Stephan Scheidegger

Effect of high dose per pulse flattening filter-free beams on cancer cell survival.

PURPOSE To investigate if there is a statistically significant difference in cancer cell survival using a high dose per pulse flattening filter-free (FFF) beam compared to a standard flattened beam. MATERIAL AND METHODS To validate the radiobiological effect of the flattened and FFF beam, two glioblastoma cell lines were treated with either 5 or 10 Gy using different dose rates. Dose verification was performed and colony formation assays were carried out. To compare the predictability of our data, radiobiological models were included. RESULTS The results presented here demonstrate that irradiation of glioblastoma cell lines using the FFF beam is more efficient in reducing clonogenic cell survival than the standard flattened beam, an effect which becomes more significant the higher the single dose. Interestingly, in our experimental setting, the radiobiological effect of the FFF beam is dependent on dose per pulse rather than on delivery time. The used radiobiological models are able to describe the observed dose rate dependency between 6 and 24 Gy/min. CONCLUSION The results presented here show that dose per pulse might become a crucial factor which influences cancer cell survival. Using high dose rates, currently used radiobiological models as well as molecular mechanisms involved urgently need to be re-examined.

Morphological computation and morphological control: Steps toward a formal theory and applications

Morphological computation can be loosely defined as the exploitation of the shape, material properties, and physical dynamics of a physical system to improve the efficiency of a computation. Morphological control is the application of morphological computing to a control task. In its theoretical part, this article sharpens and extends these definitions by suggesting new formalized definitions and identifying areas in which the definitions we propose are still inadequate. We go on to describe three ongoing studies, in which we are applying morphological control to problems in medicine and in chemistry. The first involves an inflatable support system for patients with impaired movement, and is based on macroscopic physics and concepts already tested in robotics. The two other case studies (self-assembly of chemical microreactors; models of induced cell repair in radio-oncology) describe processes and devices on the micrometer scale, in which the emergent dynamics of the underlying physical system (e.g., phase transitions) are dominated by stochastic processes such as diffusion.

A helium beam path for an imaging-plate detector system

A helium beam path for the marresearch imaging plate detector system (X-ray Research GmbH, Norderstedt, Germany) is described. The helium beam path is designed to minimize unwanted air scattering of the primary beam and to reduce absorption of the diffracted beam. The standard marresearch detector system, consisting of the imaging plate detector (online scanner) and the detector base with integrated collimation system, remains unchanged. The beam path consists of a polyethylene bag with the open end fixed to a metal ring. The ring is pressed against the entry window of the imaging plate detector. In this way a sealed volume is created. The primary beam enters into the helium bag through an additional collimating system which is sealed with a thin polyimide window. The crystal and the goniometer head are located inside the helium bag and are connected to the outside spindle axis via a linear and rotary motion feedthrough.

A LQ-based kinetic model formulation for exploring dynamics of treatment response of tumours in patients.

A kinetic bio-mathematical, linear-quadratic (LQ) based model description for clonogenic survival is presented. In contrast to widely used formulations of models, a dynamic approach based on ordinary differential equations for coupling a repair model with a tumour growth model is used to allow analysis of intercellular process dynamics and submodel interference. The purpose of the model formulation is to find a quantitative framework for investigation of tumour response to radiotherapy in vivo. It is not the intention of the proposed model formulation to give a mechanistic explanation for cellular repair processes. This article addresses bio-mathematical aspects of the simplistic kinetic approach used for description of repair. The model formulation includes processes for cellular death, repopulation and cellular repair. The explicit use of the population size in the model facilitates the coupling of the sub-models including aspects of tissue dynamics (competition, oxygenation). The cellular repair is summarized by using a kinetic model for a dose equivalent Γ describing production and elimination of sublethal lesions. This dose equivalent replaces the absorbed dose used in the common LQ- model. Therefore, this approach is called the Γ- LQ- formulation. A comparison with two kinetic radiobiological models (the LPL model of Curtis and the compartmental model of Carlone) is carried out. The resulting differential equations are solved by numerical integration using a Runge-Kutta algorithm. The comparison reveals a good agreement between the Γ- LQ- formulation and the models of Curtis and Carlone under certain, defined conditions: The proposed formulation leads to results which are identical to the model of Carlone over a wide range of investigated biological parameters and different fractionation schemes when using first order repair kinetics. The comparison with experimental data and the LPL- model of Curtis shows a good agreement of the Γ- LQ- formulation using second order repair kinetics over a wide range of dose rate. Over a limited range, the use of second order repair in the Γ- LQ- formulation approximates the same dose rate dependency of clonogenic survival using only one additional parameter to those of the common LQ model. Within the investigated range of parameters, the presented Γ-LQ- formulation may be used to describe the in-vivo tumour response to radiation. The influence of repopulation, oxygenation and other aspects of tissue dynamics may override the differences between the intrinsic radiosensitivity yielded by each of the models. The proposed model formulation can be extended with additional static and dynamic tissue behaviours. This may be useful for the understanding of the reaction of tissues to heat (hyperthermia) or combined anti-cancer treatments (chemo-radiotherapy).

Using State Variables to Model the Response of Tumour Cells to Radiation and Heat: A Novel Multi-Hit-Repair Approach

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

Kinetic model for dose equivalent : an efficient way to predict systems response of irradiated cells

The response of tumours onto ionizing radiation cannot be fully understood by commonly used radiobiological models. The reason may lie in the complex structure of the cellular systems which show a high degree of compartmentalisation and which is characterised by a network of interacting processes at different time scales. To access the dynamic response of cells onto radiation, compartmental models based on a biological dose equivalent can be used. Two different models (-LQand -IRmodel) are used to fit experimental data of the clonogenic survival of irradiated cells at very high dose rates. The models reveal the correct dose rate dependence over a wide range of the parameter space when adapting the kinetic constants to the dose rate. This adaption could be an indication for the multi-scale structure of the system.

Dynamic in vivo profiling of DNA damage and repair after radiotherapy using canine patients as a model

Time resolved data of DNA damage and repair after radiotherapy elucidates the relation between damage, repair, and cell survival. While well characterized in vitro, little is known about the time-course of DNA damage response in tumors sampled from individual patients. Kinetics of DNA damage after radiotherapy was assessed in eight dogs using repeated in vivo samples of tumor and co-irradiated normal tissue analyzed with comet assay and phosphorylated H2AX (γH2AX) immunohistochemistry. In vivo results were then compared (in silico) with a dynamic mathematical model for DNA damage formation and repair. Maximum %DNA in tail was observed at 15–60 min after irradiation, with a rapid decrease. Time-courses of γH2AX-foci paralleled these findings with a small time delay and were not influenced by covariates. The evolutionary parameter search based on %DNA in tail revealed a good fit of the DNA repair model to in vivo data for pooled sarcoma time-courses, but fits for individual sarcoma time-courses suffer from the heterogeneous nature of the in vivo data. It was possible to follow dynamics of comet tail intensity and γH2AX-foci during a course of radiation using a minimally invasive approach. DNA repair can be quantitatively investigated as time-courses of individual patients by integrating this resulting data into a dynamic mathematical model.

Novel hyperthermia applicator system allows adaptive treatment planning: preliminary clinical results in tumour-bearing animals

Hyperthermia (HT) as an adjuvant to radiation therapy (RT) is a multimodality treatment method to enhance therapeutic efficacy in different tumours. High demands are placed on the hardware and treatment planning software to guarantee adequately planned and applied HT treatments. The aim of this prospective study was to determine the effectiveness and safety of the novel HT system in tumour-bearing dogs and cats in terms of local response and toxicity as well as to compare planned with actual achieved data during heating. A novel applicator with a flexible number of elements and integrated closed-loop temperature feedback control system, and a tool for patient-specific treatment planning were used in a combined thermoradiotherapy protocol. Good agreement between predictions from planning and clinical outcome was found in 7 of 8 cases. Effective HT treatments were planned and verified with the novel system and provided improved quality of life in all but 1 patient. This individualized treatment planning and controlled heat exposure allows adaptive, flexible and safe HT treatments in palliatively treated animal patients.

Evaluation of low contrast resolution and radiation dose in abdominal CT protocols by a difference detail curve (DDC) method

Abstract The use of optimised CT protocols regarding radiation exposure is a legal requirement. Since low contrast visibility is intrinsically varying within the CT slice, there is no adequate method for optimisation of dose and image quality. We developed a method to access image quality in a way that represents the situation closer to a real patient. This method is based on a novel difference detail curve (DDC) phantom with low contrast objects representing native tissue contrast and contrast media with different densities and diameters. The position of the contrast objects have been evaluated by a noise level analysis of CT slices of different manufactures. The dose – length – product can be measured within the phantom simultaneously. For all tested manu-factures and CT protocols, the noise analysis revealed a similar spatial variation of the signal -to-noise ratio (SNR). For the DDC method, contrast steps of 6 (4-8) Hounsfield Units (HU) are adequate. For the different CT units, comparable low contrast detectability is associated with remarkably varying dose levels (CTDI range from 8 to 18 mGy for native contrast and 9-16 mGy for contrast media). The novel DDC phantom is sensitive to protocol optimisations and therefore suitable for rating subtle effects caused by protocol optimisation.

SP-0298: Hyperthermia and radiation therapy: potentials for synergy and future developments

SP-0298 Hyperthermia and radiation therapy: potentials for synergy and future developments S. Bodis, N.R. Datta, N. Kuster, C. Rohrer Bley, G. Lutters, S. Scheidegger, E. Puric Kantonsspital Aarau and University Hospital Zurich, RadioOnkologieZentrum KSA-KSB and Department of Radiation Oncology University Hospital Zurich, Aarau, Switzerland Kantonsspital Aarau, RadioOnkologieZentrum KSA-KSB, Aarau, Switzerland Foundation for Research on Information Technologies in Society, Foundation for Research on Information Technologies in Society, Zurich, Switzerland Veterinary Hospital, Radiation Oncology, Zurich, Switzerland Zurich University of Applied Sciences, ZHAW School of Engineering, Winterthur, Switzerland