Medical Physics Group

Figure 1: Series of first two images show the cellular proliferation, imaged with FLT PET/CT before the radiotherapy and after radiotherapy. Third image has radiation field overlayed over the cellular proliferation image. Series of images clearly show how the cellular proliferation disappears in the irradiated bone marrow.
Medical Physics is an applied branch of physics concerned with the application of the concepts and methods of physics to the diagnosis and treatment of disease. Medical Physics research in our group, strengthened with the research of our collaborators at the Department of Medical Physics at University of Wisconsin – Madison and our clinical colleagues at the University of Wisconsin Carbone Cancer Center, is focused into image-guided cancer* therapy.

Within this general area, our research is grouped into five focused areas:

• First focus area is quantitative imaging of cancer, with the aim to characterize biological properties of tumors or to quantify treatment response, having quantifiable imaging data becomes critically important. Most of our research involves quantification of molecular imaging techniques, predominantly positron emission tomography (PET) and dynamic contrast enhanced CT (DCE-CT).
• Second focus area is imaging for biological target definition that will facilitate personalized treatment. We are focusing on comprehensive definition of biological targets that will be used for non-uniform dose prescription - the process most often termed "dose-painting".
• Third focus area is imaging for treatment assessment, with the goal to characterize the tumor phenotypes before the therapy and stratify the patients into different treatment regimes. We are involved into a series of Phase I clinical trials utilizing advanced molecular imaging to determine early treatment response and pharmacodynamics of several novel drugs, particularly targeting angiogenesis.
• Fourth focus area is modeling of tumor growth and response to therapies. Here, the goal is to test the interplay of underlying biological processes, optimize therapies, predict treatment response, and to generate hypotheses in cancer research.
• Last focus area of our group covers open source medical devices. The goal of the Open Source Medical Devices (OSMD) initiative is to promote medical research by making medical technology (hardware and software) available as an open source to research groups around the world.

* Cancer is the second (in some statistics even the first) leading cause of death in the developed world, responsible for over a third of all deaths, with an increasing incidence from year to year. There are several ways of treatment, depending mainly on the stage of the disease. Three main cancer therapies are radiotherapy, surgery and chemotherapy.

Reference:
LIU, G., JERAJ, Robert, VANDERHOEK, M., PERLMAN, S., KOLESAR, Jill M., HARRISON, M.R., SIMOČIČ, Urban, EICKHOFF, J.C., CARMICHAEL, L., CHAO, B., MARNOCHA, R., IVY, P., WILDING, G. Pharmacodynamic Study Using FLT PET/CT in Patients with Renal Cell Cancer and Other Solid Malignancies Treated with Sunitinib Malate. Clin Cancer Res, 17(24), 2011, 7 str., doi: 10.1158/1078-0432.CCR-11-1677. [COBISS.SI-ID 25278759]

Beside head of the Medical Physics Group Dr. Robert Jeraj, members of this group are Dr. Urban Simonèiè and Damijan Valentinuzzi.

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Dr. Urban Simončič working area: Kinetic analysis of PET images – method optimization and clinical applications

Positron emission tomography (PET) is already well established imaging technique in modern oncology, but there is still an unresolved problem of PET image quantification. Quantitative measures can be extracted from PET data by kinetic analysis methods or uptake normalizations. Kinetic analysis is superior to the uptake normalization based PET quantification methods in the richness and the specificity of the results. However, kinetic analysis acceptance in clinical settings is still limited due to the complexity of data acquisition and its sensitivity to the imaging noise. In order to address this issue, our work is focused into improved kinetic analysis methodology comprising a robust PET imaging protocol involving kinetic analysis that is schematically presented below.


Figure 2: The schematic representation of the robust PET imaging protocol involving kinetic analysis. An overall output of the robust PET imaging protocol involving kinetic comprises the best possible kinetic parameter estimates and a precise characterization of their uncertainties. To obtain these estimates, concurrent optimization of the kinetic analysis method, image acquisition method and image reconstruction method is necessary. The optimization procedure is iterative, with subsequent improvement of simulation accuracy using the clinical data.

The developed methodology is then utilized in clinical settings. There are two main types of clinical applications for molecular imaging and kinetic analysis: 1) using the imaging data for individual’s treatment assessment and guidance, 2) using the imaging data in clinical studies with the aim of discovering population behavior during the treatment.


Figure 3: Here is an example of FLT PET/CT treatment response assessment for the patients treated with sunitinib malate. Upper row shows the treatment response quantification with the optimized kinetic analysis, while the lower image shows response quantification with a standardized uptake value. The example shows that optimized kinetic analysis produces considerably different values for treatment response than the SUV. Superiority of optimized kinetic analysis (in term of better accuracy) can be tested with simulations.

Preliminary results assure the improvement in individual’s treatment assessment accuracy and the feasibility of more aggressive treatment interventions. However, estimation accuracy for population observables in clinical studies could be limited with the clinical data heterogeneity and lowering the individual’s treatment response uncertainty does not necessarily affect the population response uncertainty.

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Damijan Valentinuzzi working area

One of the promising and emerging methods of treatment is targeted drug therapy, which affects the specific processes in the tumor. When tumor grows more than 1-2mm in diameter, new blood vessels are required to deliver nutrients and oxygen and they serve as an escape route for metastatic cells. Our aim is modeling the tumor response to anti-angiogenic drugs, which inhibit the growth of new blood vessels. In particular, we are going to develop a computer simulation, which will treat every patient and every single tumor individually as unicum and by which it will be possible to select the optimal therapy, that will give the best results for each individual.

Currenty, we are investigating a multiscale computer model, which combines experimental data from clinical studies on a larger population of patients with data, specific for each patient, which we obtained by using advanced imaging techniques (PET/CT), capable of determining the heterogenity within the tumor (proliferation, hypoxia, metabolism). We believe that the lack of knowledge of each individual tumor's heterogenity is an important reasons, why some treatments do not end up as we expected.

Axitinib (Pfizer) is an example of an anti-angiogenic targeted drug, which is still undergoing the clinical trials, and which we would like to include in our simulation. The drug inhibitsthe so-called VEGF TKI receptors ("vascular endothelial growth factor - tyrosine kinase receptors"), which are responsible for stimulating the growth of new tumor blood vessels. We hope that by using our model, we will be able to determine the optimal dosage for each patient, predict clinical outcome and potential interactions when using Axitinb in combination therapies, for example in combination with radio- or chemotherapy. Finally, we would also like to test different hypotheses as to why sooner or later most tumors become resistive to anti-angiogenic drugs, which is currently one of the main problems.



Figure 4 (above): Simulation of the number of tumor cells during anti-angiogenic therapy (blue) and during one-week drug holiday (red).
(below left): - real FLT PET image of cellular proliferation in the tumor after one-week drug holiday.
(below right): - simulated FLT PET image of cellular proliferation in the tumor after one-week drug holiday.