Introduction of Hypermatrix and Operator Notation into a Discrete Mathematics Simulation Model of Malignant Tumour Response to Therapeutic Schemes In Vivo. Some Operator Properties

The tremendous rate of accumulation of experimental and clinical knowledge pertaining to cancer dictates the development of a theoretical framework for the meaningful integration of such knowledge at all levels of biocomplexity. In this context our research group has developed and partly validated a number of spatiotemporal simulation models of in vivo tumour growth and in particular tumour response to several therapeutic schemes. Most of the modeling modules have been based on discrete mathematics and therefore have been formulated in terms of rather complex algorithms (e.g. in pseudocode and actual computer code). However, such lengthy algorithmic descriptions, although sufficient from the mathematical point of view, may render it difficult for an interested reader to readily identify the sequence of the very basic simulation operations that lie at the heart of the entire model. In order to both alleviate this problem and at the same time provide a bridge to symbolic mathematics, we propose the introduction of the notion of hypermatrix in conjunction with that of a discrete operator into the already developed models. Using a radiotherapy response simulation example we demonstrate how the entire model can be considered as the sequential application of a number of discrete operators to a hypermatrix corresponding to the dynamics of the anatomic area of interest. Subsequently, we investigate the operators’ commutativity and outline the “summarize and jump” strategy aiming at efficiently and realistically address multilevel biological problems such as cancer. In order to clarify the actual effect of the composite discrete operator we present further simulation results which are in agreement with the outcome of the clinical study RTOG 83–02, thus strengthening the reliability of the model developed

Applying a 4D multiscale in vivo tumor growth model to the exploration of radiotherapy scheduling: The effects of weekend treatment gaps and p53 gene status on the response of fast growing solid tumors

The present paper aims at demonstrating clinically oriented applications of the multiscale four dimensional in vivo tumor growth simulation model previously developed by our research group. To this end the effect of weekend radiotherapy treatment gaps and p53 gene status on two virtual glioblastoma tumors differing only in p53 gene status is investigated in silico. Tumor response predictions concerning two rather extreme dose fractionation schedules (daily dose of 4.5 Gy administered in 3 equal fractions) namely HART (Hyperfractionated Accelerated Radiotherapy weekend less) 54 Gy and CHART (Continuous HART) 54 Gy are presented and compared. The model predictions suggest that, for the same p53 status, HART 54 Gy and CHART 54 Gy have almost the same long term effects on locoregional tumor control. However, no data have been located in the literature concerning a comparison of HART and CHART radiotherapy schedules for glioblastoma. As non small cell lung carcinoma (NSCLC) may also be a fast growing and radiosensitive tumor, a comparison of the model predictions with the outcome of clinical studies concerning the response of NSCLC to HART 54 Gy and CHART 54 Gy is made. The model predictions are in accordance with corresponding clinical observations, thus strengthening the potential of the model

Numerical simulation of vascular tumour growth under antiangiogenic treatment: addressing the paradigm of single-agent bevacizumab therapy with the use of experimental data

Background: Antiangiogenic agents have been recently added to the oncological armamentarium with bevacizumab probably being the most popular representative in current clinical practice. The elucidation of the mode of action of these agents is a prerequisite for personalized prediction of antiangiogenic treatment response and selection of patients who may benefit from this kind of therapy. To this end, having used as a basis a preexisting continuous vascular tumour growth model which addresses the targeted nature of antiangiogenic treatment, we present a paper characterized by the following three features. First, the integration of a two-compartmental bevacizumab specific pharmacokinetic module into the core of the aforementioned preexisting model. Second, its mathematical modification in order to reproduce the asymptotic behaviour of tumour volume in the theoretical case of a total destruction of tumour neovasculature. Third, the exploitation of a range of published animal datasets pertaining to antitumour efficacy of bevacizumab on various tumour types (breast, lung, head and neck, colon).Results: Results for both the unperturbed growth and the treatment module reveal qualitative similarities with experimental observations establishing the biologically acceptable behaviour of the model. The dynamics of the untreated tumour has been studied via a parameter analysis, revealing the role of each relevant input parameter to tumour evolution. The combined effect of endogenous proangiogenic and antiangiogenic factors on the angiogenic potential of a tumour is also studied, in order to capture the dynamics of molecular competition between the two key-players of tumoural angiogenesis. The adopted methodology also allows accounting for the newly recognized direct antitumour effect of the specific agent.Conclusions: Interesting observations have been made, suggesting a potential size-dependent tumour response to different treatment modalities and determining the relative timing of cytotoxic versus antiangiogenic agents administration. Insight into the comparative effectiveness of different antiangiogenic treatment strategies is revealed. The results of a series of in vivo experiments in mice bearing diverse types of tumours (breast, lung, head and neck, colon) and treated with bevacizumab are successfully reproduced, supporting thus the validity of the underlying model.Reviewers: This article was reviewed by L. Hanin, T. Radivoyevitch and L. Edler

Dealing with diversity in computational cancer modeling.

This paper discusses the need for interconnecting computational cancer models from different sources and scales within clinically relevant scenarios to increase the accuracy of the models and speed up their clinical adaptation, validation, and eventual translation. We briefly review current interoperability efforts drawing upon our experiences with the development of in silico models for predictive oncology within a number of European Commission Virtual Physiological Human initiative projects on cancer. A clinically relevant scenario, addressing brain tumor modeling that illustrates the need for coupling models from different sources and levels of complexity, is described. General approaches to enabling interoperability using XML-based markup languages for biological modeling are reviewed, concluding with a discussion on efforts towards developing cancer-specific XML markup to couple multiple component models for predictive in silico oncology

Exploiting Clinical Trial Data Drastically Narrows the Window of Possible Solutions to the Problem of Clinical Adaptation of a Multiscale Cancer Model

The development of computational models for simulating tumor growth and response to treatment has gained significant momentum during the last few decades. At the dawn of the era of personalized medicine, providing insight into complex mechanisms involved in cancer and contributing to patient-specific therapy optimization constitute particularly inspiring pursuits. The in silico oncology community is facing the great challenge of effectively translating simulation models into clinical practice, which presupposes a thorough sensitivity analysis, adaptation and validation process based on real clinical data. In this paper, the behavior of a clinically-oriented, multiscale model of solid tumor response to chemotherapy is investigated, using the paradigm of nephroblastoma response to preoperative chemotherapy in the context of the SIOP/GPOH clinical trial. A sorting of the model's parameters according to the magnitude of their effect on the output has unveiled the relative importance of the corresponding biological mechanisms; major impact on the result of therapy is credited to the oxygenation and nutrient availability status of the tumor and the balance between the symmetric and asymmetric modes of stem cell division. The effect of a number of parameter combinations on the extent of chemotherapy-induced tumor shrinkage and on the tumor's growth rate are discussed. A real clinical case of nephroblastoma has served as a proof of principle study case, demonstrating the basics of an ongoing clinical adaptation and validation process. By using clinical data in conjunction with plausible values of model parameters, an excellent fit of the model to the available medical data of the selected nephroblastoma case has been achieved, in terms of both volume reduction and histological constitution of the tumor. In this context, the exploitation of multiscale clinical data drastically narrows the window of possible solutions to the clinical adaptation problem

MKI67 (marker of proliferation Ki-67)

Review on MKI67 (marker of proliferation Ki-67), with data on DNA, on the protein encoded, and where the gene is implicated

CONTRIBUTION OF EMPIRICAL METHODS AND SATELLITE DATA USE FOR ESTIMATING DAILY REFERENCE EVAPOTRANSPIRATION

Στην παρούσα εργασία χρησιμοποιούνται επίγεια και δορυφορικά μετεωρολογικά δεδομένα του έτους 2014 από την περιοχή της Βοιωτίας. Τα επίγεια δεδομένα προέρχονται από τον αυτόματο αγρομετεωρολογικό σταθμό (ΑΑΣ) μέτρησης της εξατμισοδιαπνοής αναφοράς (ΕΤο) του Γεωπονικού Πανεπιστημίου Αθηνών (ΓΠΑ). Τα μετεωρολογικά δορυφορικά δεδομένα (SAT) αντιστοιχούν σε πολύγωνο 0.25οΧ0.25ο εντός του οποίου λειτουργεί και ο ΑΑΣ. Χρησιμοποιώντας τα επίγεια αλλά και τα δορυφορικά δεδομένα, υπολογίσθηκε η ΕΤο με τη μέθοδο FAO-56 PM, αλλά και με τρεις εμπειρικές μεθόδους (Copais, Valiantzas και Hargreaves-Samani) και πραγματοποιήθηκαν συγκρίσεις με σκοπό να αξιολογηθεί η αξιοπιστία των μοντέλων. Ως βάση των συγκρίσεων υιοθετήθηκε η μέθοδος FAO-56 PM με χρήση επίγειων δεδομένων. Από την εργασία προκύπτει ότι τόσο για τα επίγεια όσο και για τα δορυφορικά δεδομένα η μέθοδος Copais δίνει τις καλύτερες εκτιμήσεις ακολουθούμενη από την μέθοδο Valiantzas και με σοβαρή υπερεκτίμηση η Hargreaves-Samani. In the present study we used ground and satellite meteorological data of the year 2014 from the region of Viotia-Greece. The ground data were obtained from the automatic grass reference evapotranspiration station (AAS) of the Agricultural University of Athens. The satellite data (SAT) cover an area of 0,25ο x 0,25ο that includes the AAS. By using the ground and the satellite data we calculated the reference evapotranspiration, ΕΤο, with the method FAO-56 PM and with three empirical methods (Copais, Valiantzas and Hargreaves-Samani). The FAO-56 PM was used as a benchmark method to compare and validate the performances of the others methods. The results show that for both the ground and the satellite data, Copais method is the most accurate followed by Valiantzas and Hargreaves-Samani, indicated by serious overestimation

Small bowel MRI in adult patients: not just Crohn’s disease—a tutorial

To provide an overview of less well-known small bowel and mesenteric diseases found at small bowel magnetic resonance (MR) enterography/enteroclysis and to review the imaging findings. MR enterography and enteroclysis are important techniques for evaluation of small bowel diseases. In most centres these techniques are primarily used in Crohn's disease, and most radiologists are familiar with these MRI findings. However, the knowledge of findings in other diseases is often sparse, including diseases that may cause similar clinical symptoms to those of Crohn's disease. We present a spectrum of less common and less well-known bowel and mesenteric diseases (e.g. internal hernia, intussusception, neuroendocrine tumour) from our small bowel MR database of over 2,000 cases. These diseases can be found in patients referred for bowel obstruction, abdominal pain or rectal blood loss. Further, in patients with (or suspected to have) Crohn's disease, some of these diseases (e.g. neuroendocrine tumour, familial Mediterranean fever) may mislead radiologists to erroneously diagnose active Crohn's disease. Radiologists should be familiar with diseases affecting the small bowel other than Crohn's disease, including diseases that may mimic Crohn's diseas