. Nevertheless, they cannot be translated into clinical practice unless they undergo a strict and thorough clinical validation and adaptation. In this context one of the major actions of the EC funded project ldquoAdvancing Clinico-Genomic Trials on Cancerrdquo (ACGT) is dedicated to the development of a patient specific four dimensional multiscale tumor model mimicking the nephroblastoma tumor response to chemotherapeutic agents according to the SIOP 2001/GPOH clinical trial. Combined administration of vincristine and dactinomycin is considered. The patient#x2019;s pseudoanonymized imaging, histopathological, molecular and clinical data are carefully exploited. The paper briefly outlines the basics of the model developed by the In Silico Oncology Group and particularly stresses the effect of stem/clonogenic, progenitor and differentiated tumor cells on the overall tumor dynamics. The need for matching the cell category transition rates to the cell category relative populations of free tumor growth for an already large solid tumor at the start of simulation has been clarified. A technique has been suggested and succesfully applied in order to ensure satisfaction of this condition. The concept of a nomogram matching the cell category transition rates to the cell category relative populations at the treatment baseline is introduced. Convergence issues are addressed and indicative numerical results are presented. Qualitative agreement of the modelpsilas behavior with the corresponding clinical trial experience supports its potential to constitute the basis for an optimization system within the clinical environment following completion of its clinical validation and optimization. In silico treatment experimentation in the patient individualized context is expected to constitute the primary application of the model.

The potential of cancer multilevel modeling has been particularly emphasized over the past years. Integration of multiscale experimental and clinical information pertaining to cancer via advanced computer models seems to considerably accelerate optimization of cancer treatment in the patient individualized context. However, a sine qua non prerequisite for such models to reach clinical practice is to be thoroughly tested through clinical trials for validation and optimization purposes. This is one of the major goals of the European Commission funded ldquoadvancing clinico-genomic trials on cancerrdquo (ACGT) project. This paper presents a discrete state based, four dimensional, multiscale tumor dynamics model that has been specially developed by the in silico oncology group in order to mimick the trial of principle (TOP) clinical trial concerning breast cancer treated with epirubicin. The TOP trial constitutes one of the ACGT clinical trials. A substantial part of the model can address other tumor types as well. The actual pseudoanonymized imaging, histopathological, molecular and clinical data of the patient are exploited. Special emphasis is put on the effect of cancer stem/clonogenic, progenitor, differentiated and dead cells, the cell category transition rates and the cell category relative populations within the tumor from the treatment baseline onwards. The importance of adaptation of the cell category relative populations to the cell category transition rates for free tumor growth is revealed and the concept of a pertinent nomogram is introduced. A method which ensures adaptation of these two sets of entities at the beginning of the simulation execution is proposed and subsequently successfully applied. Convergence and code checking issues are addressed. Indicative parametric/sensitivity studies are presented along with specific numerical findings. The modelpsilas behavior substantiates its potential to serve as the basis of a treatment optimization system following an eventually succesful completion of the clinical validation and optimization process.

A constantly increasing number of applications from various scientific sectors are finding their way towards adopting Grid technologies in order to take advantage of their capabilities: the advent of Grid environments made feasible the solution of computational intensive problems in a reliable and cost-effective way. The aim of this paper is to demonstrate how multilevel tumour growth and response to therapeutic treatment models can be used in order to simulate clinical trials, with the long-term intention of better designing clinical studies and understanding their outcome based on basic biological science. For this purpose, a computer simulation model of glioblastoma multiforme response to radiotherapy has been applied to perform the aforementioned simulation in a real Grid environment by also taking into account historical data. The proposed approach yields very good results for the conducted virtual trial since these are in agreement with the outcome of the real clinical study, while the use of Grid technologies demonstrate and highlight their added-value.

The concept of in silica radiation oncology is clarified in this paper. A brief literature review points out the principal domains in which experimental, mathematical, and three-dimensional (3-D) computer simulation models of tumor growth and response to radiation therapy have been developed. Two paradigms of 3-D simulation models developed by our research group are concisely presented. The first one refers to the in vitro development and radiation response of a tumor spheroid whereas the second one refers to the fractionated radiation response of a clinical tumor in vivo based on the patient's imaging data. In each case, a description of the salient points of the corresponding algorithms and the visualization techniques used takes place. Specific applications of the models to experimental and clinical cases are described and the behavior of the models is two- and three-dimensionally visualized by using virtual reality techniques. Good qualitative agreement with experimental and clinical observations strengthens the applicability of the models to real situations. A protocol for further testing and adaptation is outlined. Therefore, an advanced integrated patient specific decision support and spatio-temporal treatment planning system is expected to emerge after the completion of the necessary experimental tests and clinical evaluation.

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.