Theoretical evaluation of the impact of diverse treatment conditions by calculation of the tumor control probability (TCP) of simulated cervical cancer Hyperthermia-Radiotherapy (HT-RT) treatments in-silico.

INTRODUCTION: Hyperthermia (HT) induces various cellular biological processes, such as repair impairment and direct HT cell killing. In this context, in-silico biophysical models that translate deviations in the treatment conditions into clinical outcome variations may be used to study the extent of such processes and their influence on combined hyperthermia plus radiotherapy (HT + RT) treatments under varying conditions. METHODS: An extended linear-quadratic model calibrated for SiHa and HeLa cell lines (cervical cancer) was used to theoretically study the impact of varying HT treatment conditions on radiosensitization and direct HT cell killing effect. Simulated patients were generated to compute the Tumor Control Probability (TCP) under different HT conditions (number of HT sessions, temperature and time interval), which were randomly selected within margins based on reported patient data. RESULTS: Under the studied conditions, model-based simulations suggested a treatment improvement with a total CEM43 thermal dose of approximately 10 min. Additionally, for a given thermal dose, TCP increased with the number of HT sessions. Furthermore, in the simulations, we showed that the TCP dependence on the temperature/time interval is more correlated with the mean value than with the minimum/maximum value and that comparing the treatment outcome with the mean temperature can be an excellent strategy for studying the time interval effect. CONCLUSION: The use of thermoradiobiological models allows us to theoretically study the impact of varying thermal conditions on HT + RT treatment outcomes. This approach can be used to optimize HT treatments, design clinical trials, and interpret patient data.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study.

BACKGROUND: Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). METHODS: Patients with stages T2-4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57-58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41-43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. RESULTS: Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3-4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. CONCLUSION: Tetramodal therapy of T2-T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

Determining 3D Kinematics of the Hip Using Video Fluoroscopy: Guidelines for Balancing Radiation Dose and Registration Accuracy.

BACKGROUND: Video fluoroscopy is a technique currently used to retrieve the in vivo three-dimensional kinematics of human joints during activities of daily living. Minimization of the radiation dose absorbed by the subject during the measurement is a priority and has not been thoroughly addressed so far. This issue is critical for the motion analysis of the hip joint, because of the proximity of the gonads. The aims of this study were to determine the x-ray voltage and the irradiation angle that minimize the effective dose and to achieve the best compromise between delivered dose and accuracy in motion retrieval. METHODS: Effective dose for a fluoroscopic study of the hip was estimated by means of Monte Carlo simulations and dosimetry measurements. Accuracy in pose retrieval for the different viewing angles was evaluated by registration of simulated radiographs of a hip prosthesis during a prescribed virtual motion. RESULTS: Absorbed dose can be minimized to about one-sixth of the maximum estimated values by irradiating at the optimal angle of 45° from the posterior side and by operating at 80 kV. At this angle, accuracy in retrieval of internal-external rotation is poorer compared with the other viewing angles. CONCLUSION: The irradiation angle that minimizes the delivered dose does not necessarily correspond to the optimal angle for the accuracy in pose retrieval, for all rotations. For some applications, single-plane fluoroscopy may be a valid lower dose alternative to the dual-plane methods, despite their better accuracy.

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.

Probabilistic U-Net model observer for the DDC method in CT scan protocol optimization.

Optimizing complex imaging procedures within Computed Tomography, considering both dose and image quality, presents significant challenges amidst rapid technological advancements and the adoption of machine learning (ML) methods. A crucial metric in this context is the Difference-Detailed Curve, which relies on human observer studies. However, these studies are labor-intensive and prone to both inter- and intra-observer variability. To tackle these issues, a ML-based model observer utilizing the U-Net architecture and a Bayesian methodology is proposed. In order to train a model observer unaffected by the spatial arrangement of low-contrast objects, the image preprocessing incorporates a Gaussian Process-based noise model. Additionally, gradient-weighted class activation mapping is utilized to gain insights into the model observer's decision-making process. By training on data from a diverse group of observers, well-calibrated probabilistic predictions that quantify observer variability are achieved. Leveraging the principles of Beta regression, the Bayesian methodology is used to derive a model observer performance metric, effectively gauging the model observer's strength in terms of an 'effective number of observers'. Ultimately, this framework enables to predict the DDC distribution by applying thresholds to the inferred probabilities (Part of this work has been presented at: Stocker D, Sommer C, Gueng S, Stäuble J, Özden I, Griessinger J, Weyland M S, Lutters G, Scheidegger S (2023). Probabilistic U-Net Model Observer for the DDC Method in CT Scan Protocol Optimization. The 56th SSRMP Annual Meeting 2023, November 30. - December 1., 2023, Luzern, Switzerland).

Feasibility of a method for low contrast CT image quality assessment using difference detail curves for abdominal scans.

This work describes a measurement method for assessing dose-related image-quality of CT scans based on the difference detail curve (DDC) method, and showcases its use in a low contrast setting. The method is based on a phantom consisting of elliptical slices of different sizes into which contrast object modules can be inserted. These modules contain contrast objects based on (synthetic) resin mixtures with sucrose (native) or sodium iodine (contrast medium). Mixing ratios are provided to achieve a range of clinically relevant CT-numbers with these materials. The phantom is characterized in terms of contrast accuracy, energy dependency and long-term drift with satisfying results. Contrast accuracy and energy dependency are similar to that of water or soft tissue. Image quality of 655 scans of the phantom acquired at 30 different clinical institutions and with 16 different CT scanner models from 4 manufacturers was assessed by calculating a difference detail curve (DDC) from evaluation of up to 5 human observers using a custom-made software (RadiVates) described in this work. Based on these measurements, inter-observer variability was quantified using a bootstrap method and was shown to be a large contributor to the overall variability. This work demonstrates that assessment of CT image quality is feasible with the aforementioned phantom and DDC method.

The Effects of Heat Stress on the Transcriptome of Human Cancer Cells: A Meta-Analysis.

Hyperthermia is clinically applied cancer treatment in conjunction with radio- and/or chemotherapy, in which the tumor volume is exposed to supraphysiological temperatures. Since cells can effectively counteract the effects of hyperthermia by protective measures that are commonly known as the heat stress response, the identification of cellular processes that are essential for surviving hyperthermia could lead to novel treatment strategies that improve its therapeutic effects. Here, we apply a meta-analytic approach to 18 datasets that capture hyperthermia-induced transcriptome alterations in nine different human cancer cell lines. We find, in line with previous reports, that hyperthermia affects multiple processes, including protein folding, cell cycle, mitosis, and cell death, and additionally uncover expression changes of genes involved in KRAS signaling, inflammatory responses, TNF-a signaling and epithelial-to-mesenchymal transition (EMT). Interestingly, however, we also find a considerable inter-study variability, and an apparent absence of a 'universal' heat stress response signature, which is likely caused by the differences in experimental conditions. Our results suggest that gene expression alterations after heat stress are driven, to a large extent, by the experimental context, and call for a more extensive, controlled study that examines the effects of key experimental parameters on global gene expression patterns.

The Effect of Hyperthermia and Radiotherapy Sequence on Cancer Cell Death and the Immune Phenotype of Breast Cancer Cells.

Hyperthermia (HT) is an accepted treatment for recurrent breast cancer which locally heats the tumor to 39-44 °C, and it is a very potent sensitizer for radiotherapy (RT) and chemotherapy. However, currently little is known about how HT with a distinct temperature, and particularly, how the sequence of HT and RT changes the immune phenotype of breast cancer cells. Therefore, human MDA-MB-231 and MCF-7 breast cancer cells were treated with HT of different temperatures (39, 41 and 44 °C), alone and in combination with RT (2 × 5 Gy) in different sequences, with either RT or HT first, followed by the other. Tumor cell death forms and the expression of immune checkpoint molecules (ICMs) were analyzed by multicolor flow cytometry. Human monocyte-derived dendritic cells (moDCs) were differentiated and co-cultured with the treated cancer cells. In both cell lines, RT was the main stressor for cell death induction, with apoptosis being the prominent cell death form in MCF-7 cells and both apoptosis and necrosis in MDA-MB-231 cells. Here, the sequence of the combined treatments, either RT or HT, did not have a significant impact on the final outcome. The expression of all of the three examined immune suppressive ICMs, namely PD-L1, PD-L2 and HVEM, was significantly increased on MCF-7 cells 120 h after the treatment of RT with HT of any temperature. Of special interest for MDA-MB-231 cells is that only combinations of RT with HT of both 41 and 44 °C induced a significantly increased expression of PD-L2 at all examined time points (24, 48, 72, and 120 h). Generally, high dynamics of ICM expression can be observed after combined RT and HT treatments. There was no significant difference between the different sequences of treatments (either HT + RT or RT + HT) in case of the upregulation of ICMs. Furthermore, the co-culture of moDCs with tumor cells of any treatment had no impact on the expression of activation markers. We conclude that the sequence of HT and RT does not strongly affect the immune phenotype of breast cancer cells. However, when HT is combined with RT, it results in an increased expression of distinct immune suppressive ICMs that should be considered by including immune checkpoint inhibitors in multimodal tumor treatments with RT and HT. Further, combined RT and HT affects the immune system in the effector phase rather than in the priming phase.

Theoretical Evaluation of the Impact of Hyperthermia in Combination with Radiation Therapy in an Artificial Immune-Tumor-Ecosystem.

There is some evidence that radiotherapy (RT) can trigger anti-tumor immune responses. In addition, hyperthermia (HT) is known to be a tumor cell radio-sensitizer. How HT could enhance the anti-tumor immune response produced by RT is still an open question. The aim of this study is the evaluation of potential dynamic effects regarding the adaptive immune response induced by different combinations of RT fractions with HT. The adaptive immune system is considered as a trainable unit (perceptron) which compares danger signals released by necrotic or apoptotic cell death with the presence of tumor- and host tissue cell population-specific molecular patterns (antigens). To mimic the changes produced by HT such as cell radio-sensitization or increase of the blood perfusion after hyperthermia, simplistic biophysical models were included. To study the effectiveness of the different RT+HT treatments, the Tumor Control Probability (TCP) was calculated. In the considered scenarios, the major effect of HT is related to the enhancement of the cell radio-sensitivity while perfusion or heat-based effects on the immune system seem to contribute less. Moreover, no tumor vaccination effect has been observed. In the presented scenarios, HT boosts the RT cell killing but it does not fundamentally change the anti-tumor immune response.

Holistic View on Cell Survival and DNA Damage: How Model-Based Data Analysis Supports Exploration of Dynamics in Biological Systems.

In this work, a method is established to calibrate a model that describes the basic dynamics of DNA damage and repair. The model can be used to extend planning for radiotherapy and hyperthermia in order to include the biological effects. In contrast to "syntactic" models (e.g., describing molecular kinetics), the model used here describes radiobiological semantics, resulting in a more powerful model but also in a far more challenging calibration. Model calibration is attempted from clonogenic assay data (doses of 0-6 Gy) and from time-resolved comet assay data obtained within 6 h after irradiation with 6 Gy. It is demonstrated that either of those two sources of information alone is insufficient for successful model calibration, and that both sources of information combined in a holistic approach are necessary to find viable model parameters. Approximate Bayesian computation (ABC) with simulated annealing is used for parameter search, revealing two aspects that are beneficial to resolving the calibration problem: (1) assessing posterior parameter distributions instead of point-estimates and (2) combining calibration runs from different assays by joining posterior distributions instead of running a single calibration run with a combined, computationally very expensive objective function.

Cell line-specific efficacy of thermoradiotherapy in human and canine cancer cells in vitro.

OBJECTIVE: Aims were to investigate sensitivity of various human and canine cancer cell lines to hyperthermia and the influence of particular treatment conditions, and to analyze the DNA-damage response and mode of cell death in cell line radiosensitized by hyperthermia. Additionally, we were interested in the involvement of HSP70 in radiosensitization. METHODS: Radiosensitization by hyperthermia was determined in a panel of human and canine cancer cell lines using clonogenic cell survival assay, as well as levels of heat shock proteins (HSPs) using immunoblotting. The influence of the hyperthermia-radiotherapy time gap, different temperatures and the order of treatments on clonogenicity of hyperthermia-sensitive A549 cells was investigated. Additionally, DNA damage and cell death were assessed by Comet assay and an apoptosis/necrosis assay. Further we induced transient knockdown in A549 cells to test HSP70's involvement in radiosensitization. RESULTS: Out of eight cell lines tested, only two (A549 and Abrams) showed significant decrease in clonogenic cell survival when pre-treated with hyperthermia at 42°C. Strong induction of HSP70 upon thermoradiotherapy (HT-RT) treatment was found in all cell lines. Transient knockdown of HSP70 in A549 cells did not result in decrease of clonogenic cell survival in response to HT-RT. CONCLUSION: Tumor cell-type, temperature and order of treatment play an important role in radiosensitization by hyperthermia. However, hyperthermia has limited potency to radiosensitize canine cancer cells grown in a 2D cell culture setting presented here. DNA damage and apoptosis/necrosis did not increase upon combined treatment and cytosolic levels of HSP70 appear not to play critical role in the radiosensitization of A549 cells.

Effect of thyroid shielding during mammography: measurements on phantom and patient as well as estimation with Monte Carlo simulation.

BACKGROUND: During mammography, the thyroid is exposed to scattered radiation from breast tissue and the device. This may increase the risk of radiation induced thyroid cancer. METHODS: We investigated the scatter radiation exposition of the thyroid and the effect of a tailored thyroid protection in phantom and patient as well as by using Monte Carlo simulation (MCS). The protective effect of a modified thyroid protection, the relevance of the protective effect and acceptance by patients have been investigated. RESULTS: Phantom and patient measurements provided higher values for the surface dose at thyroid position than expected from MCS (phantom 0.32 mGy; patients 0.38 mGy; MCS 0.16 mGy). Phantom measurements indicated scatter contributions from both breast tissue and collimator/tube system. The value found in our patient study is within the range of the literature (0.22-0.39 mGy). The thyroid protection significantly reduced the surface dose but the dose (0.016 mGy) was higher than that expected from the lead equivalent value. However, the impact of the collar to the effective dose was small (< 4%). The collar was not visible on mammograms. CONCLUSIONS: Scatter from the collimator/tube system contributed with 50% to the thyroid dose. Due to the relative small fraction of dose deposited in the thyroid when compared to the mean glandular dose to the breast, a collar is not mandatory in general. Not being associated with the risk of obscuring parts of mammograms, such a collar may be used for young women considering their higher radio sensitivity.

A prospective study on insect bite hypersensitivity in horses exported from Iceland into Switzerland.

BACKGROUND: Insect bite hypersensitivity (IBH) is an IgE-mediated dermatitis caused by bites of Culicoides spp., which occurs frequently in horses imported from Iceland to continental Europe. IBH does not occur in Iceland because Culicoides species that bite horses are not present. However, Simulium vittatum (S. vittatum) are found in Iceland. In Europe, blood basophils from IBH-affected horses release significantly more sulfidoleukotrienes (sLT) than those from healthy controls after in vitro stimulation with Culicoides nubeculosus (C. nubeculosus) and S. vittatum. Aims of the study were: (I) using the sLT release assay, to test if horses living in Iceland were sensitized to S. vittatum and (II) to determine in a longitudinal study in horses imported from Iceland to Switzerland whether the sLT release assay would allow to predict which horses would develop IBH. RESULTS: Horses in Iceland, even when living in high S. vittatum areas, were usually not sensitized to S. vittatum or C. nubeculosus. Incidence of IBH in the 145 horses from the longitudinal study was 51% and mean time until IBH developed was 2.5 ± 1 year. Before import and after the first summer following import, there were no significant differences in sLT release between the endpoint healthy (H) and IBH groups. After the 2nd summer, when the number of clinically affected horses increased in the endpoint IBH group, a significantly higher sLT release after stimulation with C. nubeculosus but not with S. vittatum was observed. After the 3rd and 4th summer, the endpoint IBH group had a significantly higher sLT release with C. nubeculosus and S. vittatum than the endpoint H group. Some of the horses that remained healthy became transiently positive in the sLT release assay upon stimulation of their peripheral blood leucocytes with C. nubeculosus. CONCLUSIONS: Horses in Iceland are not sensitized to S. vittatum. In horses that develop IBH, sensitization to S. vittatum is secondary to sensitization to C. nubeculosus and probably a result of an immunological cross-reactivity. A sLT release assay cannot be used to predict which horses will develop IBH. A transient positive reaction in the sLT release assay observed in horses that remained healthy suggests that immunoregulatory mechanisms may control an initial sensitization of the healthy horses.

Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence.

UNLABELLED: Differentiation between posttherapy radiation necrosis and recurrent tumor in humans with brain tumor is still a difficult diagnostic task. The new PET tracers (18)F-fluoro-ethyl-l-tyrosine (FET) and (18)F-fluorocholine (N,N-dimethyl-N-(18)F-fluoromethyl-2-hydroxyethylammonium [FCH]) have shown promise for improving diagnostic accuracy. This study assessed uptake of these tracers in experimental radiation injury. METHODS: In a first model, circumscribed lesions were induced in the cortex of 35 rats using proton irradiation of 150 or 250 Gy. After radiation injury developed, uptake of (18)F-FET, (18)F-FCH, and (18)F-FDG was measured using autoradiography and correlated with histology and disruption of the blood-brain barrier as determined with Evans blue. In a second model, uptake of the tracers was assessed in acute cryolesions, which are characterized by the absence of inflammatory cells. RESULTS: Mean (18)F-FET, (18)F-FCH, and (18)F-FDG standardized uptake values in the most active part of the radiation lesion and the contralateral normal cortex (in parentheses) were 2.27 +/- 0.46 (1.42 +/- 0.23), 2.52 +/- 0.42 (0.61 +/- 0.12), and 6.21 +/- 1.19 (4.35 +/- 0.47). The degree of uptake of (18)F-FCH and (18)F-FDG correlated with the density of macrophages. In cryolesions, (18)F-FET uptake was similar to that in radiation lesions, and (18)F-FCH uptake was significantly reduced. CONCLUSION: Comparison of tracer accumulation in cryolesions and radiation injuries demonstrates that (18)F-FET uptake is most likely due to a disruption of the blood-brain barrier alone, whereas (18)F-FCH is additionally trapped by macrophages. Uptake of both tracers in the radiation injuries is generally lower than the published uptake in tumors, suggesting that (18)F-FET and (18)F-FCH are promising tracers for separating radiation necrosis from tumor recurrence. However, the comparability of our data with the literature is limited by factors such as different species and acquisition protocols and modalities. Thus, more studies are needed to settle this issue. Nevertheless, (18)F-FCH and (18)F-FET seem superior to (18)F-FDG for this purpose.

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.

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 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).

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.