Category: Project

11 Feb

Microsimulation of colorectal cancer screening strategies

Colorectal cancer (CRC) is the second most frequent solid cancer and the third leading cause of cancer related death. There is tremendous potential to reduce CRC incidence and CRC related death via CRC screening. The evidence for many CRC screening interventions is incomplete and for some highly relevant questions no high-quality data are available. For instance, even though colonoscopy is considered the gold standard for CRC screening, there is no randomized controlled colonoscopy study for CRC screening. Microsimulation is an attractive tool to assess effects of CRC screening on a population. Microsimulation models are used for forming medical policies which allocate billions of dollars to specific CRC screening and surveillance interventions. However, existing tools for CRC microsimulation are currently strictly proprietary, and predictions cannot be independently advanced. Moreover, sensitivity analysis is usually insufficient and the space of uncertainty in basic parameters barely explored. Finally, current microsimulation studies do not provide personalized predictions.

We recently developed the microsimulation tool Colon Modeling Open Source Tool (CMOST). CMOST captures the natural history of CRC via early and advanced adenomas, accounting for gender, age, location within the colon and individual differences in CRC risk and allows simulating screening interventions. Detailed calibration and validation was performed and we continue to develop CMOST and try to apply it to answer various clinical questions.

30 Jan

Synergy of radiation and immune system

Animal studies and clinical trials identified a synergy of fractionated irradiation and immunotherapy. This synergy stems from the fact that radiation induces cell stress and immunogenic cell death, thereby exposing a wealth of previously hidden tumor-associated antigens, stress proteins and dangerassociated molecular patterns (HSPs, DAMPs), which are endogenous immune adjuvants that can initiate and stimulate an immune response. Dendritic cells recognize these antigens, and present them to activate naïve T cells in the tumor draining lymph node. Activated T cells then travel through the lymphatic system, nter the blood circulation, and travel in cycles with the blood through the system of rteries, capillaries and veins. Post-irradiation immunotherapy stimulates rapid growth, proliferation, and differentiation of dendritic cells or T cells that are capable of specific imination of antigen-presenting tumor cell, thereby facilitating a second wave of cell kill nd overall tumor regression. Different radiation fractionation protocols in combination ith various immunotherapeutic approaches are currently being explored in more than 10 active clinical trials (7).

The goal of the project is to develop a quantitative mathematical framework that predicts systemic response of metastatic tumors to focal radiotherapy – either alone or in combination with immunotherapy. The ultimate aim of this project will be to propose such framework as a clinical decision support system to derive optimal radiation fractionation protocols and irradiation site for immune activation on a per patient basis.

30 Dec

Pulse wave propagation modeling

Intermittent hemodialysis (HD) is the main method of renal replacement therapy in patients with end stage renal disease. Cardiovascular complications related to atherosclerosis and vascular calcification are the most frequent cause of death in this group of patients. A relatively new non-invasive tool for the assessment of the status of arteries is applanation tonometry that allows for precise measurements of the pulse wave shape and its velocity in peripheral (e. g. radial) arteries. Importantly, by performing pulse-wave analysis on a peripheral artery, one can estimate the central aortic pulse shape that is crucial for the stratification of CV disease risk. The required permanent blood access, such as arteriovenous fistula, induces substantial changes in systemic and peripheral blood circulation and has substantial impact on the measured pulse wave. There are also other important factors that have to be taken into account, such as the changes in fluid overload and blood volume during hemodialysis session and the changes in vascular resistance due to modifications of vasodilatation of the capillary bed. These factors make the standard interpretation of pulse wave analysis problematic if applied to patients on hemodialysis and there is a need for a theoretical evaluation that can combine all important factors. On the other hand, applanation tonometry may help to better understand and assess the status of the arteriovenous fistula and other possible clinical complications that occur in HD patients. We hypothesize that the presence of the fistula and other abnormalities in vascular system of HD patients may influence the standard assumptions necessary for pulse wave analysis and its interpretation.

Our main objective is to investigate the role of various abnormalities in HD patients on the propagation of pulse wave using mathematical modeling of the whole arterial tree with arteriovenous fistula and compare these predictions to the respective clinical measurements.

We propose the application of a mathematical model of pulse wave propagation in the whole arterial system modified and extended by the arteriovenous fistula for the analysis of the role of various possible (patho-)physiological conditions that may have an impact on the measured pulse wave. The models of pulse wave propagation describe 1D flow in compliant arterial vessels using two variables: blood flow velocity and blood pressure (or equivalently the cross-sectional area of compliant vessel), and were previously shown to be in agreement with rich set of physiological data. The mathematical modeling will be applied for the analysis of the results of a new clinical study that involves non-invasive measurements of pulse wave at different places of arteriovenous system before, during and after hemodialysis session together with non-invasive assessment of the heart activity (by impedance cardiography) and the changes in fluid status of the patient (intracellular and extracellular water by bioimpedance, blood volume by online measurement of changes in hematocrit) that strongly influence the pulse wave propagation.